This study will determine the safety profile, tolerability, and maximum tolerated dose (MTD) and disease response of Ixazomib administered orally in participants with relapsed and/or refractory multiple myeloma.
The drug being tested in this study is ixazomib. Ixazomib is being tested to treat people who have multiple myeloma. This study will look at the safety and efficacy of ixazomib and will enroll approximately 60 participants. Participants will receive ixazomib by oral capsule twice weekly on Days 1, 4, 8, and 11 of a 21-day cycle. The study will consist of a dose escalation phase to determine the MTD, followed by an expansion phase in which participants will be treated at the MTD. This multi-center trial will be conducted in the United States. The overall time to participate in this study is 8 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Ixazomib capsules
H. Lee Moffitt Cancer Center
Tampa, Florida, United States
Emory University
Atlanta, Georgia, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death;is life-threatening;requires inpatient hospitalization or prolongation of present hospitalization;results in persistent or significant disability/incapacity;is a congenital anomaly/birth defect;or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.
Time frame: From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Number of Participants With Clinically Significant Abnormalities Reported as TEAEs
The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis.
Time frame: From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Number of Participants With a TEAE of Peripheral Neuropathy
Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.
Time frame: From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs
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M.D. Anderson Cancer Center
Houston, Texas, United States
The number of participants with any clinically significant changes in vital signs collected throughout the study that were reported as TEAEs. Measurement of vital signs, included oral temperature, blood pressure, and heart rate.
Time frame: From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Maximum Tolerated Dose (MTD) of Ixazomib
MTD was highest dose of Ixazomib, at which \<=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT was defined as any of following considered possibly related to therapy: Grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cell per cubic millimeter \[cells/mm\^3\]) for \>7 days;Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia (platelets \< 25,000/mm\^3) for \>7 days;Grade 3 thrombocytopenia with clinically significant bleeding; platelet count \<10,000/mm\^3; Grade 2 peripheral neuropathy with pain or \>=Grade 3 peripheral neuropathy; \>=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy; Grade 3 QTc prolongation (QTc \>500 millisecond \[msec\]);any \>=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia; or \<1 week Grade 3 fatigue; delay in initiation of the subsequent therapy cycle by \>2 weeks; other \>=Grade 2 study drug-related nonhematologic toxicities requiring therapy discontinuation.
Time frame: Cycle 1 (21 days)
Recommended Phase 2 Dose (RP2D) of Ixazomib
The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic data observed in Cycle 1 and beyond.
Time frame: Cycle 1 through Cycle 39 (Up to 28.3 months)
Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (up to 264 hours) postdose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 72 hours) postdose
λz: Terminal Disposition Phase Rate Constant for Ixazomib
Time frame: Cycle 1, Day 11: predose and at multiple time points (Up to 264 hours) postdose
T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib
Time frame: Cycle 1, Day 11: predose and at multiple time points (up to 264 hours) postdose
CL/F: Blood Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Ixazomib
CL/F is apparent clearance of the drug from the plasma.
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Emax: Maximum Observed Effect for Ixazomib
Emax was determined to characterize the whole blood 20S proteasome inhibition parameters.
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib
TEmax was determined to characterize the whole blood 20S proteasome inhibition parameters.
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Overall Response Rate (ORR)
ORR is defined as percentage of participants with complete response (CR) or partial response (PR) or minimal response (MR) as assessed by the investigator using International Myeloma Working Group Uniform Response criteria. CR=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. PR=≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to \<200 mg /24 h. MR=25-49% reduction in the serum monoclonal paraprotein maintained for a minimum of 6 weeks; 50-89% reduction in 24-h urinary light chain excretion, which still exceeds 200 mg/24 h, maintained for a minimum of 6 weeks; for participants with non-secretory myeloma only, 25-49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed, maintained for a minimum of 6 weeks; 25-49% reduction in the size of soft tissue plasmacytomas; no increase in the size or number of lytic bone lesions.
Time frame: Cycle 1 through Cycle 115 (Up to 80.1 months)