Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

NCT01832727 | Terminated Phase 1 Results FDA Drug

• 3 other identifiers: 2012-001201304082013-001169-18
• Study Type: interventional
• Target: 65
• Locations: 2 countries
• Sites: 13

Brief Summary

The primary objectives are: Phase 1b:

• To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oprozomib given orally, once daily, on 2 different schedules.
• To evaluate safety and tolerability Phase 2:
• To estimate the overall response rate (ORR).
• To evaluate safety and tolerability

Conditions

Multiple Myeloma

Keywords

multiple myeloma; oprozomib; OPZ; ONX 0912; Onyx; proteasome inhibitor; oprozomib tablets

Outcome Measures

Primary Outcomes (5)

• Participants With Dose-Limiting Toxicities (DLT)

  Toxicities (graded per the Common Terminology Criteria for Adverse Events v 4.03) were considered DLTs if judged by the investigator to be related to oprozomib and occurred in the first 14 days of treatment, with treatment at the dose to be studied (i.e., Cycle 1 for continuous dosing or Cycle 2 for step-up dosing). A DLT was categorized as nonhematologic or hematologic. Examples include: * Any ≥ Grade 3 nonhematologic AE, with exceptions or qualifications such as Grade 3 nausea, vomiting, diarrhea, or constipation were considered a DLT only if lasting for \> 7 days despite optimal supportive care * Grade 3 fatigue lasting \> 14 days * Grade 4 neutropenia: absolute neutrophil count (ANC) \< 500 cells/mcL lasting ≥ 7 days * Febrile neutropenia: Any single temperature ≥ 38.3°C or a sustained temperature of ≥ 38.0°C for over 1 hour with ≥ Grade 3 neutropenia (ANC \< 1000 cells/mcL) * Grade 3/4 thrombocytopenia * Others specified in the protocol

  Day 1 to Day 14 (Cycle 1) for continous dosing and Day 15 to Day 28 (Cycle 2) for step-up dosing

• Participants With Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2

  AE defined as any untoward medical occurrence in a clinical trial participant. Treatment-emergent adverse events were defined as adverse events that start on or after the first day of study treatment and within 30 days of the last day of study treatment. An adverse event that was present before the first administration of study treatment and subsequently worsens in severity during treatment was also considered to be treatment-emergent. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. IP=investigational product

  Day 1 up to Week 282

• Participants With Treatment-Related, Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2

  AE defined as any untoward medical occurrence in a clinical trial participant. TEAEs were defined as AEs that start on or after the first day of study treatment and within 30 days of the last day of study treatment. An AE that was present before the first administration of study treatment and subsequently worsens in severity during treatment was also considered a TEAE. Investigator assessed AEs for relatedness to study drug. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. IP=investigational product

  Day 1 up to Week 282

• Best Overall Response in Phase 2 as Assessed by Investigator

  Disease response and progression were determined using the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC), except for minimal response (MR) and near complete response (nCR) which was based on the European Group for Blood and Marrow Transplantation (EBMT) criteria. Evaluations reported were assessed by the investigator for participants in Phase 2.

  Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months

• Percentage of Participants Who Achieved an Overall Response As Assessed by Investigator During Phase 2

  The overall response rate (ORR) was defined as the percentage of participants with the best overall response of stringent complete response (sCR), complete response (CR), near complete response (nCR), very good partial response (VGPR), and partial response (PR) as defined by the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) and modified European Group for Blood and Marrow Transplantation (EBMT) criteria.

  Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months

Secondary Outcomes (11)

• Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Time to Maximum Serum Concentration (Tmax) on Cycle 1, Day 1

  Day 1

• Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Maximum Serum Concentration (Cmax) on Cycle 1, Day 1

  Day 1

• Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Area Under the Curve at the Last Measurable Time Point (AUClast) on Cycle 1, Day 1

  Day 1

• Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Area Under the Curve From Time 0 to Time Infinity (AUCinf) on Cycle 1, Day 1

  Day 1

• Pharmacokinetic (PK) Parameter for Oprozomib, Tablet and ER Formulation: Terminal Half-Life (t1/2,z) on Cycle 1, Day 1

  Day 1

Study Arms (9)

Cohort 180 mg 5/14 Schedule (Phase 1b)

EXPERIMENTAL

Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

Drug: Oprozomib; Drug: Dexamethasone

Cohort 210 mg 5/14 Schedule (Phase 1b)

EXPERIMENTAL

Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

Drug: Oprozomib; Drug: Dexamethasone

Cohort 150/180 mg 5/14 Schedule (Phase 1b)

EXPERIMENTAL

Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

Drug: Oprozomib; Drug: Dexamethasone

Cohort 210 mg 2/7 Schedule (Phase 1b)

EXPERIMENTAL

Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

Drug: Oprozomib; Drug: Dexamethasone

Cohort 240 mg 2/7 Schedule (Phase 1b)

EXPERIMENTAL

Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

Drug: Oprozomib; Drug: Dexamethasone

Cohort 270 mg 2/7 Schedule (Phase 1b)

EXPERIMENTAL

Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

Drug: Oprozomib; Drug: Dexamethasone

Cohort 300 mg 2/7 Schedule (Phase 1b)

EXPERIMENTAL

Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

Drug: Oprozomib; Drug: Dexamethasone

Cohort 330 mg 2/7 Schedule (Phase 1b)

EXPERIMENTAL

Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

Drug: Oprozomib; Drug: Dexamethasone

Phase 2 300 mg 2/7 Schedule

EXPERIMENTAL

The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

Drug: Oprozomib; Drug: Dexamethasone

Interventions

Oprozomib DRUG

Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

Also known as: OPZ, ONX 0912, oprozomib ER

Cohort 150/180 mg 5/14 Schedule (Phase 1b); Cohort 180 mg 5/14 Schedule (Phase 1b); Cohort 210 mg 2/7 Schedule (Phase 1b); Cohort 210 mg 5/14 Schedule (Phase 1b); Cohort 240 mg 2/7 Schedule (Phase 1b); Cohort 270 mg 2/7 Schedule (Phase 1b); Cohort 300 mg 2/7 Schedule (Phase 1b); Cohort 330 mg 2/7 Schedule (Phase 1b); Phase 2 300 mg 2/7 Schedule

Dexamethasone DRUG

Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

Cohort 150/180 mg 5/14 Schedule (Phase 1b); Cohort 180 mg 5/14 Schedule (Phase 1b); Cohort 210 mg 2/7 Schedule (Phase 1b); Cohort 210 mg 5/14 Schedule (Phase 1b); Cohort 240 mg 2/7 Schedule (Phase 1b); Cohort 270 mg 2/7 Schedule (Phase 1b); Cohort 300 mg 2/7 Schedule (Phase 1b); Cohort 330 mg 2/7 Schedule (Phase 1b); Phase 2 300 mg 2/7 Schedule

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of multiple myeloma with measureable disease as indicated by 1 or more of the following:
• a. Serum M-protein ≥ 500 mg/dL
• b. Urine M-protein ≥ 200 mg/24 hours
• c. Only for subjects without measurable serum and urine M-protein, serum free light chain: Involved free light chain (FLC) level ≥ 10 mg/dL, provided serum FLC ratio is abnormal
• Patients requiring therapy who have relapsed and/or are refractory to their last therapy and have been treated with at least 1, but not more than 5, lines of multiple myeloma therapy. Prior therapy must have consisted of at least 1 regimen that included lenalidomide and/or bortezomib. Patients should be considered to be appropriate candidates for a clinical study by their treating physicians. Relapsed patients must have previously achieved ≥ minimal response (MR) on at least 1 line of therapy, as assessed by the treating physician. Refractory patients are allowed, but it is not required that patients be refractory to their last therapy. Primary refractory patients are allowed in the Phase 1b portion of the study only.
• Males and females ≥ 18 years of age
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2
• Adequate hepatic function, with bilirubin ≤ 1.5 times the upper limit of normal (ULN) in the absence of Gilbert's disease or hemolysis, aspartate aminotransferase (AST) ≤ 3 times ULN, and alanine aminotransferase (ALT) ≤ 3 times ULN
• Absolute neutrophil count (ANC) ≥ 1000 cells/mcL, hemoglobin ≥ 7.0 g/dL, and platelet count ≥ 30,000 cells/mcL:
• a. Patients must not have received platelet transfusions for at least 1 week prior to Screening.
• b. Screening ANC must be independent of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for
• ≥ 2 weeks prior to first dose.
• c. Patients may receive red blood cell (RBC) transfusions or receive supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines.
• Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault (\[140 - Age\] \* Mass (kg) / \[72 \* creatinine mg/mL\]). Multiply result by 0.85 if female.
• Uric acid, if elevated, must be corrected to within laboratory normal range before dosing.

You may not qualify if:

• Radiation therapy within 2 weeks prior to first dose; localized radiation therapy within 1 week prior to first dose
• Immunotherapy/standard myeloma therapy within 2 weeks prior to first dose (except for antibody therapy, where 6 weeks are required, and alkylator therapy, where 3 weeks are 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-versus-host disease (GvHD).
• 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 Screening period, this patient will be considered ineligible and should not be enrolled.
• Glucocorticoid therapy within 14 days prior to enrollment that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent
• Participation in an investigational therapeutic study within 3 weeks prior to first dose
• Prior oprozomib exposure
• Known hypersensitivity/toxicity or intolerance to dexamethasone
• Major surgery within 3 weeks prior to first dose
• Congestive heart failure (\[CHF\] New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to first dose
• Uncontrolled hypertension or uncontrolled diabetes
• Active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to first dose
• Known or suspected human immunodeficiency virus (HIV) infection or patients who are HIV seropositive
• Active hepatitis A, B, or C infection
• History of previous clinically significant GI bleed in the last 6 months prior to first dose
• Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose

Sponsors & Collaborators

• Amgen: lead

Study Sites (13)

USC/Norris Comprehensive Cancer Center

Los Angeles, California, United States

Location

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, United States

Location

University of Kansas Cancer Center and Medical Pavilion

Westwood, Kansas, United States

Location

Center for Cancer and Blood Disorders

Bethesda, Maryland, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, United States

Location

Division of Hematology/ Oncology, UNC at Chapel Hill

Chapel Hill, North Carolina, United States

Location

Gabrail Cancer Center Research

Canton, Ohio, United States

Location

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Location

CHRU, Hopital Huriez - Department of Hematology

Lille, France

Location

CHU Hotel Dieu - Service d'Hematologie Clinique

Nantes, France

Location

CHU de NANCY - Hopital de BRABOlS

Vandœuvre-lès-Nancy, France

Location

Related Publications (1)

• Hari P, Paba-Prada CE, Voorhees PM, Frye J, Chang YL, Moreau P, Zonder J, Boccia R, Shain KH. Efficacy and safety results from a phase 1b/2, multicenter, open-label study of oprozomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Leuk Res. 2019 Aug;83:106172. doi: 10.1016/j.leukres.2019.106172. Epub 2019 Jun 17.

  PMID: 31229804 RESULT

MeSH Terms

Conditions

Multiple Myeloma

Interventions

ONX 0912; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Study Director
• Organization: Amgen, Inc

medinfo@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2013
• First Posted: April 16, 2013
• Study Start: July 2, 2013
• Primary Completion: June 25, 2019
• Study Completion: June 25, 2019
• Last Updated: July 13, 2020
• Results First Posted: July 13, 2020

Record last verified: 2020-06

Locations

US (10); FR (3)