Developmental Therapeutics-Experimental Therapeutics
Phase I clinical trial of gemcitabine (GEM) in combination with PF-00477736 (PF-736), a selective inhibitor of CHK1 kinase.
Background: The S-phase and G2-checkpoints are critical mediators of the cell cycle response to cytotoxic therapy. PF-736 is a selective inhibitor of the S/G2-checkpoint kinase CHK1, displaying >10-fold selectivity over CHK2. Preclinical studies show that PF-736 can enhance response to GEM that is associated with abrogation of the S/G2 checkpoint with cells entering mitosis prematurely.
Methods: We undertook a phase I, dose escalation study to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics of PF-736 in combination with GEM in sequential cohorts of 3 to 6 gemcitabine naive patients (Pts) with advanced solid tumors. Pts received IV PF-736 alone on days 1 and 8 in cycle 0 (C0) and then started the combination of GEM and PF-736 in C1, days 1 and 8 and 2 and 9 respectively, with PF-736 starting 20-24 hrs after completion of GEM, in 21-day cycles. C0 and C1 were considered for dose-limiting toxicity (DLT).
Results: 36 Pts to date have been treated with GEM 750mg/m2 and escalating doses of PF-736. 17 Pts were treated in cohorts of 3-8 with PF-736 50-80 mg infused over 3 h. 19 Pts have been treated in cohorts of 3-7 with PF-736 80-340 mg infused over 24 h. AEs were infrequent in C0. DLT of thrombocytopenia, sudden death, mucositis, and elevated lipase were seen in C1. The MTD was 270mg of PF-736 with GEM 750mg/m2. One Pt treated at PF-736 80 mg was admitted with elevated liver function tests on C10D9 and died from hepatic veno-occlusive disease 3 weeks later. Common drug-related AEs occurring in >30% Pts were pyrexia, fatigue, neutropenia, nausea, vomiting, and diarrhea. 42% of Pts had dose delays due to G3 neutropenia making the days 1 and 8 schedule difficult to maintain. The exposure of PF-736 increased proportionally with increased dose from 50mg to 270mg. Mean T 1/2 ranged from 8 to 20 hrs. Three partial responses were observed in Pts with SCC of the skin, non-small cell lung cancer, and mesothelioma.
Conclusions: The combination of PF-736 and GEM 750mg/m2 is clinically active, and can be safely given to Pts. Future studies will determine the MTD of PF-736 with GEM 1,000mg/m2 and examine biomarkers, including inhibition of the S/G2 checkpoint by serial tumor biopsies at the MTD.
|Employment or Leadership Position||Consultant or Advisory Role||Stock Ownership||Honoraria||Research Funding||Expert Testimony||Other Remuneration|