Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors

Abstract

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: 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.

Fig 1

Patients received flavopiridol as a 1-hour infusion (t=0 hr), concurrently with oxaliplatin at a starting dose of 60 mg/m², and leucovorin at 400 mg/m² administered over two hours (t=0 hr). This was followed by 5-fluorouracil given as a bolus infusion starting at 400 mg/m² (t=2 hr), and then a 48-hour continuous infusion at either 1800 or 2400 mg/m² over 48 hours (t=2:15 hr).

Fig 2

Radiographic examples of germ cell tumor response. Two cisplatin-refractory germ cell tumor patients demonstrated areas of disease pre-treatment (circled in black) which decreased by 65% (Example 1) and 43% (Example 2) post-treatment.

Fig 2

Radiographic examples of germ cell tumor response. Two cisplatin-refractory germ cell tumor patients demonstrated areas of disease pre-treatment (circled in black) which decreased by 65% (Example 1) and 43% (Example 2) post-treatment.