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

Phase 1

Completed

Brief Summary: 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.

Recruitment & Eligibility

Inclusion Criteria

Newly diagnosed symptomatic multiple myeloma patients who are transplant ineligible with measureable disease as indicated by one or more of the following:
1. Serum M-protein ≥ 500 mg/dL
2. Urine M-protein ≥ 200 mg/24 hour
3. 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

Arm && Interventions

Group	Intervention	Description
Oprozomib with Melphalan and Prednisone (OMP)	Melphalan	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.
Oprozomib with Melphalan and Prednisone (OMP)	Prednisone	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.
Oprozomib with Melphalan and Prednisone (OMP)	Oprozomib	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.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) - Phase 2	39 months	ORR defined as a best overall response of sCR, CR, VGPR, or PR according to the IMWG-URC.
Maximum Tolerated Dose (MTD) - Phase 1b	42 weeks	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.
Complete Response Rate (CRR) - Phase 2	39 months	CRR defined as a best overall response of sCR or CR according to the IMWG-URC.

Secondary Outcome Measures

Name	Time	Method
Population Pharmacokinetic (PK) parameters - apparent clearance and volume of distribution	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	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.
Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 2	Collected from signing of informed consent and throughout study until 30 days after the last dose of study treatment (up to 58 weeks)	Adverse Events (AEs) and Serious Adverse Events (SAEs) graded according to the NCI-CTCAE (Version 4.03).
Duration of Response (DOR)	39 months	Duration of Response (DOR) is defined as the time from evidence of PR or better to disease progression or death due to any cause.
Progression-free Survival (PFS)	39 months	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.

Locations (8): Hospital City of Health and Science of Turin, Hematology 1 Division
🇮🇹
Turin, Italy
Ospedale Oncologico Regionale
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Rionero in Vulture, Potenza, Italy
Erasmus MC, Department of Hematology
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Rotterdam, Netherlands
University of Rome
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Rome, Italy
Department of Clinical Therapeutics, University of Athens
🇬🇷
Athens, Attica, Greece
AOU Maggiore della Carita, SCDU Heamatology
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Novara, Italy
Vrijc Universiteit Medisch Centrum, Department of Hematology
🇳🇱
Amsterdam, Netherlands
Azienda Ospedaliera Universitaria S Martino
🇮🇹
Genova, Italy