Clinical trial NCT01999335: A Study of Oprozomib, Pomalidomide, and Dexamethasone in Adults With Primary Refractory or Relapsed and Refractory Multiple Myeloma
Official title: Phase 1b/3 Multicenter Study of Oprozomib, Pomalidomide, and Dexamethasone in Primary Refractory or Relapsed and Refractory Multiple Myeloma Subjects
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Multiple Myeloma
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2013-12-03
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Key Inclusion Criteria:

1. Multiple myeloma that is primary refractory or relapsed and refractory after at least 2 lines of standard for multiple myeloma including:

   1. ≥ 2 consecutive cycles of both bortezomib and lenalidomide or thalidomide (alone or in combination)
   2. 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
2. Disease progression on or within 60 days of completion of the last therapy
3. Measurable disease as indicated by 1 or more of the following:

   1. Serum M-protein ≥ 500 mg/dL
   2. Urine M-protein ≥ 200 mg/24 h
   3. 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
4. Males and females ≥ 18 years old
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

Key Exclusion Criteria:

1. 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
2. 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.
3. Radiation therapy within 3 weeks before first dose. Radioimmunotherapy within 8 weeks before first dose.
4. 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
5. 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).
6. Known hypersensitivity to any immunomodulatory drugs (IMiDs), including Grade 4 rash
7. Prior treatment of any duration with pomalidomide
8. Known hypersensitivity or intolerance to dexamethasone
9. Prior exposure to oprozomib
10. 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.

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1, 28 days
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: 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.
measure: Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities
timeFrame: 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 outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 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.
measure: Clinical Benefit Rate (CBR)
timeFrame: 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.
measure: Maximum Plasma Concentration (Cmax) of Oprozomib
timeFrame: 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.
measure: Time to Maximum Plasma Concentration (Tmax) of Oprozomib
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib
timeFrame: 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.
Other outcomes:
Locations:
city: Encinitas
country: United States
facility: California Cancer Associates For Research and Exellence, cCare
state: California
city: West Hollywood
country: United States
facility: James R. Berenson, MD, Inc.
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Omaha
country: United States
facility: Oncology Hematology West PC, dba Nebraska Cancer Specialists
state: Nebraska
city: New York
country: United States
facility: Weill Cornell Medical College-New York Presbyterian Hospital
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Springfield
country: United States
facility: Willamette Valley Cancer Institute and Research Center
state: Oregon
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania at Perelman Center for Advanced Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC / Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas-HOAST
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Yakima
country: United States
facility: Yakima Valley Memorial Hospital/North Star Lodge
state: Washington
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: