Phase I Evaluation of

Single Dose Every

SARAH TAYLOR, MD,* ROBERT J. BELT, MD,t CHARLES

Chlorozotocin:

Six Weeks

D. HAAS, MD,* RONALD L. STEPHENS, MD,§ AND BARTH HOOGSTRATEN, MD

A phase I trial of chlorozotocin was completed for the single dose every six week schedule. At 250 mg/m2 i.v. push, excessive thromhocytopenia, nausea, and anorexia occurred. Two cases of cholestatic jaundice were seen, and one patient had worsening of his diabetes mellitus after one course. Partial response or prolonged disease stabilization with increased survival was documented in four of seven patients with non-small cell carcinoma of the lung. A starting dose of 225 mg/m2 is recommended for good risk patients with little or no prior hone marrow toxicity from chemoa therapy or irradiation. A dose of 200 mg/mL is recommended for patients with limited previous treatment and good bone marrow reserve.

Cancer 46:2365-2368, 1980.

HLOROZOTOCIN IS A PYRANOSYL-GLUCOSE con- C jugated chloroethyl nitrosourea similar to strep- tozotocin. Structure activity and preclinical toxicology studies suggested that chlorozotocin might be less myelosuppressive than other nitrosoureas while main- taining equivalent activity to BCNU against L1210 mouse leukemia.

Drug-related toxicities in animals were emesis, diarrhea, anorexia, renal impairment, and liver dys- function. Leukopenia was present at high doses in dogs but was not observed in monkeys. The toxic dose low in the dog on a five-day schedule was 7.5 rnglm'i day and on a single dose low schedule the highest nontoxic dose was 15 mglm'.'

From the Departments of Medicine, Division of Clinical Oncology, University of Kansas Medical Center, Kansas City, Kansas, and Kansas City Veterans Administration Medical Center, Kansas City, Missouri.

Supported by NCI grant #NCI-CM-RFP-74-01. * Fellow, Division of Clinical Oncology, University O f Kansas

Medical Center. i Assistant Professor, Division of Clinical Oncology, University

of Kahsas Medical Center and Kansas City Veterans Administra- tion Medical Center.

$ Chief. Medical Oncology Section, Medical Service, Veterans Administration Hospital, Kansas City, Missouri.

5 Associate Professor, Division of Clinical Oncology, University of Kansas Medical Center.

I ' Professor of Medicine, Director, Division of Clinical Oncology, University of Kansas Medical Center, Kansas City, Kansas.

Address for reprints: Sarah Taylor, MD, Division of Clinical Oncology, University of Kansas Medical Center, 39th and Rainbow Blvd., Kansas City, KS 66103.

We thank Lyn Cain, RN, Maryann Daniels, R N . and Vicki Whipple, RN, for completing these studies.

Accepted for publication December 20, 1979.

A previous phase I evaluation of single dose chloro- zotocin yielded a recommended phase I1 dose of 120 mg/mz. A review of their toxicity data suggested that higher doses could be t ~ l e r a t e d . ~ Therefore, phase I studies at 150 mg/m2 were initiated.

Materials and Methods

Phase I studies with chlorozotocin at the University of Kansas were begun in 1977 at 150 mg/m2 given intravenously over 15 minutes every six weeks. Sub- sequent groups of three or more patients each were escalated, as shown in Table 1, to a final dose of 250 mg/m2. Individual patients were escalated, provided excessive toxicity was not observed. Pa- tients experiencing excessive toxicity had dose reductions of 25 to 50%. Courses were given every six weeks or when the patient had recovered from the drug toxicities.

Chlorozotocin was provided by the NCI in 50 mg vials of lyophilized drug.

Patient eligibility criteria were histologic proof of malignancy in which established forms of treatment had been ineffective; ineligibility for or refractori- ness to regimens or protocols of potentially higher efficacy; solid tumors only; life expectancy of 12 weeks or more; off prior chemotherapy, radiotherapy, and/ or immunotherapy for four weeks before entry and recovered from the acute toxic effects of the prior treatment; adequate liver function with alkalifie phosphatase and SGOT no more than 50% above the upper limit of normal and serum bilirubin less than

0008-S43X/80/1201/236S $0.70 0 American Cancer Society

2365

2366 CANCER December I 1980 Vol. 46

T A B I . ~ 1. Patient Characteristics, Response. and First Course Myelosuppression with Chlororotocin

First course nadirs x I03/mm

Starting dose P.S. Tumor type Response (mgim') WBC P1,T

Patient 1: Patient 2* Patient 3* Patient 4: Patient 5* Patient 6: Patient 7: Patient 8 Patient 9 Patient 10 Patient 11 Patient 12: Patient 13: Patient 14 Patient 15

60 80 40 5 0 90 60 80 80 50 70 90 70 90 30 50

Gastric Sq. H & 1v Sq. H & N Rectal. adeno. L.ung. large Colon Lung. adeno. I a n g . adeno. sq. ? l " I.ung, adeno. 1,ung. sq. I.ung. alv. Melanoma Adeno. '?I" Lung, sq.

W S W W

Imp. S S S W W PR W W W W

1 50 175 175 200 200 200 200 225 225 225 225 225 2.50 250 250

9.0 9.6 5.7 7.1 4.2 4.9 3.2 4.3 3.1

10.1 3.0 3.3 2.5 2.3 2.9

182 180 193

14 95

160 200 165 120 168 59 55 30 16

130

* Prior chemotherapy. t Prior chemotherapy: including mitomycin C andior nitrosourea9.

W -- worse; S = stable; PR Performance Status.

partial remission; P.S. Karnofsky

2.5 mg/dl: serum creatinine less than 1.5 mg/dl and/or creatinine clearance greater than or equal to 60 ml/ min.; signed informed consent in keeping with the policy of the Human Experimentation Committee of the University of Kansas Medical Center or the Kansas City Veterans Administration Hospital.

Pretreatment evaluation included 1) a complete history and physical examination, which comprised documentation of measurable disease and signs and symptoms as well as performance status; 2) laboratory studies including complete blood count with white blood cell differential; erythrocyte, platelet and reticulocyte count: urinalysis; SGOT, alkaline phos- phatase: electrolytes; bilirubin-total and direct; uric acid: calcium: phosphorus; amylase: lipase: protein electrophoresis: serum iron and TIBC; BUN, creati- nine; 24 hour urine for creatinine clearance: fasting and two hour post 100 gram carbohydrate load blood sugars; bone marrow aspiration; and biopsy; 3 ) in- dicated x-rays or scans. Evaluation during the study included weekly complete blood count with white blood cell differential. reticulocyte count and platelet count: weekly SGO'T, alkaline phosphatase, LDH, total and direct serum bilirubin; uric acid, urinaly- sis, BUN, creatinine, and fasting blood sugar. Every six weeks and off study, all weekly studies, appro- priate history, and physical weight and tumor measure- ment(s), performance status, and creatinine clearance were done.

A partial response was defined as a 50% or greater decrease in the sums of the products of all measurable tumors with no other evidence of increasing disease for at least four weeks. N o change or stable disease included lesions that decreased in size but less

than 50% or enlarging lesions that increased less than 25% in size. Increasing disease was defined as an unequivocal increase of at least 25% in size of measured lesions and/or the appearance of new lesions.

Results

Fifteen patients received 33 courses of chloro- zotocin (range 1-7 courses). Two patients received dose escalations at the lower dose levels, and one patient required two successive dose reductions be- cause of severe thrombocytopenia.

Table 2 summarizes the hematologic toxicities. Thrombocytopenia is dose limiting and excessive at 250 mg/m2 with a median nadir of 30,000 platelets/mm3 occurring 30 days after treatment, while leukopenia is moderate with a median nadir of 2500 (2.3-2.9). Two of the three patients treated at the 250 mg/m2 level had not received prior chemotherapy. Myelo- suppression is worse in those patients with previous treatment with drugs producing bone marrow impair- ment (Tables 3 and 4). At 225 mg, the median WBC nadir was 3300imm:'. and the median platelet nadir was 120,000/mm". Of the six patients treated at the 225 mg/m2 dose level, two had received prior therapy. The median platelet count and WBC nadir for the previously treated group was lower than the respective nadirs for patients without prior chemo- therapy (55,000/mm" vs. 143,000/mm" and 3300/mm" vs. 3700imm:'). Anemia was seen primarily in associa- tion with blood loss, i .e., hemoptysis.

Five patients received two or more courses of chlorozotocin. Cumulative myelotoxicity was evi-

No. 11 EVALUATION OF CHLOROZOTOCIN . Toylor et a / . 2367

dent only in two patients who received a total of seven courses.

Transient elevations of the SGOT were seen in 10 of 35 courses. These were reversible and did not appear to be dose related. Two patients had ir- reversible cholestatic jaundice. The first patient had cholestatic jaundice after four courses and the second after his sixth course. Both had biopsy- proven cholestasis without evidence of tumor, inflammation, or obstruction. Both died of tumor progression elsewhere without resolution of their jaundice one and five months, respectively, after the last dose of chlorozotocin.

Mild, reversible proteinuria was seen in five pa- tients. Renal function remained normal despite repeated courses in two of these patients.

Mild pretreatment glucose intolerance may predict for development of frank diabetes mellitus. One patient with mildly elevated fasting blood sugars (130 mgidl) and an elevated serum cortisol had hyper- osmolar nonketotic hyperglycemic coma requiring insulin therapy. Two other patients experienced intermittent glycosuria, one with elevated 2 hour postprandial glucoses. A fourth patient had a transient increase in his fasting blood sugar to 246 mg/dl. Subsequent courses of chlorozotocin were not as- sociated with evidence of glucose intolerance.

Nausea was common at all dose levels, but vomit- ing and anorexia were severe only at the 250 mgi m' dose.

Response Data

A partial response lasting six months was seen in a patient with squamous cell carcinoma of the lung.

TABLE 2. Myelotoxicity of Chlorotozotocin

WBC nadir Platelet nadir x 10Ymm' x IO?/mm'

Course No. of median median no. patients (range) (range)

Dose (mglm?) 150 1 1 9.0 182

I75 1 2 6.3 (3.0-9.6) 186 (180- 193)

200 1 4 4.5 (3.2-7.1) 127 (14*-200) 2 4 3.8 (2.8-5.4) 109 (74- 142) 3 2 3.5 (2.2-4.9) 115 (92-138) 4 I 2.6 163 5 1 3.2 120

225 I 5 3.3 (3.0-10.1) 120 2 2 3 . 1 ( 3 . 1 - 3 . 2 ) 60 3 3 3.0 (1.6-3.7) 50 4 2 5 . S (5.0-6.0) 78 5 1 3.3 50

250 1 3 2.5 (2.3-2.9) 30 (16- 130)

* Prior MMC and B C N U . t Includes one patient escalated after two doses of 200 mg/m'.

Four patients had improvement or stable disease last- ing 4 to 23+ months. Two had adenocarcinoma of the lung, one had large cell carcinoma of the lung. and the fourth had a squamous cell carcinoma of the head and neck.

Discussion

Thrombocytopenia is the acute dose-limiting tox- icity of chlorozotocin and is more frequent in patients previously treated with drugs producing bone marrow impairment. Leukopenia is usually less significant. Cumulative marrow toxicity occurs but is not prominent.

TABLF 3. Untreated Patients

I50 mgim' 175 mglm' 200 mglm' 225 mgim' 250 mg/m'

Czt dose (mglm') Median WBC Nadir x IO'lmm:' - >4.0 ,4.0 3.7 2.6

Median platelet nadir x IO'imm:' 150 95 143 73

(range) - (3.0-->4.0) (2 .3 -2 .9 )

(range) (59- 150) (16- 130)

TABLF 4. Treated Patients (NTS. MMC)

150 mgim' 175 mglm' 200 mglm' 225 mglm' 250 mglm'

Czt dose ( m g l d ) Median WBC Nadir X 1O'imm:' >4.0 >4.0 3.6 3.3 2.5

(range) (3 .2 - 4.0)

Median platelet nadir x IO'lmm" >I50 >I50 65 55 30 (range) (14- 150)

NTS = nitrosurea: MMC = mitomycin-C.

2368 CANCER December I 1980 Vol. 46

Mild pretreatment glucose intolerance may predict for development of frank diabetes mellitus after treatment. Nausea, vomiting, and anorexia are common, but prolonged afid severe only at higher dose levels (225 mg/m2 and 250 mg/m2).

Two cases of possibly nonreversible cholestatic jaundice were probably induced by chlorozotocin. This toxicity should be watched for carefully in future trials with high-dose chlorozotocin.

Our data as well as the phase I studies by the Maya Clinic and Memorial Sloan-Kettering for high-dose chlorozotocin given over five days suggest that with careful selection of patients higher doses are feasi- b l e . :~~ The recommended starting doses for phase I1 studies are 225 mg/mz for good risk patients (no prior chemotherapy or extensive bone marrow irradiation) and 200 mg/m2 for previously treated patients who tolerated their prior therapy well and are judged not to have impaired bone marrow reserve. Patients with extensive prior nitrosourea and/or mitomycin-C treatment should probably be treated in accordance with the recommendations of H ~ t h . ~ .

Four of seven patients with advanced non-small

cell carcinoma of the lung had clinically significant improvement or disease stabilization and survived ten or more months aftel‘ starting high dose chloro- zotocin therapy. These preliminary findings warrant further testing, which is in progress in the South- west Oncology Group.

REFERENCES

1. Anderson T. McMenamin MG, Schein PS. Chlorozotocin. 24 3-(2-chloroethyl)-3-nitrosoureidoI-D glucopyranose, an antitumor agent with modified bone marrow toxicity. Cancer Res 1975; 35:761-765, 2. Clinical brochure for ChloroLotocin (NSC 178248) Feb. 1976. 3. Erickson LC. Measurement of DNA damage in Chinese

hamster cells treated with equitoxic and equirnutagenic doses of nitrosureas (Abstr. 839). Proc Am Assoc Cancer Rrs 1978: 19: 2 10.

4. Hoth D. Schein P. MacDonald J , Buscaglia D, Haller ,D. Phase I trial and clinical pharmacology of chlorozotocin (CTZ) (Abstr. C-169) Proc Am Assoc Cancer Res 1977; 18:309.

5. Kovach JS, Moertel CG, Schutt AJ. O’Connell MJ. A Phase I study of chlorozotocin (Abstr. C-408). Pror Am Soc CIin Oncol 1978; 19:408. 6. Schein PS, Panasci I* , Wooley PV, Anderson ‘I. Pharmacology

of chlorozotocin (NSC 178248), a new nitrosourea antitumor agent. Cancer clzemother Rep 1976; 60:801-806. 7. Tan C. Grdki R. Steinherz P. Young CW. Phase I study of

chlorozotocin (Abstr. 501). Proc Am Sot, Clin On(~o/ 1978; 19: 126.

Erratum

In the article. “Management of Locally Advanced and Disseminated Breast Cancer-Chemotherapy.” the second sentence in the fourth paragraph on p. 1081 should read as follows:

The latter treatment schedule employs cyclophosphamide (Cytoxan) 400 mg/m2, doxorubicin (Adriamycin) 40 rng/rn2, and cis-platinum 40 mg/rn‘-all drugs given as a single infusion on day I .