levoleucovorin and alvocidib

Phase I/II studies suggest that the combination of irinotecan with capecitabine is feasible and has promising activity. Diarrhea and neutropenia are dose limiting. Overall response rates (RRs) in the 40% to 60% range are seen from preliminary data. Work in progress is assessing the combination of irinotecan with UFT/leucovorin (LV). The use of irinotecan together with raltitrexed is also being investigated, as is its combination with oxaliplatin. Two phase II studies of irinotecan plus oxaliplatin in second-line patients report median survivals of 11-12 months. It seems possible to safely escalate the dose of single-agent irinotecan to 500 mg/m(2) in patients showing good tolerance of the drug. Irinotecan can be used in combination with LV5FU2 at doses up to 260 mg/m(2), especially if only one bolus of 5-fluorouracil (5-FU) is given. Control of tumor growth is achieved in 90% of patients. Preliminary data suggest that regimens based on 5-FU/LV and irinotecan can safely be combined with the anti-epidermal growth factor receptor (EGFR) antibody cetuximab. In patients with EGFR-positive tumors, this may prove an effective means of increasing response rate or combating treatment resistance. Following evidence that COX-2 inhibition can slow progression in familial adenomatous polyposis, celecoxib is to be studied in metastatic colorectal cancer (CRC). In vitro, the cyclin-dependent kinase inhibitor flavopiridol enhances the induction of apoptosis by chemotherapy. Clinically, it can safely be administered with irinotecan, and studies in CRC are planned.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; Cyclooxygenase 2; Deoxycytidine; Drug Administration Schedule; Enzyme Inhibitors; Flavonoids; Fluorouracil; Humans; Immunologic Factors; Irinotecan; Isoenzymes; Leucovorin; Membrane Proteins; Organoplatinum Compounds; Oxaliplatin; Piperidines; Prostaglandin-Endoperoxide Synthases; Quinazolines; Thiophenes; Treatment Outcome

The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors.. FOLFIRI + flavopiridol were administered every 2 weeks. Based on sequence-dependent inhibition, flavopiridol was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses were determined, one with flavopiridol administered over 1 h, and one with flavopiridol split as a 30-min bolus followed by a 4-h infusion.. A total of 74 patients were enrolled and 63 were evaluable. The MTD with FOLFIRI was flavopiridol 80 mg/m(2) over 1 h or 35 mg/m(2) bolus + 35 mg/m(2) over 4 h. Dose-limiting toxicities were diarrhea, fatigue, neutropenia, and neuropathy. Clinical activity included 2 partial responses in small bowel cancer and bladder cancer and 1 complete response in mucosal melanoma. Stable disease was seen in 22 patients. Pharmacokinetic studies showed increasing C(max) with increasing flavopiridol dose. Clinical benefit was correlated with the presence of wild-type p53. Of 25 patients with colorectal cancer, 11 had as best response SD for >3 m (median 6 m, range 4.2-15.4 m), despite failing ≥1 irinotecan-containing regimen.. Treatment with flavopiridol and FOLFIRI is a safe and effective regimen. Concentrations of flavopiridol that enhance the effects of FOLFIRI can be achieved. Clinical activity is encouraging and includes prolonged stable disease in patients with irinotecan-refractory colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Flavonoids; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner.. We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated.. Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m(2)) and 5FU (2,400 mg/m(2)), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m(2) flavopiridol, 85 mg/m(2) oxaliplatin, and 1,800 mg/m(2) 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders.. Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cyclin-Dependent Kinases; Female; Flavonoids; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Piperidines; Tumor Suppressor Protein p53