A Dose Escalation Study of RP6530, a Novel Dual PI3K Delta/Gamma Inhibitor, in Patients with Relapsed/Refractory Hematologic Malignancies
Authors: Carlo-Stella Carmelo , Delarue Richard , Barde Prajak J , Scarfo Lydia , Saheb Thamila , Kumar Uday , Viswanadha Srikant , Gandolfi Sara , Pittari Valeria , Santoro Armando , Locatelli Silvia Laura , Vakkalanka Swaroop , Ghia Paolo , Ferreri Andres J.M. 
Published: October 2019

Abstract
Introduction: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta (δ) and gamma (γ) isoforms of PI3K are often dysregulated in various hematologic malignancies and therefore key targets for the treatment of lymphomas/ leukemia. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency that effectively inhibits AKT phosphorylation and induces apoptosis in lymphoma/leukemic cell lines. We herein present results from an ongoing Phase I, first-in-human, dose escalation study of RP6530 (NCT02017613).
Methods: The dose escalation will determine the maximum tolerated dose (MTD) of RP6530 using a standard 3+3 design. Patients (pts) with a confirmed diagnosis of hematological malignancy and at least one prior therapy are eligible. Additional eligibility criteria include an ECOG performance status ≤ 2, measurable/evaluable disease, and life expectancy of at least 12 weeks. Primary endpoints are safety and pharmacokinetic (PK) and are supported by secondary endpoints such as pharmacodynamic and efficacy parameters (overall and complete response rates) and correlative biomarkers. RP6530 is given orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal from study. The study is designed to enroll up to 120 pts in the dose-escalation and expansion phase. Adverse events (AE) are assessed using the CTCAE v4.0/IWCLL guidelines as applicable. Efficacy evaluations are conducted every 8 wks.
Results: Twenty six pts were enrolled to date across various dose levels: BID 25mg, 50mg, 100mg, 200mg, 400mg, 600mg and 800mg. Sixteen were males; ECOG score was 0/1/2 in 20/3/3 pts, respectively, with a mean age of 59 yrs (range 20-83). Pts had a median of 5 (range: 1-11) prior treatment regimens, and 19 were refractory to prior treatments. Malignancy categories included HL (9), TCL (4), DLBCL (4), MCL (3), CLL/SLL (2), FL (1), MZL (1), WM (1), and MM (1). Majority of them were considered as "high tumor burden patients" as per different prognostic scores. Sixteen patients were discontinued mainly due to disease progression.
RP6530 was well tolerated with no DLT reported to date. Majority of AEs were mild and resolved with/without concomitant medication. None of Grade III/IV AEs or SAEs were deemed related to RP6530. No drug related increase in ALT/AST, colitis, pneumonia, or neutropenia was observed to date. Dose escalation is currently ongoing at 800 mg BID. Single agent activity, manifested by a reduction in tumor size by CT or PET scan, was noticed at ≥ 200 mg BID. The efficacy observations are mostly in indications, that are difficult-to-treat or with minimal therapeutic options. The ORR is 20 % [CR 2 (10 %) + PR 2 (10%)] with disease control rate of 65%. The responders are HL (2), PTCL (1) and DLBCL (1). The CLL/SLL patients, known to be the best responders to selective PI3K inhibitors, were not included in dose-cohorts ≥ 200 mg BID. Clinical response was associated with a significant reduction in pAKT expression. Dose-proportional increase in plasma concentrations were observed upon oral administration of RP6530.
Conclusions: To date, RP6530 has been well tolerated in pts with heavily pre-treated relapsed/refractory hematologic malignancies. Reported toxicities were manageable with no DLTs. Single agent activity was evident in difficult-to-treat patients at ≥ 200 mg BID. Enrolment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented at the annual meeting.

Disclosures
Barde: Rhizen Pharmaceuticals SA: Employment. Kumar:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen: Employment. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership. Ghia:Adaptive: Consultancy; GSK: Research Funding; Acerta Pharma BV: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau.