TAK-981 is being tested in combination with pembrolizumab to treat participants who have select advanced or metastatic solid tumors. The study aims are to evaluate the safety, tolerability, and preliminary efficacy of TAK-981 in combination with pembrolizumab. Participants will be on this combination treatment for 21-day cycles. They will continue with this treatment for up to 24 months or until participants meet any discontinuation criteria.
The drug being tested in this study is called TAK-981. TAK-981 is being tested to treat people who have select advanced or metastatic solid tumors. The study will include a dose escalation phase and a dose expansion phase. The study will enroll approximately 231 participants, approximately 32 participants in the dose escalation phase 1 and approximately 76 to 199 participants in the 8 cohorts of dose expansion phase 2. Participants will receive escalating doses of TAK-981 and fixed dose of pembrolizumab until recommended phase 2 dose (RP2D) is determined: • Dose Escalation: TAK-981 + Pembrolizumab (Fixed Dose) Once Phase 2 doses are identified, participants of select advanced or metastatic solid tumors will receive TAK-981 in below defined cohorts in the expansion phase 2: * Dose Expansion Phase: Cohort A: Non-squamous Non-small Cell Lung Cancer (NSCLC) * Dose Expansion Phase: Cohort B: Cervical Cancer * Dose Expansion Phase: Cohort C: Microsatellite Stable Colorectal Cancer (MSS-CRC) * Dose Expansion Phase: Cohort D: Cutaneous Melanoma * Dose Expansion Phase: Cohort E: Squamous NSCLC * Dose Expansion Phase: Cohort F: Checkpoint Inhibitors (CPI) Refractory Squamous or Nonsquamous NSCLC This multi-center trial will be conducted worldwide. The overall time to participate in this study is 60 months. Participants will make multiple visits to the clinic, and progression-free survival follow-up for maximum up to 12 months after last dose of study drug.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
161
TAK-981 IV infusion.
Pembrolizumab IV infusion.
Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
An adverse event (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. 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. AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 except cytokine release syndrome (CRS), which was graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS.
Time frame: Up to approximately 24 months
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
DLTs were evaluated according to NCI CTCAE Version 5.0 except CRS, which was graded according to ASTCT Consensus Grading for CRS.
Time frame: Up to Cycle 1 (each cycle was of 21 days)
Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)
AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. A severity grade was evaluated as per the NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT Consensus Grading for CRS.
Time frame: Up to approximately 24 months
Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs)
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.
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HonorHealth
Scottsdale, Arizona, United States
University of California Irvine Medical Center
Orange, California, United States
Stanford Cancer Institute (SCI)
Stanford, California, United States
Yale Cancer Center
New Haven, Connecticut, United States
Georgia Cancer Center at Augusta University
Augusta, Georgia, United States
The Center for Cancer and Blood Disorders - PPDS
Bethesda, Maryland, United States
Morristown Medical Center
Morristown, New Jersey, United States
Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Montefiore Einstein Cancer Center - BRANY - PPDS
The Bronx, New York, United States
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
...and 42 more locations
Time frame: Up to approximately 24 months
Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation
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. 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: Up to approximately 24 months
Phase 1: Number of Participants With Clinically Significant Laboratory Values
Laboratory parameters included clinical chemistry, hematology, and urinalysis. Participants with at least 1 Grade 3 or 4 Lab Abnormalities were reported.
Time frame: Up to approximately 24 months
Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1
ORR is defined as the percentage of participants who achieve Complete Response (CR) and Partial Response (PR) (determined by the investigator) during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
Time frame: Up to approximately 25 months
Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phases 1 and 2: Disease Control Rate (DCR)
DCR is defined as the percentage of participants who achieved stable disease (SD) or better (CR + PR + SD determined by the investigator) \>6 weeks during the trial in the response-evaluable population.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Durable Response Rate (DRR)
DRR is defined as the rate of objective responses (CR + PR) maintained for at least 6 months initiating at any time within 12 months of commencing therapy.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Duration of Response (DOR)
DOR is defined as a time from the time of first documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Progression-free Survival (PFS)
PFS is defined as time from the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Time to Response (TTR)
TTR is defined as time from the date of the first dose administration to the date of first documented PR or better.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Time to Progression (TTP)
TTP is defined as the from the date of the first dose administration to the date of the first documentation of PD as defined by standard disease criteria.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phase 2: Overall Survival (OS)
OS is defined as the time from the date of the first dose administration to the date of death. Participants without documentation of death at the time of analysis were censored at the date last known to be alive.
Time frame: Up to approximately 25 months
Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes
The level of TAK-981-SUMO adduct formation was evaluated by flow cytometry as the percentage of adduct formed in peripheral blood lymphocytes. Fold change from baseline was calculated as: Post-treatment value / Baseline value. Positive change denotes improvement.
Time frame: Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days)
Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes
SUMO pathway inhibition in blood was evaluated by flow cytometry in peripheral blood lymphocytes with an antibody recognizing SUMO 2/3 chains. Fold change from baseline was calculated as: Post-treatment value / Baseline value.
Time frame: Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days)
Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
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. 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. AEs were evaluated according to NCI CTCAE, Version 5.0 except CRS, which was graded according to ASTCT Consensus Grading for CRS.
Time frame: Up to approximately 25 months
Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)
An AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. A severity grade was evaluated as per the NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT Consensus Grading for CRS.
Time frame: Up to approximately 25 months
Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation
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. 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: Up to approximately 25 months