A Phase 1 Study of Everolimus and Bendamustine in Patients with Relapsed or Refractory Lymphoid Malignancies and Myeloma

Abstract Introduction: Bendamustine, an alkylating agent, and everolimus, an oral mTOR inhibitor, have independently shown single-agent activity in relapsed/refractory lymphoid malignancies and myeloma. Preclinical data supports a synergistic effect between the two agents via pro-apoptotic mechanisms. Methods: Patients (pts) aged ≥18 with relapsed/refractory (R/R) lymphoid cancers and myeloma were enrolled in a phase 1, dose-escalation, single-center study to determine the safety and efficacy of bendamustine and everolimus combination therapy. We present initial data on the safety profile and efficacy as of July 27th, 2017. Everolimus was administered daily with bendamustine 90mg/m2 IV on days 1 and 2 of each 28-day cycle. Successive everolimus dose escalation cohorts were 5mg, 7.5mg, and 10mg using a standard 3+3 design. Rituximab 375mg/m2 on day 1 of each cycle was also allowed for CD20-positive NHL. The primary outcome measure of the study was to maximum tolerated dose (MTD) and the secondary outcome measure was to assess the response rate. Four 28-day cycles were planned, with disease status/response assessments with CT imaging or bone marrow biopsy at baseline and after cycles 2 and 4. Adverse events (AEs) were graded according to NCI-CTCAE version 4.0. Lymphoma response was assessed using 2007 Cheson IWG response criteria. Multiple myeloma response was assessed per 2016 IMWG criteria. Dose-limited toxicity (DLT) were defined as grade 4 neutropenia lasting > 5 days, grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding or any requirement for platelet transfusion, febrile neutropenia of any duration and/or any grade 3 or 4 non-hematological toxicity. Patients were evaluable on the study if they received a minimum of 14 of the planned 28 doses of everolimus during cycle 1. Results: A total of 19 pts have been enrolled as of July 27, 2017, of which 2 needed to be replaced as they did not receive ≥75% of planned everolimus in the first cycle, resulting in 17 evaluable patients for safety analysis. Diagnoses were: Hodgkin's lymphoma (HL, n=4), diffuse large B-cell lymphoma (DLBCL, n=4), mantle cell lymphoma (MCL, n=1), follicular lymphoma (FL, n=2), and multiple myeloma (MM, n=6). Median age was 62 (range: 22-74). In total, 6/17 pts (35%) completed planned 4 cycles of everolimus and bendamustine combination therapy. Premature discontinuation was due to: progressive disease (n=5), physician discretion (n=3), adverse event (n=2), and patient choice (n=1). Treatment-related AEs of any grade in ≥20% of all 19 pts were: lymphopenia, thrombocytopenia, leukopenia, nausea, anemia, neutropenia, anorexia, sinus tachycardia, and elevated liver enzymes. Non-hematologic grade 3/4 AEs were: fatigue (n=3), hypokalemia (n=1), and hypophosphatemia (n=1). Hematologic grade 3/4 AEs were: lymphopenia (n=11), thrombocytopenia (n=4), leukopenia (n=3), neutropenia (n=2), and anemia (n=1). There were no treatment-related deaths. One pt in the 1st cohort and 2/6 pts in 3rd cohort experienced DLTs (fatigue and thrombocytopenia) therefore MTD was deemed to be 7.5mg everolimus daily. One pt with myeloma chose to withdraw prior to 1st assessment, thus 16 pts were evaluable for response. ORR for the 16 pts evaluable was 56% (4 with CR, 5 with PR or VGPR). Among the 5 evaluable pts with MM, the ORR was 80% (1 pt had VGPR, 3 had a PR, 1 had PD). The median number of prior therapies in this group was 6 (range 5-10), including at least 1 autologous stem cell transplant in all patients. Among the 4 pts with HL, 1 had CR, 1 had PR, and 2 had PD, for an ORR of 50%. Among the 7 pts with NHL, 3 pts had CR (2 with FL, 1 with MCL), and 3 had PD (all with DLBCL, 2 of which were transformed FL). 1 additional pt with DLBCL had a DLT prior to first response assessment and was not evaluable. Thus, the ORR for the NHL cohort was 50%. Conclusions: The combination of everolimus and bendamustine demonstrated a very tolerable safety profile in a wide spectrum of patients with R/R hematologic malignancies. Several pts in responded to therapy. The overall response rate in MM and indolent NHL were particularly high (80-100%). Data on the final cohort after completion of accrual will be presented at the meeting. Further investigation using MTD of 7.5mg daily everolimus with bendamustine is warranted in a phase 2 study, particularly in follicular lymphoma and multiple myeloma. Disclosures Jonas: Rigel: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding. Tuscano: Celgene: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Research Funding; Novartis: Research Funding; Spectrum: Research Funding. Rosenberg: Amgen: Speakers Bureau. Abedi: Amgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; California Institute of Regenerative Medicine: Research Funding; BMS: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau.