A Dose Escalation Study of MLN7243 (TAK-243) in Adult Participants With Advanced Solid Tumors
- Registration Number
- NCT02045095
- Lead Sponsor
- Millennium Pharmaceuticals, Inc.
- Brief Summary
The purpose of this study is to evaluate safety and tolerability (establish maximum tolerated dose \[MTD\], inform the recommended phase 2 dose \[RP2D\], and identify the dose-limiting toxicities \[DLTs\]) of MLN7243.
- Detailed Description
This is a single arm Phase I study with multiple dosing cohorts as noted below:
* Schedule A: MLN7243 1 mg
* Schedule A: MLN7243 2 mg
* Schedule A: MLN7243 4 mg
* Schedule A: MLN7243 8 mg
* Schedule A: MLN7243 12 mg
* Schedule A: MLN7243 18 mg
* Schedule A: MLN7243 Homozygous Mutant 4 mg
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 29
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Schedule A: MLN7243 2 mg MLN7243 MLN7243 2 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD, or discontinuation of study for another reason, or until study is stopped. Schedule A: MLN7243 4 mg MLN7243 MLN7243 4 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. Schedule A: MLN7243 Homozygous Mutant 4 mg MLN7243 MLN7243 homozygous mutant 4 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. Schedule A: MLN7243 12 mg MLN7243 MLN7243 12 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. Schedule A: MLN7243 18 mg MLN7243 MLN7243 18 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped. Schedule A: MLN7243 1 mg MLN7243 MLN7243 1 milligram (mg), infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or disease progression (PD) or discontinuation of study for another reason, or until study is stopped. Schedule A: MLN7243 8 mg MLN7243 MLN7243 8 mg, infusion, intravenously over 10-minutes, on Days 1, 4, 8, and 11 followed by 10 days of rest in a 21-day treatment cycle for a maximum of 12 months, or until symptomatic deterioration or PD or discontinuation of study for another reason, or until study is stopped.
- Primary Outcome Measures
Name Time Method Number of Participants With Vital Sign Related TEAEs by Preferred Term (PT) Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) Number of Participants With Laboratory Related TEAEs by System Organ Class (SOC) Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities Cycle 1 Day 1 up to Cycle 1 Day 11 Number of Participants With Clinically Significant Echocardiogram Abnormalities Cycle 1 Day 2 up to 30 days after last dose of study drug (Cycle 10 Day 41) Number of Participants With TEAEs Related to Tropinin I and T Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41) Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Baseline up to 30 days after last dose of study drug (Cycle 10 Day 41)
- Secondary Outcome Measures
Name Time Method CL: Total Clearance After Intravenous Administration for TAK-243 Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose Change From Baseline in Immunohistochemistry (IHC) Biomarkers in Tumor Biopsies at Cycle 1 Day 12 (C1D12) as Assessed by Histological Score (H-score) Baseline and Cycle 1 Day 12 The pharmacodynamics IHC biomarkers included polyubiquitin marker and ubquityl (Ub)-histone H2B marker. H-score was a composite score that comprised of intensity and percentage of staining and was used for assessing the amount of protein or phospho-protein present in a biopsy sample. The composite score obtained by H-score is derived by summing the percentages of cell staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+; where 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). The composite H-score ranges from 0 to 300, with a score of 0 representing the absence of any of the target protein and an H-score of 300 representing maximum staining and intensity of the target protein.
Change From Baseline in IHC Biomarkers in Tumor Biopsies at C1D12 as Assessed by Positive Index Baseline and Cycle 1 Day 12 The pharmacodynamics IHC biomarkers included polyubiquitin marker and Ub-histone H2B marker. Positive index was calculated by taking the number of positive cells over the total number of cells.
Duration of Response Baseline up to end of study (approximately 7 months) Duration of any response (CR or PR) was defined as the time (in both days and months) from the date of first documented response per the investigator response assessment to the date of first progressive disease after the first documented response or, if the participant discontinues treatment, the date of last disease assessment as per RECIST version 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target and non target) must have reduction in short axis to \<10 mm. PR: at least 30% decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter.
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-243 Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose Aet: Amount of TAK-243 Excreted Unchanged in Urine Cycle 1 Day 1; Cycle 1 Day 11 AUCτ: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-243 Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-243 Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose Vss: Volume of Distribution at Steady State for TAK-243 Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose Ceoi: Plasma Concentration at the End of Infusion for TAK-243 Cycle 1 Day 1 and 11: pre-infusion to end of infusion (up to 10 minutes) Fet: Percentage of TAK-243 Excreted Unchanged in Urine Cycle 1 Day 1; Cycle 1 Day 11 Terminal Phase Elimination Half-life (T1/2) for TAK-243 Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose Percentage of Participants With Best Overall Response Baseline up to end of study (approximately 7 months) Best overall response for participant is best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target and non target) must have reduction in short axis to less than (\<) 10 millimeter (mm). Partial Response (PR): at least 30 percent (%) decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameter; PD: at least 20% increase in sum of diameter of target lesions, taking as reference, smallest sum on study (this includes baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least mm. The appearance of 1 or more new lesions is also considered progression.