SAFETY AND CLINICAL ACTIVITY OF RP6530, A DUAL PI3Kδ/γ INHIBITOR, IN PATIENTS WITH ADVANCED HEMATOLOGIC MALIGNANCIES: FINAL ANALYSIS OF A PHASE 1 MULTI‐CENTER STUDY (2017)

Background: RP6530 is a novel, next generation, highly specific dual PI3K δ/γ inhibitor with nano-molar inhibitory potency. Preliminary results demonstrated acceptable safety profile and anti-tumour activity in patients (pts) with advanced hematologic malignancies (ASH 2015). Herein, we present the final analysis from a Phase 1 study of RP6530 (NCT02017613). Methods: A standard 3 + 3 dose escalation design was implemented. Pts with relapsed or refractory hematologic malignancies having ECOG performance status (PS) ≤2, measurable/evaluable disease, and life expectancy of at least 12 weeks were eligible. Primary endpoints included assessment of DLTs, determination of MTD. RP6530 was given orally twice/three times a day in 28-day cycles. Fine immuno-monitoring of lymphocyte populations and subsets was performed on thawed peripheral blood cells. Results: From Dec 2013 to May 2016, 35 pts (63% males) with median age of 54 years (range 20–83 years) were enrolled across various dose levels (25–1200 mg BID and 600–800 mg TID). Pts were heavily pre-treated and the median number of prior therapy was 6 (range 1–13)] with 26 (74.2%) pts being refractory to the last treatment regimen. The ECOG PS was ≤1 in 32 cases. The median number of treatment cycles was 2.5 (range, 0.26–19 cycles). There was no DLT. Majority of AEs were mild and resolved either spontaneously or with concomitant medications. Except three Grade 3 events [hypertriglyceridemia (n = 1), neutropenia (n = 2)], no other grade 3–5 AEs or SAEs were deemed related to RP6530. There was no withdrawal or dose reduction due to related events. Activity of study drug was noticed at ≥200 mg BID. The ORR was 19% (95% CI: 7–36%); 2 CR (6%) and 4 PR (13%). Responding pts included HL (n = 4), PTCL (n = 1) and DLBCL (n = 1). Interestingly, HL pts (n = 15) showed an ORR of 29% with median DoR of 8 months (range 2–14). Clinical responses (CR/PR) were associated with a progressive reduction in pAKT expression in circulating lymphocytes as early as 2 hours after the first dose. PK indicated a dose-proportional increase in plasma concentrations. We identified dose-independent leukocyte dynamics in the peripheral blood of pts that were associated with response to treatment. Pts with CR or PR displayed a decrease in circulating CD4+ conventional and regulatory T cells as well as B cells, but not CD8+ T or NK cells at 2 months after treatment. Conclusions: RP6530 demonstrated an acceptable safety with no DLT and a promising clinical activity in pts with advanced, heavily pre-treated relapsed/refractory hematologic malignancies. Clinical activity was manifested by a significant reduction in peripheral blood cell pAKT expression levels. Decrease in conventional and regulatory CD4+ T cells and B cells was associated with response. RP6530 is an attractive therapeutic option in combination with targeted agents. Phase II study in NHL pts is ongoing at an optimal dose. Keywords: classical Hodgkin lymphoma (cHL); non-Hodgkin lymphoma (NHL); PI3K/AKT/mTOR.