DUAL PI3K δ/γ INHIBITOR RP6530 IN PATIENTS WITH RELAPSED/REFRACTORY T‐CELL LYMPHOMA: DOSE ESCALATION FINDINGS.

Abstract

Introduction: The δ and γ isoforms of PI3K play a distinct role in the growth and survival of T-cell lymphoma (TCL). RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nano-molar inhibitory potency for both isoforms. Herein, we present results from an ongoing Phase 1/1b, dose escalation study in TCL (NCT02567656). Methods: The study consists of a standard 3 + 3 dose escalation cohort to determine the maximum tolerated dose (MTD), followed by two expansion cohorts: Peripheral TCL (PTCL) (n = 20) and Cutaneous TCL (CTCL) (n = 20). Patients (Pts) with a diagnosis of TCL who have received at least one prior systemic therapy were eligible. The study also evaluated pharmacokinetics, pharmacodynamics, and anti-tumor activity of RP6530 administered orally twice daily (BID) in 28-day cycles. Dose limiting toxicity (DLT) was defined by a toxicity of ≥ grade 3 using the CTCAE V4.03 that is considered related to treatment during the first cycle. Results: To date, nineteen pts (9 PTCL and 10 CTCL; 12 males and 9 females) have been enrolled at four dose levels: 200 mg BID (n = 4), 400 mg BID (n = 4), 800 mg BID (fasting) (n = 5) and 800 mg BID (fed) (n = 6). The median age was 63 years (range 40–76). Pts received a median of 3 (range: 1–7) prior treatment regimens; 12 pts had relapsed disease after last treatments whereas 7 pts had refractory disease. RP6530 was well tolerated up to 800 mg (fasting) dose. No DLT was not observed at dose levels 200 mg BID, 400 mg BID and 800 mg BID (fasting). At 800 mg BID (fed), which theoretically provides higher drug exposure than fasting dose, three DLTs were observed (transaminitis grade 3, rash grade 3 and neutropenia grade 3) in 6 patients. Therefore, 800 mg BID (fasting) was considered a MTD. The most common related adverse events were transaminitis (32%), fatigue (26%) and rash (26%). There were no related SAEs. In all related grade 3 events, withholding study drug and monitoring at least once weekly until the event resolves to grade 1 was recommended. In two cases of transaminitis, steroid was started as it was deemed immune mediated. No pt discontinued treatment due to safety reason. Dose-proportional increases in plasma concentrations were observed in PK. Five pts experienced rapid disease progression during first cycle and discontinued treatment prematurely. Response assessment in fourteen pts at Cycle 3, Day 1 demonstrated an overall response rate of 36% with one complete response in PTCL (7%) and four partial responses (2 PTCL and 2 CTCL) (29%). Six pts had stable disease (43%). Conclusion: Dose escalation study demonstrated an acceptable safety and tolerability up to RP6530 800 mg BID (Fasting) with promising clinical activity in pts with TCL. A dose of 800 mg BID (fasting) was considered a MTD. The results support further evaluation of RP6530 in pts with mature T-cell lymphomas. Dose expansion at 800 mg BID (fasting) is currently ongoing. Keywords: PI3K/AKT/mTOR; T-cell lymphoma (TCL).