Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma (INTREPID-1)

(INTREPID-1) A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of Oprozomib in Combination With Pomalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

A study evaluating two new formulations of oprozomib plus pomalidomide and dexamethasone in participants with relapsed refractory multiple myeloma.

Study Overview

• Status: Completed
• Conditions: Relapsed or Refractory Multiple Myeloma
• Intervention / Treatment: Drug: Dexamethasone; Drug: Immediate Release (IR) Formulation; Drug: Gastro-Retentive (GR) Formulation; Drug: Pomalidomide

Detailed Description

A multicenter, non-randomized, open-label, dose-exploration study evaluating two new formulations of oprozomib plus pomalidomide and dexamethasone in participants with relapsed refractory multiple myeloma. The study will be conducted in two parts. Part 1 will evaluate the formulations of oprozomib in combination with dexamethasone only. Part 2 will evaluate the formulations of oprozomib administered at increasing dose levels (dose escalation) in combination with pomalidomide and dexamethasone.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Research Site
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Research Site
    • Perth, Western Australia, Australia, 6000
      • Research Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C1
      • Research Site
• Spain
  • Castilla León
    • Salamanca, Castilla León, Spain, 37007
      • Research Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Research Site
• United States
  • California
    • West Hollywood, California, United States, 90069
      • Research Site
  • Florida
    • Tampa, Florida, United States, 33612
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637-6613
      • Research Site
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Research Site
  • New York
    • New York, New York, United States, 10021
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Research Site
  • Ohio
    • Canton, Ohio, United States, 44718
      • Research Site
    • Cleveland, Ohio, United States, 44195
      • Research Site
  • Texas
    • San Antonio, Texas, United States, 78229
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Participant must have a pathologically documented, definitively diagnosed, multiple myeloma relapse, or refractory progressive disease after at least 2 lines of therapy for multiple myeloma. Prior therapeutic treatment or regimens must include a proteasome inhibitor and lenalidomide.
• Participant must be willing and able to undergo bone marrow aspirate per protocol (with or without bone marrow biopsy per institutional guidelines).
• Measurable disease (assessed within 28 days prior to day 1).
• Eastern Cooperative Oncology Group (ECOG) performance status of <= 2.
• Other Inclusion Criteria May Apply

Exclusion Criteria

• Currently receiving treatment in another investigational device or drug study, or less than 28 days or 5 half-lives whichever is shorter since ending treatment on another investigational device or drug study(s).
• Previously received an allogeneic stem cell transplant and the occurrence of one or more of the following: received the transplant within 6 months prior to study day 1; received immunosuppressive therapy within the last 3 months prior to study day 1; having signs or symptoms of acute or chronic graft-versus-host disease.
• Autologous stem cell transplant < 90 days prior to study day 1.
• Multiple myeloma with IgM subtype.
• POEM syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
• Plasma cell leukemia (> 2.0 X10^9/L circulating plasma cells by standard differential).
• Waldenstrom's macroglobulinemia.
• Other Exclusion Criteria May Apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Oprozomib Immediate-release (IR) + Dexamethasone; Oprozomib IR plus dexamethasone	Drug: Dexamethasone; Dexamethasone; Drug: Immediate Release (IR) Formulation; Immediate Release (IR) Formulation
Experimental: Part 1 Oprozomib Gastro-retentive (GR) + Dexamethasone; Oprozomib GR plus dexamethasone	Drug: Dexamethasone; Dexamethasone; Drug: Gastro-Retentive (GR) Formulation; Gastro-Retentive (GR) Formulation
Experimental: Part 2 Oprozomib IR + Pomalidomide + Dexamethasone; Oprozomib IR plus pomalidomide and dexamethasone	Drug: Dexamethasone; Dexamethasone; Drug: Immediate Release (IR) Formulation; Immediate Release (IR) Formulation; Drug: Pomalidomide; Pomalidomide
Experimental: Part 2 Oprozomib GR + Pomalidomide + Dexamethasone; Oprozomib GR plus pomalidomide and dexamethasone	Drug: Dexamethasone; Dexamethasone; Drug: Gastro-Retentive (GR) Formulation; Gastro-Retentive (GR) Formulation; Drug: Pomalidomide; Pomalidomide
Experimental: Open-label Roll-over; Oprozomib GR monotherapy, or oprozomib GR plus dexamethasone	Drug: Dexamethasone; Dexamethasone; Drug: Gastro-Retentive (GR) Formulation; Gastro-Retentive (GR) Formulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Dose-Limiting Toxcity (DLT)	DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and included the below, if judged by the investigator/medical monitor to be possibly related to study treatment: Non-hematologic DLTs were any ≥ Grade 3 toxicity, except: Grade 3 asymptomatic electrolyte abnormalities (except hypophosphatemia > 24 hours); Grade 3 nausea, vomiting and diarrhea < 3 days; Grade 3 fatigue < 14 days; ≥ Grade 3 hyperglycemia/toxicity due to dexamethasone; ≥ Grade 3 rash due to pomalidomide. Hematologic DLTs included: Grade 4 neutropenia if absolute neutrophil count < 0.5 x 10^9/L ≥ 7 days; febrile neutropenia; Grade 4 thrombocytopenia ≥ 7 days; Grade ≥ 3 with ≥ Grade 2 bleeding/requiring platelet transfusion.	Day 1 to day 28 of cycle 1, where each cycle was 28 days
Maximum Tolerated Dose (MTD) of Each Formulation of Oprozomib in Combination With Pomolidomide and Dexamethasone	The MTD was the dose with the highest posterior probability of having a DLT rate within the target toxicity interval (15% to 25%), while the posterior probability of excessive/unacceptable toxicity (>25% to 100%) is <40%. DLTs were graded using CTCAE version 4.03 and included the below, if judged by the investigator/medical monitor to be possibly related to study treatment: Non-hematologic DLTs were any ≥ Grade 3 toxicity, except: Grade 3 asymptomatic electrolyte abnormalities (except hypophosphatemia > 24 hours); Grade 3 nausea, vomiting and diarrhea < 3 days; Grade 3 fatigue < 14 days; ≥ Grade 3 hyperglycemia/toxicity due to dexamethasone; ≥ Grade 3 rash due to pomalidomide. Hematologic DLTs included: Grade 4 neutropenia if absolute neutrophil count < 0.5 x 10^9/L ≥ 7 days; febrile neutropenia; Grade 4 thrombocytopenia ≥ 7 days; Grade ≥ 3 with ≥ Grade 2 bleeding/requiring platelet transfusion.	Day 1 to Day 28 of cycle 1, where each cycle was 28 days
Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Oprozomib in Combination With Dexamethasone and/or Pomalidomide)	An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. TEAEs were any AE that started on or after receiving the first dose of investigational product and up to and including 30 days after the last dose of investigational product or the end of study date, whichever is earlier. Treatment-related TEAEs were those considered related to study treatment by the investigator. Any clinically significant changes in electrocardiograms, vital signs, physical examination with a neurological assessment and clinical laboratory tests were recorded as TEAEs.	Day 1 of cycle 1 to 30 (+7) days after the last dose of study treatment or end of study date, whichever is earlier (where each cycle was 28 days). Median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks
Number of Participants With TEAEs and Treatment-emergent Serious AEs (Open-label Roll-over)	TEAEs were any AE that started on or after receiving the first dose of investigational product and up to and including 30 days after the last dose of investigational product or the end of study date, whichever is earlier. Treatment-related TEAEs were those considered related to study treatment by the investigator. Serious TEAEs were any AE meeting at least 1 of the following criteria: fatal; life-threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event.	Day 1 to 30 (+7) days after the last dose of study treatment or end of study date, whichever is earlier (where each cycle was 28 days). Median treatment duration for the open-label roll-over arm was 75.14 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Concentration (Cmax) of Oprozomib	The mean Cmax of oprozomib is presented following dosing on cycle 1 day 8 and cycle 1 day 22 for the IR and GR oprozomib formulations.	Cycle 1 days 8 and 22: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose. GR only: cycle 1 day 8: 8 hours post-dose
Time to Cmax (Tmax) of Oprozomib	The median Tmax of oprozomib is presented following dosing on cycle 1 day 8 and cycle 1 day 22 for the IR and GR oprozomib formulations.	Cycle 1 days 8 and 22: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose. GR only: cycle 1 day 8: 8 hours post-dose
Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Oprozomib	The mean AUClast of oprozomib is presented following dosing on cycle 1 day 8 and cycle 1 day 22 for the IR and GR oprozomib formulations.	Cycle 1 days 8 and 22: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose. GR only: cycle 1 day 8: 8 hours post-dose
Best Overall Response (BOR) According to Revised International Myeloma Working Group Uniform Response Criteria (IMWG-URC)	BOR was the best response per IMWG-URC from best to worst: stringent complete response (sCR; complete response [CR], normal serum free light chain ratio, no clonal cells in bone marrow [BM]), CR (negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, < 5% plasma cells in BM), very good partial response (VGPR; serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein [urine M-protein level < 100 mg/24-h]), partial response (PR; ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or < 200 mg/24-h), minimal response (MR; 25-49% reduction of serum M-protein and 50-89% in 24-h urinary M-protein, exceeding 200 mg/24-h), stable disease (SD; not CR, VGPR, PR or progressive disease [PD]), and PD (≥ 25% increase in serum or urine M-component, development of new or increased size of existing bone lesions or soft tissue plasmacytomas, hypercalcemia attributed to the plasma cell proliferative disorder).	Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks
Overall Response Rate (ORR) According to IMWG-URC	The ORR was defined as the percentage of participants with a BOR of sCR, CR, VGPR, and PR per the IMWG-URC. Complete response (CR): Negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, < 5% plasma cells in bone marrow (BM). Stringent CR (sCR): CR and normal serum free light chain ratio and no clonal cells in BM. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level < 100 mg/24-h). PR: ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or to < 200 mg/24-h. The 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method.	Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks
Number of Participants With Progression Free Survival (PFS) Events	PFS was defined as the number of months from a participant's first dose of study treatment to the earlier of disease progression or death due to any cause. The number of participants who had a PFS event or who were censored are presented. PFS events were an assessment of progressive disease according to the IMWG-URC or death due to any cause. PFS data was censored: participants alive and no documented disease progression at time of analysis were censored at date of last disease assessment; participants alive with no disease assessment were censored at the first study dose date; participants alive without documented disease progression, with withdrawn consent were censored at date of last disease assessment before consent withdrawal; and for participants who started anti-cancer therapy other than study treatment prior to documentation of disease progression were censored at date of last disease assessment prior to starting new therapy.	Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks
Kaplan-Meier Estimate of PFS	PFS was defined as the number of months from a participant's first dose of study treatment to the earlier of disease progression or death due to any cause. Median PFS was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. PFS data was censored: participants alive and no documented disease progression at time of analysis were censored at date of last disease assessment; participants alive with no disease assessment were censored at the first study dose date; participants alive without documented disease progression, with withdrawn consent were censored at date of last disease assessment before consent withdrawal; and for participants who started anti-cancer therapy other than study treatment prior to documentation of disease progression were censored at date of last disease assessment prior to starting new therapy.	Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks
Kaplan-Meier Estimate of Duration of Response (DOR)	DOR, presented in months, was defined as the number of days between the date of the first tumor assessment indicating an objective response (PR or better) through to the subsequent date of progression or death due to any cause, or where applicable date of censoring (date of first progressive disease assessment or death or date of censoring - date of the first objective response result + 1/30.4). Median PFS was estimated using the Kaplan-Meier method. 95% confidence intervals were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.	Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2017
• Primary Completion (Actual): October 6, 2022
• Study Completion (Actual): October 6, 2022

Study Registration Dates

• First Submitted: October 18, 2016
• First Submitted That Met QC Criteria: October 18, 2016
• First Posted (Estimated): October 19, 2016

Study Record Updates

• Last Update Posted (Actual): September 26, 2024
• Last Update Submitted That Met QC Criteria: September 20, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Multiple Myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Pomalidomide
• Other Study ID Numbers: 20160104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR