Oprozomib and Dexamethasone,in Combination With Lenalidomide or Oral Cyclophosphamide to Treat Newly Diagnosed Multiple Myeloma

Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone, in Combination With Lenalidomide or Oral Cyclophosphamide in Patients With Newly Diagnosed Multiple Myeloma

The primary objectives of this study included the following:

Phase 1b:

• To establish the maximum tolerated dose (MTD) of oprozomib given in combination with lenalidomide and dexamethasone (ORd) or with cyclophosphamide and dexamethasone (OCyd)
• To evaluate the safety and tolerability of oprozomib and dexamethasone administered in combination with lenalidomide or oral cyclophosphamide

Phase 2:

• To estimate the antitumor activity of each combination regimen, as measured by overall response rate (ORR) and complete response rate (CRR)
• To evaluate the safety and tolerability of each combination regimens, as assessed by the type, incidence, severity and seriousness of adverse events, and abnormalities in selected laboratory analytes

Phase 1b used a standard 3 + 3 dose-escalation scheme to determine the MTD. For each combination regimen, oprozomib doses were to be escalated in sequential cohorts of 3 participants with expansion to up to 6 participants if a dose-limiting toxicity (DLT) was observed in 1 of the first 3 participants. The doses of lenalidomide, cyclophosphamide, and dexamethasone were to remain fixed in all dose cohorts.

The phase 2 portion of the study was to include up to 35 additional participants in each of the 2 combination regimens, treated at the recommended phase 2 dose (RP2D) of oprozomib that was identified during the phase 1b portion of the study in order to better characterize safety and tolerability, and antimyeloma activity.

This study was stopped by sponsor decision during the dose escalation in phase 1b prior to initiation of phase 2.

Key Inclusion Criteria:

• Newly diagnosed, symptomatic multiple myeloma patients for whom treatment is indicated per the National Comprehensive Cancer Network (NCCN) guidelines, and for whom a hematopoietic stem cell transplant is not planned or scheduled during the study or are considered ineligible for hematopoietic stem cell transplant, with measurable disease
• Creatinine clearance of ≥ 50 mL/min (measured or calculated using the Cockcroft and Gault formula)

Key Exclusion Criteria:

• Any prior systemic antimyeloma therapy except oral steroids (dexamethasone up to a total dose of 160 mg or equivalent within 14 days prior to the first dose of study treatment). Use of topical or inhaled steroids is acceptable
• Radiation therapy within 2 weeks prior to first dose
• Major surgery within 3 weeks prior to first dose
• Active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to first dose
• Clinical significant gastrointestinal bleeding in the 6 months prior to Cycle 1 Day 1 (C1D1) first dose
• Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of first dose
• Other malignancy within the past 3 years except those considered cured by surgical resection including some cases of: with the exception of adequately treated basal or squamous cell carcinoma of the skin, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the breast or cervix, carcinoma in situ of the breast, prostate cancer with Gleason Score 6 or less with stable prostate specific antigen levels, or cancer considered cured by surgical resection