Phase III Study of Idelalisib and Rituximab for Previously Treated Patients with Chronic Lymphocytic Leukaemia

Study met primary endpoint of progression-free survival and secondary endpoints of overall response, lymph node response and overall survival

A phase III randomised, double-blind, placebo-controlled study evaluating idelalisib in combination with rituximab in previously treated chronic lymphocytic leukaemia (CLL) patients who were not fit for chemotherapy demonstrated statistically significant improvement with acceptable safety over placebo plus rituximab in term of progression-free survival (PFS), overall response rate (ORR), lymph node response (LNR) and overall survival (OS). The benefit was observed even in heavily pretreated patients, including those with adverse genetic features. The results were presented in the Late-Breaking Abstracts Session of the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans, USA (7-10 December, 2013) by Dr Richard Furman, Assistant Professor of Clinical Medicine in the Division of Hematology/Oncology, Weill Cornell Medical Center, New York Presbyterian Hospital.

The study was stopped early based on a pre-specified interim analysis performed by an external Data Monitoring Committee (DMC) showing a highly statistically significant effect on the primary endpoint of PFS.

Idelalisib is an investigational, highly selective oral inhibitor of phosphoinositide 3-kinase (PI3K) delta. PI3K delta signalling is critical for the activation, proliferation, survival and trafficking of B lymphocytes and is hyperactive in many B-cell malignancies. Phase I trials demonstrated that idelalisib is highly active as a single agent or in combination with rituximab in heavily pretreated patients with CLL. Patients in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile. Patients with early progression and significant co-morbidities have limited treatment options with single-agent rituximab as an option in these patients.

The study results

The study was a randomised, double-blind, placebo-controlled, phase III study evaluating the efficacy and safety of idelalisib in combination with rituximab. The study enrolled 220 adult patients at approximately 70 study sites in the United States and Europe. Eligible patients had previously treated recurrent CLL, with measurable lymphadenopathy that had progressed within 24 months since completion of prior therapy. The patients required treatment based on IWCLL criteria but were not fit to receive cytotoxic therapy.

Patients were randomised to receive eight infusions of rituximab over 24 weeks plus either idelalisib 150 mg or placebo taken orally twice daily continuously until disease progression or unacceptable toxicity. Patients randomised to the control arm (placebo plus rituximab) were eligible to receive open-label idelalisib therapy in an extension study.

Primary endpoint was PFS. Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). The results were reviewed by an external DMC. Presented results are from a pre-specified interim analysis after approximately 50% of the total number of 119 planned events of CLL progression or death from any cause. Data cut-off was 30 August 2013.

Patient characteristics included a median age of 71 years with 78% of patients of ≥ 65 years; CIRS > 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anaemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 years, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV.

PFS in the idelalisib plus rituximab arm was superior to placebo plus rituximab (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 10‑11). Median PFS of patients treated with idelalisib plus rituximab was not reached and for placebo plus rituximab was 5.5 months. At 24 weeks, the PFS rate for idelalisib plus rituximab was 93% compared to 46% for placebo plus rituximab. PFS strongly favoured idelalisib plus rituximab in all subgroups, including those with del(17p)/TP53 or unmutated IGHV.

Patients treated with idelalisib plus rituximab and with ≥1 post-baseline assessment also had a superior ORR relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 10‑19) and a higher LNR rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, patients treated with idelalisib plus rituximab also had a significant improvement in OS: HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018.

Adverse events (AEs) occurring in ≥20% of patients (any grade/grade ≥3) by arm were: pyrexia (idelalisib plus rituximab 29%/3%; placebo plus rituximab 16%/1%), fatigue (idelalisib plus rituximab 24%/3%; placebo plus rituximab 27%/2%), nausea (idelalisib plus rituximab 24%/0%; placebo plus rituximab 22%/0%), chills (idelalisib plus rituximab 22%/2%; placebo plus rituximab 16%/0%), infusion-related reactions (idelalisib plus rituximab 16%/0%; placebo plus rituximab 28%/4%), and cough (idelalisib plus rituximab 15%/0%; placebo plus rituximab 25%/2%).

Other selected AEs (any grade/grade ≥3) included diarrhoea (idelalisib plus rituximab 19%/4%; placebo plus rituximab 14%/0%) and rash (idelalisib plus rituximab 10%/2%; placebo plus rituximab 6%/0%). Select laboratory abnormalities (any grade/grade ≥3) included ALT elevation (idelalisib plus rituximab 31%/6%; placebo plus rituximab 9%/1%), anaemia (idelalisib plus rituximab 26%/6%; placebo plus rituximab 30%/14%), neutropenia (idelalisib plus rituximab 55%/34%; placebo plus rituximab 49%/22%), and thrombocytopenia (idelalisib plus rituximab 17%/10%; placebo plus rituximab 26%/16%).

The most common serious AEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in idelalisib plus rituximab, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnoea (3.7%) in placebo plus rituximab. AEs led to study drug discontinuation in 9 patients (8.2%) in idelalisib plus rituximab and 11 patients (10.3%) in placebo plus rituximab.

Safety was in line with previous observations, and was largely consistent with advanced disease patients receiving CD20 antibody therapy.

New drug applications

In addition to this study, the development program in CLL includes two ongoing phase III studies of idelalisib in previously treated patients. Gilead's clinical development program for idelalisib in indolent non-Hodgkin's lymphoma (iNHL) includes a phase II study in highly refractory patients and two phase III studies of idelalisib in previously treated patients. Combination therapy with idelalisib and GS-9973, Gilead's novel spleen tyrosine kinase (Syk) inhibitor, also is being evaluated in a phase II trial of patients with relapsed or refractory CLL, iNHL and other lymphoid malignancies.

Gilead plans for regulatory filings for idelalisib in the United States and European Union. On September 11, 2013, Gilead submitted a New Drug Application (NDA) to the USA Food and Drug Administration (FDA) for idelalisib for the treatment of iNHL. Following Gilead's NDA submission for iNHL, FDA granted idelalisib a Breakthrough Therapy designation for CLL in relapsed patients based on results from this study. Gilead is now engaging in a dialogue with the FDA regarding a regulatory filing in CLL. Gilead filed for approval in iNHL and CLL with the European Medicines Agency (EMA) on October 28, 2013.

Disclosures from the abstract authors: Richard Furman: Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Jeff Sharman: Gilead Sciences: Consultancy, Research Funding. Steven Coutre: Gilead Sciences: Research Funding. Bruce Cheson: Gilead Sciences: Research Funding. John Pagel: Gilead Sciences: Research Funding. Peter Hillmen: Gilead Sciences: Research Funding. Jacqueline Barrientos: Gilead Sciences: Research Funding. Andrew Zelenetz: Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Thomas Kipps: Gilead Sciences: Research Funding. Ian Flinn: Gilead Sciences: Research Funding. Paolo Ghia: Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Herbert Eradat: Gilead Sciences: Research Funding. Thomas Ervin: Gilead Sciences: Research Funding. Nicole Lamanna: Gilead Sciences: Research Funding. Michael Hallek: Gilead Sciences: Research Funding. Bertrand Coiffier: Gilead Sciences: Research Funding. Andrew Pettitt: Gilead Sciences: Research Funding. Shuo Ma: Gilead Sciences: Research Funding. Stephan Stilgenbauer: Gilead Sciences: Honoraria, Research Funding. Maria Aiello: Gilead Sciences: Employment. Dave Johnson: Gilead Sciences: Employment, Equity Ownership. Langdon Miller: Gilead Sciences: Employment, Equity Ownership. Daniel Li: Gilead Sciences: Employment. Thomas Jahn: Gilead Sciences: Employment. Roger Dansey: Gilead Sciences: Employment, Equity Ownership. Susan O'Brien: Gilead Sciences: Research Funding.