PRECLINICAL AND PHASE I STUDY OF OXALIPLATIN AND TOPOTECAN IN COMBINATION IN HUMAN CANCER.

BACKGROUND: DNA damage caused by platinum agents is frequently followed by induction of topoisomerase I, providing a rationale for use of platinum-based compounds with topoisomerase I inhibitors. MATERIALS AND METHODS: We studied the effect of a sequential schedule of oxaliplatin on day I and topotecan on days 2-5, in human colon and ovarian cancer cells in vitro, in nude mice bearing human cancer xenografts and finally in cancer patients in a phase I trial. RESULTS: We demonstrated a supra-additive effect of this combination on inhibition of colony formation and induction of apoptosis in vitro. We then demonstrated that the two agents in combination markedly inhibit tumor growth in nude mice. We translated these results into a clinical setting, conducting a phase I study in cancer patients with oxaliplatin 85 mg/m2 on day 1 and topotecan at doses escalating from 0.5 to 1.5 mg/m2 on days 2-5. Sixty cycles of treatment were administered to 18 patients affected prevalently by ovarian and colorectal cancer. Combination with topotecan 1.5 mg/m2 caused a dose-limiting toxicity. Therefore the maximum tolerated dose of topotecan was 1.25 mg/m2, at which six patients experienced a mild hematological and gastrointestinal toxicity. We also obtained evidence of clinical activity, particularly in ovarian cancer. CONCLUSIONS: Our results provide a solid biological and clinical rationale for a phase II trial at the recommended doses of oxaliplatin 85 mg/m2 and topotecan 1.25 mg/m2, possibly in ovarian cancer patients

ADDITION OF ERLOTINIB TO FLUROPYRIMIDINE-OXALIPLATIN-BASED CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB: TWO SEQUENTIAL PHASE I TRIALS.

The combination of EGFR inhibitors and anti-angiogenic drugs has a strong pre-clinical rationale, yet its use has produced controversial clinical results. We conducted two sequential phase I trials to evaluate the feasibility and the recommended dose of erlotinib when combined with fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab. A total of 21 metastatic colorectal cancer (mCRC) patients were treated in two sequential phase I trials. In the first trial, 12 patients were treated with escalating doses of erlotinib plus FOLFOX. In the second, 9 patients were treated with escalating doses of erlotinib combined with oxaliplatin, capecitabine and bevacizumab. No MTD was reached in either of the trials. The only dose-limiting toxicities observed were neutropenia and diarrhea. No unexpected toxicities were noted. Hematological toxicity was the most frequently noted adverse event with infusional 5FU therapy, while gastrointestinal toxicity was the most common adverse event. In the second trial most patients withdrew from treatment due to toxicity, and less than half completed the therapeutic program as per protocol, mostly due to toxicity. In conclusion, the present study confirms the disappointing results of the double combination of EGFR inhibitors and anti-angiogenic drugs in mCRC patients

Manuale di Oncologia Clinica

Manuale di Oncologia Clinica rivolto agli studenti delle Facolt\ue0 di Medicina e Chirurgia e agli specializzandi in Oncologia Medic

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FLFOX-4) as first-line treatment of advanced gastric cancer patients.

Background: The purpose of this study was to assess the toxicity and clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil and folinic acid administered every 2 weeks (FOLFOX4 regimen) in patients with advanced gastric cancer (AGC). Patients and methods: Sixty-one previously untreated AGC patients were treated with oxaliplatin 85mg/m2 on day 1, folinic acid (FA) 200mg/m2 as a 2-h infusion followed by bolus 5-fluorouracil (5-FU), 400 mg/m2 and a 22-h infusion of 5-FU, 600 mg/m2, repeated for two consecutive days every 2 weeks. Results: All patients were assessable for toxicity and response to treatment. Patient characteristic were: sex (male, 38; female, 23); median age, 64 years (range, 47–75 years); Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, nine patients; 1, 39 patients; 2, 13 patients; metastatic disease, 56 patients; locally advanced disease, five patients. Four (7%) complete responses (CR) and 19 partial responses (PR) were observed (overall response rate, 38%). Stable disease (SD) was observed in 22 (36%) patients, with progressive disease (PD) in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. NCI common toxicity criteria grade 3 and 4 hematologic toxic effects were neutropenia, anemia and thrombocytopenia in 36%, 10% and 5% patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. No treatment-related deaths were observed. Conclusion: FOLFOX-4 is an active and well tolerated chemotherapy. RR, TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer

Manuale di Oncologia Clinica

Manuale di Oncologia Clinica rivolto agli studenti delle Facoltà di Medicina e Chirurgia e agli specializzandi in Oncologia Medic