Introduction: 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: This was a standard 3+3 dose escalation study in pts with relapsed or refractory hematologic malignancies having ECOG performance status (PS) ≤2, measurable/evaluable disease, and life expectancy of at least 12 weeks. Endpoints were safety, pharmacokinetic (PK), pharmacodynamics (PD) and efficacy [overall response rate (ORR), complete response (CR), partial response (PR)]. RP6530 was given orally twice/thrice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal from the study.

Results: Thirty-five pts (median age 54 years; range: 20-83; 22 males) were enrolled across various dose levels (25-1200 mg BID and 600-800 mg TID). Pts were highly pre-treated [median prior therapy: 6 (range: 1-13)], had a good PS (ECOG 0/1/2 recorded in 29/3/3 cases, respectively) and 26 (74.2%) were refractory to last therapy. Unlike studies with other PI3k inhibitors, recruitment was limited to aggressive NHL (e.g. DLBCL, MCL, and PTCL) and HL with very few pts of CLL and indolent diseases. Majority (74%) had stage 3/4 disease.

RP6530 was well tolerated with no DLT up to the dose of 1200 mg BID and 800 mg TID. The median duration of therapy was 2.78 cycles (range: 0.28-19 cycles). Majority of AEs were mild and resolved with/without concomitant medication. None of grade 3/4 AEs or SAEs were deemed related to RP6530, except four Grade 3 events [hypertriglyceridemia (n=1), neutropenia (n=2) and diarrhea (n=1)]. No drug related elevated ALT/AST, colitis or pneumonia was observed. None of the pts were withdrawn or dose reduction required due to related AEs/SAEs.

Thirty pts were evaluated for responses. Single agent activity was noticed at ≥ 200 mg BID. The ORR was 20% (95% CI: 08-36%), including 2 CR (7%) and 4 PR (13%), with a disease control rate (CR+PR+SD) of 60%. Responding pts included HL (n=4), PTCL (n=1) and DLBCL (n=1). Median duration of response was 6 cycles (3.5-19 cycles). Clinical response (CR/ PR) were associated with a progressive reduction in pAKT expression in circulating lymphocytes as early as two hours after the first dose and peaked on Day 8 when the median percentage of pAKT+ lymphocytes was reduced by 44%. PK demonstrated dose-proportional increase in plasma concentrations.

Conclusions: RP6530 was well tolerated with no DLT and a promising clinical activity in pts with advanced, heavily pre-treated relapsed/refractory hematologic malignancies. Phase II studies are recommended to evaluate anti-tumor activity at an optimal dose of 800 mg BID. Safety profile further supports combination therapy with existing/novel targeted agents, given the very low incidence of toxicity with RP6530.


Carlo-Stella:Boehringer Ingelheim: Consultancy; Rhizen Pharmaceuticals: Research Funding. Barde:Rhizen Pharmaceuticals SA: Employment. Kumar:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen Therapeutics: Employment.

Author notes


Asterisk with author names denotes non-ASH members.

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