Open-label Study of the Safety and Activity of Oprozomib in Patients With Hematologic Malignancies

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose (MTD), activity, and safety of oprozomib in patients with hematologic malignancies.

Official Title
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Phase 1b/2, Multicenter, Open-label Study of the Safety and Activity of Oprozomib in Patients With Hematologic Malignancies

Conditions
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Multiple Myeloma, Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: oprozomib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Phase 1b Histologically confirmed diagnosis of a hematologic malignancy, excluding patients with acute leukemia or MDS. Relapsed after standard therapy for their malignancy and considered to be an appropriate candidate for a Phase 1 clinical study by their treating physician. Phase 2 Multiple myeloma with measurable disease Waldenström macroglobulinemia with symptomatic relapse Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2. Ethical/Other Patients must sign a written informed consent form in accordance with federal, local, and institutional guidelines. Female patients of childbearing potential must have a negative serum or urine pregnancy test and agree to use effective contraception. Male patients must use an effective barrier method of contraception. EXCLUSION CRITERIA: Chemotherapy with approved or investigational anticancer therapeutics, including steroid therapy intended to treat underlying malignancy, within 3 weeks prior to first dose or 6 weeks for antibody therapy. Radiation therapy within 3 weeks prior to first dose. Radioimmunotherapy within 8 weeks prior to first dose. Localized radiation therapy within 1 week prior to first dose. Immunotherapy within 3 weeks prior to first dose (except for antibody therapy, where 6 weeks is required). Prior stem cell transplant (SCT) therapy (autologous SCT within the prior 8 weeks; allogeneic SCT within the prior 16 weeks). Patients with prior allogeneic SCT should not have evidence of moderate-to-severe graft-vs-host disease (GvHD; as defined in Filipovich 2005). Evidence of central nervous system (CNS) lymphoma. Prior treatment with carfilzomib unless in the phase 2. Major surgery within 3 weeks prior to first dose. Symptomatic Congestive heart failure, ischemia, conduction abnormalities, or myocardial infarction within 6 months. Acute active infection requiring systemic antibiotics, antivirals, or antifungals. Known or suspected human immunodeficiency virus (HIV) infection or patients who are HIV seropositive. Active hepatitis A, B, or C infection. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose. Patients with pleural effusions requiring routine thoracentesis or ascites requiring routine paracentesis. History of previous clinically significant GI bleed in the last 6 months prior to first dose. Female patients who are pregnant or lactating.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QDx2 Dosing Schedule<br>QDx2 is defined as patients receiving Oprozomib Tablets once daily on Days 1, 2, 8, and 9 of the 14-day cycle. The schedule will be evaluated in Phase 1 for MTD in patients with hematologic malignancies, and will also be evaluated in Phase 2 for ORR in patients with MM and WM. | Drug: oprozomib<br>* Patients enrolled will receive Oprozomib Tablets once daily either on Days 1-5 (QDx5 schedule) or on Days 1, 2, 8, and 9 (QDx2 weekly schedule) of the 14-day treatment cycle.<br>|
| Experimental: QDx5 Dosing Schedule<br>QDx5 is defined as patients receiving Oprozomib Tablets once daily on Days 1 to 5 of the 14-day cycle. The schedule will be evaluated in Phase 1 for MTD in patients with hematologic malignancies, and will also be evaluated in Phase 2 for ORR in patients with MM and WM. | Drug: oprozomib<br>* Patients enrolled will receive Oprozomib Tablets once daily either on Days 1-5 (QDx5 schedule) or on Days 1, 2, 8, and 9 (QDx2 weekly schedule) of the 14-day treatment cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the MTD (Phase 1) and ORR (Phase 2). | Phase 1- Determine Maximum Tolerated Dose (MTD) with 3 + 3 Dose Escalation Cohorts in patients hematologic malignancies. Phase 2- The Phase 2 portion of this trial will enroll patients with Multiple Myeloma (MM) and Waldenstrom Macroglobulinemia (WM) into separate arms to assess activity of oprozomib in these patient groups. The purpose of the Phase 2 portion of the study is to estimate the best ORR (for each group separately). | 6 weeks to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the duration of response (DOR) | Duration of Response is defined as the time from first evidence of partial response (PR) or better to confirmation of disease progression or death due to any cause. | 64 months | 
| Estimate the clinical benefit response (CBR) | CBR is defined as Overall Response Rate (ORR) plus Minimal Response (MR) of oprozomib in patients with multiple myeloma (MM) | 64 months | 
| Estimate the major response for Waldenström macroglobulinemia (WM) | Major response for WM subjects is defined as Complete Response (CR) plus Very Good Partial Response (VGPR) plus Partial Response (PR). Major response to be equal or greater than (PR) | 64 months | 
| Evaluate progression-free survival (PFS) for multiple myeloma (MM) subjects | Progression-Free Survival is defined as the time from the start of treatment to disease progression or death (due to any cause), whichever comes first | 64 months | 
| Evaluate the PFS for Waldenström macroglobulinemia (WM) subjects | Progression-Free Survival is defined as the time from the start of treatment to disease progression or death (due to any cause), whichever comes first | 64 months | 
| PK parameters - maximum plasma concentration (Cmax) | PK analyses to be performed on oprozomib and its metabolite(s) concentrations in order to estimate the maximum observed drug concentration (Cmax) value after oral administration | 55 months | 
| PK parameters - time of maximum plasma concentration (tmax) | PK analyses to be performed on oprozomib and its metabolite(s) concentrations in order to estimate the time to reach Cmax (tmax) | 55 months | 
| PK parameters - plasma concentration-time curve (AUC) | PK analyses to be performed on oprozomib and its metabolite(s) concentrations in order to estimate the area under the plasma concentration-time curve | 55 months | 
| Assess renal elimination of oprozomib and its metabolites (Phase 1b only) | Urine will be collected over 24 hours to assess renal elimination of oprozomib and its metabolites following dosing on Day 1 of Cycle 1 for all patients. | 55 months | 
| Change from Baseline in hematology laboratory results | Assess the change from baseline in hematology panel | 64 months | 
| Change from Baseline in serum chemistry results | Assess the change from baseline in serum chemistry panel | 64 months | 
| Change from Baseline in vital signs | Assess the change from baseline in vital signs including blood pressure, pulse, and temperature | 64 months | 
| Change from Baseline in weight | Assess the change from baseline in weight | 64 months | 
| Evaluate safety of oprozomib in Phase 2 | Safety to be defined by incidence, nature, severity, and relatedness of adverse events (AEs), including all serious adverse events (SAEs) | Until 30 days after the end of study (64 months) | 
| Assess the effect on transfusion/ red blood cell (RBC) growth factor requirements (Phase 2 only) for WM only | Change from Baseline (prior 1 month) transfusion/RBC growth factor requirement in frequency and volume in WM (Phase 2 only) | 64 months | 
| Assess the effect on plasmapheresis requirements (Phase 2 only) for WM only | Change from Baseline (prior 1 month) plasmapheresis requirement in frequency and volume in WM (Phase 2 only) | 64 months | 
| Assess the effect on lymphoplasmacytic cells in the bone marrow (Phase 2 only) for WM only | Change from Baseline in percent of lymphoplasmacytic cells in the bone marrow in WM (Phase 2 only) | 64 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, waldenstrom macroglobulinemia