EFFECT OF ADDING IDELALISIB TO FRONTLINE OFATUMUMAB PLUS EITHER CHLORAMBUCIL OR BENDAMUSTINE IN LESS FIT PATIENTS WITH CLL: PRELIMINARY RESULTS FROM THE NCRI RIALTO TRIAL.

Introduction: The Phase 3 RIAltO trial opened in December 2011 to compare ofatumumab plus chlorambucil (O + C) with ofatumumab plus bendamustine (O + B) in patients with previously untreated chronic lymphocytic leukaemia (CLL) considered unfit for FCR (fludarabine, cyclophosphamide, rituximab). A protocol amendment was introduced in September 2014 to investigate the addition of idelalisib (first-in-class inhibitor of the p110δ isoform of phosphoinositol-3 kinase) or placebo. Review of safety data in January 2016 revealed excessive toxicity due to idelalisib, and recruitment was suspended. All idelalisib/placebo treatment was withdrawn from the trial in March 2016 following safety analysis of idelalisib registration studies and recommendations from Gilead Sciences Ltd and regulatory authorities. Here, we present a preliminary analysis of the cohort of patients in RIAltO who received idelalisib or placebo. Methods: Patients were eligible for inclusion if they had previously untreated CLL requiring treatment by NCI/IWCLL criteria, were considered unfit for FCR and did not have any contraindications to the study drugs. Consenting patients underwent an unblinded 1:1 randomisation to ofatumumab (300 mg iv day 1 and 1000 mg iv day 8 of cycle 1; 1000 mg iv day 1 of cycle 2 onwards) plus either chlorambucil (10 mg/m2 day 1-7, repeated every 28 days for 3-12 cycles) or bendamustine (70 mg/m2 iv day 1-2 for 3-6 cycles) and a double-blinded 1:1 randomisation to concurrently administered placebo or idelalisib (150 mg bd for up to 3 years). Co-trimoxazole prophylaxis was recommended. Study drugs were continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The post-treatment reporting period for serious adverse events (SAEs) was 6 months for grade 3-4 infections and 28 days for other events. Results: 145 patients received idelalisib (73) or placebo (72), with a median idelalisib exposure time of 2.5 months. As of March 2017, SAEs were reported in 77% of idelalisib-treated patients (81 grade 3-4 and 8 grade 5) compared to 39% in the placebo group (35 grade 3-4 and 2 grade 5). The frequency of SAEs in the idelalisib-treated group was similar in both chemotherapy arms. Grade 5 events in this group included sepsis (1), lung infection (3), febrile neutropenia (2), myocardial infarction (1) and sudden death NOS (1). After a median follow-up of 15 months, 17 PFS events have been observed in the placebo group compared with 11 in the idelalisib group. Keywords: chronic lymphocytic leukemia (CLL); Idelalisib (CAL-101, GS-1101); ofatumumab.