A multicenter, open-label, randomized, three-armcontrolled study was conducted in the US and Canada comparing the efficacy and safety of ELOXATIN in combination with an infusional schedule of 5-FU/LV to the same dose and schedule of 5-FU/LV 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-FU/LV 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 22 – Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical Trial

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 23 – Patient Demographics in Refractory and Relapsed Colorectal Cancer Clinical Trial

The median number of cycles administered per patient was 6 for the ELOXATIN and 5-FU/LV combination and 3 each for 5-FU/LV alone and ELOXATIN alone.

Patients treated with the combination of ELOXATIN and 5-FU/LV had an increased response rate compared to patients given 5-FU/LV or oxaliplatin alone. The efficacy results are summarized in the tables below.

Table 24 - Response Rates (ITT Analysis)

Table 25 - Summary of Radiographic Time to Progression*

At the time of the interimanalysis 49% of the radiographic progression events had occurred. In this interimanalysis an estimated 2-month increase in median time to radiographic progression was observed compared to 5-FU/LV alone.

Of the 13 patients who had tumor response to the combination of ELOXATIN and 5-FU/LV, 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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