This study is in 2 parts. The main aims of the 1st part of the study are to check if people with advanced solid tumors or cancers in the immune system (lymphomas) have side effects from TAK-981, and to check how much TAK-981 they can receive without getting side effects from it. The main aims of the 2nd part of the study are to learn if the condition of people with specific cancers improves after treatment with TAK-981. Another aim is to check for side effects from TAK-981. In the 1st part of the study, participants will receive TAK-981. In the 2nd part of the study, participants with specific tumor types will receive TAK-981 at the recommended phase 2 dose determined during the 1st part of the study. In both parts of the study, participants can receive TAK-981 for up to 1 year or longer if their condition stays improved. Participants will receive TAK-981 through vein.
The drug being tested in this study is called TAK-981. TAK-981 is being tested to evaluate safety, tolerability, preliminary efficacy and PK in participants with advanced or metastatic solid tumors or relapsed/refractory hematologic malignancies. The study will include 2 phases: Phase 1 dose escalation and Phase 2 dose expansion cohorts (cancer treatment expansions). The study will enrol approximately 202 participants, approximately 70 participants in the dose escalation phase, approximately 132 participants in cancer treatment expansion phase. In the dose escalation, dose levels will be escalated based on safety, and available PK and pharmacodynamic data and will also determine the single agent RP2D. Participants in dose expansion phase will be enrolled, once RP2D is determined. There will be 6 cohorts in cancer treatment expansions. * Cohort A: Nonsquamous NSCLC * Cohort B: Cervical cancer * Cohort C: MSS-CRC * Cohort D: Relapsed/refractory DLBCL progressed or relapsed after CAR T-cells therapy * Cohort E: Relapsed/refractory DLBCL that have not received prior cellular therapy * Cohort F: Relapsed/refractory FL This multi-center trial will be conducted in European Union, China and United States. The overall time to participate in this study is approximately 2 years. The overall time to receive treatment in the dose escalation and cancer treatment is approximately 1 year. Based on decision of sponsor, participants with demonstrated clinical benefit can continue treatment beyond 1 year. Participants will make multiple visits to the clinic and will make a final visit 30 days after receiving their last dose of drug or before the start of subsequent anticancer therapy, whichever occurs first for a follow-up assessment.uroped
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
109
Intravenous infusion.
University of California San Diego Moores Cancer Center
La Jolla, California, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States
HealthPartners Cancer Care Center - Regions Hospital
Saint Paul, Minnesota, United States
University Hospitals Seidman Cancer Center
Cleveland, Ohio, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Froedtert and the Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Phase 1: Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs)
TEAEs were adverse events (AEs) that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. 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. Any abnormal laboratory results were considered as TEAEs.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 35.3 months)
Phase 1: Number of Participants With Grade 3 or Higher TEAEs
The severity grade was evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0, except for Cytokine Release Syndrome (CRS), which was assessed by American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Where Grade 3 was severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living (ADL), Grade 4 was life-threatening consequences; urgent intervention indicated, and Grade 5 was death related to AE. TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 35.3 months)
Phase 1: Duration of TEAEs
TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. 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.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 35.3 months)
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
DLTs were evaluated according to NCI CTCAE version 5.0. Grade 5 AE. Hematologic toxicity: Nonfebrile Grade 4 neutropenia/Grade greater than or equal to (\>=) 3 febrile neutropenia; Significant Grade 3 thrombocytopenia; Grade 4 thrombocytopenia. Nonhematologic Grade 3 or higher toxicities; Grade 2 nonhematologic toxicities that were considered by the investigator to be related to study drug and dose-limiting.
Time frame: Cycle 1 (Cycle length is equal to [=] 21 days)
Phase 2: Overall Response Rate (ORR)
ORR was defined as percentage of participants who achieved complete response (CR) or partial response (PR) during the study as determined by the investigator according to response assessments based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) for solid tumors or Lugano classification for lymphoma.
Time frame: From the first dose of study drug until first disease progression (PD) or death, whichever occurred first (up to 11.2 months)
Phase 1, Cmax: Maximum Observed Plasma Concentration for TAK-981
Cmax for TAK-981 was reported.
Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose; Cycle 1 Day 8: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 21 days)
Phase 1, Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for TAK-981
Tmax for TAK-981 was reported.
Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose; Cycle 1 Day 8: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 21 days)
Phase 1, AUC0-last: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-981
AUC0-last for TAK-981 was reported.
Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose; Cycle 1 Day 8: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 21 days)
Phase 1, AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981
AUC0-inf for TAK-981 was reported.
Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose; Cycle 1 Day 8: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 21 days)
Phase 1, t1/2z: Terminal Disposition Phase Half-life for TAK-981
t1/2z for TAK-981 was reported.
Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose; Cycle 1 Day 8: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 21 days)
Phase 1, CL: Total Clearance for TAK-981
CL for TAK-981 was reported.
Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose; Cycle 1 Day 8: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 21 days)
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Phase 1, Vss: Volume of Distribution at Steady State for TAK-981
Vss for TAK-981 was reported.
Time frame: Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 48 hours) post-dose; Cycle 1 Day 8: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 21 days)
Phase 1: ORR
ORR was defined as percentage of participants who achieved CR or PR during the study as determined by the investigator according to response assessments based on RECIST v1.1 for solid tumors or Lugano classification for lymphoma.
Time frame: From the first dose of study drug until first PD or death, whichever occurred first (up to 34.3 months)
Phase 1 and 2: Disease Control Rate (DCR)
DCR was defined as the percentage of participants who achieved stable disease (SD) (greater than \[\>\] 6 weeks) or better as determined by the investigator according to RECIST v1.1 for solid tumors or Lugano classification for lymphoma.
Time frame: From first dose of study drug up to 34.3 months (for Phase 1) and up to 11.2 months (for Phase 2)
Phase 1 and 2: Duration of Response (DOR)
DOR was defined as the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders (PR or better) and determined by the investigator according to RECIST v1.1 with solid tumors or Lugano classification for lymphoma.
Time frame: From first documented confirmed CR or PR until first documentation of PD up to 34.3 months (for Phase 1) and up to 11.2 months (for Phase 2)
Phase 1 and 2: Time to Progression (TTP)
TTP was defined as the time from the date of the first dose administration to the date of first documented PD as determined by the investigator according to RECIST v1.1 for solid tumors or Lugano classification for lymphoma.
Time frame: From first dose of study drug to the date of the first documentation of PD up to 34.3 months (for Phase 1) and up to 11.2 months (for Phase 2)
Phase 1 and 2: Time to Response (TTR)
TTR was defined as the time from the date of first study drug administration to the date of first documented PR or better by the investigator for responders according to RECIST v1.1 for solid tumors or Lugano classification for lymphoma. Here, "overall number of participants analyzed" signifies participants who had CR or PR.
Time frame: From first dose of study drug to the date of the first documentation of PR or better, whichever occurred first up to 34.3 months (for Phase 1) and up to 11.2 months (for Phase 2)
Phase 1 and 2: Progression-free Survival (PFS)
PFS was defined as the 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 as determined by the investigator according to RECIST v1.1 for solid tumors or Lugano classification for lymphoma.
Time frame: From the first dose of study drug to date of PD or death, whichever occurred first up to 34.3 months (for Phase 1) and up to 11.2 months (for Phase 2)
Phase 1 and 2: Overall Survival (OS)
OS was defined as the time from the date of the first dose administration to the date of death.
Time frame: From date of first dose of study drug up to death up to 34.3 months (for Phase 1) and up to 11.2 months (for Phase 2)
Phase 1: Fold Change From Baseline in Levels of TAK-981 Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Blood Lymphocytes
TAK-981-SUMO adduct formation in peripheral blood lymphocytes was tested by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formation during the inhibition of the SUMO-activating enzyme by TAK-981.
Time frame: Cycle 1 Day 1: 1, 4 and 8 hours post-dose; Cycle 1 Day 8: Pre-dose, 1, 4 and 8 hours post-dose (Cycle length = 21 days)
Phase 1: Fold Change From Baseline in Levels of TAK-981 SUMO Adduct Formation in Skin
TAK-981-SUMO adduct formation in skin was tested by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formation during the inhibition of the SUMO-activating enzyme by TAK-981.
Time frame: Cycle 1 Day 8 (Cycle length = 21 days)
Phase 1: Fold Change From Baseline in SUMO Pathway Inhibition in Blood Lymphocytes
SUMO pathway inhibition in peripheral blood lymphocytes was tested by flow cytometry with an antibody recognizing SUMO-2/3 chains.
Time frame: Cycle 1 Day 1: 1, 4 and 8 hours post-dose; Cycle 1 Day 8: Pre-dose, 1, 4 and 8 hours post-dose (Cycle length = 21 days)
Phase 1: Fold Change From Baseline in SUMO Pathway Inhibition in Skin
SUMO pathway inhibition in skin was tested by flow cytometry with an antibody recognizing SUMO-2/3 chains.
Time frame: Cycle 1 Day 8 (Cycle length = 21 days)
Phase 2: Number of Participants Reporting One or More TEAEs
TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. 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. Any abnormal laboratory results were reported as TEAEs.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 12.2 months)
Phase 2: Number of Participants With Grade 3 or Higher TEAEs
The severity grade was evaluated as per the CTCAE Version 5.0, except for CRS, which was assessed by ASTCT consensus grading. Where Grade 3 was severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4 was 4 Life-threatening consequences; urgent intervention indicated. and Grade 5 was death related to AE. TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 12.2 months)
Phase 2: Duration of TEAEs
TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. 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.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 12.2 months)