First-in-Human study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics and Pharmacodynamics, in Patients with Metastatic Cancer
Mené sur 38 patients atteints d'une tumeur solide métastatique, cet essai de phase I évalue la doxe maximale tolérée et l'activité clinique d'un composé appelé CH5132799, un inhibiteur de PI3K
Purpose: This Phase I dose-escalation study investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary clinical activity of CH5132799. Patients and Methods: Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily (QD) or twice daily (BID) in 28-day cycles. Results: Thirty-eight patients with solid tumors received CH5132799 at 2-96 mg QD or 48-72 mg BID. The MTD was 48 mg on the BID schedule but was not reached on the QD schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/ml and 1,550 ng∙hr/ml respectively, consistent with efficacious exposure based on preclinical modelling. Reduction in SUVmax with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in five of seven patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pre-treated patient with triple negative breast cancer had marked improvement in her cutaneous skin lesions lasting 6 cycles. Conclusion: CH5132799 is well tolerated at the MTD dose 48 mg BID. At this dose the drug had a favorable PK and PD profile and preliminary evidence of clinical activity.