Phase I/II Trial of Docetaxel plus Oxaliplatin and 5-Fluorouracil (D-FOX) in Patients with Untreated, Advanced Gastric or Gastroesophageal CancerJaffer A. Ajani, Alexandria T. Phan, Linus Ho, Eric D. Tetzlaff, and Jackie Baker University of Texas M. D. Anderson Cancer Center, Houston, Texas

Supported by sanofi-aventis, Bridgewater, NJ

IntroductionGastric Cancer is the second most common cause of cancer death worldwide. It is often diagnosed in late stages where treatment is palliative and the prognosis is poor. Advances in the treatment of gastric cancer is desperately needed

The V325 phase III study in patients with advanced gastric cancer showed that adding docetaxel to cisplatin and 5-FU (DCF) significantly improved time to progression, survival, and overall response rate compared with cisplatin and 5-FU (CF). As expected, there was an increase in related grade 3 or 4 treatment adverse events.

Oxaliplatin when combined with 5-FU is an active regimen for the treatment of advanced gastric cancer. In addition, The REAL 2 trial, using a 2x2 trial design demonstrated the non-inferiority of oxaliplatin to cisplatin in advanced gastric cancer.

To improve the safety of docetaxel-based therapy, a phase I/II study was initiated to study docetaxel when given in combination with oxaliplatin and 5-FU.

Methods

The maximum tolerated dose (MTD) of docetaxel given concomitantly with fixed doses of oxaliplatin and 5-FU will be identified using a standard 3+3 algorithm

Dose escalation of docetaxel proceeded at 2.5 mg/m2 increments starting at a dose of 20mg/m2 on Day 1.

Oxaliplatin was administered at a dose of 85 mg/m2 on Day 1, and 5-Fluorouracil by continuous infusion pump at a dose of 2.2g/m2 over 48 hours on Day 1. All 3 drugs administered every 2 weeks (4 weeks = 1 cycle)

The MTD is the highest dose at which 1 or fewer dose limiting toxicities (DLT’s) are observed in 6 patients.

We defined a dose limiting toxicity as any non-hematologic grade III/IV toxicity or neutropenia-associated (infection or fever treated in the hospital) toxicity attributable to this therapy.

MTD and DLT determinations are based on the first cycle only. Fatigue, incompletely treated nausea, and oxaliplatin/5-flurouracil-related toxicities were excluded to determine the MTD.

Results

41 patients have been enrolled on the trial and the toxicity data is presented for all patients. Response rate, time to progression, and overall survival is assessable in 35 patients.

Patients were more often male and the average age of all patients was 54.8 years. Baseline patient characteristics are presented in Table 1.

All 41 patients have completed cycle #1 of chemotherapy. The MTD has not yet been reached. The current dose level of docetaxel is 50 mg/m2 q 2 weeks and we continue to escalate.

The most common grade 3/4 hematologic toxicities during cycle #1 were anemia (7.3%) and neutropenia (7.3%). Non-hematolgic 3/4 toxicities were rare; nausea (4.9%), vomiting (2.4%) and anorexia (4.9%). No complicated neutropenia has yet been observed in the first cycle. See table #2.

During any cycle of therapy, the most common grade 3/4 hematologic toxicity was neutropenia (26.8%) and anemia (7.3%). Non-hematologic grade 3/4 toxicity included nausea, vomiting and anorexia (4.9% for each toxicity). See table 3.

Maximum Grade Toxicity

Cycle #1

Grade 1 Grade 2 Grade 3 Grade 4

Leukopenia 4 (9.8) 6 (14.6) 1 (2.4) 0

Neutropenia 3 (7.3) 3 (7.3) 2 (4.9) 1 (2.4)

Anemia 20 (48.8) 5 (12.2) 3 (7.3) 0

Platelets 1 (2.4) 0 0 0

Nausea 14 (34.1) 9 (22) 2 (4.9) 0

Vomiting 13 (31.7) 7 (17.1) 1 (2.4) 0

Diarrhea 17 (41.5) 3 (7.3) 0 0

Stomatitis 13 (31.7) 1 (2.4) 0 0

Neuropathy 20 (48.8) 3 (7.3) 0 0

Anorexia 14 (34.1) 15 (36.6) 2 (4.9) 0

Fever 1 (2.4) 0 0 0

Infection 0 1 (2.4%) 0 0

Table 2 Results Cont.Febrile neutropenia or neutropenic infection has not occurred. Uncomplicated infection is also low (9.8%; all grades). There were no treatment related deaths during the study.

Treatment-related delays were a result of neutropenia (34.1%) and elevated hepatic transaminases (2.4%).

Hypersensitivity reactions were common with docetaxel (43.9%). However only 4.9% of patients had to discontinue docetaxel as a result of allergic reactions.

35 patients have discontinued protocol chemotherapy. The median number of cycles received was 4 (range 4-16).

The reasons for discontinuation of protocol chemotherapy were disease progression (58%), neuropathy (25%), consolidation chemoradiotherapy (8.3%), maximum response achieved (2.8%) and prolonged hematologic toxicity (2.8%).

Fig. 2. The Kaplan-Meier curve of the overall survival. The median overall survival time was 13 months (95% CI 10 – 17 months).

ConclusionThe MTD of docetaxel when given in combination with oxaliplatin and 5-FU (D-FOX) has not yet been established. The current dose level of docetaxel is 50 mg/m2 every 2 weeks.

The safety profile of the three drug regimen is excellent. Toxicities are easily managed and complicated grade 3/4 events are not common.

Neutropenic infection and febrile neutropenia has not occurred (no GCSF prophylaxis is provided during cycle #1). The rate of uncomplicated infection (9.8%; all grades) is also lower than in the V325 study.

In addition, D-FOX appears to be an active regimen for patients with untreated gastric and gastroesophageal cancer. Response rate (43%), time to progression (6 months), and overall survival (13 months) are all promising.

After the MTD has been established, the phase II portion of the trial will be completed with clinical and translational studies to be reported.

D-FOX may provide an excellent foundation for the addition of biologic agents in treatment of advanced gastric cancer.

References

1) Karpeh MS, Kelsen DP, Tepper JE. Cancer of the stomach in cancer: Principles and Practice of Oncology. 6th edition. Devita V, Hellman S, Rosenberg S, Lippincott-William & Wilkins, Philadelphia 2001;1092-1125.

2) Van Cutson E., Moiseyenko VM, Tjulandin S, et al. Phase III Study of Docetaxel and Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for Advanced Gastric Cancer: A Report of the V325 Study Group. J Clin Oncol 24:4991-4997, 2006.

3) Cunningham D, Rao S, Starling N, et al. Randomized multicenter phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced esophagogastric cancer. The REAL 2 trial. Proc Am Soc Clin Oncol 24:18S, 2006 (Abstract no. LBA4017).

Objectives

Primary

•The primary objective of this study is to determine the maximum tolerated dose (MTD) of docetaxel combined with 5-FU and oxaliplatin (D-FOX) in patients with untreated, locally unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ)

Secondary

•To determine the qualitative and quantitative toxicity and reversibility of toxicity of this combination.

Baseline Characteristics (n=41)

N (%)

Male 32 (78.0)

Female 9 (22.0)

Age (Mean, Range) 54.8 (24-76)

ECOG PS (median, range) 1 (0-1)

Gastric 10 (24.4)

GE Junction 31 (75.6)

Locally advanced 2 (4.9%)

Metastatic 39 (95.1%)

Table 1

Maximum Grade Toxicity

All Cycles

Grade 1 Grade 2 Grade 3 Grade 4

Leukopenia 8 (19.5) 11 (26.8) 2 (4.9) 0

Neutropenia 8 (19.5) 6 (14.6) 8 (19.5) 3 (7.3)

Anemia 20 (48.8) 8 (19.5) 3 (7.3) 0

Platelets 10 (24.4) 1 (2.4) 0 0

Nausea 15 (36.6) 22 (53.7) 2 (4.9) 0

Vomiting 15 (36.6) 10 (24.4) 1 (2.4) 0

Diarrhea 25 (61) 8 (19.5) 0 0

Stomatitis 16 (39) 2 (4.9) 1 (2.4) 0

Neuropathy 14 (34.1) 21 (51.2) 2 (4.9) 0

Anorexia 12 (29.3) 22 (53.7) 2 (4.9) 0

Fever 6 (14.6) 3 (7.3) 0 0

Infection 0 2 (4.9) 2 (4.9) 0

F.N. 0 0 0 0

TEE 0 0 1 (2.4) 0

F.N. = Febrile Neutropenia, TEE = Thromboembolic Event

Table 3

Time (months)

Pro

gre

ssio

n F

ree

pro

ba

bili

ty

0 5 10 15

0.0

0.2

0.4

0.6

0.8

1.0

N (progression or death) / N = 26/35Median = 6 months (95% C.I.: 4 - 12)

Time (months)

Ove

rall

surv

iva

l pro

ba

bili

ty

0 5 10 15 20

0.0

0.2

0.4

0.6

0.8

1.0

N (death) / N = 23/35Median = 13 months (95% C.I.: 10 - 17)

Fig. 1 The Kaplan-Meier curve of the progression-free survival. The median time to progression was estimated to be 6 months with (95% CI 4-12 months).

Results Cont.The overall confirmed response rate for assessable patients (n=35) is 43% (95% CI = 28-59%). The disease control rate (PR + SD) is 83% (95% C.I = 67-92%)

Median time to progression is 6 months (95% CI = 4-12 months). See Figure 1. The median overall survival is 13 months (95% CI 10-17 months). See Figure 2.