A Nonrandomized, Phase II Study of Sequential Irinotecan and Flavopiridol in Patients With Advanced Hepatocellular Carcinoma.

Background: Flavopiridol, a Cdk inhibitor, potentiates irinotecan-induced apoptosis. In a phase I trial of sequential irinotecan and flavopiridol, 2 patients with advanced hepatocellular carcinoma (HCC) had stable disease (SD) for ≥14 months. We thus studied the sequential combination of irinotecan and flavopiridol in patients with HCC.

Methods: Patients with advanced HCC naïve to systemic therapy, Child-Pugh ≤B8, and Karnofsky performance score (KPS) ≥70% received 100 mg/m(2) irinotecan followed 7 hours later by flavopiridol 60 mg/m(2) weekly for 4 of 6 weeks. The primary end point was an improvement in progression-free survival at 4 months (PFS-4) from 33% to 54%, using a Simon's two-stage design. Tumors were stained for p53.

Results: Only 16 patients in the first stage were enrolled: median age, 64 years; median KPS, 80%; Child-Pugh A, 87.5%; and stage III/IV, 25%/75%. The primary end point was not met; PFS-4 was 20%, leading to early termination of the study. Ten patients were evaluable for response: 1 had SD >1 year and 9 had disease progression. Grade 3 fatigue, dehydration, diarrhea, neutropenia with or without fever, lymphopenia, anemia, hyperbilirubinemia, and transaminitis occurred in ≥10% of the patients. Of the 9 patients who progressed, 5 had mutant p53 and 4 had wild-type p53. The patient with stable disease had wild-type p53.

Conclusion: Sequential irinotecan and flavopiridol are ineffective and poorly tolerated in patients with advanced HCC. Despite our limited assessments, it is possible that the presence of wild-type p53 is necessary but not sufficient to predict response in HCC.