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

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 27^th, 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 1^st 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.