GYNECOLOGIC ONCOLOGY GROUP ADMINISTRATIVE OFFICE

GYNECOLOGIC ONCOLOGY GROUPADMINISTRATIVE OFFICEFOUR PENN CENTER • 1600 JOHN F. KENNEDY BLVD • SUITE 1020 •PHILADELPHIA, PA 19103 • 215-854-0770 FAX 215-854-0716

Philip J. DiSaia, M.D.Chairman

John R. Kellner Executive Director of Operations

PROTOCOL GOG-0204A RANDOMIZED PHASE III TRIAL OF PACLITAXEL PLUS CISPLATIN VERSUS

VINORELBINE PLUS CISPLATIN VERSUS GEMCITABINE PLUS CISPLATIN VERSUS TOPOTECAN PLUS CISPLATIN IN STAGE IVB, RECURRENT OR PERSISTENT CARCINOMA

OF THE CERVIXNCI VERSION: July 7, 2004

Includes Revisions 1-3 POINTS:

PER CAPITA –20MEMBERSHIP –6

STUDY CHAIR QUALITY OF LIFE STUDY CHAIRBRADLEY J. MONK, M.D. DAVID CELLA, PH.D.UNIV OF CALIF, IRVINE MED CTR CENTER ON OUTCOMES RSCH & EDU DIVISION OF GYN/ONC EVANSTON NORTHWESTERN HEALTHCARE 101 THE CITY DRIVE BLDG 56, RM 262 1001 UNIVERSITY PLACE, SUITE 100ORANGE, CALIFORNIA 92868 EVANSTON, IL 60201(714) 456-6570 (847) 570-7300FAX: (714) 456-7754 FAX: (847) 570-8033EMAIL: [email protected] EMAIL: [email protected]

MEDICAL ONCOLOGIST PATHOLOGISTFRANCO M. MUGGIA, M.D. JO BENDA, M.D.NYU MEDICAL CENTER UNIV OF IOWA HOSPITALSKAPLAN CANCER CENTER ANATOMIC PATHOLOGYDIVISION OF MEDICAL ONCOLOGY 5244-A, RCP462 FIRST AVE C&D BLDG, ROOM 556 IOWA CITY, IA 52242-1009NEW YORK, NY 10016 (319) 356-4436(212) 263-6485 FAX: (319) 384-8052FAX: (212) 263-8210 EMAIL: [email protected]: [email protected]

STATISTICIAN NURSE CONTACTMIKE SILL, PH.D. SUSAN SPICER, R.N.GOG STATISTICAL & DATA CTR UCI MEDICAL CENTERROSWELL PARK CANCER INST 101 THE CITY DRIVEELM & CARLTON STREETS BLDG. 23, SUITE 403BUFFALO, NY 14263-0001 ORANGE, CA 92868(716) 845-5702 (714) 456-8478FAX: (716) 845-8393 FAX: (714) 456-6463EMAIL: [email protected] EMAIL: [email protected]

OPEN TO PATIENT ENTRY MAY 27, 2003 REVISED JANUARY 26, 2004 REVISED AUGUST 30, 2004

This protocol was designed and developed by the Gynecologic Oncology Group (GOG). It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized

by GOG nor does GOG assume any responsibility for unauthorized use of this protocol.

GOG-0204SCHEMA (8/30/04)

Patients With:

•Primary Stage IVB or recurrent/persistent carcinoma of the cervix•measurable disease

•GOG performance status 0-1 •ANC ≥ 1500/µl

•platelets ≥100,000/µl•serum creatinine ≤ 1.5 mg/dl

•no CNS disease•no past or concomitant invasive cancer (see Sections 3.25 and 3.26)

•no prior chemotherapy (unless concurrent with radiation)

Baseline Quality of Life Assessment

R A N D O M I Z EREGIMEN IV (1/26/04)Topotecan 0.75 mg/m2 IV over 30 min days 1,2,3 and cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks x 6*

REGIMEN I (1/26/04) REGIMEN II REGIMEN III (1/26/04)Paclitaxel 135 mg/m2 IV over 24 h Vinorelbine 30 mg/m2 IV Gemcitabine 1000 mg/m2 IVand cisplatin 50 mg/m2 IV day 2 day 1& 8 and cisplatin 50 mg/m2 day 1 & 8 and cisplatin 50 mg/m2

cycles repeated q 3 weeks x 6* IV day 1 repeated q 3 weeks x 6* IV day 1 cycles repeated q 3 weeks x 6*

ALL REGIMENSQuality of life Assessment:BaselineBefore cycle 2Before cycle 59 mo. after study entry atfollow-up visit

Quality of life assessments are still required even if patient is no longer on protocol therapy.

* Therapy may be discontinued prior to the completion of six cycles if there is evidence of disease progression or cumulative adverse effects dictate cessation of therapy.

GOG-0204TABLE OF CONTENTS (11/4/03)

PAGE

1.0 OBJECTIVES 1

2.0 BACKGROUND AND RATIONALE 1

3.0 PATIENT ELIGIBILITY AND EXCLUSIONS 5

4.0 STUDY MODALITIES 7

5.0 TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 15

6.0 TREATMENT MODIFICATIONS 21

7.0 STUDY PARAMETERS 40

8.0 EVALUATION CRITERIA 41

9.0 DURATION OF STUDY 44

10.0 STUDY MONITORING & REPORTING PROCEDURE 45

11.0 STATISTICAL CONSIDERATIONS 48

12.0 BIBLIOGRAPHY 51

13.0 SECTION OF CONFIDENTIALITY 54

SUGGESTED PATIENT INFORMATION/INFORMED CONSENT

APPENDIX I - Clinical Staging (FIGO)APPENDIX II - Quality of life questionnaireAPPENDIX III - Electronic patient registration (1/26/04)APPENDIX IV - Quality of life cover sheet (1/26/04)

GOG-0204-1-

1.0 OBJECTIVES (1/26/04)

1.1 To determine if cisplatin plus vinorelbine, cisplatin plus gemcitabine, or cisplatin plus topotecan improves survival compared to cisplatin plus paclitaxel in stage IVB, recurrent or persistent carcinoma of the cervix. Response will be compared as a secondary end-point.

1.2 To compare the toxicities of these four regimens in advanced cervical cancer.

1.3 To compare health-related quality of life across the four treatment regimens through four cycles of therapy and at nine months follow-up.

2.0 BACKGROUND AND RATIONALE (1/26/04)

There will be approximately 12,200 new patients with invasive cervical cancer diagnosed in the United States in 2003 with about 4,100 deaths from this disease.1 This accounts for approximately 17% of all deaths due to gynecologic cancers. Radiation has been the primary treatment modality for locoregionally advanced cervical cancer. Recent trials of concomitant systemic cisplatin chemotherapy and radiation have shown high response rates (RR) with improvements in durable remissions and overall survival among women with primary untreated disease.2 Single-agent cisplatin chemotherapy has also been used for nearly three decades to treat recurrent and metastatic cervical cancer with a RR of approximately 20%.3 Unfortunately, the impact of cisplatin alone on survival or quality of life among these incurable patients is unproven. However, the addition of paclitaxel to cisplatin (GOG protocol 169) has shown a statistically significant improvement in RR without significant toxicity making this combination the new standard of care for treating women with recurrent or advanced cervical cancer.4 Disappointingly however, the survival rates still did not change in this study. Recently, the survival data from GOG protocol 179 have been analyzed. Although, the quality of life data are still immature, there is an adjusted (covariates: performance status, age, disease status at entry and time from diagnosis to study entry) survival relative risk of 0.713 [95% confidence interval 0.542, 0.936] with a two tailed P value of p=0.015 for the topotecan and cisplatin regimen compared to cisplatin alone. In contrast to protocol 169, protocol 179 was completed after chemotherapy and radiation became standard in the upfront management of advanced disease. Thus, the response rates to cisplatin alone and the overall survival in 179 are vastly inferior to the previous study (169) investigating paclitaxel and cisplatin. Although intriguing, comparing these two protocols (169 and 179) to each other is impossible especially since they were completed in two very different eras. For the patients treated on 179, chemotherapy for their recurrent disease was frequently “second line” chemotherapy rather than “first line” as in 169 since those on 179 frequently received cisplatin with radiation as part of their initial therapy.

In an attempt to improve the response rates and survival even further as well as to settle the issues regarding the addition of paclitaxel or topotecan to cisplatin, we propose to study the effect of adding vinorelbine or gemcitabine to cisplatin and comparing these combinations to cisplatin plus paclitaxel or topotecan in a four arm study. Vinorelbine has demonstrated a promisingly high RR with cisplatin in phase II GOG studies and gemcitabine and cisplatin have shown promise outside of the GOG.

GOG-0204-2-

For three decades, cisplatin has been known as the most active agent as well as the standard therapy in the treatment of stage IVB, recurrent or persistent carcinoma of the cervix. Three strategies have been shown to increase the RR of single-agent cisplatin in this setting without prolonging survival. First, increasing the dose of cisplatin is associated with an increase in RR. The GOG conducted a study of cisplatin at three dose schedules to determine whether improved results could be achieved through increased dose intensity. Although the RR increased from 21% to 31% with an increase in dose from 50 mg/m2 to 100 mg/m2 every three weeks, there was no associated improvement in the complete response rate, progression-free interval, or survival.5 Second, the addition of ifosfamide to cisplatin as demonstrated in GOG Protocol #110 has a similar increase in RR.6 However, the increased gastrointestinal toxicity which includes predominantly nausea and vomiting associated with increasing doses of cisplatin and the neurotoxicity associated with ifosfamide make these two strategies unattractive given the lack of prolonged survival. Finally, the addition of paclitaxel to cisplatin (GOG Protocol #169) increases the RR to 36.2% for this combination.4 Since this regimen is well tolerated and associated with almost twice the RR of single-agent cisplatin, this has now become the standard approach to this disease. The combination of cisplatin and topotecan was recently studied in a phase III trial (GOG Protocol #0179). Although preliminary, the data show an improved survival to the topotecan containing arm. As of June 2003, the analysis for both of these studies is as follows:

Protocol 179

Progression Free Survival (PFS) -- Relative Risk Stats from the Cox Model

Factor Rel. Risk 95% CI P-value (2-tail)Topo unadjusted 0.703 [0.546, 0.905] p=0.0062Topo adjusted* 0.634 [0.491, 0.819] p=0.00048*covariates: performance status, age, disease status at entry & time from diagnosis to study entry.

Survival -- Relative Risk Stats from the Cox Model

Factor Rel. Risk 95% CI P-value (2-tail)Topo unadjusted 0.771 [0.59, 1.01] p=0.056 Topo adjust* 0.713 [0.542, 0.936] p=0.015 *covariates: performance status, age, disease status at entry & time from diagnosis to study entry.

Protocol 169

PFS -- Relative Risk Stats from the Cox Model

Factor Rel. Risk 95% CI P-value (2-tail)Taxol unadjusted 0.679 [0.529, 0.872] p=0.0024Taxol adjust 1* 0.664 [0.517, 0.854] p=0.0014Taxol adjust 2** 0.681 [0.530, 0.876] p=0.0027*covariates: performance status**covariates: performance status, age, disease status (recurrent vs. other)& time from diagnosis to study entry.

GOG-0204-3-

Survival Relative Risk Stats from the Cox Model Factor Rel. Risk 95% CI P-value (2-tail)Taxol unadjusted 0.869 [0.674, 1.120] p=0.28 Taxol adjust 1* 0.846 [0.656, 1.091] p=0.20Taxol adjust 2** 0.863 [0.667, 1.115] p=0.26Taxol adjust 3*** 0.878 [0.679, 1.134] p=0.32 *covariates: performance status**covariates: performance status, age, disease status (recurrent vs. other)***covariates: same as above plus time from diagnosis to study entry

Vinorelbine (Navelbine, Glaxo-Smith-Kline) is a semi-synthetic vinca alkaloid, which differs from other vinca alkaloids by a modification of the Catharanthine moiety. The mechanism of action of vinorelbine is similar to that of other vinca alkaloids, i.e., disruption of microtubules by their reversible binding to tubulin, resulting in mitotic spindal dissolution in metaphase arrest in dividing cells. The inhibition of tubulin polymerization with vinorelbine is equal to or greater than that obtained with Vincristine or Vinblastine. Vinorelbine is equally as active on mitotic microtubules of the tectal plate of mouse embryos as Vincristine and Vinblastine. This suggests a better efficacy/toxicity ratio and consequently an improved therapeutic index compared with both Vinblastine and Vincristine. The limiting toxicity of weekly vinorelbine is neutropenia, which is reversible, non-cumulative and of short duration.

Two recent phase II trials have been reported among patients with cervical carcinoma using vinorelbine. The first study was performed by the EORTC and involved 46 patients. The response rate as a single agent was 17% (95% ci = 7-32%) and eight stable diseases (20%).7

A second study reported by Pignata et al.8 reported 50 patients treated with cisplatin and vinorelbine together as first-line chemotherapy. The overall response rate was 46.7%. Hematologic and non-hematologic toxicity of this combination was mild. Finally, the GOG has piloted this combination at a dose of vinorelbine 30 mg/m2 IV bolus every week and cisplatin 75 mg/m2 IV infusion q 4 weeks in protocol 76-Z with a response rate of 30% and only mild toxicity. This response rate may be an under estimation since most of those patients treated on 76-Z received previous cisplatin-based chemotherapy as a radiosensitizer. Because of the excessive myelosuppression with this dose and schedule, the day 15 dose of Vinorelbine has been eliminated making this a more tolerable combination.

Gemcitabine has limited activity as a single agent in previously treated cervix cancer patients but has been shown to have in vitro activity in cervical cancer cell lines. 9, 10 However, studies have demonstrated synergy between gemcitabine and cisplatin in vitro and in vivo. 11,12 A randomized comparison of gemcitabine alone versus gemcitabine plus cisplatin in advanced pancreatic cancer demonstrated synergy in this tumor type.13 The combination has been reported to result in response rates of 40 - 95% in small Phase II trials in advanced cervix cancer patients.14-17 For example, Dr. Burnett and colleague’s at USC published their experience investigating gemcitabine in cisplatin in patients with advanced or persistent or recurrent squamous cell carcinoma of the cervix. They demonstrated an overall response rate of 41% (7/17).15

GOG-0204-4-

As a follow-up to these studies, we propose a randomized phase III study of cisplatin plus one of four drugs paclitaxel, vinorelbine, gemcitabine or topotecan in stage IVB, recurrent or persistent carcinoma of the cervix.

Quality of Life

Patient-reported health-related QOL is an important endpoint following chemotherapy for recurrent or persistent squamous cell carcinoma of the cervix. This is true since a number of regimens have now shown activity in this setting and survival differences are small when compared to best supportive care. Prior to GOG Protocol 169, only toxicity data were available to the clinician and the patient considering treatment alternatives. Such information lacks the specificity that can be achieved with validated QOL instruments and limits informed decisions regarding symptom relief and overall impact of treatment on quality of life.18,19 Protocol 169 showed that the higher response rate of paclitaxel plus cisplatin compared to cisplatin alone was not associated with worse quality of life in the paclitaxel-containing arm. There was no significant difference between the two treatment arms of Protocol 169. Furthermore, responding patients on either arm showed better quality of life than non-responding patients on either arm, suggesting that even in the face of drug toxicity, there is a measurable benefit to tumor response in these patients. However, patient-reported neurotoxicity was not collected on 169, so it remains uncertain whether there is noticeably elevated neurotoxicity in the combined therapy. If the current trial demonstrates no survival advantage for the investigational regimen, QOL and neurotoxicity data will be extremely important in treatment planning, because it can help balance the potential benefit of tumor response with toxicity. QOL data may demonstrate an important improvement in symptoms including a decrease in pain, or may indicate that treatment is not able to show a measurable benefit to patient-reported QOL, in light of additional toxicities.

2.1 Inclusion of Women and Minorities

The Gynecologic Oncology Group and GOG participating institutions will not exclude potential subjects from participating in this or any study solely on the basis of ethnic origin or socioeconomic status. Every attempt will be made to enter all eligible patients into this protocol and therefore address the study objectives in a patient population representative of the entire cervical carcinoma population treated by participating institutions.

GOG-0204-5-

3.0 PATIENT ELIGIBILITY AND EXCLUSIONS

3.1 Eligible Patients

3.11 Patients must have histologically proven stage IVB, recurrent or persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy.

3.12 All patients must have measurable disease. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be ≥ 20 mm when measured by conventional techniques, including palpation, plain x-ray, CT, and MRI, or ≥ 10 mm when measured by spiral CT. Biopsy confirmation is required if the lesion measures < 30 mm or if the treating physician determines it is clinically indicated. Patients must have at least one “target lesion” to be used to assess response on this protocol as defined by RECIST (Section 8.1). This lesion should be the one that was biopsied if one was performed. Patients with tumors within and outside a previously irradiated field should have the lesion outside of the irradiated area preferentially designated as the “target” lesion.

3.13 Patients must have adequate:

3.131 Hematologic function: ANC ≥ 1500/µl; platelets ≥ 100,000/µl.

3.132 Renal function: Serum creatinine less than or equal to 1.2 mg/dl. Patients with a serum creatinine greater than 1.2 mg/dl but less than 1.5 mg/dl must have a 24-hour creatinine clearance determination of > 50 cc/min to be eligible.

3.133 Hepatic function: bilirubin ≤ 1.5 x institutional normal; SGOT, alkaline phosphatase ≤ 3 x institutional normal

3.14 Patients must have a GOG Performance Status of 0 or 1.

3.15 Patients must have recovered from the effects of surgery, radiation therapy, or chemoradiotherapy. At least six weeks must have elapsed from the last administration of chemoradiotherapy, and at least three weeks must have elapsed from the last administration of radiation therapy alone.

3.16 Patients must have signed an approved informed consent and authorization permitting release of personal health information. (8/30/04)

3.17 Patients must meet all of the pre-entry requirements specified in Section 7.0, including baseline QOL questionnaire.

3.18 Patients must be free of clinically significant infection.

GOG-0204-6-

3.2 Ineligible Patients

3.21 Patients with bilateral hydronephrosis which cannot be alleviated by ureteral stents or percutaneous drainage. Patients with a serum creatinine greater than 1.2 mg/dl but less than 1.5 mg/dl with a 24-hour creatinine clearance determination of < 50 cc/min. Patients with a serum creatinine of 1.5 mg/dl or greater.

3.22 Patients previously treated with chemotherapy except when used concurrently with radiation therapy.

3.23 Patients who are pregnant or lactating.

3.24 Patients with craniospinal metastases.

3.25 Patients with a concomitant malignancy other than non-melanoma skin cancer.

3.26 Patients with a prior invasive malignancy (except non-melanoma skin cancer) who have had any evidence of disease within the last 5 years or whose prior malignancy treatment contraindicates the current protocol therapy.

GOG-0204-7-

4.0 STUDY MODALITIES

4.1 Cisplatin (Platinol®-AQ) (NSC #119875)

4.11 Formulation: Cisplatin or cis diamminedichloroplatinum (CDDP) is an inorganic compound that is widely used for the treatment of a variety of tumors.

4.12 Supplier/How Supplied: Commercially available from Bristol-Myers Oncology*. Cisplatin is a sterile aqueous solution, each mL containing 1 mg cisplatin and 9 mg sodium chloride. Cisplatin is supplied in multidose vials with 50 mg and 100 mg of cisplatin.

NOTE: Aluminum reacts with Platinol® causing precipitation formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of Platinol®.

4.13 Solution Preparation: If reconstitution is necessary the 50 and 100 mg vials should be reconstituted with 50 or 100 ml of sterile water for injection, USP respectively. Each ml of the respective solutions will contain 1 mg/ml of cisplatin. Reconstitution as recommended results in a clear colorless solution.

4.14 Storage/Stability: Store at 15° to 20°C. Do not refrigerate. Protect unopened container from light. The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

4.15 Adverse effects: Leukopenia, thrombocytopenia, anemia, nausea, vomiting, nephrotoxicity, ototoxicity, peripheral neuropathy, electrolyte imbalance, hypocalcemia, hypomagnesemia, aminoglycoside ototoxicity, ocular toxicity, and allergic reactions. Infrequent: Cardiac abnormalities, anorexia, elevated SGOT, rash, alopecia, and acute myeloid leukemia.

NOTE: Aminoglycoside antibiotics given before, with, or after cisplatin may potentiate renal toxicity and should be avoided whenever possible.

Severe renal toxicity can be largely avoided by induction of a diuresis before, during and after treatment.

*Refer to Package Insert for additional information.

GOG-0204-8-

4.2 Paclitaxel (Taxol®) (NSC#673089)

4.21 Formulation: Paclitaxel is a poorly soluble plant product from the western yew, Taxus brevifolia. Improved solubility requires a mixed solvent system with further dilutions of either 0.9% sodium chloride or 5% dextrose in water.

4.22 Supplier/How Supplied: Commercially available from Bristol-Myers Oncology*. A sterile solution concentrate, 6 mg/ml available in 5 ml (30mg/vial), 16.7 ml (100mg/vial) and 50 ml (300mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 50%. The contents of the vial must be diluted just prior to clinical use.

4.23 Solution Preparation: Paclitaxel, at the appropriate dose, will be diluted in 500 –1000 cc of 0.9% Sodium Chloride injection, USP or 5% Dextrose injection, USP (D5W) (500 cc’s is adequate if paclitaxel is a single agent). Paclitaxel must be prepared in glass or polyolefin containers due to leaching of diethylhexlphthalate (DEHP) plasticizer from polyvinylchloride (PVC) bags and intravenous tubing by the Cremophor vehicle in which paclitaxel is solubilized.

NOTE: Formation of a small number of fibers in solution (within acceptable limits established by the USP Particulate matter test for LVP’s) have been observed after preparation of paclitaxel. Therefore, in-line filtration is necessary for administration of paclitaxel solutions. In-line filtration should be accomplished by incorporating a hydrophilic, microporous filter of pore size not greater than 0.22 microns (e.g.: IVEX-II, IVEX-HP or equivalent) into the IV fluid pathway distal to the infusion pump. Although particulate formation does not indicate loss of drug potency, solutions exhibiting excessive particulate matter formation should not be used.

4.24 Storage/Stability: The intact vials should be stored under refrigeration (2-8°C). Commercially available paclitaxel will be labeled with an expiration date. All solutions of paclitaxel exhibit a slight haziness directly proportional to the concentration of drug and the time elapsed after preparation, although when prepared as described above, solutions of paclitaxel (0.3 – 1.2 mg/ml) are physically and chemically stable for 27 hours.

4.25 Adverse Effects:Hematologic: MyelosuppressionGastrointestinal: Nausea and vomiting, diarrhea, stomatitis, mucositis, pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitisHeart: Arrhythmia, heart block, ventricular tachycardia, myocardial infarction (MI), bradycardia, atrial arrhythmiaPulmonary: PneumonitisBlood Pressure: Hypotension, hypertension (possibly related to concomitant medication--Dexamethasone)Neurologic: Sensory (taste), peripheral neuropathy, seizures, mood swings, hepatic encephalopathy, encephalopathy

GOG-0204-9-

Skin: Infiltration: erythema, induration, tenderness, rarely ulceration, radiation-recall reactions, erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, pruritusLiver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase, hepatic failure, hepatic necrosisOther: Alopecia, fatigue, arthralgia, myalgia, light-headedness, myopathyOther, Vision: Sensation of flashing lights, blurred vision, scintillating scotomata

*Refer to Package Insert for additional information

4.3 Vinorelbine (Navelbine®) (NSC #608210)

4.31 Formulation: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid. The chemical name is 3',4'-didehydro-4-deoxy-c’-norvincaleukoblastine [R-(r,r)-2,3-dihydroxybutanedioate (1:2) (salt)]. Vinorelbine interferes with microtubule assembly. The antitumor activity is thought to be primarily due to inhibition of mitosis at metaphase through its interaction with tubulin. It may also interfere with 1) amino acid, cyclic AMP and glutathione metabolism, 2) calmodulin-dependent calcium transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. Vinorelbine binds highly to platelets and lymphocytes. It undergoes substantial hepatic elimination. One metabolite, deacetylvinorelbine, has been shown to have antitumor activity.

4.32 Supplier/How Supplied: Commercially available from GlaxoSmithKline*, Vinorelbine (Navelbine injection) is a clear colorless to pale yellow solution in water for injection, containing 10 mg of vinorelbine per ml. Vinorelbine injection is available in single-use, clear glass vials in the following sizes: 10 mg/1 ml and 50 mg/5ml.

4.33 Solution Preparation: Vinorelbine Injection must be diluted in either a syringe or IV bag using one of the recommended solutions. The diluted vinorelbine should be administered over 6 to 10 minutes into the side port of a free-flowing IV closest to the IV bag followed by flushing with at least 75 to 125 mL of one of the solutions. Syringe: The calculated dose of vinorelbine should be diluted to a concentration between 1.5 and 3.0 mg/mL. The following solutions may be used for dilution: 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP. IV Bag: The calculated dose of vinorelbine should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution: 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; 5% Dextrose and 0.45% Sodium Chloride Injection, USP; Ringer's Injection, USP; Lactated Ringer's Injection, USP

GOG-0204-10-

4.34 Storage/Stability: Diluted vinorelbine may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F). (8/30/04)

4.35 Adverse Effects: Granulocytopenia is the major dose-limiting toxicity encountered with vinorelbine. Grade 4 granulocytopenia occurred in 29% of patients with non-squamous cell lung carcinoma; hospitalizations due to granulocytopenic complications occurred in 8%. Granulocyte nadirs occur 7-10 days after the dose with recovery usually within the following 7-14 days. Thrombocytopenia and severe anemia (Hb < 8 g/dl) are unusual. Peripheral neuropathy was observed in 20% of patients, but grade 3-4 neuropathy occurred in less than 2% of patients. Nausea and vomiting are mild with vinorelbine. Paravenous pain and phlebitis are very common. (Delivery of drug via IV ports or other devices is often recommended particularly when venous access is thought to be difficult) Constipation was reported in 29% of patients, but severe cases (paralytic ileus) was uncommon (2%). Transient asymptomatic elevation of liver enzymes were reported. Cardiac and pulmonary toxicities were unusual.

*Refer to Package Insert for additional information

**Maximum body surface area used for calculations will be 2.0m2 as per GOG Chemotherapy Procedures Manual.

4.4 Gemcitabine (NSC #613327) (1/26/04) (8/30/04)

4.41 Formulation: Gemzar (gemcitabine HCl) is a nucleoside analogue that exhibits antitumor activity. Gemcitabine HCl is 2'-deoxy-2',2'-difluorocytidine monohydrochloride (®-isomer). The empirical formula for gemcitabine HCl is C9H11F2N3O4 • HCl. It has a molecular weight of 299.66. Gemcitabine HCl is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

4.42 Supplier/How Supplied: Gemcitabine is commercially available from Eli Lilly. The clinical formulation is supplied in a sterile form for intravenous use only. Vials of Gemzar contain either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

4.43 Solution Preparation: The lyophilized product will be reconstituted with normal saline added to the vial in order to make a solution ideally containing 10 mg/ml or ≤ 40 mg/ml for 200 mg and 1 g vials. An appropriate amount of drug will be administered as prepared or diluted with an additional 100 ml of normal saline.

GOG-0204-11-

4.44 Storage/Stability: The lyophilized product should be stored below 30°C. Once the drug has been reconstituted, it should be stored at controlled room temperature and used within 24 hours.

4.45 Adverse effects: Pulmonary: rare reports of adult respiratory distress syndrome.Hematologic: leukopenia, thrombocytopenia and anemia.Gastrointestinal: nausea, vomiting, mucositis and elevated transaminases.Genitourinary: reversible proteinuria and hematuria.Skin: reversible pruritic rash.Other: flu-like syndrome, alopecia and peripheral edema.


4.5 Topotecan (NSC #609699) (1/26/04) (8/30/04)

4.51 Formulation: Topotecan is a cell cycle specific inhibitor of the nuclear enzyme topoisomerase I. It has a mean half-life of approximately three hours. Topotecans metabolism and clearance are complex but it is estimated that approximately 40% of the drug undergoes renal clearance. It is supplied as a lyophilized, light-yellow powder as the base Topotecan AS with 48 mg mannitol and 20 mg tartaric acid, NF.

4.52 Supplier/How Supplied: Topotecan is commercially available from GlaxoSmithKline* and is supplied in a sterile form for intravenous use only. Topotecan is supplied as a lyophilized, light-yellow powder in vials containing 4 mg Topotecan AS (as the base) and 48 mg mannitol and 20 mg tartaric acid, NF. It has a reverse magenta label for identification purposes.

4.53 Solution Preparation: The contents of each 4 mg vial will be reconstituted with 4 ml Sterile Water for Injection, USP, yielding a 1 mg/ml solution of Topotecan AS. The ph is adjusted to 3.0. The vial can also be reconstituted with Bacteriostatic Water for Injection, USP. The vials reconstituted with Sterile Water for Injection, USP, contain no antibacterial preservative and must be used within 24 hours; those reconstituted with Bacteriostatic Water for Injection, USP, are stable for 21 days when stored in the refrigerator (2-8°C).

The reconstituted solution will be further diluted in plastic bags to concentrations of 10 mcg/ml to 500 mcg/ml in Dextrose 5% in Water, Normal Saline, or Bacteriostatic Water for Injection, USP. The plastic bags for infusion are stable at room temperature for 24 hours if reconstituted with Dextrose 5% in Water or Normal Saline and are stable for 7 days if reconstituted with Bacteriostatic Water for Injection, USP. No incompatibilities with other drugs have been described. The drug is stable in IV solutions as stated above.

GOG-0204-12-

4.54 Storage/Stability: Un-reconstituted vials are stored at room temperature, 15-30°C (59- 86°F). The reconstituted vials, when reconstituted with Sterile Water for Injection, USP, will contain no antibacterial preservative and should be used within 24 hours.

4.55 Adverse effects: Hematologic: thrombocytopenia, leukopenia, anemia, neutropeniaGastrointestinal: nausea and vomiting, mucositis, diarrheaSkin: rashOther: alopecia, fever, flu-like symptoms


4.6 Quality of Life Assessments (1/26/04)

In evaluating quality of life of women with advanced cervix cancer, we are concerned with assessment burden and therefore attempt to focus on the most relevant quality of life targets in this advanced and often rapidly progressing disease. A search of appropriate instruments revealed only one specific to advanced cervix cancer (The Functional Assessment of Cancer Therapy – Cervix, or FACT-Cx). In addition, because we are interested in comparing results from this study to 169 and 179 data on similar regimens, we will draw the most commonly-used single item from the Brief Pain Inventory (BPI), and the four most responsive items from the 11-item FACT-Neurotoxicity (FACT-Ntx) subscale. Selection of specific items rather than use of the entire questionnaires for pain and neurotoxicity will reduce assessment burden, and can be justified based on their previous usage and demonstrated responsiveness in similar trials.

1) The Functional Assessment of Cancer Therapy – Cervix (FACT-Cx): The FACT-Cx is the FACT-G plus a cervix cancer-specific subscale.20 The FACT-G is a 27-item self report QOL measure developed and validated with cancer patients and designed for clinical trials.21 It includes four subscales (physical well-being, social well-being, functional well-being and emotional well-being). Each scale produces a separate score which can be summed into one total quality of life score. Although we believe it is important to get a measurement of overall (“total”) quality of life in these patients over time, we do not anticipate differences across treatment arms in the ‘general’ FACT-G. Because the Physical Well Being (PWB) subscale was most predictive of outcome in GOG 169, and contains questions most relevant to the management of these symptomatic patients (pain, fatigue, nausea, etc), it was selected as the co-primary endpoint for comparing treatment arms with regard to relative benefit to patient. The other two co-primary endpoints are below.

1a) The cervix (Cx) subscale of the FACT consists of 15 items nominated as important by experts and patients with advanced cervical cancer. It has been validated in previous GOG trials, and will be a second co-primary quality of life endpoint.

GOG-0204-13-

1b) Along with the cervix subscale, four items from the FACT-Neurotoxicity (Ntx) subscale will be included to take into account the side effects that may result from different treatment arms. This is the third co-primary quality of life endpoint. (Ntx subscale). From data analyzed on GOG-0177 it is evident that the first four questions on the subscale correctly classify the vast majority of patients based on the physician reported CTC grade. These four questions can also be used to explain approximately 50% of the variation in the total Ntx score. It is important to note that the Ntx subscale may also be measuring things such as myalgia and arthralgia and thus may account for some of the variation as well. This instrument is available in Spanish and some other languages. Patients will still be eligible if they are unable to complete the QOL assessment due to language barriers.

2) The Brief Pain Inventory (BPI): The BPI is a 23-item, self-report instrument designed to assess pain in cancer and other diseases.22 The BPI measures the intensity of pain (sensory dimension, six items plus one item regarding medications the patient is taking) and interference of pain in the patient’s life (reactive dimension, seven items). Since pain may be a likely outcome of disease progression or differential effects of the treatment arms, this may be a particularly important area to measure. The BPI has demonstrated reliability and validity across cultures and languages and has been used to study the effectiveness of pain treatment.23 This instrument is available in Spanish and other languages. Patients will still be eligible if they are unable to complete the QOL assessment due to language barriers. Due to the fact that patients on this study will be increasingly disabled over time, only one question will be used from the BPI regarding the worst pain a patient experiences. This item is typically used as the primary BPI endpoint in trials even when the entire instrument is administered. The BPI single item comparison will provide secondary confirmation of FACT-Cx and FACT-Ntx results.

Please note: All QOL measures have been combined into one Scantron Form. (Appendix II)

4.7 Timing of Quality of Life Assessments

The timing of the first three assessments is scheduled to coincide with regular treatment follow-up visits and to take account of expected changes in this patient population. The final or 4th assessment at 9 months post baseline will measure quality of life after patients have completed chemotherapy on this protocol.

1) Baseline: All baseline assessments will be conducted prior to the initiation of chemotherapy and before the patients have been randomized to one arm or another. This QOL assessment should be conducted at the treatment site before randomization; at the same time, the Fast Fact Sheet should be completed, including the specific question as to whether or not the patient has completed the QOL baseline assessment.

The questionnaire is to be administered by the nurse/data manager or physician. Standardized instructions on the questionnaire should be read to the patient and any questions she has should be answered. Patients should be told that they will be asked to complete the same questionnaire again at specific time intervals that coincide with appointments/treatment. If patients need assistance, they may be helped. Please record

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the reason for assistance. Patients should be instructed to answer all questions and report any symptoms even if they are not related to cancer or treatment. Family members should be asked to wait in another room while the patient completes the questionnaire.

2) Follow-up Quality of Life assessments will be performed prior to cycle 2, prior to cycle 5, and then 9 months after entry onto study (e.g. Day 1 of first cycle of chemotherapy). All QOL forms should be completed even if the patient is no longer on study even if telephonic completion is necessary.

4.8 Pathology Requirement

Pathology materials will be submitted as per Section 10.4.

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5.0 TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE

Before patient entries will be accepted, an official signed CTSU IRB Certification Form and a CTSU IRB/Regulatory Approval Transmittal Sheet (forms can be downloaded at www.ctsu.org) must be received by the CTSU Regulatory Office. These forms can be faxed or mailed to:

CTSU Regulatory OfficeCoalition of National Cancer Cooperative Groups

1818 Market Street, Suite 1100Philadelphia, PA 19103

1-888-823-5923FAX 215-569-0206 (5/27/03) (8/30/04)

5.1 Telephone Entry

When a suitable candidate has been obtained for protocol entry, the following steps should be taken:

5.11 An approved informed consent and authorization permitting release of personal health information must be signed by the patient or guardian. (8/30/04)

5.12 Make certain all eligibility requirements according to Section 3.0 have been met.

5.13 Fast Fact Sheet data should be gathered. With this data in hand, the GOG Statistical and Data Center should be called at: 1-800-523-2917, Monday through Friday, 9 am to 5 pm EST/EDT.

5.14 Entry/Randomization will take place on the telephone after consideration of Fast Fact Sheet data.

5.15 The institution will enter the patient's name, GOG number, and assigned regimen in the appropriate place in their Log Book to verify the patient's entry.

5.2 Treatment Plan

5.21 Regimen I paclitaxel 135 mg/m2 IV over 24 hours and cisplatin 50 mg/m2 IV Day 2 repeated every 3 weeks up to a maximum of 6 cycles or until disease progression or unacceptable adverse effects prohibit further therapy. Maximum body surface area used for dose calculations will be 2.0 m2 as per GOG Chemotherapy Procedures Manual. (1/26/04) (8/30/04)

5.211 Suggested Method of Administration:The starting dose for paclitaxel is 135 mg/m2 over 24 hours. This is then followed by cisplatin 50 mg/m2 on day 2. The patient is premedicated with dexamethasone (Decadron) 20mg orally 12 and 6 hours prior to the anticipated initiation of the paclitaxel infusion. (Note: IV Decadron instead of oral Decadron should be substituted in patients who cannot tolerate oral Decadron). Thirty minutes before the paclitaxel infusion is to begin the patient is further premedicated with Decadron 20 mg IV,

GOG-0204-16-

diphenhydramine (Benadryl) 50mg IV, and an H2 receptor antagonist: cimetidine 300 mg IV, or ranitidine 50 mg IV, or Pepcid 20 mg IV. If the patient has had two cycles of paclitaxel with no allergic reaction, oral/IV Decadron 12 and 6 hours prior to the anticipated initiation of the paclitaxel may be deleted. Never delete IV Decadron 30 minutes prior to paclitaxel. Paclitaxel, at the appropriate dose and dilution, will be given as a 24-hour continuous IV infusion. The 24-hour infusion may be given over 20-22 hours if necessary for insurance coverage of outpatient admission less than 24 hours. See Section 4.23. Vital signs, including blood pressure, respiratory rate, and temperature must be taken every 15 minutes for the first hour of the paclitaxel infusion. Since no acute gastrointestinal toxicity is expected from the paclitaxel, maintenance of good oral hydration should be possible. As the end of the paclitaxel infusion nears, additional intravenous hydration is recommended. Cisplatin is then administered immediately (in less than four hours) after the completion of paclitaxel with the use of an antiemetic regimen as outlined below in Section 5.212. Hydration before/after the cisplatin with a total of at least 1 liter of IV ½ normal saline is recommended. (8/30/04)

5.212 Antiemetic RegimenThe proper prophylaxis for cisplatin-based chemotherapy regimens is a 5HT3 receptor antagonist (ondansetron, granisetron, and dolasetron) in combination with dexamethasone, usually 20mg administered 30 to 60 minutes prior to starting chemotherapy. Additional antiemetic medications from other therapeutic classes (e.g. dopamine blocking agents - promethazine, prochlorperazine and benzodiazepines -lorazepam) should be available for breakthrough use. Prophylaxis for delayed emesis should be strongly considered with dexamethasone 8mg PO BID x 2 days then 4mg PO BID x 1 day in combination with either aprepitant, metoclopramide or a 5HT3 antagonist. Aprepitant has been approved by the FDA to mitigate both acute and delayed chemotherapy-induced nausea and vomiting in combination with serotonin antagonists and dexamethasone. Aprepitant has potential drug interactions with paclitaxel, vinorelbine and topotecan via inhibition with the CYP3A4 isoenzyme, which could increase serum concentrations of the cited agents. Physicians choosing to use aprepitant are advised that this interaction could result in unexpected toxicity. Institutional guidelines may be utilized if they are literature-based and closely model the above recommendations. Paclitaxel (Section 5.21) may not induce nausea or vomiting when given alone; therefore, other antiemetics may or may not be given when paclitaxel (Section 5.21) is being administered as single agent.24,25 (1/26/04) (8/30/04)

5.213 Treatment will continue up to a maximum of six cycles. Therapy may be discontinued prior to the completion of six cycles if there is evidence of disease progression or cumulative adverse effects dictate cessation of therapy. Patients in continued response or with stable disease may

GOG-0204-17-

continue on study beyond the six cycles with consent of the Study Chair, but must be reported using GOG forms (See Section 9.1). (8/30/04)

5.214 Cytokines are usually not necessary for patients treated on this regimen and should not be used. (8/30/04)

5.22 Regimen II vinorelbine 30 mg/m2 IV bolus day 1 and 8 and cisplatin 50 mg/m2

IV day 1 repeated every 3 weeks up to a maximum of 6 cycles or until disease progression or unacceptable adverse effects prohibit further therapy. Maximum body surface area used for dose calculations will be 2.0 m2 as per GOG Chemotherapy Procedures Manual. (1/26/04) (8/30/04)

5.221 Suggested Method of Administration:The starting dose of cisplatin is 50 mg/m2 and is administered on Day 1. The starting dose of vinorelbine is 30 mg/m2 and is administered on Days 1 and 8. The cycle is repeated on Day 22.

Vinorelbine should be administered over 6-10 minutes into the side port of a free-flowing I.V. solution followed by flushing with at least 75-125 ml of one of the solutions listed in Section 4.33. (8/30/04)

Cisplatin is then administered immediately (in less than four hours) after the completion of vinorelbine with the use of an antiemetic regimen as outlined below in Section 5.222. Hydration before/after the cisplatin with a total of at least 1 liter of IV ½ normal saline is recommended. (8/30/04)

5.222 Antiemetic RegimenThe proper prophylaxis for cisplatin-based chemotherapy regimens is a 5HT3 receptor antagonist (ondansetron, granisetron, and dolasetron) in combination with dexamethasone, usually 20mg administered 30 to 60 minutes prior to starting chemotherapy. Additional antiemetic medications from other therapeutic classes (e.g. dopamine blocking agents - promethazine, prochlorperazine and benzodiazepines -lorazepam) should be available for breakthrough use. Prophylaxis for delayed emesis should be strongly considered with dexamethasone 8mg PO BID x 2 days then 4mg PO BID x 1 day in combination with either aprepitant, metoclopramide or a 5HT3 antagonist. Aprepitant has been approved by the FDA to mitigate both acute and delayed chemotherapy-induced nausea and vomiting in combination with serotonin antagonists and dexamethasone. Aprepitant has potential drug interactions with paclitaxel, vinorelbine and topotecan via inhibition with the CYP3A4 isoenzyme, which could increase serum concentrations of the cited agents. Physicians choosing to use aprepitant are advised that this interaction could result in unexpected toxicity. Institutional guidelines may be utilized if they are literature-based and closely model the above recommendations. Vinorelbine (Section 5.22) may not induce nausea or vomiting when given alone; therefore, other antiemetics may or may not

GOG-0204-18-

be given when vinorelbine (Section 5.22) is being administered as a single agent.20,21 (5/27/03) (8/30/04)

5.223 Treatment will continue up to a maximum of six cycles. Therapy may be discontinued prior to the completion of six cycles if there is evidence of disease progression or cumulative adverse effects dictate cessation of therapy. Patients in continued response or with stable disease may continue on study beyond the six cycles with consent of the Study Chair, but must be reported using GOG forms (See Section 9.1). (8/30/04)


5.23 Regimen III gemcitabine 1000mg/m2 IV day 1 and 8 and cisplatin 50 mg/m2 IV day 1 repeated every 3 weeks up to a maximum of 6 cycles or until disease progression or unacceptable adverse effects prohibit further therapy. Maximum body surface area used for dose calculations will be 2.0 m2 as per GOG Chemotherapy Procedures Manual. (1/26/04) (8/30/04)

5.231 Suggested Method of Administration:The starting dose of cisplatin is 50 mg/m2 and is administered on Day 1. The starting dose of gemcitabine is 1000 mg/m2 and is administered on Days 1 and 8. The cycle is repeated on Day 22. (8/30/04)

Gemcitabine (see 4.43) should be administered over 30 (UP TO 60) minutes into the side port of a free-flowing I.V. solution followed by flushing with at least 75-125 ml of a saline solution. (8/30/04)

Cisplatin is then administered immediately (in less than four hours) after the completion of gemcitabine with the use of an antiemetic regimen as outlined below in Section 5.232. Hydration before/after the cisplatin with a total of at least 1 liter of IV ½ normal saline is recommended. (8/30/04)

5.232 Antiemetic RegimenThe proper prophylaxis for cisplatin-based chemotherapy regimens is a 5HT3 receptor antagonist (ondansetron, granisetron, and dolasetron) in combination with dexamethasone, usually 20mg administered 30 to 60 minutes prior to starting chemotherapy. Additional antiemetic medications from other therapeutic classes (e.g. dopamine blocking agents - promethazine, prochlorperazine and benzodiazepines -lorazepam) should be available for breakthrough use. Prophylaxis for delayed emesis should be strongly considered with dexamethasone 8mg PO BID x 2 days then 4mg PO BID x 1 day in combination with either aprepitant, metoclopramide or a 5HT3 antagonist. Aprepitant has been approved by the FDA to mitigate both acute and delayed chemotherapy-induced nausea and vomiting in combination with serotonin antagonists and dexamethasone. Aprepitant has potential drug interactions with paclitaxel, vinorelbine and topotecan via inhibition with the CYP3A4

GOG-0204-19-

isoenzyme, which could increase serum concentrations of the cited agents. Physicians choosing to use aprepitant are advised that this interaction could result in unexpected toxicity. Institutional guidelines may be utilized if they are literature-based and closely model the above recommendations. Gemcitabine may not induce severe nausea or vomiting when given alone; therefore, other antiemetics may or may not be given when Gemcitabine alone is being administered (see Section 5.231). (8/30/04)

5.233 Treatment will continue up to a maximum of 6 cycles. Therapy may be discontinued prior to the completion of six cycles if there is evidence of disease progression or cumulative adverse effects dictate cessation of therapy. Patients in continued response or with stable disease may continue on study beyond the six cycles with consent of the Study Chair, but must be reported using GOG forms (See Section 9.1). (8/30/04)


5.24 Regimen IV Topotecan 0.75 mg/m2 over 30 minutes days 1, 2, and 3 and cisplatin 50 mg/m2 IV day 1, every 3 weeks up to a maximum of 6 cycles or until disease progression or unacceptable adverse effects prohibit further therapy. Maximum body surface area used for dose calculations will be 2.0 m2

as per GOG Chemotherapy Procedures Manual. (1/26/04) (8/30/04)

5.241 Suggested Method of Administration: The starting dose of topotecan is 0.75 mg/m2 and is administered on Days 1, 2 and 3. The starting dose of cisplatin is 50 mg/m2 and is administered on Day 1. The cycle is repeated on Day 22.

Topotecan is diluted in 100 mL D5W and infused intravenously over 30 minutes through the Y injection site of a running IV solution (see Section 4.53)

After the administration of topotecan on day 1, cisplatin is then administered immediately (in less than four hours) after the completion of topotecan with the use of an antiemetic regimen as outlined below in Section 5.242. Hydration before/after the cisplatin with a total of at least 1 liter of IV ½ normal saline is recommended. (8/30/04)

5.242 Antiemetic RegimenThe proper prophylaxis for cisplatin-based chemotherapy regimens is a 5HT3 receptor antagonist (ondansetron, granisetron, and dolasetron) in combination with dexamethasone, usually 20mg administered 30 to 60 minutes prior to starting chemotherapy. Additional antiemetic medications from other therapeutic classes (e.g. dopamine blocking agents - promethazine, prochlorperazine and benzodiazepines -lorazepam) should be available for breakthrough use. Prophylaxis for delayed emesis should be strongly considered with dexamethasone 8mg

GOG-0204-20-

PO BID x 2 days then 4mg PO BID x 1 day in combination with either aprepitant, metoclopramide or a 5HT3 antagonist. Aprepitant has been approved by the FDA to mitigate both acute and delayed chemotherapy-induced nausea and vomiting in combination with serotonin antagonists and dexamethasone. Aprepitant has potential drug interactions with paclitaxel, vinorelbine and topotecan via inhibition with the CYP3A4 isoenzyme, which could increase serum concentrations of the cited agents. Physicians choosing to use aprepitant are advised that this interaction could result in unexpected toxicity. Institutional guidelines may be utilized if they are literature-based and closely model the above recommendations. Topotecan may not induce severe nausea or vomiting when given alone; therefore, other antiemetics may or may not be givenwhen Topotecan alone is being administered. (see Section 5.241) (8/30/04)

5.243 Treatment will continue up to a maximum of 6 cycles. Therapy may be discontinued prior to the completion of six cycles if there is evidence of disease progression or cumulative adverse effects dictate cessation of therapy. Patients in continued response or with stable disease may continue on study beyond the six cycles with consent of the Study Chair, but must be reported using GOG forms (See Section 9.1). (8/30/04)


GOG-0204-21-

6.0 TREATMENT MODIFICATIONS

6.1 Treatment Modifications for Regimen I paclitaxel 135 mg/m2 IV over 24 hours and cisplatin 50 mg/m2 IV Day 2 repeated every 3 weeks up to a maximum of 6 cycles or until disease progression or unacceptable adverse effects prohibit further therapy. (8/30/04)

Dose Levels for Treatment Modification of CisplatinInitial dose =50 mg/m2

-1 level dose reduction = 37.5 mg/m2

-2 level dose reduction = 25 mg/m2

Dose Levels for Treatment Modification of PaclitaxelInitial dose = 135 mg/m2

-1 level dose = 110 mg/m2

-2 levels dose = 90 mg/m2

6.11 Dose Modifications for Hematologic Toxicity Following a Cycle of TreatmentNo cycle of treatment is to begin until ANC ≥ 1500/µl and platelets ≥100,000/µl. Initiation of a new cycle will be delayed for a maximum of two weeks until these values are achieved. Patients who fail to recover adequate counts within a two week delay will be removed from study, but follow-up will continue.

Dose modifications for hematologic toxicity are based on nadir counts. Dosage modification criteria are found in section 6.1.

6.111 CisplatinNo reduction is made in the dose of cisplatin for any degree of hematologic toxicity.

6.112 Paclitaxel

ThrombocytopeniaGrade 4 thrombocytopenia requires a 1 dose level reduction in paclitaxel each time it occurs. If more than 2 dose reductions are necessary contact the study chair. Patients will NOT receive prophylactic platelet growth factors.

NeutropeniaUncomplicated (absence of sepsis or fever) neutropenia of any grade does not require dose modification. A one dose level reduction in the paclitaxel dose is required for neutropenic fever (defined as grade 3 or 4 nadir neutropenic toxicity with temperature of 38.0°C or 100.4°F twice within a day, or single temperature of 38.3°C or 101°F ). Patients who are hospitalized for fever with either grade 3 or 4 neutropenia may be treated with growth factors during the episode at the discretion of the treating physician. At least two days should elapse between the discontinuation of growth factors and the initiation of another cycle of

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chemotherapy in order to allow bone marrow progenitors to cease cell cycling. If febrile neutropenia occurs despite a one dose level reduction, then with subsequent cycles the patient will receive growth factors starting 24-48 hours after the completion of the subsequent cycle of chemotherapy and continuing until the ANC is ≥ 10,000/µl. At least two days should elapse between the last dose of growth factors and the initiation of another treatment cycle. If febrile neutropenia occurs despite the use of growth factors then with subsequent cycles the patient will receive a second dose reduction of paclitaxel. If a dose reduction below the lowest dose in Section 6.1 is required, a dose reduction of 20% may take place after consulting with the Study Chair. (8/30/04)

AnemiaAnemia is not an indication for dose reduction in any patient; however, a record of transfusions required should be detailed on the D2R Form. Erythropoietin may be utilized at the discretion of the treating physician in the event that patient’s hemoglobin drops below 10 g/dl while on therapy, and should be documented on the D2R Form. (1/26/04)

6.12 Dose Modification for Non-hematologic Toxicity Following a Cycle of Treatment (1/26/04)

6.121 Cisplatin (8/30/04)

Toxicity Grade

Renal Peripheral Neuropathy

Ototoxicity GI Other

0 None None None None None1 None None None None None2 ** Decrease 2

levels Decrease 2 levels

None *

3 ** Hold Hold None *4 ** Hold Hold Decrease

1 level*** *

* Notify Study Chair prior to treatment** Hold Cisplatin until serum Cr < 1.5 mg/dL*** Second event of toxicity only

6.1211Adjustments to Cisplatin for Renal ToxicityPersistent elevation of serum creatinine > 2.0 mg/dL or grade 2 renal toxicity or worse (which on workup is not secondary to prerenal causes or obstructive uropathy) requires withholding treatment until creatinine is < 1.5 mg/dl. If this creatinine elevation persists beyond 2 weeks after a cycle is due to be given (5 weeks after a previous dose), then the Study Chair should be called. If cisplatin is considered to have contributed to this

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degree of irreversible renal toxicity, it will be omitted from all subsequent treatments. (8/30/04)

Selective renal tubular defects are observed with cisplatin. Hypocalcemia, hypomagnesemia, and hypokalemia are common and potentially severe. Replacement of calcium, magnesium, and potassium are usually effective. Hyponatremia may occur secondary to inappropriate ADH secretion. Severe defects, although uncommon, may require chronic replacement therapy and rare discontinuation of protocol drugs. Alternative mechanisms (e.g. gastrointestinal) for electrolyte losses should be considered.

6.1212 Adjustments to Cisplatin for Peripheral NeuropathyGrade 3 or 4 peripheral neuropathy requires interruption of cisplatin therapy until adverse effects resolve to grade 1 or less. Grade 2 peripheral neuropathy will require a two dose level reduction in cisplatin. The Study Chair should be notified if grade 3 or 4 neuropathy does not resolve to a grade 1 neuropathy or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration will be given to removing the patient from study. Follow-up will continue for any patient removed from study. (8/30/04)

6.1213 Adjustments to Cisplatin for OtotoxicityAudiography is not required before the start of therapy but is left to the discretion of the individual investigator. Tinnitus and symptomatic hearing loss (grade 2) will require a two dose level reduction in cisplatin. Further worsening of ototoxicity requires cessation of cisplatin therapy and notification of the Study Chair. (8/30/04)

Grade 3 or 4 ototoxicity requires interruption of cisplatin therapy until adverse effects resolve to grade 1 or less. Grade 2 ototoxicity will require a two dose level reduction in cisplatin. The Study Chair should be notified if grade 3 or 4 ototoxicity does not resolve to a grade 1 toxicity or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration will be given to removing the patient from study. Follow-up will continue for any patient removed from study. (8/30/04)

6.1214 Adjustments to Cisplatin for Gastrointestinal ToxicityThe only adjustment allowed for gastrointestinal toxicity is, in the event of two successive episodes of grade 4 nausea and vomiting, the cisplatin will be reduced by one dose level. If volume contraction becomes a problem, the investigator is encouraged to admit the patient to the hospital for more vigorous pre- and post-treatment hydration and antiemetics (see Section 5.212).

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Chemotherapy treatment should be delayed until toxicity is grade 1 or less. If GI toxicity beyond grade 1 continues for more than 2 weeks after a cycle is due (5 weeks after the last dose), the Study Chair should be notified. In addition, the Study Chair should be notified if a third episode of GI toxicity grade 2 or worse occurs. (8/30/04)

6.1215 Supportive CareIn addition to other aspects of supportive care, particular attention should be paid to adequate control of nausea and vomiting,including use of HT3 receptor antagonists, and treatment of severe non-hemolytic anemia after several cycles of therapy. The patient should be transfused as needed without interruption of therapy. Platelet transfusions may also be required.

6.122 Paclitaxel (8/30/04)

Toxicity Grade

Peripheral Neuropathy

GI Hepatic Other

0 None None None None1 None None None None2 Decrease 2

levels None Decrease 1

level *

3 Hold None * *4 Hold None * *

* Notify Study Chair prior to treatment

6.1221 Management of Hypersensitivity ReactionsHypersensitivity reactions to paclitaxel or its vehicle (Cremophor) occur almost universally during the first few minutes of infusion. Continued treatment may be considered if the reaction was not life-threatening; however, patients must be cautioned of potential recurrences of the reaction. Should the patient decide to continue with treatment it is preferable that this be done on the same day of the occurrence. A suggested procedure would be to repeat the patient’s premedication with dexamethasone 20mg IV, cimetidine 300mg (or ranitidine 50mg) IV, and diphenhydramine 50mg IV 30 minutes before the paclitaxel reinfusion is to begin. Slowly infuse the paclitaxel by administering the drug first with 1 ml of the original IV solution diluted in 100 ml over one hour, then 5 ml in 100 ml over one hour, then 10 ml in 100 ml over one hour, and finally the original solution at the original infusion rate. No additional dose adjustments should be made for other hypersensitivity reactions.26 Discontinuation of therapy due to hypersensitivity reaction requires notification of the Study Chair. (1/26/04)

6.1222 Adjustments for Cardiac Toxicity

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Asymptomatic bradycardia is not an indication for discontinuation of therapy or for routine monitoring. If any other arrhythmia is documented, monitoring may be required. A paclitaxel infusion may be discontinued for a cardiac arrhythmia that shows evidence of AV nodal block (eg. Mobitz type I or II or complete heart block). Any arrhythmia that is felt to necessitate discontinuation of paclitaxel should be discussed with the Study Chair.

6.1223 Adjustments to Paclitaxel for Peripheral Neuropathy (8/30/04)Grade 3 or 4 peripheral neuropathy requires interruption of paclitaxel therapy until adverse effects resolve to grade 1 or less. Grade 2 peripheral neuropathy will require a two dose level reduction in paclitaxel. The Study Chair should be notified if grade 3 or 4 neuropathy does not resolve to a grade 1 neuropathy or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration will be given to removing the patient from study. Follow-up will continue for any patient removed from study.

6.1224 Adjustments to Paclitaxel for Hepatic Toxicity (8/30/04)Paclitaxel has significant hepatic metabolism. No dose modification is necessary for grade 1 or 2 toxicities but a grade 2 toxicity requires a dose reduction of one level after resolution of the toxicity to grade 1 or less. If resolution from grade 2 to grade 1 or lower does not occur within 2 weeks after a dose of paclitaxel is due (5 weeks after the last dose), the Study Chair should be notified.

Grade 3 and 4 hepatic toxicity requires notification of the Study Chair.

6.13 Dose Re-escalationThere will be no dose re-escalation.

6.2 Treatment Modifications for Regimen II vinorelbine 30 mg/m2 IV bolus days 1 and 8 and cisplatin 50 mg/m2 IV day 1 repeated every 3 weeks up to a maximum of 6 cycles or until disease progression or unacceptable adverse effects prohibit further therapy. (8/30/04)

Dose Levels for Treatment Modification of CisplatinInitial dose = 50 mg/m2



Dose Levels for Treatment Modification of VinorelbineInitial dose = 30 mg/m2



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Notify Study Chair if more dose reductions are needed. (8/30/04)

6.21 Dose Modifications for Hematologic Toxicity

Dosage modification criteria are found in section 6.2.


6.212 Vinorelbine (8/30/04)Dose limiting toxicity for vinorelbine is hematologic, usually neutropenia. The starting dose of vinorelbine for day 1 of cycle 1 is 30 mg/m2. Dose reductions in vinorelbine at any time after day 1 of cycle 1 will be continued throughout the rest of the study.Chemotherapy on day 1 for all cycles should only be given if the ANC on that day is > 1500/µl and the platelet count is ≥100,000/µl.

The dose of vinorelbine on day 8 is based on blood results obtained on the day of treatment, prior to dosing, according to the following schedule:

ANC/µl Day of Treatment (Day 8) OR

Platelets/µlDay of Treatment

Vinorelbine Dose(mg/m2)

≥1500/µl1000-1499/µl< 1000/µl

≥100,000/µl75,000-99,000/µl< 75,000/µl

3020 skip

No chemotherapy will ever be given on day 15. As outlined above, if the ANC is < 1000/µl OR the platelet count is < 75,000/µl on day 8, the day 8 dose of vinorelbine will be skipped and the next earliest date of chemotherapy will be with the beginning of the next cycle (2 weeks later). If the day 8 dose is skipped, the day 1 dose of the next cycle will require one dose reduction.

Uncomplicated (absence of sepsis or fever) neutropenia of any grade does not require dose modification. Patients who require a delay of dosing for two weeks or more beyond when a cycle is due to start (5 weeks from day 1, 4 weeks from day 8), or who experience fever and/or sepsis while neutropenic, are at risk for subsequent severe myelosuppression. Upon return to the clinic, on Day 1, if the patient has ANC ≥ 1500/µl and platelets ≥ 100,000/µl a maximum dose of 20 mg/m2

of vinorelbine should be administered. Patients who require a cycle

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delay of three weeks or greater (6 weeks from day 1) or experience fever and/or sepsis while neutropenic on the reduced dosage will possibly be taken off study after consultation with the Study Chair. Follow-up will continue even if patient has been taken off study.

Patients who are hospitalized for fever with either grade 3 or 4 neutropenia may be treated with growth factors during the episode at the discretion of the treating physician. At least two days should elapse between the discontinuation of growth factors and the initiation of another cycle of chemotherapy in order to allow bone marrow progenitors to cease cell cycling. Growth factors will not be used between doses of chemotherapy in the absence of febrile neutropenia.

If febrile neutropenia occurs despite a one dose level reduction, then with subsequent cycles the patient will receive G-CSF 5 µg/kg/d SQ or equivalent starting 24-48 hours after the completion of the subsequent cycle of chemotherapy and continuing until the ANC is ≥ 10,000.

Patients will NOT receive prophylactic platelet growth factors.

AnemiaAnemia is not an indication for dose reduction in any patient; however, a record of transfusions required should be detailed on the D2R Form. Erythropoietin may be utilized at the discretion of the treating physician in the event that patient’s hemoglobin drops below 10 g/dl while on therapy, and should be documented on the D2R Form. (1/26/04)

6.22 Dose Modification for Non-hematologic Toxicity Following a Cycle of Treatment

6.221 Cisplatin (8/30/04)Toxicity Grade





None *


1 level****

* Notify Study Chair prior to treatment** Hold Cisplatin until serum Cr < 1.5 mg/dL*** Second event of toxicity only (1/26/04)

6.2211 Adjustments to Cisplatin for Renal ToxicityPersistent elevation of serum creatinine > 2.0 mg/dL or grade 2 renal toxicity or worse (which on workup is not secondary to

GOG-0204-28-

prerenal causes or obstructive uropathy) requires withholding treatment until creatinine is < 1.5 mg/dl. If this creatinine elevation persists 2 weeks after a cycle is due to be given (5 weeks after a previous dose), then the Study Chair should be called. If cisplatin is considered to have contributed to this degree of irreversible renal toxicity, it will be omitted from all subsequent treatments. (8/30/04)


6.2212 Adjustments to Cisplatin for Peripheral NeuropathyDosing delays will be based on signs and symptoms on the day of treatment for either drug. Grade 3 or 4 peripheral neuropathy requires interruption of cisplatin therapy until adverse effects resolve to grade 1 or less. Grade 2 peripheral neuropathy will require a two dose level reduction in cisplatin. The Study Chair should be notified if grade 3 or 4 neuropathy does not resolve to a grade 1 neuropathy or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration will be given to removing the patient from study. Follow-up will continue for any patient removed from study. (8/30/04)


Grade 3 or 4 ototoxicity requires interruption of cisplatin therapy until adverse effects resolve to grade 1 or less. Grade 2 ototoxicity will require a two dose level reduction in cisplatin. The Study Chair should be notified if grade 3 or 4 ototoxicity does not resolve to a grade 1 toxicity or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration will be given to removing the patient from study.Follow-up will continue for any patient removed from study. (8/30/04)

6.2214 Adjustments to Cisplatin for Gastrointestinal Toxicity

GOG-0204-29-

The only adjustment allowed for gastrointestinal toxicity is, in the event of two successive episodes of grade 4 nausea and vomiting, reducing cisplatin by one dose level.. If volume contraction becomes a problem, the investigator is encouraged to admit the patient to the hospital for more vigorous pre- and post-treatment hydration and antiemetics (see Section 5.222). Chemotherapy treatment should be delayed until toxicity is grade 1 or less. The Study Chair should be notified if GI toxicity beyond grade 1 continues for more than 2 weeks after a cycle is due (5 weeks after the last dose). In addition, the Study Chair should be notified if a third episode of a grade 2 or worse GI toxicity occurs. (8/30/04)

6.2215 Supportive CareIn addition to other aspects of supportive care, particular attention should be paid to adequate control of nausea and vomiting, including use of HT3 receptor antagonists, and treatment of severe non-hemolytic anemia after several cycles of therapy. The patient should be transfused as needed without interruption of therapy. Platelet transfusions may also be required.

6.222 Vinorelbine (8/30/04)

Toxicity Grade Mucositis/Diarrhea Neurotoxicity Other0 None None None1 Hold until resolved None None2 Decrease 1 level Hold *3 Decrease 1 level Hold *4 Notify Study Chair Hold *

*Notify the Study Chair

6.2221 Dose Modifications to Vinorelbine For Gastrointestinal Toxicity (Mucositis/Diarrhea)It is not anticipated that vinorelbine will cause significant nausea and vomiting. Thus dose modifications for these GI toxicities will consist of a dose modification of cisplatin and will be according to Section 6.2214 However, if a patient should experience Grade 2 or 3 GI toxicity other than nausea and vomiting, treatment should be delayed until the toxicity resolves and then resume treatment at a single dose reduction. The Study Chair should be notified if a Grade 4 toxicity occurs; or if GI toxicity persists for more than 2 weeks; or if repeated episodes of grade 2 or worse toxicity occur. (8/30/04)

6.2222 Dose Modifications to Vinorelbine For Neurologic ToxicityIt is not anticipated that vinorelbine will cause significant neurotoxicity. Thus dose modifications for these GI toxicities

GOG-0204-30-

will consist of a dose modification of cisplatin and will be according to Section 6.2212. (8/30/04)

6.2223 Dose Modifications for Hepatic Insufficiency (8/30/04)Vinorelbine should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with vinorelbine, the dose should be adjusted for total bilirubin according to the table below. (5/27/03)

Total Bilirubin (mg/dL)

VINORELBINE

≤ 2.0 100%2.1 to 3.0 50%

> 3.0 25%


6.3 Treatment Modifications for Regimen III gemcitabine 1000mg/m2 IV day 1 and 8 and cisplatin 50 mg/m2 IV day 1 repeated every 3 weeks up to a maximum of 6 cycles or until disease progression or unacceptable adverse effects prohibit further therapy. (1/26/04) (8/30/04)




Dose Levels for Treatment Modification of GemcitabineInitial dose = 1000 mg/m2




6.31 Dose Modifications for Hematologic Toxicity Dosage modification criteria are found in section 6.3.No cycle (day 1) of treatment is to begin until ANC ≥ 1500/mcl and platelets ≥100,000/µl. Initiation of a new cycle will be delayed for a maximum of two weeks until these values are achieved. Patients who fail to recover adequate counts within a three week delay will be removed from study and the Study Chair should be notified. Follow-up will continue for any patient removed from study. There will be no dose modifications on the basis of uncomplicated neutrophil nadirs lasting < 7 days. Dose reductions in gemcitabine at any time after day 1 of cycle 1 will be continued throughout the rest of the study. (8/30/04)

6.311 Cisplatin

GOG-0204-31-

No reduction is made in the dose of cisplatin for any degree of hematologic toxicity.

6.312 Gemcitabine (8/30/04)Dose limiting toxicity for gemcitabine is hematologic, usually neutropenia and/or thrombocytopenia. The starting dose of gemcitabine for day 1 of cycle 1 is 1000 mg/m2. Dose reductions in gemcitabine at any time after day 1 of cycle 1 will be continued throughout the rest of the study. Chemotherapy on day 1 for all cycles should only be given if the ANC on that day is > 1500/µl and the platelet count is ≥100,000/µl.

The dose of gemcitabine on day 8 is based on blood results obtained on the day of treatment, prior to dosing, according to the following schedule:

ANC/µl Day of Treatment (Day 8) OR

Platelets/µlDay of Treatment

Gemcitabine Dose(mg/m2)

≥1500/µl1000-1499/µl< 1000/µl

≥100,000/µl75,000-99,000/µl< 75,000/µl

1000800 skip

No chemotherapy will ever be given on day 15. As outlined above, if the ANC is < 1000/µl OR the platelet count is < 75,000/µl on day 8, the day 8 dose of gemcitabine will be skipped and the next earliest date of chemotherapy will be at the beginning of the next cycle (2 weeks later). If the day 8 dose is skipped, the day 1 dose of the next cycle will require one dose reduction.

Uncomplicated (absence of sepsis or fever) neutropenia of any grade does not require dose modification. Patients who require a delay of dosing for two weeks or more beyond when a cycle is due to start (5 weeks from day 1, 4 weeks from day 8), or who experience fever and/or sepsis while neutropenic, are at risk for subsequent severe myelosuppression. Upon return to the clinic, on Day 1, if the patient has ANC ≥ 1500/µl and platelets ≥ 100,000/µl a maximum dose of 800 mg/m2 of gemcitabine should be administered. Patients who require a cycle delay of three weeks or greater (6 weeks from day 1) or experience fever and/or sepsis while neutropenic on the reduced dosage will possibly be taken off study after consultation with the Study Chair. Follow-up will continue for any patient taken off study.

Patients who are hospitalized for fever with either grade 3 or 4 neutropenia may be treated with growth factors during the episode at the discretion of the treating physician. At least two days should elapse between the discontinuation of growth factors and the initiation of another cycle of chemotherapy in order to

GOG-0204-32-

allow bone marrow progenitors to cease cell cycling. Growth factors will not be used between doses of chemotherapy in the absence of febrile neutropenia.

If febrile neutropenia occurs despite a one dose level reduction, then with subsequent courses the patient will receive G-CSF 5 µg/kg/d SQ or equivalent starting 24-48 hours after the completion of the subsequent course of chemotherapy and continuing until the ANC is ≥ 10,000.

Patients will NOT receive prophylactic platelet growth factors.

AnemiaAnemia is not an indication for dose reduction in any patient; however, a record of transfusions required should be detailed on the D2R Form. Erythropoietin may be utilized at the discretion of the treating physician and should be documented on the D2R Form.

Erythropoietin may be utilized at the discretion of the treating physician in the event that patient’s hemoglobin drops below 10 g/dl while on therapy, and should be documented on the D2R Form.


6.321 Cisplatin (8/30/04)

Toxicity Grade





None *


1 level****


6.3211Adjustments to Cisplatin for Renal ToxicityPersistent elevation of serum creatinine > 2.0 mg/dL or grade 2 renal toxicity or worse (which on workup is not secondary to prerenal causes or obstructive uropathy) requires withholding treatment until creatinine is < 1.5 mg/dl. If this creatinine elevation persists beyond 2 weeks after a cycle is due to be given (5 weeks after a previous dose), then the Study Chair should be called. If cisplatin is considered to have contributed to this

GOG-0204-33-

degree of irreversible renal toxicity, it will be omitted from all subsequent treatments. (8/30/04)


6.3212 Adjustments to Cisplatin for Peripheral NeuropathyDosing delays will be based on signs and symptoms on the day of treatment for either drug. Grade 3 or 4 peripheral neuropathy requires interruption of cisplatin therapy until adverse effects resolve to grade 1 or less. Grade 2 peripheral neuropathy will require a two dose level reduction in cisplatin. The Study Chair should be notified if grade 3 or 4 neuropathy does not resolve to a grade 1 neuropathy or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration will be given to removing the patient from study. Follow-up will continue for any patient removed from study. (8/30/04)


Grade 3 or 4 ototoxicity requires interruption of cisplatin therapy until adverse effects resolve to grade 1 or less. Grade 2 ototoxicity will require a two dose level reduction in cisplatin. The Study Chair should be notified if grade 3 or 4 ototoxicity does not resolve to a grade 1 toxicity or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration will be given to the patient being removed from the study. Follow-up will continue for any patient removed from study. (8/30/04)

6.3214 Adjustments to Cisplatin for Gastrointestinal ToxicityThe only adjustment allowed for gastrointestinal toxicity is, in the event of two successive episodes of grade 4 nausea and vomiting, reducing cisplatin by one dose level. If volume contraction becomes a problem, the investigator is encouraged to admit the

GOG-0204-34-

patient to the hospital for more vigorous pre- and post-treatment hydration and antiemetics (see Section 5.232). Chemotherapy treatment should be delayed until toxicity is grade 1 or less. The Study Chair should be notified if GI toxicity beyond grade 1 continues for more than 2 weeks after a cycle is due (5 weeks after the last dose). In addition, the Study Chair should be notified if a third episode of grade 2 or worse GI toxicity occurs. (8/30/04)


6.322 Gemcitabine (8/30/04)



6.3221 Dose Modifications to Gemcitabine for Gastrointestinal Toxicity (Mucositis/Diarrhea)It is not anticipated that gemcitabine will cause significant nausea and vomiting. Thus dose modifications for these GI toxicities will consist of dose modification of cisplatin and will be according to Section 6.2214 However, if a patient should experience Grade 2 or 3 GI toxicity other than nausea and vomiting, treatment should be delayed until the toxicity resolves and then treatment resumed at a single dose reduction. The Study Chair should be notified if Grade 4 toxicity occurs; or if GI toxicity persists for more than 2 weeks; or if repeated episodes of grade 2 or worse toxicity occur.

6.3222 Dose Modifications to Gemcitabine for Neurologic ToxicityIt is not anticipated that gemcitabine will cause significant neurotoxicity. Thus dose modifications for these GI toxicities will consist of a dose modification of cisplatin and will be according to Section 6.2212.

GOG-0204-35-

6.3223 Dose Modifications for Hepatic InsufficiencyGemcitabine should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with gemcitabine, the dose should be adjusted for total bilirubin according to the table below. (5/27/03)


Percentage of Starting Dose ofGEMCITABINE

≤ 2.0 100%2.1 to 3.0 50%

> 3.0 25%


6.4 Treatment Modifications for Regimen IV Topotecan 0.75 mg/m2 over 30 minutes days 1, 2, and 3 and cisplatin 50 mg/m2 IV day 1, every 3 weeks up to a maximum of 6 cycles or until disease progression or unacceptable adverse effects prohibit further therapy. (1/26/04) (8/30/04)




Dose Levels for Treatment Modification of TopotecanInitial = 0.75 mg/m2

-1 = 0.60 mg/m2

-2 = 0.45 mg/m2


6.41 Dose Modifications for Hematologic Toxicity Dosage modification criteria are found in section 6.4.


6.412 Topotecan (8/30/04)Dose limiting toxicity for topotecan is hematologic, usually neutropenia and or thrombocytopenia. The starting dose of topotecan is 0.75 mg/m2

Dose reductions in topotecan at any time after day 1 of cycle 1 will be continued throughout the rest of the study. Chemotherapy on day 1 for all cycles should only be given if the ANC on that day is > 1500/µl and the platelet count is ≥100,000/µl.

GOG-0204-36-

ThrombocytopeniaThere will be no dose reduction for grade 2 or 3 thrombocytopenia. Grade 4 thrombocytopenia requires a 1 dose level reduction. The Study Chair should be notified if the toxicity does not resolve within 2 weeks after the cycle of chemotherapy is due (5 weeks from the start of the last cycle).

NeutropeniaUncomplicated neutropenia does not require dose modification.

A one dose level reduction in the Topotecan dose is required for neutropenic fever defined as grade 3 or 4 nadir neutropenia toxicity with temperature of 38.0° C or 100.4°F twice within a day, or single temperature of 38.3°C or 101°F. Patients who are hospitalized for fever with either grade 3 or 4 neutropenia may be treated with growth factors during the episode. At least two days should elapse between the discontinuation of growth factors and the initiation of another cycle of chemotherapy in order to allow bone marrow progenitors to cease cell cycling.

If febrile neutropenia occurs despite a one dose level reduction, then with subsequent courses the patient will receive G-CSF 5 µg/kg/d SQ or equivalent starting 24-48 hours after the completion of the subsequent course of chemotherapy and continuing until the ANC is ≥ 10,000. At least two days should elapse between the last dose of G-CSF and the initiation of another treatment course. If febrile neutropenia occurs despite the use of G-CSF then with subsequent courses the patient will receive a second dose reduction of Topotecan. If a dose reduction below the lowest dose in section 6.21 is required, a dose reduction of 20% may take place after consulting with the study chair.

AnemiaAnemia is not an indication for dose reduction in any patient; however, a record of transfusions required should be detailed on the D2R Form. Erythropoietin may be utilized and should be documented on the D2R Form.

Erythropoietin may be utilized at the discretion of the treating physician in the event that patient’s hemoglobin drops below 10 g/dl while on therapy, and should be documented on the D2R Form.

GOG-0204-37-


6.421 Cisplatin (8/30/04)Toxicity Grade





None *


1 level****


6.4211Adjustments to Cisplatin for Renal ToxicityPersistent elevation of serum creatinine > 2.0 mg/dL or grade 2 renal toxicity or worse (which on workup is not secondary to prerenal causes or obstructive uropathy) requires withholding treatment until creatinine is < 1.5 mg/dl. If this creatinine elevation persists beyond 2 weeks after a cycle is due to be given (5 weeks after a previous dose), then the Study Chair should be called. If cisplatin is considered to have contributed to this degree of irreversible renal toxicity, it will be omitted from all subsequent treatments. (8/30/04)


6.4212 Adjustments to Cisplatin for Peripheral NeuropathyDosing delays will be based on signs and symptoms on the day of treatment for either drug. Grade 3 or 4 peripheral neuropathy requires interruption of cisplatin therapy until adverse effects resolve to grade 1 or less. Grade 2 peripheral neuropathy will require a two dose level reduction in cisplatin. The Study Chair should be notified if grade 3 or 4 neuropathy does not resolve to a grade 1 neuropathy or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration

GOG-0204-38-

will be given to removing the patient from study. Follow-up will continue for any patients removed from study. (8/30/04)


Grade 3 or 4 ototoxicity requires interruption of cisplatin therapy until adverse effects resolve to grade 1 or less. Grade 2 ototoxicity will require a two dose level reduction in cisplatin. The Study Chair should be notified if grade 3 or 4 ototoxicity does not resolve to a grade 1 toxicity or less 2 weeks after a cycle is due to be given (5 weeks after a previous dose). At this time consideration will be given to removing the patient from study. Follow-up will continue for any patient removed from study. (8/30/04)

6.4214 Adjustments to Cisplatin for Gastrointestinal ToxicityThe only adjustment allowed for gastrointestinal toxicity is, in the event of two successive episodes of grade 4 nausea and vomiting, reducing cisplatin by one dose level. If volume contraction becomes a problem, the investigator is encouraged to admit the patient to the hospital for more vigorous pre- and post-treatment hydration and antiemetics (see Section 5.242). Chemotherapy treatment should be delayed until toxicity is grade 1 or less. The Study Chair should be notified if GI toxicity beyond grade 1 continues for more than 2 weeks after a cycle is due (5 weeks after the last dose). In addition, the Study Chair should be notified if a third episode of grade 2 or worse GI toxicity occurs. (8/30/04)


GOG-0204-39-

6.422 Topotecan (8/30/04)



6.4221 Dose Modifications to Topotecan for Gastrointestinal Toxicity (Mucositis/Diarrhea)It is not anticipated that topotecan will cause significant nausea and vomiting. Thus dose modifications for these GI toxicities will consist of dose modification of cisplatin and will be according to Section 6.2214 However, if a patient should experience Grade 2 or 3 GI toxicity other than nausea and vomiting, treatment should be delayed until the toxicity resolves and then treatment resumed at a single dose reduction. The Study Chair should be notified if Grade 4 toxicity occurs; or if GI toxicity persists for more than 2 weeks; or if repeated episodes of grade 2 or worse toxicity occur.

6.4222 Dose Modifications to Topotecan for Neurologic ToxicityIt is not anticipated that topotecan will cause significant neurotoxicity. Thus dose modifications for these GI toxicities will consist of a dose modification of cisplatin and will be according to Section 6.2212.

6.4223 Dose Modifications for Hepatic InsufficiencyTopotecan should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with topotecan, the dose should be adjusted for total bilirubin according to the table below. (5/27/03)


Percentage of Starting Dose ofTOPOTECAN

≤ 2.0 100%2.1 to 3.0 50%

> 3.0 25%

6.43 Dose Re-escalationThere will be no dose re-escalation. (8/30/04)

GOG-0204-40-

7.0 STUDY PARAMETERS

Observations and Tests:

7.1 Regimens I – IV (1/26/04) (8/30/04)

Prior to Study Weekly Prior to Each Cycle

Q 3 Months after Completing Tx

x 2 years

Q 6 Months x 3 years

History 3 X X X

Physical Exam 3 X X X

Performance Status 3 X X X

Quality of Life Questionnaire

X 1 1

Tumor Measurements

3 X* X X

Chest X-ray 3 X*

EKG 3 4

Other Imaging 4* 4*

Pregnancy Test†

(Serum) 2

CBC with diff, platelets

2 X X 4 4

Creatinine 2 X 4 4

Electrolytes 2 X 4 4

Urinalysis 2 X 4 4

SGOT 2 X 4 4

Bilirubin 2 X 4 4

Alkaline Phosphatase 2 X 4 4

Magnesium 2 X 4 4

Calcium 2 X 4 4

Audiogram 4

* As required to assess measurable disease. Disease that can be assessed clinically (physical examination) should be evaluated every cycle (every 3 weeks) while disease which is assessed by imaging modalities (CXR, CT, MRI) should be evaluated every other cycle unless other evidence of a change mandates earlier assessment. Tumor measurements should be done just prior (within one week) to the next planned cycle of therapy. Tumor measurements should also be done after the sixth cycle.

† Excludes patients who have had a hysterectomy or bilateral tubal ligation prior to study entry.

1. For a total of 4 assessments (Baseline, before cycle 2, before cycle 5 and 9 months after study entry) (See Section 4.7).2. Must be obtained within 14 days prior to initiating protocol therapy.3. Must be obtained within 28 days prior to initiating protocol therapy. 4. As clinically indicated.

GOG-0204-41-

8.0 EVALUATION CRITERIA

8.1 Parameters of Response – GOG RECIST Criteria

8.11 Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be ≥ 20 mm when measured by conventional techniques, including palpation, plain x-ray, CT, and MRI, or ≥ 10 mm when measured by spiral CT. This should be the same lesion in 3.12.

8.12 Baseline documentation of “Target” and “Non-Target” lesions

All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest dimension) and their suitability for accurate repetitive measurements by one consistent method of assessment (either by imaging techniques or clinically). A sum of the longest dimension (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease.

All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as “present” or “absent”.

All baseline evaluations of disease status should be performed as close as possible to the start of treatment and never more than 4 weeks before the beginning of treatment.

8.13 Best Response

Measurement of the longest dimension of each lesion size is required for follow-up. Change in the sum of these dimensions affords some estimate of change in tumor size and hence therapeutic efficacy. All disease must be assessed using the same technique as baseline. Reporting of these changes in an individual case should be in terms of the best response achieved by that case since entering the study.

8.131 Complete Response (CR) is disappearance of all target and non-targetlesions and no evidence of new lesions documented by two disease assessments at least 4 weeks apart. Normalization of CA125, if elevated at baseline, is required for ovarian carcinoma studies.

GOG-0204-42-

8.132 Partial Response (PR) is at least a 30% decrease in the sum of longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD. There can be no unequivocal progression of non-target lesions and no new lesions. Documentation by two diseaseassessments at least 4 weeks apart is required. In the case where the ONLY target lesion is a solitary pelvic mass measured by physical exam, which is not radiographically measurable, a 50% decrease in the LD is required.

8.133 Increasing Disease is at least a 20% increase in the sum of LD of targetlesions taking as references the smallest sum LD or the appearance of new lesions within 8 weeks of study entry. Unequivocal progression of existing non-target lesions, other than pleural effusions without cytological proof of neoplastic origin, in the opinion of the treating physician within 8 weeks of study entry is also considered increasing disease (in this circumstance an explanation must be provided). In the case where the ONLY target lesion is a solitary pelvic mass measured by physical exam, which is not radiographically measurable, a 50% increase in the LD is required.

8.134 Symptomatic deterioration is defined as a global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression.

8.135 Stable Disease is any condition not meeting the above criteria.

8.136 Inevaluable for response is defined as having no repeat tumor assessments following initiation of study therapy for reasons unrelated to symptoms or signs of disease.

8.14 Progression (measurable disease studies) is defined as ANY of the following:

• At least a 20% increase in the sum of LD target lesions taking as reference the smallest sum LD recorded since study entry

• In the case where the ONLY target lesion is a solitary pelvic mass measured by physical exam which is not radiographically measurable, a 50% increase in the LD is required taking as reference the smallest LD recorded since study entry

• The appearance of one or more new lesions • Death due to disease without prior objective documentation of progression• Global deterioration in health status attributable to the disease requiring a

change in therapy without objective evidence of progression • Unequivocal progression of existing non-target lesions, other than pleural

effusions without cytological proof of neoplastic origin, in the opinion of the treating physician (in this circumstance an explanation must be provided)

GOG-0204-43-

8.15 Survival is the observed length of life from entry into the study to death or the date of last contact.

8.16 Progression-Free Survival (measurable disease studies) is the period from study entry until disease progression, death or date of last contact.

8.17 Recurrence-Free Survival (non-measurable disease studies) is the period from study entry until disease recurrence, death or date of last contact.

8.18 Subjective Parameters including performance status, specific symptoms, and side effects are graded according to the CTC.

GOG-0204-44-

9.0 DURATION OF STUDY

9.1 Each patient will continue on study up to a maximum of six cycles or until disease progression or toxicity prohibits further therapy. Patients in continued response or with stable disease may continue on study beyond the six cycles with consent of the Study Chair, but must be reported using GOG forms. (1/26/04) (8/30/04)

9.2 Patient should be followed until death.

9.3 Report all therapies and toxicities on GOG forms even if the patient is taken off protocol therapy until progression is documented.

-45 - GOG-0204

10.0 STUDY MONITORING & REPORTING PROCEDURE

10.1 A consent form must be signed by the patient or guardian prior to entry into study. Current FDA, NCI and institutional regulations concerning informed consent will be followed.

10.2 Before patient entries will be accepted, an official signed CTSU IRB Certification Form and a CTSU IRB/Regulatory Approval Transmittal Sheet (forms can be downloaded at www.ctsu.org) must be received by the CTSU Regulatory Office. These forms can be faxed or mailed to:

CTSU Regulatory OfficeCoalition of National Cancer Cooperative Groups

1818 Market Street, Suite 1100Philadelphia, PA 19103

1-888-823-5923FAX 215-569-0206 (5/27/03) (8/30/04)

10.3 ADVERSE EVENT REPORTING FOR COMMERCIAL DRUG STUDIES (1/26/04)

If clearly related to the commercial agent(s), adverse effects that are either severe or for which the cause is unknown must be reported using the rules listed below.

This study will utilize the CTC version 2.0 for toxicity and Adverse Event Reporting. A copy of the CTC version 2.0 can be downloaded from the CTEP home page. However, a copy of this document is available on the GOG web site (http://www.gog.org under section 2, MANUALS). A GOG CTC Booklet will be mailed to the institution registering a patient to this study if needed. All CTC toxicities must be reported on form T. Both form T and D2 are available on the GOG website. Each clinic should produce a supply of blank forms by photo-copying the originals in the appendix.

Toxicity Grade

Typea IDB Via

mail/fax1

MedWatchVia

mail/fax1

GOG Via

E-mail2

4,5 Unknown Yes Yes Yes5 Known No No Yes3

2,3 Unknown No No Yes4 (non-myelo) Known No No Yes

4 (myelob) Known No No No

1Written report to IDB and MedWatch within 10 working days.2 Report to GOG within 2 working days.3 If clearly related to the commercial agent(s).

ªType is based on toxicities included in the NCI list of known toxicities included in the packaging insert or literature of known toxicities associated with the study drug(s).bMyelosuppression, which includes neutropenia, anemia, thrombocytopenia

10.31 NCI – Adverse events for commercial agents should be reported to the Investigational Drug Branch, Cancer Therapy Evaluation Program, within 10

-46 - GOG-0204

working days. Report the ADR on the FDA MedWatch Form. The form should be mailed or faxed to:

Investigational Drug BranchPO Box 30012Bethesda, MD 20824Or faxed to: (301) 402-1584

and 1 copy to the GOG Administrative Office

1600 John F. Kennedy Blvd, Suite 1020 Philadelphia, PA 19103

10.32 FDA – Any unexpected (not listed in the package label), life-threatening (Grade 4) or unexpected, fatal (Grade 5) adverse event with an attribution of possible, probably or definite should be reported in 10 working days. The AE should be reported on the FDA Form 3500 MedWatch (available from the FDA: www.fda.gov/medwatch.) The completed form should be forwarded to the FDA:

MedWatch5600 Fishers LaneRockville, MD 20852Or faxed to: 1-800-332-0178

10.33 GOG – Complete a GOG Toxicity Form. This form is available for downloading on the GOG Website (www.gog.org). If required, phone the Administrative Office: 1-800-225-3053 to report patient’s GOG #, grade, and type of event. E-mail the completed form to [email protected]. Fax (1-215-854-0716) may be used, if necessary. All adverse reactions will be immediately directed to the Study Chair for further action.

-47 - GOG-0204

10.4 The following forms must be completed for all patients and the original must be received in the GOG Statistical and Data Center in accordance to the schedule below. Note: Pathology material (Form F, path report & slides) must be submitted together. (8/30/04)

Due withinForm

Weeks EventCopies(M*)

Notes

Form R (Registration Form) N/A N/A 1 See GOG website

Quality of Life Form (Baseline) QOL cover sheet-Appendix IV 2 Registration 1

Must be original Scantron

Form F Pathology ReportSlides (Primary Surgery)Form F RecurrencePathology Report RecurrenceSlides (Recurrence)Form F Persistent DiseasePathology Report Persistent DiseaseSlides (Persistent Disease)

6 Registration111

See GOG website Representative stained slides documenting primary and stage IVB (if applicable).

Form OSR (Recurrent Gynecologic Cancer On Study Form)

2 Registration 1 See GOG website

Form D2R (Cycle Dose Drug Form) (cycles 1-6) 2

At completion of cycle of therapy 1 See GOG website

Form T (Transmittal for Common Toxicity Form) (cycles 1-6) 2

At beginning of next cycle of therapy 1 See GOG website

Form D2M (Solid Tumor Evaluation Form) 2

At baseline, at beginning of each cycle of therapy, and after cycle 6

1 See GOG website

Quality of Life Form (twice during & once after therapy) QOL cover sheet -Appendix IV

2Prior to cycle 2,

Prior to cycle 5, 9 mo. Follow-up visit.

See section 4.6

1 Must be original Scantron

Form Q0“Treatment Completion”

2 Completing Rx & changing Rx

1 See GOG website

Form Q (Follow up Form) 2Progression, death,

and normal follow-up**

1 See GOG website

* Must send the original to the Statistical and Data Center.** Quarterly for the first two years, semi-annually for an additional three years, and thereafter

annually.

This study will be monitored by the Abbreviated Clinical Data Update System (CDUS) Version 1.x. CDUS data will be submitted quarterly to CTEP by electronic means. (1/26/04)

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11.0 STATISTICAL CONSIDERATIONS (1/26/04)

11.1 Study Design: The design for this study is a randomized phase III trial of four chemotherapy doublets: cisplatin/paclitaxel (control), cisplatin/vinorelbine, cisplatin/topotecan and cisplatin/gemcitabine employing the intent-to-treat (ITT) of eligible patients principle. The random assignment of the treatment regimen will be balanced within disease status at registration (recurrent, persistent and stage IVB primary) and performance status. Patient entry will be accomplished via telephone or the GOG web site using the fast fact sheet to determine eligibility.

11.2 Data Collection: The principal parameters to be collected, analyzed and reported to determine the relative benefit of the experimental regimens are:11.21 Outcome variables: survival (primary), progression-free survival (secondary)

and frequency of response (tertiary).11.22 Disease characteristics: disease status (recurrent, persistent or primary), time

from primary diagnosis to study entry, location of lesion(s) and previous treatment.

11.23 Host characteristics: age, performance status and race (race will be evaluated as a prognostic factor only).

11.24 Adverse effects grade and type (CTC version 2.0).11.25 Therapy administered: Dose and courses of chemotherapy.

11.3 Accrual: The annual accrual is 150 patients.

11.4 Hypothesis & Sample Size: There are three hypotheses to be tested using a pair-wise log-rank test. The survival of the three treatment groups: cisplatin/vinorelbine, cisplatin/topotecan and cisplatin/gemcitabine will be compared to cisplatin/paclitaxel (one-sided tests). Each hypothesis is based on the whether or not any experimental doublet improves survival over cisplatin/paclitaxel. The median survival for the cisplatin/paclitaxel group is anticipated to be 8.5 months using the GOG-169 data. A decrease in the death rate of 33% (∆=1.5, e.g., survival rate from 14% to 27% at 2 yrs.) is important to detect. This difference will require the observation of 232 deaths in the two treatment groups to be compared.27 This net sample size will produce a statistical power (probability of a true- positive study) of 0.845 when keeping the probability of a type I error at 0.019. The total number of deaths over the entire study will be set at 464.

The sample size goal for this trial will be 600 eligible patients (150 per regimen). Using DeMorgan’s law, the chance committing any type I error by the three hypothesis tests is bounded from above by 0.0559. However, due to the dependence of the three tests the actual probability is very close to 0.05 (simulation studies). The increase in the type II by performing three tests, with all three alternative hypotheses being true, was not considered a realistic concern, and therefore, no adjustment was made. The operating characteristics when testing progression-free survival will be maintained. The statistical power is 0.80 when keeping the type I error set at 0.019 to detect a relative odds of response (partial + complete) equal to 2.09 for the experimental regimen (frequency of response for control and experimental groups is 0.276 and 0.444, respectively).28

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11.5 Study Duration: The accrual period will be 4 years with an additional follow-up period of 6 months.27

11.6 Interim Analysis: There will be one interim analysis conducted just prior to the GOG business meeting which reports for the first time 232 or more deaths in the entire study. This should occur at approximately two-thirds of the way through the accrual period. The goal will be to close accrual to one of the regimens or the entire study, whichever is appropriate, because there is a lack of any decrease in the death rate (futility analysis) orthe decrease in risk is dramatic in one or more of the experimental regimens. In the event of a dramatic improvement in survival among an experimental group, as determined by the log-rank test, the control regimen will be considered for early closure. The interim stopping rule is based on the spending function ∀(t*) = ∀t*

1.5 as outlined by Lan and DeMets.29 The critical values, in terms of z-scores, are 2.472 (t*=0.5) and 2.172 (t*=1.0) at the interim and final analysis, respectively. This stopping rule will maintain the type I error at 0.01929 for each hypothesis test. Simulation studies indicate that the type II error is increased by approximately ½ % (i.e., 83.9 %).

Conversely, the experimental regimen will be closed if there is any degree of excess risk of death in the experimental group compared to the control group. In this event, the null hypothesis will be accepted. The critical region during interim analysis will be any excess deaths above expected in the experimental group, that is, the numerator without squaring (i.e., Oe - Ee) from the log-rank test is greater than 0. Simulation studies indicate that this additional stopping rule increases the type II error only negligibly. Consequently, the statistical power with all stopping rules employed is approximately 83.8 % for each hypothesis test.

11.7 Statistical Considerations for Quality of Life Component

11.71 Power and Sample Size

The quality of life question is: Is there a difference in QOL between the patients treated with cisplatin/vinorelbine and those treated with cisplatin/ paclitaxel? All the patients eligible for survival analysis will be eligible also for QOL analysis. Two QOL instruments will be used: FACT-Cx (with 4-item Ntx) and BPI single item. The analysis of QOL will be concentrated in comparing three FACT-Cx subsets between two treatments. Theses three primary QOL outcomes include the benefits of treatment upon self-reported physical status (FACT PWB and Cx Subscales) as well as neurotoxicity (FACT-Ntx).

Since there are three major hypotheses in this study, the type I error probability is controlled at 0.02 for each comparison to attain an overall 5% level of significance (Bonferroni method).

Assuming 20% invalid forms, there will be 89 patients in each treatment group for QOL analyses. This sample size has a power of 0.80 to detect a difference of 0.47 standard deviation at α of 0.02 (two-sided). 30

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The QOL analysis using secondary outcome (BPI) or other additional analyses will be considered exploratory, and the exact p-values will be reported as suggestive of confidence in the inferential results.

11.72 Strategy of Analysis

11.721 Intention-to-Treat Analysis: The QOL data will be analyzed according to assigned treatment.

11.722 Validation of QOL Form: A QOL form will be defined as valid if a patient completes 80% of all items. For valid form with some missing values, the pattern of missing values will be examined and appropriate imputation method will be used to estimate the missing values. However, for three primary QOL outcomes (FACT PWB, Cx Subscale and FACT Ntx), the subscale score will be not calculated if more than 50% of items are missing in that subscale.

11.723 Cross-Sectional AnalysesQOL between four groups will be compared for baseline and concentrated in comparisons at three follow-up assessment times (prior cycle 2, prior to cycle 5 and 9 months after entry of the study) using independent t-test.

11.724 Longitudinal Analyses The changes of QOL from pre-treatment assessment to the follow-up

assessments (3 time points) will be analyzed by paired t-test for each group. Mixed model with repeated measures will be also performed to compare the difference in QOL over time between four groups.

11.725 Other AnalysesAdditional QOL analyses may be performed depending on the clinical findings from this study, which may include the assessment of relationship between QOL and clinical response, or relationship between QOL and toxicities. These analyses will be considered exploratory and descriptive, offering information to clinicians regarding the impact that tumor response versus toxicity has upon patients’ lives.

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12.0 BIBLIOGRAPHY (1/26/04)

1. Cancer Facts and Figures, American Cancer Society 2003.

2. Rose PG, Eifel PJ. Combined radiation therapy and chemotherapy for carcinoma of the cervix. Cancer J Mar-Apr, 7(2):86-94, 2001.

3. Moore DH. Advances in the treatment of cervical cancer. Cancer Treatment and Research95:149-76, 1998.

4. Moore DH, McQuellon RP, Blessing JA, Thaler H, Benda J, Miller DS, Olt G, King S, Boggess J, Rocereto TF. A Randomized Phase III Study of Cisplatin Versus Cisplatin Plus Paclitaxel in Stage IVB, Recurrent or Persistent Squamous Cell Carcinoma of the Cervix: a Gynecologic Oncology Group Study. Proc Am Soc Clin Onc abstract #801, 2001.

5. Bonomi P, Blessing J, Stehman FB, et al. A Randomized trial of three cisplatin doseschedules in squamous-cell carcinoma of the cervix; A Gynecologic Oncology Groupstudy. J Clin Oncol 3:1079-85, 1985.

6. Omura GA, Blessing J, Vaccarello L, Berman M, Mutch D, Clarke-Pearson D, Anderson B. A randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 15:165-171, 1997.

7. Lhommé C, Vermorken JB, Mickiewicz E, Chevalier B, Alvarez A, Mendiola C, Pawinski A, Lentz MA, Pecorelli S. A Phase II trial of vinorelbine in patients with advanced and/or recurrent cervical carcinoma: an EORTC Gynecological Cancer Cooperative Group Study. European Journal of Cancer Jan, 36(2):194-9, 2000.

8. Pignata S, Silvestro G, Ferrari E, Selvaggi L, Perrone F, Maffeo A, Frezza P, Di Vagno G, Casella G, Ricchi P, Cormio G, Gallo C, Iodice F, Romeo F, Fiorentino R, Fortuna G, Tramontana S. A Phase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix. J Clin Oncol Mar, 17(3):756-60, 1999.

9. Schilder RJ, Blessing JA, Morgan M, et al. Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 76:204-207, 2000.

10. Greggi S, D’Agostino G, Smaniotto D, et al. Gemcitabine is ineffective in recurrent, preirradiated cervical cancer. Gynecol Oncol 78:76-77, 2000.

11. Hernandez P, Olivera P, Duenas-Gonzalez A, et al. Gemcitabine activity in cervical cancer cell lines. Cancer Chemother Pharmacol 48:488-492, 2001.

12. Peters GJ, Bergman AM, Ruiz van Halperen VW, et al. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 22:72-79, 1995.

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13. Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic cancer: A prospective, randomized phase III study of the Gruppo Oncologica d’Italia Meridionale. Cancer 94:902-910, 2002.

14. Duenas-Gonzalez A, Lopez-Graniel C, Gonzalez A, et al. A phase II study of gemcitabine and cisplatin combination as induction chemotherapy of untreated locally advanced cervical carcinoma. Ann Oncol 12:541-547, 2001.

15. Burnett AF, Roman LD, Garcia AA, et al. A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 76:63-66, 2000.

16. Lorvidhaya V, Chitaparanarux I, Kamnerdpaphon P. Gemcitabine and cisplatin in patients with metastatic cervical cancer. Proc ASCO 19:393a(abst #1554), 2000.

17. Mahouf H, Bouzid K. Gemcitabine (G) and cisplatin ( C ) in recurrent, advanced or metastatic cervical squamous cell carcinoma. Proc ASCO 20:207(abst #801), 2001.

18. Nayfield SG, Ganz PA, Moinpour CM, Cella DF, Hailey BJ. Report from a National Cancer Institute (USA) workshop on quality of life assessment in cancer clinical trails. Qual Life Rsch1:203-210, 1992.

19. McCabe MS. A cooperative group report on quality of life research: Lessons learned. Monogr Natl Cancer Inst 63-65, 1996.

20. Cella DF. Manual for the Functional Assessment of Cancer Therapy (FACT) Measurement System (version 4). Center for Outcomes, Research and Education (CORE), Northwestern University, Chicago, 1997.

21. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 11:570-579, 1993.

22. Cleeland CS. Pain assessment in cancer. In: Effect of cancer on quality of life. Osoba, D. (Ed.) Boston: CRC Press, 1991.

23. Payne R, Mathias SD, Pasta DJ, Wanke LA, Williams R, Mahmoud R. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol 16:1588-1593, 1998.

24. Gralla RJ, et al. Recommendations for the use of antiemetics: Evidence-based, clinical practice guidelines. J Clin Oncol 17:2971, 1999.

25. Koeller JM, et al. Antiemetic guidelines: creating a more practical treatment approach. Support Care Cancer 10:519, 2002.

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26. Monk BJ, Burger RA, Commentary: Study finds that hypersensitivity to paclitaxel may not preclude its continued but cautious use. Evidence-based Oncology 1: 122, 2000.

27. Rubenstein LF, Gail MH, Santner TJ. Planning the duration of a comparative clinical trial with loss to follow-up and a period of continued observation. J of Chronic Diseases 34:469, 1981.

28. Casagrande JT, Pike MC, and Smith PG. The power function of the "Exact" test for comparing two binomial distributions. Applied Statistics 27, #2, pp.176-801, 1978.

29. Lan KKG, DeMets DL. Discrete Sequential Boundaries For Clinical Trials. Biometrika70:659-663, 1983.

30. Dupont WD, Plummer WD. Power and Sample Size Calculation: A Review and Computer Program. Controlled Clinical Trials 11:116-28, 1990

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13.0 SECTION OF CONFIDENTIALITY

The GOG has been issued a Certificate of Confidentiality from the Department of Health and Human Services (DHHS) through the National Institutes of Health. This certificate protects the privacy of research subjects by protecting investigators and institutions like the GOG from being compelled to release information that could be used to identify study participants. It allows GOG investigators who have access to research records to refuse to disclose identifying information in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. Identifying information is broadly defined as any item or combination of items in the research data that could lead directly or indirectly to the identification of a research subject. Individuals who participate as research subjects (i.e., about whom the investigator maintains identifying information) in this research project during any time the Certificate is in effect are protected permanently.

Personally identifiable information protected by a Certificate may be disclosed under the following circumstances: 1) Voluntary disclosure of information by study participants themselves or any disclosure that the study participant has consented to in writing, such as to insurers, employers, or other third parties; 2) Voluntary disclosure by the researcher of information on such things as child abuse, reportable communicable diseases, possible threat to self or others, or other voluntary disclosures provided that such disclosures are spelled out in the informed consent form; 3) Voluntary compliance by the researcher with reporting requirements of state laws, such as knowledge of communicable disease, provided such intention to report is specified in the informed consent form or HIPAA authorization; or 4) Release of information by researchers to DHHS as required for program evaluation or audits of research records or to the FDA as required under the federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.). Organizations that may inspect and/or copy personally identifiable information include groups such as:

Gynecologic Oncology GroupCancer Trials Support Unit (CTSU) – an NCI sponsored organizationNational Cancer InstituteFood and Drug AdministrationOther regulatory agencies and/or their designated representatives [ADD OTHER STUDY SPONSORS HERE IF APPLICABLE]

Personal identifying information includes things such as: name, zip code, social security or other identifying number, photographs, genetic information or tissue samples, or any other item or combination of data about a research participant which could reasonably lead, directly or indirectly by reference to other information, to identification of that research subject.

To further protect the privacy of those individuals involved in GOG trials, the employees of those agents who work for the GOG and have access to identifiable personal health information (i.e. GOG Statistical and Data Center, Administrative Office and Tissue Bank) are required to receive HIPAA training and be aware of the GOG’s policy regarding patient privacy. (5/27/03)

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GYNECOLOGIC ONCOLOGY GROUP ADMINISTRATIVE OFFICE