Oxaliplatin (Page 8 of 9)

14.3 Combination Therapy with Oxaliplatin and 5-fluorouracil/leucovorin in Previously Treated Patients with Advanced Colorectal Cancer

A multicenter, open-label, randomized, three-arm controlled study was conducted in the US and Canada comparing the efficacy and safety of oxaliplatin in combination with an infusional schedule of 5-fluorouracil/leucovorin to the same dose and schedule of 5-fluorouracil/leucovorin alone and to single agent oxaliplatin in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line therapy with bolus 5-fluorouracil/leucovorin and irinotecan. The study was intended to be analyzed for response rate after 450 patients were enrolled. Survival will be subsequently assessed in all patients enrolled in the completed study. Accrual to this study is complete, with 821 patients enrolled. Patients in the study had to be at least 18 years of age, have unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status >50%. Patients had to have SGOT(AST) and SGPT(ALT) ≤2x the institution’s upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case ≤5x ULN was permitted. Patients had to have alkaline phosphatase ≤2x the institution’s ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases ≤5x ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization. The dosing regimens of the three arms of the study are presented in the table below.

Table 23 – Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical Trial

Treatment Arm Dose Regimen
Oxaliplatin + 5-FU/LV (N =152) 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
5-FU/LV (N=151) 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
Oxaliplatin (N=156) Day 1: Oxaliplatin 85 mg/m2 (2-hour infusion) every 2 weeks

Patients entered into the study for evaluation of response must have had at least one unidimensional lesion measuring ≥20mm using conventional CT or MRI scans, or ≥10mm 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.The demographics of the patient population entered into this study are shown in the table below.

Table 24 – Patient Demographics in Refractory and Relapsed Colorectal Cancer Clinical Trial

    5-FU/LV (N = 151) Oxaliplatin   (N = 156)  Oxaliplatin + 5-FU/LV (N = 152)  
Sex: Male (%)   54.3 60.9   57.2 
  Female (%)   45.7 39.1   42.8 
Median age (years)   60.0 61.0  59.0 
Range   21 to 80 27 to 79   22 to 88 
Race (%)
Caucasian 87.4 84.6   88.8 
Black  7.9 7.1   5.9 
Asian  1.3   2.6   2.6 
Other  3.3   5.8   2.6 
KPS (%)  
70 to 100 94.7   92.3   95.4 
50 to 60  2.6   4.5   2.0 
Not reported  2.6   3.2   2.6 
Prior radiotherapy (%)  25.2   19.2   25.0 
Prior pelvic radiation (%) 18.5   13.5   21.1 
Number of metastatic sites (%)  
1 27.2   31.4   25.7 
≥2  72.2   67.9   74.3 
Liver involvement (%) 
Liver only  22.5   25.6   18.4 
Liver + other  60.3   59.0  53.3 

The median number of cycles administered per patient was 6 for the oxaliplatin and 5-fluorouracil/leucovorin combination and 3 each for 5-fluorouracil/leucovorin alone and oxaliplatin alone. Patients treated with the combination of oxaliplatin and 5-fluorouracil/leucovorin had an increased response rate compared to patients given 5-fluorouracil/leucovorin or oxaliplatin alone. The efficacy results are summarized in the tables below.

Table 25 — Response Rates (ITT Analysis)

Best Response 5-FU/LV (N=151) Oxaliplatin (N=156) Oxaliplatin + 5 FU/LV (N=152)
CR 0 0 0
PR 0 2 (1%) 13 (9%)
p-value 0.0002 for 5-FU/LV vs. Oxaliplatin + 5-FU/LV
95%CI 0 to 2.4% 0.2 to 4.6% 4.6 to 14.2%

Table 26 — Summary of Radiographic Time to Progression*

Arm 5-FU/LV (N=151) Oxaliplatin (N=156) Oxaliplatin +5-FU/LV (N=152)
*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 5-fluorouracil/leucovorin alone.
No. of Progressors 74 101 50
No. of patients with no radiological evaluation beyond baseline 22 (15%) 16 (10%) 17 (11%)
Median TTP (months) 2.7 1.6 4.6
95% CI 1.8 to 3.0 1.4 to 2.7 4.2 to 6.1

Of the 13 patients who had tumor response to the combination of oxaliplatin and 5-fluorouracil/leucovorin, 5 were female and 8 were male, and responders included patients <65 years old and ≥65 years old. The small number of non-Caucasian participants made efficacy analyses in these populations uninterpretable.

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