Phase I Study of Intravenous PI3K Inhibitor Bay 80–6946: Preliminary Activity in Patients with Relapsed Non-Hodgkin Lymphoma (NHL) Treated in an MTD Expansion Cohort

BAY 80–6946 is a potent and highly selective, reversible, pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor, with broad antitumor activity in a panel of preclinical models including both indolent and aggressive NHL. Even in the absence of PIK3CA mutations, the PI3 pathway has been demonstrated to be constitutively activated in the majority of B-cell lymphomas. BAY 80–6946 was more potent than CAL-101 in inhibiting the in vitro growth of a panel of leukemia/lymphoma cell lines.

In a phase I dose escalation study, BAY 80–6946 was previously reported to be tolerated as a 1-hr infusion at a dose of 0.8 mg/kg (MTD) on days 1, 8 and 15 every 28 days (J Clin Oncol 29: 2011 suppl; abstr 3035). Additional patients were treated in MTD expansion cohorts to assess safety, PK, biomarkers and clinical benefit in selected patient populations, including one expansion cohort in NHL. Based upon the beneficial clinical responses observed in 5 follicular lymphoma (FL) patients (J Clin Oncol 30: 2012 suppl; abstr 3019), the NHL cohort was expanded up to a total of 12 patients. Samples were collected for pharmacokinetic analyses. Exploratory analyses of changes in several plasma proteins, chosen with emphasis on B-cell homing/survival, were performed. Response was assessed using International Working Group response criteria, including ¹⁸FDG-PET.

To date, 9 NHL patients have been enrolled (FL, n=6, DLBCL, n=3). There were 5 females/4 males with a median age of 72 years (range, 40–84). Among these 9 patients, 5 (56%) had received 3 or more prior regimens. All have received prior Rituximab and 6/9 prior anthracycline and 4/9 prior Bendamustine. Eight patients were evaluable for safety and tolerability. The most frequently drug-related adverse events reported in >20% of the patients were hyperglycemia, nausea, diarrhea, anemia, mucositis, and fatigue. Interstitial pneumonitis was observed in 2 patients with FL. Both patients responded to corticosteroids and one continued on treatment at full dose without recurrence of the pneumonitis. The pharmacokinetic parameters of BAY 80–6946, including the Cmax and AUC, were consistent with those seen in solid tumour patients. Changes in the plasma levels of CXCL13 and BAFF were observed in subjects treated with BAY 80–6946. Median time on study was 129 days (3–487). Best response in 6 evaluable patients (FL, n=5, DLBCL, n=1) was 5 PR and 1 PD, all 5 evaluable FL patients achieving a PR, the longest of which is >16 months. Pharmacodynamic effects were demonstrated with significant lymphoma shrinkage observed as early as 48 hours after the first dose of BAY 80–6946 on ¹⁸FDG-PET/CT in both FL and DLBCL patients.

In this MTD expansion cohort study in NHL lymphoma, BAY 80–6986 was generally well tolerated and showed very promising clinical activity in NHL patients. Updated clinical, PK and pharmacodynamic results will be presented. Based on these preliminary results, further clinical development as a single agent or in combination regimens in NHL is warranted.

Patnaik:Bayer: Research Funding. Ramanathan:Bayer: Research Funding. Appleman:Bristol-Myers: Research Funding; Bayer Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; Abbott: Research Funding; Cougar Biotechnology/Ortho Biotech: Research Funding; Medivation: Research Funding; Excelixis: Research Funding. Beerham:Bayer: Research Funding. Weiss:Bayer: Honoraria; Roche/Ventana: Honoraria; Merrimack: Honoraria; Cephalon: Honoraria; Eli Lilly: Honoraria; Cytrx: Consultancy; Genentech: Speakers Bureau; Pfizer: Speakers Bureau; Caris Life Sciences: Speakers Bureau; Bayer: Research Funding. Rajagopalan:Bayer Pharmaceuticals: Employment. Jeffers:Bayer Pharmaceuticals: Employment. Kelly:Bayer Pharmaceuticals: Employment. Genvresse:Bayer Pharma AG: Employment.