Preliminary Results Of a Phase II Study Of Single Agent Bay 80-6946, a Novel PI3K Inhibitor, In Patients With Relapsed/Refractory, Indolent Or Aggressive Lymphoma

BAY 80–6946 is a potent and reversible Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with significant activity against both PI3K-δ and PI3K-α isoforms. The PI3K-α inhibitory activity may overcome a PI3K-mediated mechanism of resistance triggered by PI3K-δ inhibition. A phase I dose-escalation study (Patnaik et al, ASH 2012) established the maximum tolerated dose of BAY 80-6946 (0.8 mg/kg) and reported promising activity (6/6 PR) in follicular lymphoma. In the present study we further investigated the activity and safety of BAY 80-6946 in patients with indolent or aggressive lymphoma subtypes that have progressed after standard therapy.

Patients with histologically confirmed indolent or aggressive lymphoma relapsed or refractory to ≥2 prior lines of treatment were eligible. Patients received BAY 80-6946 at a dose of 0.8 mg/kg as a 1 hour infusion on days 1, 8 and 15 of a 28-day cycle. Patients continued on therapy until disease progression or unacceptable toxicity. Responses were assessed every two cycles according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL; Hallek et al., Blood111:5446-56, 2008).

As of July 31, 2013, a total of 61 lymphoma patients (27 indolent and 34 aggressive) were enrolled and 56 started study treatment. Patients were similarly distributed among indolent and aggressive cohorts with respect to gender (52% female), median age (68 yr, range 22-90) and ethnicity (76% Caucasian) and were heavily pretreated (median number of prior therapies: 3; prior Rituximab: 84%; prior ASCT: 20%). Other characteristics included advanced stage III-IV in 85% and B symptoms in 17%. The following entities were represented: follicular (FL; n=13); CLL (n= 11); marginal zone (MZL; n=3; none staged to date); diffuse large B-cell (DLBCL; n=18); mantle cell (MCL; n=7); transformed (n=5); and peripheral T-cell (PTCL; n=4). At the time of analysis patients had received between 1 and 5 cycles of treatment. Objective responses were seen across histologic subtypes (Table 1). At the time of this interim analysis, the overall response rate (RR) and complete RR were 40% and 20% in FL, 67% and 0% in CLL, 83% and 17% in MCL, and 50% and 0% in PTCL, respectively.

CR – complete response; CRu – CR unconfirmed; PR – partial response; SD – stable disease; PD – progressive disease

Grade 3 adverse events (AE) were reported in 49% of patients, and grade 4 AE (all neutropenia) occurred in 15% of patients. Grade 3/4 AEs occurring in ≥5% of patients included hypertension (31%), neutropenia (16%), hyperglycemia (13%), diarrhea (5%) and fatigue (5%). Hyperglycemia of any grade occurred in 47%. Four patients required insulin therapy, but no grade 4 hyperglycemia was observed. Hypertension of any grade occurred in 46% of patients. Eight patients required antihypertensive treatment, but no grade 4 hypertension was reported. Diarrhea of any grade occurred in 25% of cases. No case of colitis was reported. There were two cases of interstitial pneumonitis, with both cases resolved following corticosteroid administration. Withdrawal of study drug due to AEs occurred in 10 patients (16%), and 4 patients required a dose reduction. Four deaths occurred; 1 due to progressive disease, 1 due to acute respiratory insufficiency, 1 due to Cryptococcal meningitis and 1 due to sepsis after start of a salvage chemotherapy regimen.

The novel PI3K inhibitor BAY 80-6946 is clinically active as a single agent and appears to have an acceptable toxicity profile in relapsed/refractory lymphoma. Preliminary efficacy results are encouraging, as promising activity has been observed in FL, CLL, MCL, and PTCL. The safety profile was consistent with prior studies. Further studies of this compound in patients with lymphoma are warranted.

Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau. Mappa:Bayer S.p.A.: Employment. Giurescu:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.