A Study of Oprozomib, Melphalan, and Prednisone in Transplant Ineligible Patients With Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of Phase 1b of the study is to determine the maximum tolerated dose (MTD) of oprozomib in combination with melphalan and prednisone (OMP). The purpose of Phase 2 of the study is to estimate the overall response rate (ORR) and complete response rate (CRR) of the OMP combination.

Official Title
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Phase 1b/2, Multicenter, Open-label Study of Oprozomib, Melphalan, and Prednisone in Transplant Ineligible Patients With Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Oprozomib
* Drug: Melphalan
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Newly diagnosed symptomatic multiple myeloma patients who are transplant ineligible with measureable disease as indicated by one or more of the following: Serum M-protein ≥ 500 mg/dL Urine M-protein ≥ 200 mg/24 hour Serum Free Light Chain: Involved free light chain (FLC) level ≥ 10 mg/dL, provided serum FLC ratio is abnormal Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Creatinine clearance (CrCl) ≥ 30 mL/min, either measured or calculated using the formula of Cockcroft and Gault [(140 - age) × mass (kg) / (72 × serum creatinine mg/dL)]. Multiply result by 0.85 if female. 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 is allowed). Use of topical or inhaled steroids is acceptable. Congestive heart failure (New York Hearth Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to first dose Known or suspected HIV, active Hepatitis A, B C or virus infection (Exception: Subjects with chronic or cleared HBV and HCV infection and stable liver function tests [bilirubin, AST] will be allowed). Significant neuropathy (Grade 2 with pain or higher) at the time of first dose. Plasma cell leukemia. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Known amyloidosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oprozomib with Melphalan and Prednisone (OMP)<br>Subjects will receive oprozomib administered orally. The combination of oprozomib, melphalan, and prednisone (OMP) will be administered until progression of disease, unacceptable toxicity, discontinuation of study treatment for reasons other than progression or toxicity, or a maximum of 9 cycles (54 weeks), whichever occurs first. | Drug: Oprozomib<br>* Study subjects will receive oprozomib administered orally.<br>Drug: Melphalan<br>* Study subjects will receive melphalan 9 mg/m2.<br>Drug: Prednisone<br>* Study subjects will receive prednisone 60 mg/m2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) - Phase 1b | MTD is defined as the highest dose at which a DLT is observed in less than 2 of 6 evaluable subjects occurring within the 4 weeks after the first dose of combination therapy. | 42 weeks | 
| Overall Response Rate (ORR) - Phase 2 | ORR defined as a best overall response of sCR, CR, VGPR, or PR according to the IMWG-URC. | 39 months | 
| Complete Response Rate (CRR) - Phase 2 | CRR defined as a best overall response of sCR or CR according to the IMWG-URC. | 39 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 2 | Adverse Events (AEs) and Serious Adverse Events (SAEs) graded according to the NCI-CTCAE (Version 4.03). | Collected from signing of informed consent and throughout study until 30 days after the last dose of study treatment (up to 58 weeks) | 
| Population Pharmacokinetic (PK) parameters - apparent clearance and volume of distribution | Evaluate population pharmacokinetic (PK) parameter estimates of oprozomib and variability in these estimates when administered in combination with melphalan and prednisone using a sparse sampling strategy and population-based analysis methodology. | 2 postdose time points in Cycle 1 Day 1, 1 predose and 2 postdose time points on Cycle 3 Day 1 and Cycle 5 Day 1 | 
| Duration of Response (DOR) | Duration of Response (DOR) is defined as the time from evidence of PR or better to disease progression or death due to any cause. | 39 months | 
| Progression-free Survival (PFS) | Progression-free survival is defined as the time from the first day of study treatment (Cycle 1 Day 1) to the earlier of disease progression or death due to any cause. | 39 months |