A Phase II Clinical Trial of the Pan PI3K Inhibitor, Buparlisib, for the Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia: Canadian Cancer Trials Group IND.216

Abstract

Introduction: Inhibition of the phospho-inositol 3 kinase (PI3K) delta isoform is effective in the treatment of relapsed and refractory chronic lymphocytic leukemia (CLL) (Pongas G, et al. Semin Oncol 2016; 43: 647). The efficacy of this class of drugs is limited by the potency of the inhibitor and its toxicity profile. Buparlisib is an orally available pan-Class I PI3K inhibitor which has greater potency than idelalisib in vitro . Low P70S6k and raptor levels, both of which are downstream regulators of the PI3K/mTOR pathway, correlate with sensitivity to PI3K inhibitor activity in CLL lymphocytes in vitro (Amrein L, et al. Int J Cancer 2013; 133: 247-52). The recommended phase II dose of buparlisib is 100 mg daily po and the main toxicities in Phase I were hyperglycemia, hypertension and mood disturbance (Bendell JC, et al. J Clin Oncol. 2012;30:282-90). We conducted a single arm phase II trial of buparlisib in patients with relapsed and refractory CLL (NCT02340780) and attempted to correlate response with P70S6k and raptor levels.Methods: Patients with CLL requiring re-treatment after at least one prior line of therapy were eligible. Buparlisib 100 mg daily was administered continuously on 28-day cycles with dose reductions to 80 mg and 60 mg in the event of toxicity. Mood questionaires (PHQ-9 and GAD-7) were administered at study entry and with each treatment cycle. The primary endpoint was overall response rate, defined according to the Revised International Workship on CLL (Hallek 2008) incorporating updated recommendations for novel targeted agents (Cheson 2012). Additional endpoints included safety, duration of response and progression free survival. Levels of P70S6k and raptor were measured in isolated CLL cells prior to therapy with buparlisib and compared with mean values as per Amrein et al. Int J Cancer 2013;133: 247-52).Results: Between April 2015 and January 2017, fourteen patients were enrolled; Rai stage high (n=7), intermediate (n=6) and low (n=1). Of these, 13 were eligible for toxicity (1 ineligible due to inadequate washout period) and 11 for response assessment (2 did not complete 1 cycle of therapy). The median age was 74 years (61-87), male:female 8:5, ECOG 0-1 and median number of prior therapies 1 (range 1-3). No patients received prior therapy with idelalisib or other PI3K inhibitor; 3 received prior ibrutinib, including the ineligible patient. Six of 13 patients had a partial response (46.2%, 95%, CI: 19.2,74.9%), with a median duration of response of 14.4 months. Five patients with a best response of stable disease all experienced tumor shrinkage (figure). There were no complete responses. Patients received a median of 5 cycles of therapy (range 1 to 20), the dose intensity was 485.6 mg per week and 27.3% received > 90% of planned doses. Ten patients have stopped protocol therapy, 1 for progressive disease and 9 for therapy-related adverse events: hyperglycemia (n=4), mood disorder (n=3), fatigue and generalized muscle weakness (n=1), elevated AST (n=1), hypertension (n=1) and thrombocytopenia (n=1). Mood disorders improved after stopping therapy in all 3 patients. The most common related adverse events (>15%) were diarrhea, nausea, fatigue, anorexia and dysguesia; all were <grade 3 except for fatigue. Hyperglycemia was seen in 9/13 patients. There were no related serious adverse events. Among the 8 patients tested, no correlation was observed between biomarker level and response or progression free survival.Conclusion: The response rates of single-agent idelalisib (Brown JR, et al. JCO ASCO Annual Meeting Abstracts. 2013;31 abstract 7003) and buparlisib are comparable with a different toxicity profile, making buparlisib another potential therapeutic option in CLL. Better mitigation of toxicity is required to make this an acceptable therapy for patients and rational drug combinations are needed to improve the efficacy of this agent. We could not confirm the importance of P70S6K or raptor in this small clinical trial. Validating these biomarkers in a larger cohort may help to predict which CLL patients are most likely to benefit from therapy with a PI3K inhibitor. [Display omitted] DisclosuresAssouline:Bristol Myer Squibb: Speakers Bureau; Novartis Canada Inc.: Honoraria; Pfizer: Speakers Bureau; Paladin: Speakers Bureau; Janssen: Honoraria. Banerji:Roche: Research Funding; Lundbeck: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Caplan:Janssen: Honoraria. Owen:Roche: Consultancy, Honoraria, Research Funding; Lundbeck: Honoraria; Gilead: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria; Celgene: Honoraria; AstraZeneca: Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding. Robinson:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Abbvie: Honoraria. Prica:Celgene: Honoraria; Janssen: Honoraria. Peters:Abbvie: Honoraria; Roche: Honoraria; Lundbeck: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Hay:Roche: Research Funding; Abbvie: Research Funding; Kite: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding.