Long-Term Follow-up of a Phase 1 Study of Idelalisib (ZYDELIG®) in Combination with Anti-CD20 Antibodies (Rituximab [R] or Ofatumumab [O]) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Authors: Furman Richard R. , de Vos Sven , Barrientos Jacqueline C. , Schreeder Marshall T. , Flinn Ian W. , Sharman Jeff P. , Boyd Thomas E , Fowler Nathan , Leonard John P. , Rai Kanti R. , Kim Yeonhee , Viggiano Anthony , Jahn Thomas M. , Coutre Steven E. 
Published: October 2019

Abstract
Introduction: PI3Kδ signaling is critical for the proliferation, survival and homing/tissue retention of malignant B cells. Idelalisib is a first-in-class, highly selective, oral inhibitor of PI3Kδ recently approved for the treatment of relapsed CLL in combination with R. This report summarizes the long-term follow-up of the Phase 1 combination experience of idelalisib with anti-CD20 antibodies.
Methods: This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 100 mg BID (4 of the pts receiving R) or 150 mg BID (all other pts) 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 and 21 with O.
Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (23, 58%), refractory disease (15, 38%), multiple prior therapies (median 2, range: 1-9). Almost all pts (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 48% 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 7/15/2014, the median (range) treatment duration was 18 (0-44) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. Primary reasons for study discontinuation (as reported by investigators) included disease progression (14, 35%), adverse events (AEs) (12, 30%), investigator request (3, 8%), withdrawal of consent (n=1), BMT (n=1). There were a total of 8 deaths on study: 2 deaths occurred after disease progression, and 6 pts died because of AEs (all assessed as unrelated/unlikely related to idelalisib by investigators). A total of 4 pts (10%) were continuing idelalisib treatment on the extension study at time of analysis.
Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (55%/23%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (20%/18%), and pneumonitis (8%/5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Re-exposure to idelalisib after resolution of TA elevation generally was successful; only 1 patient discontinued the study because of (recurrent) TA elevation. Other AEs leading to study discontinuation and reported as possibly/probably related to idelalisib included diarrhea/colitis (4, 10%), pyrexia (n=1), interstitial lung disease (n=1), pneumonia (n=1), rash (n=1), psoriasis (n=1). Secondary malignancies leading to discontinuation (all reported as unrelated) were breast cancer (n=1), recurrent colon cancer (n=1), AML (n=1). There was no obvious overall difference in the toxicity reported for pts receiving idelalisib with rituximab compared to those with ofatumumab.
The ORR (N=40) was 83% (33/40), with 2 CRs (5%) reported. Median PFS (N=40) and duration of response (DOR) (n=33) were 24 months. Median (range) time to response was 1.9 (range 1.7-16.9) months. Median overall survival (OS) has not been reached with a KM estimate for OS of 80% at 24 months. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73%, and the median PFS and DOR were 20 and 24 months, respectively.
Conclusions: Combinations of idelalisib with anti-CD20 antibodies such as R or O represent non-cytotoxic regimens with acceptable safety profiles and considerable activity resulting in durable tumor control in pts with relapsed/refractory CLL, including those with high risk factors such as del(17p) or TP53 mutations. A Phase 3 trial evaluating the efficacy of idelalisib in combination with ofatumumab is ongoing (NCT01659021).

Disclosures
Furman: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. de Vos: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. Leonard:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment, Equity Ownership. Viggiano:Gilead Sciences: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Coutre:Gilead Sciences: Research Funding.