This is an open-label, multicenter, phase 1, dose escalation study of IXAZOMIB. The primary purpose of this study is to determine the safety profile, establish the maximum tolerated dose, and inform the phase 2 dose of IXAZOMIB administered intravenously in participants with nonhematologic malignancies.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
116
All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days. The first stage of the study will be initiated at a starting dose of 0.125 mg/m\^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States
Emory University
Atlanta, Georgia, United States
University of Michigan
Ann Arbor, Michigan, United States
Duke University
Durham, North Carolina, United States
Part 1: Number of Participants With Dose Limiting Toxicity (DLT)
Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. DLT is any of following related to ixazomib:Grade (GR) 4 neutropenia (absolute neutrophil count\<500 cells/cubic meter\[cells/mm\^3\])for\>7 days; GR 3 neutropenia with coincident fever and/or infection; GR 4 thrombocytopenia (platelets \<25,000 cells/mm3)for\>7 days; GR 3 thrombocytopenia with clinically significant bleeding; Platelet count\<10,000 cells/mm3; GR 3 peripheral neuropathy;\>=GR 3 nausea/emesis in absence of optimal antiemetic therapy; \>=GR 3 diarrhoea in absence of optimal supportive therapy;GR 3 QTc prolongation noted on average of 3 electrocardiograms (ECGs);\>=GR 3 nonhematological toxicity except GR 3 arthralgia/myalgia or GR 3 fatigue for\<1 week; Delay in initiation of subsequent therapy cycle by\>7 days due to treatment-related toxicity Other\>=GR 2 nonhematological toxicity that opinion of investigator, requires discontinuation of therapy with Ixazomib.
Time frame: Part 1: Cycle 1 Day 1 up to Cycle 1 Day 21
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Event (SAEs)
Time frame: Part 1: Cycle 1 Day 1 up to Cycle 10 Day 41; Part 2: Cycle 1 Day 1 up to Cycle 12 Day 41
Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities
Time frame: Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41)
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Vital sign measurements included diastolic and systolic blood pressure, heart rate, weight and oral temperature.
Time frame: Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41)
Part 1: AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post-dose for Ixazomib
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Sarah Cannon Research Institute
Nashville, Tennessee, United States
University of Washington- Seattle Cancer Care
Seattle, Washington, United States
Princess Margaret Hospital
Toronto, Ontario, Canada
AUC (0-72) is a measure of the area under the plasma concentration-time curve from time 0 to 72 hours post-dose for ixazomib.
Time frame: Part 1: Cycle 1 Days 1 and 11: pre-dose and at multiple time points (up to 72 hours) post-dose
Part 1: C0: Initial Plasma Concentration After Bolus Intravenous Administration
C0 is the plasma drug concentration at time zero following bolus intravenous injection.
Time frame: Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose
Part 1: Rac: Accumulation Ratio for Ixazomib
Rac was estimated as the ratio of AUC (0-72) on Day 11 and AUC (0-72) on Day 1. AUC (0-72) is the area under the plasma concentration-time curve from time 0 to 72 hours post-dose.
Time frame: Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose
Part 1: Terminal Phase Elimination Half-life (T1/2) for Ixazomib
T1/2 is the time required for half of the drug to be eliminated from the plasma.
Time frame: Part 1: Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose
Part 1: E Max: Maximum Observed Effect for Ixazomib
E max is the maximum inhibition of 20S proteasome activity in whole blood.
Time frame: Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose
Part 1: TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib
TEmax is the time to reach the Emax, equal to time (hours) to Emax.
Time frame: Part 1: Cycle 1 Days 1 and 11 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose
Number of Participants With Best Overall Response
Best overall response for a participant is best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Complete Response (CR): disappearance of all target lesions, non-target lesions and normalization of tumor marker level. Partial Response (PR): at least 30% decrease in sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the baseline smallest sum of longest diameter; persistence of 1 or more non-target lesion(s) or maintenance of tumor marker level above normal limits. Progressive disease: at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions.
Time frame: Day 18 up to Day 21 of each cycle (Part 1: up to Cycle 10; Part 2: up to Cycle 12)
Part 2: Ixazomib Concentration in Postdose Clinical Tumor Samples in Ixazomib 1.76 mg/m^2-TPEC
The average data of Days 1 and 4 of Cycle 1 was reported.
Time frame: Cycle 1 Days 1 and 4: Predose and (from 4-20 hours) post-dose
20S Proteasome Activity of Ixazomib in the Tumor Tissue
Time frame: Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose
Expression of Biomarker (ATF-3) in Tumor Tissue
Time frame: Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose