Phase I Trial of Bortezomib and Everolimus in Relapsed/Refractory Non-Hodgkin Lymphoma

INTRODUCTION: Non-Hodgkin lymphomas (NHL) are characterized by dysregulation of pathways controlling cell proliferation and apoptosis. Proteosome inhibitors and mTOR inhibitors target these pathways and have single-agent activity in NHL, though their safety and efficacy when used in combination requires further study. We conducted a prospective, phase I dose-escalation study to determine the safety, efficacy and maximum tolerated dose (MTD) of everolimus in combination with bortezomib in patients (pts) with relapsed/refractory NHL.

METHODS: Eligibility criteria included: (1) relapsed or relapsed/refractory NHL with no limit on prior therapy; (2) measurable disease by standard radiographic findings (or monoclonal protein assessment for pts with lymphoplasmacytic lymphoma (LPL)); (3) ECOG PS ≤ 2 and adequate organ function. Hematologic parameters initially include platelets > 100,000 but subsequent amendments permitted >75,000. Dose levels for bortezomib were 0.7, 1, or 1.3 mg/m² given either IV or SC on d1, 4, 8, and 11 every 21 days. Everolimus was given orally 5 mg every other day (qod) or daily (qd), or 10 mg qd. Dose levels were increased using a standard 3 x 3 design (see table). Pts were assessed for response after every 2 cycles and maintained on treatment continuously until disease progression, death, intolerance to treatment or patient choice.

RESULTS: 28 pts were enrolled from July 2008 to June 2014. The median age was 65 (range, 40–86) years and 20/28 (61%) were male. Diagnoses included: follicular lymphoma (FL, 9), mantle cell lymphoma, (MCL, 5), diffuse large B-cell lymphoma (5), small lymphocytic lymphoma (SLL, 2), T-cell lymphoma, NOS (1), nodal marginal zone lymphoma (2), anaplastic large cell lymphoma (1), LPL (1), and splenic marginal zone lymphoma (SMZL, 1). Median number of prior therapies was 3 (range, 1-5) with no pts previously receiving bortezomib. Median number of cycles of therapy on study was 3 (range, 1-41). Hematologic toxicities included anemia (36 grade I/II, 6 grade III), neutropenia (10 grade I/II, 2 grade III), and lymphopenia (14 grade I/II, 3 grade III). Thrombocytopenia (44 grade I/II, 6 grade III) was the AE most commonly leading to treatment interruptions. Non-hematologic grade III toxicities included: cardiac (n=1), fatigue (n=1), skin infection (n = 1), low testosterone (n = 1), pneumonia (n=1), LFT elevation (n=4), hyperglycemia (n=1), hypercalcemia (n=1), electrolyte abnormalities (n=2), muscle weakness (n=1), syncope (n=1), herniated disc (n=1), flu-like symptoms (n=1). There were two grade IV toxicities: hyperkalemia (n=1) and secondary malignancy (n=1). Escalation of everolimus to 10 mg qd with bortezomib 1.3 mg/m^2 on d1, 4, 8 and 11 (dose level 5) resulted in dose-limiting thrombocytopenia requiring protocol amendment to declare the MTD to be dose level 4: 5 mg everolimus qd with 1.3 mg/m² bortezomib d1, 4, 8, and 11 every 21 days. Of 24 response-evaluable pts there was 1 complete response in an MCL patient and 3 partial responses (2 MCL, 1 FL) for an overall response rate of 17%. There were 9 pts with stable disease (5 FL, 1 MCL, 1 SLL and 1 SMZL) and 11 pts had progressive disease. All but one patient have discontinued treatment. Reasons for discontinuation included disease progression (15), adverse event (10) or patient choice (2).

CONCLUSIONS: The combination of everolimus and bortezomib results in dose limiting thrombocytopenia at maximal single agent doses. Everolimus at 5 mg qd can be safely combined with standard dose bortezomib (1.3 mg/m² d1, 4, 8 and 11 q 21d). This combination has modest clinical activity in heavily pre-treated aggressive and follicular NHL. Notable responses were found in 3 of 5 MCL patients, warranting further investigation of this combination for mantle cell lymphoma.