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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Oprozomib
* Drug: Lenalidomide
* Drug: Dexamethasone
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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

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 + Lenalidomide + 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 lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>* Other names: Oprozomib ER tablets;Drug: Lenalidomide<br>* Administered orally at a dose of 25 mg on days 1 through 21 of each 28-day cycle for a maximum of 24 cycles.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Administered at 20 mg, orally, on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. After the first cycle the dose may be decreased to 10 mg/day in participants > 75 years of age, at the discretion of the investigator.<br>|
| Experimental: Oprozomib 180 mg 5/14 + Lenalidomide + Dexamethasone<br>Participants received oprozomib 180 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 lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>* Other names: Oprozomib ER tablets;Drug: Lenalidomide<br>* Administered orally at a dose of 25 mg on days 1 through 21 of each 28-day cycle for a maximum of 24 cycles.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Administered at 20 mg, orally, on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. After the first cycle the dose may be decreased to 10 mg/day in participants > 75 years of age, at the discretion of the investigator.<br>|
| Experimental: Oprozomib 210 mg 5/14 + Lenalidomide + Dexamethasone<br>Participants received oprozomib 210 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 lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>* Other names: Oprozomib ER tablets;Drug: Lenalidomide<br>* Administered orally at a dose of 25 mg on days 1 through 21 of each 28-day cycle for a maximum of 24 cycles.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Administered at 20 mg, orally, on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. After the first cycle the dose may be decreased to 10 mg/day in participants > 75 years of age, at the discretion of the investigator.<br>|
| Experimental: Oprozomib 210 mg 2/7 + Lenalidomide + 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 lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>* Other names: Oprozomib ER tablets;Drug: Lenalidomide<br>* Administered orally at a dose of 25 mg on days 1 through 21 of each 28-day cycle for a maximum of 24 cycles.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Administered at 20 mg, orally, on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. After the first cycle the dose may be decreased to 10 mg/day in participants > 75 years of age, at the discretion of the investigator.<br>|
| Experimental: Oprozomib 240 mg 2/7 + Lenalidomide + 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 lenalidomide 25 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 24 cycles, whichever occurred first. After completing 24 cycles of treatment, participants with stable disease or better could have continued on oprozomib with or without dexamethasone pretreatment. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>* Other names: Oprozomib ER tablets;Drug: Lenalidomide<br>* Administered orally at a dose of 25 mg on days 1 through 21 of each 28-day cycle for a maximum of 24 cycles.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Administered at 20 mg, orally, on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. After the first cycle the dose may be decreased to 10 mg/day in participants > 75 years of age, at the discretion of the investigator.<br>|
| Experimental: Oprozomib 210 mg 2/7 + Cyclophosphamide + 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 oral cyclophosphamide 300 mg/m² on days 1, 8, and 15 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23, until progression of disease, unacceptable toxicity, or for 8 cycles, whichever occurred first. After completing 8 cycles of treatment, participants with stable disease or better were to continue on oprozomib with dexamethasone premedication for a total of 24 cycles or until progression of disease or unacceptable toxicity. After completing 24 cycles of treatment, participants without evidence of disease progression could have continued on oprozomib with or without dexamethasone pretreatment. | Drug: Oprozomib<br>* Extended release (ER) tablets administered orally<br>* Other names: Oprozomib ER tablets;Drug: Dexamethasone<br>* Administered at 20 mg, orally, on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. After the first cycle the dose may be decreased to 10 mg/day in participants > 75 years of age, at the discretion of the investigator.<br>Drug: Cyclophosphamide<br>* Administered orally at 300 mg/m² (up to a maximum of 600 mg) on days 1, 8, and 15 of each 28-day cycle for a maximum of 8 cycles of therapy (approximately 8 months).<br>* Other names: Cytoxan;|

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 (NCI CTCAE) version 4.03. A DLT is defined as any of the following treatment-related events: Any ≥ Grade 3 nonhematologic toxicity with the following conditions: ≥ Grade 3 nausea, vomiting, diarrhea, or constipation only if for > 7 days despite optimal supportive care Asymptomatic Grade 3 hypophosphatemia, Grade 3 hyperglycemia or toxicity solely due to dexamethasone, ≥ Grade 3 rash attributed to lenalidomide, and Grade 3 fatigue for < 14 days were not considered DLTs Grade 4 neutropenia: absolute neutrophil count (ANC) < 0.5 × 10^9/L lasting ≥ 7 days, despite myeloid growth factor support Febrile neutropenia Grade 4 thrombocytopenia for ≥ 7 days or < 7 days with ≥ Grade 2 clinically significant bleeding or < 10,000 platelets requiring platelet transfusion, or Grade ≥ 3 with clinically significant bleeding or requiring platelet transfusion. | Cycle 1, 28 days | 
| Number of Participants With Treatment-emergent Adverse Events (AEs) | Adverse events (AEs) were graded using 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 are those considered related to at least 1 study drug by the investigator. | From first dose of any study treatment to 30 days after last dose; median duration of treatment was 29.1, 12.4, 11.3, 66.6, 7.8, and 46.4 weeks in each treatment group, respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Oprozomib Concentration | Plasma samples for oprozomib concentration assays were only collected for participants in the 5/14 dosing schedule groups. Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. | Cycle 1 day 1 at 1 to 2.5 hours and 2.75 to 5 hours after end of infusion (EOI) and cycle 3 day 1 at predose and 1 to 2.5 hours and 2.75 to 5 hours after EOI. | 
| 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 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 SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and <5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). | Disease response was assessed every 4 weeks for 24 cycles then every 8 weeks until end of treatment; median duration of treatment at the analysis cutoff date of 18 July 2016 was 29.1, 12.4, 11.3, 66.6, 7.8 and 46.4 weeks in each group, respectively | 
| Duration of Response (DOR) | Duration of response was defined as the time from first evidence of partial response (PR) or better to confirmation of disease progression or death due to any cause. Median DOR was estimated using Kaplan-Meier methods. Participants who started a new anticancer therapy before documentation of disease progression or death, or who were alive without documentation of disease progression before the data cut-off date or who died or had disease progression immediately after more than 1 consecutively missed disease assessment visit were censored at the date of last disease assessment. | Disease response was assessed every 4 weeks for 24 cycles then every 8 weeks until end of treatment; median time on follow-up at the analysis cut-off date of 18 July 2016 was 14.1, 3.5, 2.6, 16.0, 3.6, and 11.2 months in each group, respectively. | 
| Progression-Free Survival (PFS) | Progression-free survival is defined as the time from the start of treatment to disease progression or death (due to any cause), whichever occurred first. Median PFS was estimated using Kaplan-Meier methods. Participants who started a new anticancer therapy before documentation of disease progression or death, or who were alive without documentation of disease progression before the data cut-off date or who died or had disease progression immediately after more than 1 consecutively missed disease assessment visit were censored at the date of last disease assessment. | From first dose of study drug through the data cut-off date of 18 July 2016; median time on follow-up was 14.1, 3.5, 2.6, 16.0, 3.6, and 11.2 months in each group, respectively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, proteasome inhibitor, oprozomib, orpozomib tablets