A Phase I Dose Escalation Study of RP6530, a Novel, Dual PI3K-γδ Inhibitor, for Patients with Relapsed or Refractory Hematologic Malignancies
Authors: Scarfò Lydia , Barde Prajak J , Fazi Claudia , Kumar Uday , Viswanadha Srikant , Vakkalanka Swaroop , Ghia Paolo , Ferreri Andres J.M. 
Published: October 2019

Abstract
Introduction: Phosphoinositide-3-kinases (PI3Ks) are pivotal in various cellular functions including cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta (δ) and gamma (γ) isoforms of PI3K are highly expressed in cells of hematopoietic origin, and often dysregulated in various hematologic malignancies. Because these isoforms contribute to the development, maintenance, transformation, and proliferation of immune cells, dual targeting of PI3K δ and γ represents a promising approach in the treatment of lymphomas. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency at the enzyme and cellular level. Besides, RP6530 was effective in inhibiting Akt phosphorylation and inducing apoptosis in various lymphoma and leukemic cell lines. Herein we present preliminary results of a Phase I, first in human, open label study of an oral PI3K δ/ γ inhibitor, 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 B-cell non-Hodgkin lymphoma, peripheral T-cell lymphoma, chronic lymphocytic leukemia, Acute lymphoblastic leukemia (CLL), Primary central nervous system lymphomas or Multiple myeloma who have at least one prior therapy are eligible. Additional eligibility criteria include ECOG performance status ≤ 2, and measurable/evaluable disease with a life expectancy of at least 12 weeks. Primary endpoints are safety and pharmacokinetic (PK) parameters; secondary endpoints include pharmacodynamic and drug activity (overall and complete response rates). Correlative biomarker samples including quantitative/qualitative measurements of cytokines, chemokines and aberrations indicative of PI3K function and RP6530 efficacy will be analyzed. RP6530 is given orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal from treatment. The study is designed to enroll up to 30 pts in the dose-escalation phase with up to an additional 42 pts in the cohort expansion phase. Efficacy evaluations are planned every 8 weeks. Adverse events (AE) are assessed using the CTCAE v4.0/ IWCLL guidelines as applicable.
Results: Nine pts were enrolled to date across 3 dose levels: BID 25mg, 50mg and 100mg. Five pts were males; ECOG score was 0/1/2 in 5/1/3 pts, respectively, with mean age of 74 yrs (range: 54-82). Pts had median 5 (range: 1-11) prior treatment regimens, and 6 were refractory to prior treatments. Lymphoma categories included DLBCL (2 pts), Mantle Cell Lymphoma (2 pts), follicular lymphoma (1 pt), Marginal Zone Lymphoma (1 pt); and CLL/SLL (2 pts); one pt had multiple myeloma. All nine pts are evaluable for DLT assessment. Of the 9 evaluable pts, 6 are currently on study; 1 patient discontinued treatment due to disease progression. Pts tolerated the treatment well. To date, there have been no DLTs. One pt experienced G4 neutropenia that was unrelated to RP6530. No other G3/4 related hematologic or non-hematologic toxicities were observed. Of the six pts who completed 2 cycles of treatment (8 wks) at 50 mg daily dosing or less, 5 showed stable disease while 1 had disease progression. Three pts did not reach the first response assessment.
Mean PK parameters determined on Day 1 of Cycle 1(C1D1) are: median Tmax of 1 hrs (range 0.5-2.0hrs), harmonic mean t1/2 of 2 (± 0.47) hr, and CL/F of 39.55 (± 19.3) L/hr. A linear relationship exists between dose and both AUC (r2 = 0.97) and Cmax (r2 = 0.97). The average accumulation index represented by Cmin on Cycle 2 day 1 is 1.12 (± 0.1). PK data from the first 3 cohorts on C1D1 is summarized below. Table 1.Dose25 mg (n=3)50 mg (n=3)100 mg (n=3)Cmax (µg/mL)0.356 (± 0.08)0.563 (± 0.12)1.329 (± 0.55)AUC (µg*hr/mL)0.775 (± 0.32)1.619 (± 0.67)2.482 (± 1.18)
Conclusions: To date, RP6530 has been well tolerated in pts with heavily pre-treated relapsed/refractory hematologic malignancies. There were no DLTs and toxicities were minimal. Enrollment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented.

Disclosures
Scarfò: Rhizen Pharmaceuticals SA: Research Funding. Barde:Rhizen Pharmaceutical SA: Employment. Fazi:Rhizen Pharmaceuticals SA: Research Funding. Kumar:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen: Employment. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership. Ghia:Rhizen Pharmaceuticals SA: Research Funding. Ferreri:Rhizen Pharmaceuticals SA: Research Funding.