This study is about a medicine called TAK-981 given with rituximab, used to treat adults with relapsed or refractory CD20-positive non-Hodgkin lymphoma. This study has 2 parts. The main aims of the study are: * To check for side effects from treatment with TAK-981 given with rituximab. * To check how much TAK-981 participants can tolerate. * To check if participants with diffuse large B-cell lymphoma or follicular lymphoma respond well to treatment. Participants will receive TAK-981 and rituximab in 21-day cycles. They will continue treatment for about 12 months unless their condition gets worse (disease progression), they cannot tolerate the treatment, or they leave the study for certain reasons.
The drug being tested in this study is called TAK-981 in combination with rituximab. The study will include a dose escalation phase (Phase 1) and an expansion phase in select non-Hodgkin lymphoma (NHL) indications (Phase 2). The study will enroll approximately 180 participants, approximately 35 participants in Phase 1 and approximately 145 participants in Phase 2. The participants with indolent or aggressive relapsed or refractory (r/r) NHL in Phase 1 will identify the maximum tolerated dose (MTD) and/or pharmacologically active dose (PAD). PAD can be defined retrospectively once MTD is reached and it can below MTD or coincide with it. In the dose escalation phase, the starting dose of TAK-981 will be 10 mg. The RP2D will be determined based on the available safety, preliminary pharmacokinetic (PK), pharmacodynamic information data, and after any early antitumor activity observed along with the statistical inference from the Bayesian logistic regression modeling (BLRM). Participants in the Phase 2 will be enrolled once the Phase 1 of the study is completed, and MTD and/or PAD is determined. Phase 2 will explore the efficacy and safety of TAK-981 in combination with rituximab in participants with select NHL types and indications. Participants in Phase 2 will be enrolled in one of the three treatment arms based on Cohorts: * Phase 2, Cohort A r/r DLBCL Progressed after CAR T-cell therapy:TAK-981+Rituximab * Phase 2, Cohort B:r/r DLBCL;no CAR T-cell Therapy;2-3 Prior Lines: Two Dose Levels of TAK-981+Rituximab * Phase 2, Cohort C:r/r FL;no CAR T-cell Therapy;2-3 Prior Lines: Two Dose Levels of TAK-981+Rituximab This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 72 months. Participants will make multiple visits to the clinic, and will attend the end of treatment (EOT) visit 30 days after receiving their last dose of drug or before the start of subsequent systemic anticancer therapy, whichever occurs first for a follow-up assessment.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
38
University of Alabama at Birmingham
Birmingham, Alabama, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Mayo Clinic - Cancer Center - Rochester - PPDS
Rochester, Minnesota, United States
Levine Cancer Institute - Charlotte
Chapel Hill, North Carolina, United States
East Carolina University
Greenville, North Carolina, United States
Phase 1: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs)
Adverse event (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. 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.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
Phase 1: Number of Participants With Grade 3 or Higher 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 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 criteria.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
Phase 1: Duration of 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. As per planned analysis, data for this outcome measure were collected and analyzed for the combined population (Phase 1: TAK-981 60mg QW+Japan Lead-in: TAK-981 60mg QW) based on regimen in which same dose groups in Phase 1 irrespective of nationality were pooled.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) Per Dose Level
DLTs were evaluated according to NCI CTCAE, Version 5.0.
Time frame: Up to 42 months
Phase 2: Overall Response Rate (ORR)
ORR was defined as the percentage of participants who achieved complete response (CR) and partial response (PR), as defined by the investigator according to Lugano classification for lymphomas during the study.
Time frame: Up to 42 months
Cmax: Maximum Observed Plasma Concentration for TAK-981
As per planned analysis, data for this outcome measure were collected and analyzed for the combined population (Phase 1: TAK-981 60mg QW+Japan Lead-in: TAK-981 60mg QW) based on regimen in which same dose groups in Phase 1 irrespective of nationality were pooled. This outcome measure was planned to be analyzed for Phase 1 only.
Time frame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
Tmax: Time of First Occurrence of the Maximum Plasma Concentration (Cmax) for TAK-981
As per planned analysis, data for this outcome measure were collected and analyzed for the combined population (Phase 1: TAK-981 60mg QW+Japan Lead-in: TAK-981 60mg QW) based on regimen in which same dose groups in Phase 1 irrespective of nationality were pooled. This outcome measure was planned to be analyzed for Phase 1 only.
Time frame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981
As per planned analysis, data for this outcome measure were collected and analyzed for the combined population (Phase 1: TAK-981 60mg QW+Japan Lead-in: TAK-981 60mg QW) based on regimen in which same dose groups in Phase 1 irrespective of nationality were pooled. This outcome measure was planned to be analyzed for Phase 1 only.
Time frame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
AUC0-∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981
As per planned analysis, data for this outcome measure were collected and analyzed for the combined population (Phase 1: TAK-981 60mg QW+Japan Lead-in: TAK-981 60mg QW) based on regimen in which same dose groups in Phase 1 irrespective of nationality were pooled. This outcome measure was planned to be analyzed for Phase 1 only.
Time frame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
University of Cincinnati
Cincinnati, Ohio, United States
University Hospitals Cleveland Medical Center
Cleveland, Ohio, United States
Ohio State University Wexner Medical Center
Columbus, Ohio, United States
City of Hope - Comprehensive Cancer Center (CCC)
Portland, Oregon, United States
Western Pennsylvania Hospital
Pittsburgh, Pennsylvania, United States
...and 49 more locations
t1/2z: Terminal Disposition Phase Half-life for TAK-981
As per planned analysis, data for this outcome measure were collected and analyzed for the combined population (Phase 1: TAK-981 60mg QW+Japan Lead-in: TAK-981 60mg QW) based on regimen in which same dose groups in Phase 1 irrespective of nationality were pooled. This outcome measure was planned to be analyzed for Phase 1 only.
Time frame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
CL: Total Clearance After Intravenous Administration for TAK-981
As per planned analysis, data for this outcome measure were collected and analyzed for the combined population (Phase 1: TAK-981 60mg QW+Japan Lead-in: TAK-981 60mg QW) based on regimen in which same dose groups in Phase 1 irrespective of nationality were pooled. This outcome measure was planned to be analyzed for Phase 1 only.
Time frame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981
As per planned analysis, data for this outcome measure were collected and analyzed for the combined population (Phase 1: TAK-981 60mg QW+Japan Lead-in: TAK-981 60mg QW) based on regimen in which same dose groups in Phase 1 irrespective of nationality were pooled. This outcome measure was planned to be analyzed for Phase 1 only.
Time frame: Cycle 1: Days 1 and 8, pre-infusion and at multiple timepoints (Up to 24 hours) post end of infusion (cycle length=21 days)
Phase 1: Overall Response Rate (ORR)
ORR is defined as the percentage of participants who achieved CR and PR, as defined by the investigator according to Lugano classification for lymphomas during the study.
Time frame: Up to 42 months
Phase 1: Disease Control Rate (DCR)
DCR is defined as the percentage of participants who achieved CR, PR, and stable disease (SD) as defined by the investigator according to Lugano classification for Lymphomas during the study.
Time frame: Up to 42 months
Phase 1: Duration of Response (DOR)
DOR is 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). DOR was assessed by the investigator according to Lugano classification for lymphoma during the study.
Time frame: Up to 42 months
Phase 1: Time to Progression (TTP)
TTP is defined as the time from the date of first study drug administration to the date of first documented disease progression. TTP was assessed by the investigator according to Lugano classification for lymphoma during the study.
Time frame: Up to 42 months
Phase 1: Progression-Free Survival (PFS)
PFS is 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. PD was determined by Response Evaluation Criteria in Lymphoma. PFS was assessed by the investigator according to Lugano classification for lymphoma during the study.
Time frame: Up to 42 months
Phase 1: Fold Change From Baseline in Levels of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Blood as Assessed by Flow Cytometry During Phase 1
The level of TAK-981-SUMO adduct formation was evaluated as the percentage of adduct formed in blood. 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)
Phase 1: Levels of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Skin as Assessed by Immunohistochemistry (IHC) During Phase 1
The level of TAK-981-SUMO adduct formation was evaluated as the percentage of adduct formed in skin.
Time frame: Cycle 1 Days 1 and 8 (Cycle length = 21 days)
Phase 1: Fold Change From Baseline in SUMO Pathway Inhibition in Blood as Assessed by Flow Cytometry During Phase 1
SUMO pathway inhibition in blood was evaluated by flow cytometry with an antibody recognizing SUMO2/3 chains.
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 1: SUMO Pathway Inhibition in Skin as Assessed by Immunohistochemistry (IHC) During Phase 1
SUMO pathway inhibition in skin was evaluated with skin tissue biopsies by IHC.
Time frame: Cycle 1 Days 1 and 8 (Cycle length = 21 days)
Phase 2: Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs)
Adverse event (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. 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.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
Phase 2: Number of Participants With Grade 3 or Higher 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 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 criteria.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
Phase 2: Duration of 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.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 42 months)
Phase 2: Disease Control Rate (DCR)
CR is defined as the percentage of participants who achieved CR, PR, and SD as defined by the investigator according to Lugano classification for Lymphomas during the study.
Time frame: Up to 42 months
Phase 2: Duration of Response (DOR)
DOR is 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). DOR was assessed by the investigator according to Lugano classification for lymphoma during the study.
Time frame: Up to 42 months
Phase 2: Time to Progression (TTP)
TTP is defined as the time from the date of first study drug administration to the date of first documented disease progression. TTP was assessed by the investigator according to Lugano classification for lymphoma during the study.
Time frame: Up to 42 months
Phase 2: Progression-Free Survival (PFS)
PFS is 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. PD was determined by Response Evaluation Criteria in Lymphoma. PFS was assessed by the investigator according to Lugano classification for lymphoma during the study.
Time frame: Up to 42 months