The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.
The drug being tested in this study is called MLN2480 (TAK-580). MLN2480 was tested to evaluate side effects and determine the maximum tolerated dose (MTD) and recommended dose for future studies when administered in combination with five other medications. This study was to assess the safety of MLN2480 as well as how it is processed by the body in participants with solid nonhematologic malignancies who have failed standard therapies. The study was to be conducted in two phases, the dose escalation phase and the dose expansion phase. A total of 71 participants were enrolled in the escalation phase. Participants in this phase were assigned to one of the five treatment groups: * MLN2480 + MLN0128 * MLN2480 + Alisertib * MLN2480 + Paclitaxel * MLN2480 + Cetuximab * MLN2480 + Irinotecan Once the MTD for each combination treatment arm was established in the escalation phase, one or more of the combination treatments will be selected for the expansion phase. A total of 10 participants were enrolled in the expansion phase. This multi-centre trial was be conducted worldwide. The overall time to participate in this study is approximately 14 months. Participants made multiple visits to the clinic including an end of study visit 30 days after last dose of study drug for a follow-up assessment.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
81
MLN2480 tablets.
MLN0128 capsules.
Alisertib tablets.
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Dana Farber Cancer Institute
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.
Time frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)
Number of Participants With Dose-Limiting Toxicities (DLTs)
DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia \<7 days duration; Grade 3 or 4 neutropenia with fever \>38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.
Time frame: From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)
Maximum Tolerated Dose (MTD) for MLN2480
Time frame: Day 1, Cycle 1 up to 28 days
Recommended Phase 2 Dose (RP2D) of MLN2480
Time frame: Day 1, Cycle 1 up to 28 days
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Paclitaxel IV infusion.
Cetuximab IV infusion.
Irinotecan IV infusion.
Boston, Massachusetts, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Institut Bergonie
Bordeaux, Gironde, France
Institut Claudius Regaud-Oncopole
Toulouse, Haute Garonne, France
Institut Gustave Roussy
Villejuif, Val De Marne, France
Hospital Universitari Vall d'Hebron
Barcelona, Spain
START Madrid. Fundacion Jimenez Diaz
Madrid, Spain
...and 4 more locations
Cmax : Maximum Observed Plasma Concentration for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Terminal Elimination Half-life (T1/2) for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Time frame: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)
Duration of Response
Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.
Time frame: From first documented response until disease progression (Up to 13 months)
Time to Response
Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.
Time frame: From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)
Progression Free Survival (PFS)
PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)