Safety and Anti-Tumour Activity of RP6530, Dual PI3K δ/γ Inhibitor, in Relapsed/Refractory T-Cell Lymphoma: Updated Results from the Dose Expansion Cohort of an on-Going Phase I/Ib Study

Introduction: RP6530 is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. Preliminary results from the ongoing Phase 1/1b T-cell lymphoma (TCL) study were presented at ASH 2016 (NCT02567656). The updated results from the escalation phase and further data on the expansion cohort treated at the maximum tolerated dose (MTD) is presented.

Methods: This multicenter, open-label, Phase 1/1b study consists of dose escalation cohorts followed by two expansion cohorts enrolling 20 pts with peripheral TCL (PTCL) and 20 pts with cutaneous TCL (CTCL). The primary objective of the study is to determine the MTD and dose limiting toxicity (DLT), and to describe the safety and pharmacokinetic profiles. The secondary objectives are assessment of the overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2014) and the modified Severity Weighted Assessment Tool (mSWAT) respectively.

Results: As of June 20, 2017, a total of thirty seven patients (17 PTCL and 20 CTCL) have been enrolled across the dose escalation and expansion cohorts. The results presented are the pooled data across both cohorts. Nineteen pts (9 PTCL, 10 CTCL) were enrolled in dose escalation [(200 mg BID, n=4; 400 mg BID, n=4; 800 mg BID (Fasting), n=5; 800 mg BID (Fed), n=6)] and eighteen patients (8 PTCL and 10 CTCL) in expansion (800 mg BID Fasting) in a 28 day cycle. Patients had a median of 3 (range: 1-7) and 5 (range: 1-15) prior treatment regimens for PTCL & CTCL respectively.

Based on DLTs (transaminitis, rash & neutropenia), MTD was determined to be 800 mg BID fasting. A dose-proportional increase in plasma concentrations was observed in the PK. Safety assessment of 37 patients receiving at least one dose of RP6530 demonstrated an acceptable safety profile. Treatment related AE ≥Grade 3 were observed in thirteen (35%) patients which included elevated ALT/AST (n=9, 24%), rash (n=3, 8%), and neutropenia (n=1, 3%). These events were reversible and managed by withholding study drug. Steroid was given in some cases of transaminitis. There were no treatment related serious adverse events (SAE). Two patients discontinued treatment due to safety reasons. Dose reduction was done in seven patients (19%).

As defined by the protocol, response assessments of the twenty evaluable patients receiving at least two cycles of RP6530 showed an ORR of 45% (9/20 patients) out of which 2 (10%) were complete responses [CR] and 7 (35%) were partial responses [PR]. Eight patients showed stable disease (40%). Indication specific analysis showed an ORR of 57% (4/7, 2 CR, 2 PR) in PTCL and 38% (5/13, 5 PR) in CTCL. Twelve patients (12/37, 32%) who discontinued treatment due to a rapid progression of disease before the first efficacy assessment were not considered for efficacy analysis.

Conclusion: Based on the updated emerging data, RP6530 shows encouraging preliminary clinical activity as a single agent and appears to have an acceptable and manageable safety profile in relapsed/refractory TCL. Recruitment in the expansion cohort is currently on-going to reach a total of 40 patients and results will be further evaluated.