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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Oprozomib
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Multiple myeloma that is primary refractory or relapsed and refractory after at least 2 lines of standard for multiple myeloma including: ≥ 2 consecutive cycles of both bortezomib and lenalidomide or thalidomide (alone or in combination) 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 Disease progression on or within 60 days of completion of the last therapy Measurable disease as indicated by 1 or more of the following: Serum M-protein ≥ 500 mg/dL Urine M-protein ≥ 200 mg/24 h 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 Males and females ≥ 18 years old Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Key Exclusion Criteria: 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 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. Radiation therapy within 3 weeks before first dose. Radioimmunotherapy within 8 weeks before first dose. 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 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). Known hypersensitivity to any immunomodulatory drugs (IMiDs), including Grade 4 rash Prior treatment of any duration with pomalidomide Known hypersensitivity or intolerance to dexamethasone Prior exposure to oprozomib 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.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone<br>Participants received oprozomib 150 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg/day on days 1 to 21 and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>Drug: Pomalidomide<br>* Capsules for oral administration<br>* Other names: POMALYST®;Drug: Dexamethasone<br>* Tablets for oral administration<br>|
| Experimental: Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone<br>Participants received oprozomib 150 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with pomalidomide 2 mg/day on days 1 to 21 and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>Drug: Pomalidomide<br>* Capsules for oral administration<br>* Other names: POMALYST®;Drug: Dexamethasone<br>* Tablets for oral administration<br>|
| Experimental: Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone<br>Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>Drug: Pomalidomide<br>* Capsules for oral administration<br>* Other names: POMALYST®;Drug: Dexamethasone<br>* Tablets for oral administration<br>|
| Experimental: Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone<br>Participants received oprozomib 240 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>Drug: Pomalidomide<br>* Capsules for oral administration<br>* Other names: POMALYST®;Drug: Dexamethasone<br>* Tablets for oral administration<br>|
| Experimental: Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase<br>Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>Drug: Pomalidomide<br>* Capsules for oral administration<br>* Other names: POMALYST®;Drug: Dexamethasone<br>* Tablets for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) | DLTs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, defined as any of the following treatment-related events occurring within 4 weeks after the first dose of therapy: Any grade ≥ 3 nonhematologic toxicity, except: Grade 3 asymptomatic electrolyte abnormalities or hypophosphatemia for < 24 hours; Grade 3 nausea, vomiting or diarrhea unless for > 3 days despite optimal supportive care; Grade 3 fatigue for < 14 days; Grade ≥ 3 hyperglycemia or toxicity attributed to dexamethasone and Grade ≥ 3 rash attributed to pomalidomide. Hematologic toxicities: Grade 4 neutropenia: Absolute neutrophil count < 0.5 × 10^9/L for ≥ 7 days despite adequate growth factor support; febrile neutropenia Thrombocytopenia: Grade 4 for ≥ 7 days, or Grade 4 for < 7 days with grade 2 clinically significant bleeding or < 10,000 platelets requiring transfusion, or Grade 3 with clinically significant bleeding or requiring platelet transfusion. | Cycle 1, 28 days | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse events (AEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 and according to the following: Grade 1 = mild AE, Grade 2 = Moderate AE, Grade 3 = a severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. A serious AE is an event that met 1 or more of the following criteria: Death Life-threatening experience Required inpatient hospitalization or prolongation of an existing hospitalization Resulted in persistent or significant disability/incapacity A congenital anomaly birth defect in the offspring of an exposed female subject or offspring of a female partner of a male subject Important medical events that, based upon appropriate medical judgment, jeopardized the participant and may have required medical or surgical intervention to prevent an outcome listed above. Treatment-related AEs (TRAE) are those considered related to at least 1 study drug by the investigator. | From first dose of any study drug up to 30 days after the last dose; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively. | 
| Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Laboratory abnormalities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Full chemistry panel included sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total protein, albumin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), phosphorous, and magnesium. Complete blood count (CBC) with differential included hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell (RBC) count, and platelet count. | Cycles 1 and 2 days 1, 5, 15, and 19 and days 3 and 8 of cycle 1, and day 1 of each cycle from cycle 3 thereafter until the end of treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. PR: ≥ 50% reduction of serum M-protein and ≥90% reduction in urine M-protein or to < 200 mg/24 hrs, or a ≥50% decrease in the difference between involved and uninvolved free light chain levels (dFLC). A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein <100 mg/24 hrs. If disease measurable only by serum FLC (SFLC), ≥ 90% decrease in dFLC. CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow (BM). Normal SFLC ratio if disease measurable only by SFLC. sCR: As for CR, and absence of clonal plasma cells in BM. | Disease response was assessed every 4 weeks for the first 18 months and then every 8 weeks for the remainder of study treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively. | 
| Clinical Benefit Rate (CBR) | Clinical benefit rate is defined as the percentage of participants with a best overall response of minimal response (MR) per modified European Group for Blood and Marrow Transplantation criteria, or PR, VGPR, CR, or sCR as determined by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). MR: ≥ 25% but < 49% reduction in serum M-protein and a 50 - 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg per 24 hours If the serum and urine M-protein were not measurable, a decrease of 25 - 49% in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria. For patients with nonsecretory myeloma only, 25 - 49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed 25 - 49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination) | Disease response was assessed every 4 weeks for the first 18 months and then every 8 weeks for the remainder of study treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively. | 
| Maximum Plasma Concentration (Cmax) of Oprozomib | Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. | Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose. | 
| Time to Maximum Plasma Concentration (Tmax) of Oprozomib | Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. | Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose. | 
| Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib | Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. The area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was estimated using the linear trapezoidal method. | Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose. | 
| Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib | Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. The area under the plasma concentration-time curve from time 0 to time infinity (AUCinf), estimated as the sum of AUClast and Clast/λz, where Clast is the last predicted concentration and λz is the first-order terminal rate constant estimated via linear regression of the terminal log-linear decay phase. | Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose. |