Oxaliplatin (Page 8 of 10)

14.3 Previously Treated Advanced Colorectal Cancer

The efficacy of oxaliplatin injection in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a multicenter, open-label, randomized, three-arm controlled trial was conducted in the US and Canada in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line treatment with bolus fluorouracil/leucovorin and irinotecan (A multicenter, open-label, randomized, three-arm study of 5-fluorouracil (5-FU) + leucovorin (LV) or oxaliplatin or a combination of 5-FU/LV + oxaliplatin as second-line treatment of metastatic colorectal carcinoma: NCT00008281). Patients were randomized to one of three regimens; the dosing regimens are presented in Table 22. Eligible patients were at least 18 years of age, had unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status (KPS) greater than 50%. Patients had to have aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase less than or equal to 2x upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case less than or equal to 5x ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization. The main efficacy outcome measure was 3-year disease-free survival (DFS) and an additional outcome measure was overall survival (OS).

Table 22: Dosing Regimens in Refractory and Relapsed Colorectal Cancer Trial
Treatment Arm Dose Regimen
Oxaliplatin Injection + FU/LV (N =152) Day 1: Oxaliplatin Injection: 85 mg/m2 (2-hour infusion) + LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) Day 2: LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) every 2 weeks
FU/LV (N=151) Day 1: LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) Day 2: LV 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) every 2 weeks
Oxaliplatin Injection (N=156) Day 1: Oxaliplatin Injection 85 mg/m2 (2-hour infusion) every 2 weeks

Patients must have had at least one unidimensional lesion measuring greater than or equal to 20 mm using conventional CT or MRI scans or greater than or equal to 10 mm using a spiral CT scan. Tumor response and progression were assessed every 3 cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first. Confirmed responses were based on two tumor assessments separated by at least 4 weeks. Baseline characteristics are shown in Table 23.

Table 23: Baseline Characteristics in Refractory and Relapsed Colorectal Cancer Trial
Oxaliplatin Injection + FU/LV N = 152

Oxaliplatin Injection

N = 156

FU/LV N = 151
Sex: Male (%) 57.2 60.9 54.3
Female (%) 42.8 39.1 45.7
Median age (years) 59.0 61.0 60.0
Range 22–88 27–79 21–80
Race (%)
Caucasian 88.8 84.6 87.4
Black 5.9 7.1 7.9
Asian 2.6 2.6 1.3
Other 2.6 5.8 3.3
KPS (%)
70-100 95.4 92.3 94.7
50-60 2.0 4.5 2.6
Not reported 2.6 3.2 2.6
Prior radiotherapy (%) 25.0 19.2 25.2
Prior pelvic radiation (%) 21.1 13.5 18.5
Number of metastatic sites (%)
1 25.7 31.4 27.2
≥2 74.3 67.9 72.2
Liver involvement (%)
Liver only 18.4 25.6 22.5
Liver + other 53.3 59.0 60.3

The median number of cycles administered per patient was 6 for the oxaliplatin injection and fluorouracil/leucovorin combination and 3 each for fluorouracil/leucovorin alone and oxaliplatin injection alone. Patients treated with the combination of oxaliplatin injection and fluorouracil/leucovorin had an increased response rate compared to patients given fluorouracil/leucovorin or oxaliplatin alone. Efficacy results are summarized in Tables 24 and 25.

Table 24: Response Rates in Refractory and Relapsed Colorectal Cancer Clinical Trial — ITT Analysis
Best Response Oxaliplatin Injection + FU/LV N=152 Oxaliplatin Injection N=156 FU/LV N=151
Complete Response 0 0 0
Partial Response 13 (9%) 2 (1%) 0
P-value 0.0002 FU/LV vs. Oxaliplatin Injection + FU/LV
95% CI 4.6%, 14.2% 0.2%, 4.6% 0, 2.4%
Table 25: Radiographic Time to Progression (TTP)* in Refractory and Relapsed Colorectal Cancer Clinical Trial
Arm Oxaliplatin Injection + FU/LV N=152 Oxaliplatin Injection N=156 FU/LV N=151
Number of progressors 50 101 74
Number of patients with no radiological evaluation beyond baseline 17 (11%) 16 (10%) 22 (15%)
Median TTP (months) 4.6 1.6 2.7
95% CI 4.2, 6.1 1.4, 2.7 1.8, 3.0
* This is not an ITT analysis. Events were limited to radiographic disease progression documented by independent review of radiographs. Clinical progression was not included in this analysis, and 18% of patients were excluded from the analysis based on unavailability of the radiographs for independent review.

At the time of the interim analysis 49% of the radiographic progression events had occurred. In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to fluorouracil/leucovorin alone.

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