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

Multiple Myeloma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01881789
• Other study ID #: OPZ003
• Secondary ID: 20130410
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: October 28, 2013
• Est. completion date: September 23, 2019

Study information

• Verified date: November 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 22
• Est. completion date: September 23, 2019
• Est. primary completion date: September 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Oprozomib
Extended release (ER) tablets administered orally
• Lenalidomide
Administered orally at a dose of 25 mg on days 1 through 21 of each 28-day cycle for a maximum of 24 cycles.
• Dexamethasone
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.
• Cyclophosphamide
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).

Locations

Country	Name	City	State
United States	Center for Cancer & Blood Disorders	Bethesda	Maryland
United States	Providence St. Joseph's Hospital	Burbank	California
United States	The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	University of Texas M.D. Anderson Cancer Center	Houston	Texas
United States	Clearview Cancer Institute	Huntsville	Alabama
United States	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	Froedtert Hospital and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Monterey Bay Oncology Corp DBA Pacific Cancer Care	Salinas	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	H. Lee Moffit Cancer Center & Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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.
Secondary	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
Secondary	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.
Secondary	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

External Links

•   AmgenTrials clinical trials website