A Phase 1 Study Of The Selective PI3Kδ Inhibitor Idelalisib (GS-1101) In Combination With Therapeutic Anti-CD20 Antibodies (Rituximab or Ofatumumab) In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia
Authors: Furman Richard R. , De Vos Sven , Leonard John P. , Barrientos Jacqueline C. , Schreeder Marshall T. , Flinn Ian W. , Sharman Jeff P. , Boyd Thomas , Fowler Nathan , Rai Kanti R. , Kim Yeonhee , Holes Leanne M. , Dansey Roger , Jahn Thomas M. , Coutre Steven E. 
Published: October 2019

Abstract

Introduction
PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in patients with heavily pretreated CLL.

Methods
This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 150 mg BID in combination with a total of 8 infusions of rituximab (R, 375 mg/m2 weekly x 8), or a total of 12 infusions of ofatumumab (O, 300mg initial dose either on Day 1 or Day 2 relative to the first dose of idelalisib, then 1,000 mg weekly x 7, then 1,000 mg every 4 wks x 4). Pts on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012).

Results
40 pts (12F/28M) with a median (range) age of 66 (43-87) years and a WHO performance status of 0 (24, 60%) or 1 (16 40%) were enrolled. 19 pts received idelalisib in combination with R, 21 with O.
Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (24, 60%), refractory disease (14, 35%), multiple prior therapies (median 2, range: 1-;9). Almost all patients (39, 98%) had at least 1 prior therapy containing R, and 3 of the 21 pts (14%) receiving idelalisib + O had received prior O. 63% of the pts receiving idelalisib + R, and 43% of the pts receiving idelalisib + O were refractory to R. Prior therapies also included alkylating agents (31, 78%, [bendamustine: 20, 50%]) and purine analogs (31, 78%, [fludarabine: 28, 70%]). Data available from 39 pts showed that 11 (28%) pts had evidence of del(17p) and/or TP53 mutations and 30 (75%) had unmutated IGHV.
As of May 2013, the median (range) treatment duration was 18 (0-33) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. A total of 14 pts (35%) were continuing idelalisib treatment on the extension study. The most common reasons for discontinuation either from the primary or extension study were disease progression (10, 25%) and adverse events (AEs) (9, 23%). There were 6 deaths reported on study; 3 pts experienced PD before death.
Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea (53%/10%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (18%/15%), colitis (10%/10%) and pneumonitis (10%/7.5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Of those, only 1 pt discontinued the study because of (recurrent) TA elevation.
The ORR (N=40) was 83% (33/40), with 3 CRs (8%), and a median (range) time to response of 1.9 (1.7-21.8) months. Median progression-free survival (PFS) for all patients (N=40) and duration of response (n=33) were 20 and 19 months, respectively. Median overall survival (OS) has not been reached. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73% (8/11) and the median PFS and DOR were 19 months.

Conclusions
Combinations of idelalisib with therapeutic anti-CD20 antibodies such as rituximab or ofatumumab represent non-cytotoxic regimens with acceptable safety profiles and high activity resulting in durable tumor control in pts with heavily pretreated relapsed/refractory CLL. Phase 3 trials evaluating the efficacy of idelalisib in combination with R or O are ongoing (NCT01539512, NCT01659021).

Disclosures:
Furman: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. De Vos:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.