The purpose of this study is to determine the safety and tolerability of TAK-981 in combination with pembrolizumab in participants with select solid tumor indications and to establish the recommended phase 2 dose (RP2D) during Phase 1b of study and to evaluate the preliminary efficacy of TAK-981 at the RP2D in combination with pembrolizumab in participants with select solid tumor indications in Phase 2 of the study.
Name: TAK-981
Name: Pembrolizumab
Description: 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.
Measure: Phase 1: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) Time: Up to 48 monthsDescription: DLTs are defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v5.0 as: Any Grade 5 AE, Grade 4 hematologic AE, platelet count <10.0 x10^9/L, febrile neutropenia [>=Grade 3 neutropenia (absolute neutrophil count <1.0 ×10^9/L) with fever and/or infection], Grade 3 thrombocytopenia lasting longer than 14 days or accompanied by Grade 2 bleeding or requiring transfusion, Grade 3 immune-related adverse event such as pericarditis, pneumonitis, cardiotoxicity, hepatitis or neurotoxicity, >=Grade 3 nonhematologic toxicity, Grade 2 nonhematologic toxicities related to study drug and dose-limiting, delay in the initiation of Cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related hematological or nonhematological toxicities or missed >=1 planned dose of TAK-981 or planned dose of pembrolizumab in Cycle 1 due to treatment-related AEs.
Measure: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) Time: Up to Cycle 1 (each cycle is of 21 days)Description: 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 will be graded using NCI CTCAE 5.0.
Measure: Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) Time: Up to 48 monthsDescription: 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.
Measure: Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs) Time: Up to 48 monthsDescription: 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.
Measure: Phase 1: Number of Participants with One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation Time: Up to 48 monthsDescription: Laboratory parameters includes parameters of clinical chemistry, hematology, and urinalysis.
Measure: Phase 1: Number of Participants With Clinically Significant Laboratory Values Time: Up to 48 monthsDescription: 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) v1.1. CR is defined as disappearance of all target lesions; PR is defined as at least 30% decrease in sum of diameters (SoD) of target lesions.
Measure: Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 Time: Up to 48 monthsDescription: 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 consensus guideline developed by the RECIST Working Group for the use of modified RECIST, Version 1.1 in cancer immunotherapy trials (iRECIST). CR is defined as disappearance of all target lesions; PR is defined as at least 30% decrease in sum of diameters (SoD) of target lesions.
Measure: Phase 2: ORR as Defined by the Investigator According to iRECIST Modification Time: Up to 48 monthsDescription: 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 (up to approximately 48 months). PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure: Phase 2: Duration of Response (DOR) Time: Up to 48 monthsDescription: 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 (up to approximately 48 months). PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure: Phase 2: Progression-free Survival (PFS) Time: Up to 48 monthsDescription: TTR is defined as time from the date of first study drug administration to the date of first documented PR or better (up to approximately 48 months). PR is defined as at least 30% decrease in sum of diameters (SoD) of target lesions.
Measure: Phase 2: Time to Response (TTR) Time: Up to 48 monthsDescription: TAK-981-SUMO adduct formation in blood will be evaluated.
Measure: Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Blood Time: Up to 48 monthsDescription: SUMO pathway inhibition in blood will be evaluated.
Measure: Percent Change in Small Ubiquitin-like Modifier (SUMO) 2/3 Signal With Pre and Post-dose in Blood Time: Up to 48 monthsAllocation: Non-Randomized
Sequential Assignment
There is one SNP
epidermal growth factor receptor [EGFR], B-Raf proto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1] sensitizing mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions, and anaplastic lymphoma kinase [ALK] rearrangements) must have also shown progressive disease after treatment with a commercially available targeted therapy. --- V600E ---
epidermal growth factor receptor [EGFR], B-Raf proto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1] sensitizing mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions, and anaplastic lymphoma kinase [ALK] rearrangements) must have also shown progressive disease after treatment with a commercially available targeted therapy. --- V600E --- --- V600E ---