Oxaliplatin (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).
In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day x 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.

14 CLINICAL STUDIES

14.1 Combination Adjuvant Therapy with Oxaliplatin and Infusional 5-fluorouracil/leucovorin in Patients with Colon Cancer

An international, multicenter, randomized study compared the efficacy and evaluated the safety of oxaliplatin in combination with an infusional schedule of 5-fluorouracil/leucovorin to infusional 5-fluorouracil/leucovorin alone, in patients with stage II (Dukes’ B2) or III (Dukes’ C) colon cancer who had undergone complete resection of the primary tumor. The primary objective of the study was to compare the 3-year disease-free survival (DFS) in patients receiving oxaliplatin and infusional 5-fluorouracil/leucovorin to those receiving 5-fluorouracil/leucovorin alone. Patients were to be treated for a total of 6 months (i.e., 12 cycles). A total of 2246 patients were randomized; 1123 patients per study arm. Patients in the study had to be between 18 and 75 years of age, have histologically proven stage II (T3 –T4 N0 M0; Dukes’ B2) or III (any T N1–2 M0; Dukes’ C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥15 cm from the anal margin) and undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease. Patients had to have had no prior chemotherapy, immunotherapy or radiotherapy, and have an ECOG performance status of 0,1, or 2 (KPS ≥ 60%), absolute neutrophil count (ANC) > 1.5×109 /L, platelets ≥100×109 /L, serum creatinine ≤ 1.25 × ULN total bilirubin < 2 × ULN, AST/ALT < 2 × ULN and carcino-embyrogenic antigen (CEA) < 10 ng/mL. Patients with preexisting peripheral neuropathy (NCI grade ≥ 1) were ineligible for this trial.

The following table shows the dosing regimens for the two arms of the study.

Table 15 — Dosing Regimens in Adjuvant Therapy Study
Treatment Arm Dose Regimen
Oxaliplatin + 5-FU/LV (FOLFOX4) (N =1123) Day 1: Oxaliplatin: 85 mg/m2 (2-hour infusion) + LV: 200 mg/m2 (2-hour infusion), followed by 5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)Day 2: LV: 200 mg/m2 (2-hour infusion), followed by 5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) every 2 weeks 12 cycles
5-FU/LV (N=1123) Day 1: LV: 200 mg/m2 (2-hour infusion), followed by 5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) Day 2: LV: 200 mg/m2 (2-hour infusion), followed by 5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) every 2 weeks 12 cycles

The following tables show the baseline characteristics and dosing of the patient population entered into this study. The baseline characteristics were well balanced between arms.

Table 16 — Patient Characteristics in Adjuvant Therapy Study
Oxaliplatin + infusional 5-FU/LV N=1123 Infusional 5-FU/LV N=1123
Sex: Male (%) 56.1 52.4
Female (%) 43.9 47.6
Median age (years) 61.0 60.0
<65 years of age (%) 64.4 66.2
≥65 years of age (%) 35.6 33.8
Karnofsky Performance Status (KPS) (%)
100 29.7 30.5
90 52.2 53.9
80 4.4 3.3
70 13.2 11.9
≤60 0.6 0.4
Primary site (%)
Colon including cecum 54.6 54.4
Sigmoid 31.9 33.8
Recto Sigmoid 12.9 10.9
Other including rectum 0.6 0.9
Bowel obstruction (%)
Yes 17.9 19.3
Perforation (%)
Yes 6.9 6.9
Stage at Randomization (%)
II (T=3,4 N=0, M=0) 40.1 39.9
III (T=any, N=1,2, M=0) 59.6 59.3
IV (T=any, N=any, M=1) 0.4 0.8
Staging – T (%)
T1 0.5 0.7
T2 4.5 4.8
T3 76.0 75.9
T4 19.0 18.5
Staging – N (%)
N0 40.2 39.9
N1 39.4 39.4
N2 20.4 20.7
Staging – M (%)
M1 0.4 0.8
Table 17 — Dosing in Adjuvant Therapy Study
Oxaliplatin + infusional 5-FU/LV N=1108 Infusional 5-FU/LV N=1111
Median Relative Dose Intensity (%)
5-FU 84.4 97.7
Oxaliplatin 80.5 N/A
Median Number of Cycles 12 12
Median Number of cycles with Oxaliplatin 11 N/A

The following table and figures summarize the disease-free survival (DFS) results in the overall randomized population and in patients with stage II and III disease based on an ITT analysis. The median duration of follow-up was approximately 77 months.


Table 18 — Summary of DFS analysis – ITT analysis

ParameterOxaliplatin + infusional 5-FU/LVInfusional 5-FU/LV
Data cut off for disease free survival 1 June 2006 † Disease-free survival at 5 years ‡ A hazard ratio of less than 1.00 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin
Overall
N11231123
Number of events – relapse or death (%)304 (27.1)360 (32.1)
Disease-free survival % [95% CI]†73.3 [70.7, 76.0]67.4 [64.6, 70.2]
Hazard ratio [95% CI]‡0.80 [0.68, 0.93]
Stratified Logrank testp=0.003
Stage III (Dukes’ C)
N672675
Number of events –relapse or death (%)226 (33.6)271 (40.1)
Disease-free survival % [95% CI]†66.4 [62.7, 70.0]58.9 [55.2, 62.7]
Hazard ratio [95% CI]‡0.78 [0.65, 0.93]
Logrank testp=0.005
Stage II (Dukes’ B2)
N451448
Number of events – relapse or death (%)78 (17.3)89 (19.9)
Disease-free survival % [95% CI]†83.7 [80.2, 87.1]79.9 [76.2, 83.7]
Hazard ratio [95% CI]‡0.84 [0.62, 1.14]
Logrank testp=0.258

In the overall and stage III colon cancer populations DFS was statistically significantly improved in the oxaliplatin combination arm compared to infusional 5-fluorouracil/leucovorin alone. However, a statistically significant improvement in DFS was not noted in Stage II patients.

Figure 2 shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone for the overall population (ITT analysis).

Figure 3 shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone in Stage III patients.

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Figure 2 — DFS Kaplan-Meier curves by treatment arm (cutoff: 1 June 2006) – ITT population
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Figure 3 — DFS Kaplan-Meier curves by treatment arm in Stage III patients (cutoff: 1 June 2006) – ITT population

The following table summarizes the overall survival (OS) results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.

Table 19 — Summary of OS analysis — ITT analysis
†A hazard ratio of less than 1.00 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin Data cut off for overall survival 16 January 2007
Parameter Oxaliplatin + infusional 5-FU/LV Infusional 5-FU/LV
Overall
N 1123 1123
Number of death events (%) 245 (21.8) 283 (25.2)
Hazard ratio† [95% CI] 0.84 [0.71, 1.00]
Stage III (Dukes’ C)
N 672 675
Number of death events (%) 182 (27.1) 220 (32.6)
Hazard ratio† [95% CI] 0.80 [0.65, 0.97]
Stage II (Dukes’ B2)
N 451 448
Number of death events (%) 63 (14.0) 63 (14.1)
Hazard ratio†[95% CI] 1.00 [0.70, 1.41]

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