A Study of Oprozomib, Pomalidomide, and Dexamethasone in Adults With Primary Refractory or Relapsed and Refractory Multiple Myeloma

Phase 1b/3 Multicenter Study of Oprozomib, Pomalidomide, and Dexamethasone in Primary Refractory or Relapsed and Refractory Multiple Myeloma Subjects

The purpose of the Phase 1 part of the study is to determine the maximum tolerated dose and assess the safety, tolerability and activity of oprozomib in combination with pomalidomide and dexamethasone in adults with primary refractory or relapsed and refractory multiple myeloma.

The purpose of the Phase 3 part of the study is to compare the efficacy for adults with primary refractory or relapsed and refractory multiple myeloma who are randomized to either oprozomib or placebo in combination with pomalidomide and dexamethasone.

This was a phase 1b/3, multicenter study composed of 2 parts: part 1 was a phase 1b, open-label, dose-escalation and dose-expansion component and part 2 was to have been a phase 3, placebo-controlled, double-blind, randomized component. Part 2 was not conducted.

The Phase 1 dose-escalation portion of the study followed a standard 3 + 3 dose-escalation design. For each of the 2 schedules, groups of 3 to 6 patients were enrolled. The starting doses of oprozomib were 150 and 210 mg in the 5/14 and 2/7 schedules, respectively. The starting dose of pomalidomide was 4 mg in both schedules. As long as < 33% of patients experienced a dose-limiting toxicity (DLT) in a given cohort, the dose of oprozomib was escalated in 30-mg increments for successive cohorts.

Once the recommended dose and schedule for the expansion phase had been selected, additional participants were enrolled in the dose expansion portion of part 1 to continue the evaluation of the safety and efficacy of the regimen and determine the recommended phase 3 dose. Enrollment was halted during the dose expansion phase and part 2 was not conducted.

Key Inclusion Criteria:

1. Multiple myeloma that is primary refractory or relapsed and refractory after at least 2 lines of standard for multiple myeloma including:

   1. ≥ 2 consecutive cycles of both bortezomib and lenalidomide or thalidomide (alone or in combination)
   2. In the dose-expansion and Phase 3 portions of the study only: In addition to the above, treatment with adequate alkylator therapy, defined as:

   i. High-dose melphalan or other alkylating agent as conditioning for autologous or allogeneic stem cell transplant (SCT), or ii. ≥ 6 cycles of induction therapy, or iii. Progressive disease after ≥ 2 cycles

2. Disease progression on or within 60 days of completion of the last therapy

3. Measurable disease as indicated by 1 or more of the following:

   1. Serum M-protein ≥ 500 mg/dL
   2. Urine M-protein ≥ 200 mg/24 h
   3. For patients without measurable serum or urine M protein, serum free light chain (SFLC): Involved free light chain (FLC) concentration ≥ 10 mg/dL provided SFLC ratio is abnormal

4. Males and females ≥ 18 years old

5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

Key Exclusion Criteria:

1. Systemic chemotherapy with approved or investigational anticancer therapeutics, intended to treat underlying malignancy, within 3 weeks before the first dose or 6 weeks for antibody therapy
2. Dexamethasone at cumulative doses greater than 160 mg or equivalent within 21 days prior to the first dose of study treatment is not allowed. Use of topical or inhaled steroids is acceptable.
3. Radiation therapy within 3 weeks before first dose. Radioimmunotherapy within 8 weeks before first dose.
4. Plasmapheresis is not permitted at any time during the Screening period or while the subject is receiving study treatment. If a subject has started Screening procedures requiring plasmapheresis, or is anticipated to require plasmapheresis during or after the Screen
5. Autologous SCT within 8 weeks or allogeneic SCT within 16 weeks prior to initiation of study treatment. Patients with prior allogeneic SCT should not have evidence of moderate-to-severe graft-versus-host disease (as defined in Filipovich 2005).
6. Known hypersensitivity to any immunomodulatory drugs (IMiDs), including Grade 4 rash
7. Prior treatment of any duration with pomalidomide
8. Known hypersensitivity or intolerance to dexamethasone
9. Prior exposure to oprozomib
10. Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months before first dose.