Clinical Trials/NCT03648372

NCT03648372

Terminated

Phase 1

An Open Label, Dose-Escalation, Phase 1/2 Study to Evaluate the Safety, Tolerability, Preliminary Efficacy and Pharmacokinetics of TAK-981 in Adult Patients With Advanced or Metastatic Solid Tumors or Relapsed/Refractory Hematologic Malignancies

Takeda8 sites in 1 country109 target enrollmentOctober 1, 2018

ConditionsNeoplasms Lymphoma Hematologic Neoplasms

InterventionsTAK-981

DrugsTAK-981

Overview

Phase: Phase 1
Intervention: TAK-981
Conditions: Neoplasms
Sponsor: Takeda
Enrollment: 109
Locations: 8
Primary Endpoint: Phase 1: Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs)
Status: Terminated
Last Updated: last year

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

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.

Detailed Description

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

Registry

clinicaltrials.gov

Start Date

October 1, 2018

End Date

December 14, 2023

Last Updated

last year

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Takeda

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Adult male or female participants ≥18 years old.
•Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
•Population for Phase 1 dose escalation:
•Has histologically or cytologically confirmed advanced (local regionally recurrent not amenable to curative therapy) or metastatic solid tumors who have no standard therapeutic option with a proven clinical benefit, are intolerant, or have refused them. OR
•Has relapsed/refractory lymphoma not amenable to therapies with proven clinical benefit or who are intolerant or who refuse them. Participants with low-grade lymphomas such as FL, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, and marginal zone lymphomas, may not need to exhaust all available therapy. These participants can be enrolled after failure of at least 2 prior systemic therapies, provided that there is not an immediate need for cytoreduction. In these cases, participants who need immediate therapy for tumor bulk are not eligible for this trial.
•Population for Phase 2 dose expansion cohorts:
•o Has histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed below, that is incurable and for which prior standard first-line treatment has failed: Note: Prior neoadjuvant or adjuvant therapy included in initial treatment may not be considered first- or later-line SOC treatment unless such treatments were completed less than 12 months before the current tumor recurrence.
•o Nonsquamous NSCLC that has progressed to 1 prior systemic immune checkpoint inhibitors (CPI)/anti-PD-(1/L1)-containing therapy and no more than 2 lines of therapy. Participants must have not shown evidence of tumor progression during the first 5 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy (cohort A).
•Note: Participants with known driver mutations/genomic aberrations (example- 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.
•o CPI-naïve cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix) participants who have received no more than 1 prior systemic line of therapy for recurrent or Stage IVB cervical cancer (cohort B).

Exclusion Criteria

•Phase 1 dose escalation and Phase 2 cancer treatment expansion cohorts:
•o Has received treatment with systemic anticancer treatments or investigational products within 14 days before the first dose of study drug or 5 half-lives, whichever is shorter.
•Note: Low-dose steroids (oral prednisone or equivalent ≤20 mg per day), hormonal therapy for prostate cancer or breast cancer (as adjuvant treatment), and treatment with bisphosphonates and receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors are allowed.
•o Has received extended field radiotherapy ≤4 weeks before the start of treatment (≤2 weeks for limited field radiation for palliation), and who has not recovered to grade 1 or baseline from related side effects of such therapy (except for alopecia).
•History of any of the following ≤6 months before first dose: congestive heart failure New York Heart Association Grade III or IV, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, severe noncompensated hypertension despite appropriate medical therapy, ongoing symptomatic cardiac arrhythmias of \>Grade 2, pulmonary embolism, or symptomatic cerebrovascular events, or any other serious cardiac condition (example, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.
•Baseline prolongation of the QT interval with Fridericia correction method (QTcF) (example, repeated demonstration of QTcF interval \>480 milliseconds (ms), history of congenital long QT syndrome, or torsades de pointes).
•Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of adverse events (AEs) or has compromised ability to provide written informed consent.
•Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
•History of autoimmune disease requiring systemic immunosuppressive therapy.
•History of immune-related AEs related to treatment with immune checkpoint inhibitors that required treatment discontinuation.

Arms & Interventions

Phase 1, Dose Escalation Cohort: TAK-981

TAK-981, intravenously, administered as 60 minute-infusion, once on Days 1, 4, 8, and 11 in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study. If clinical safety, pharmacokinetics, and pharmacodynamics are supportive, the dosing schedule may be modified to evaluate a less intensive administration of TAK-981 on Day 1, or Days 1 and 8, or Day 1, Day 8, and Day 15 in 21-day cycles in participants with advanced or metastatic solid tumors or lymphomas. Dose levels will be escalated based on the Bayesian logistic regression modeling (BLRM). The dose escalation phase will determine the RP2D of TAK-981.

Intervention: TAK-981

Phase 2, Cohort A: Nonsquamous NSCLC

TAK-981 intravenously administered as 60 minute-infusion in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study in participants with nonsquamous non-small cell lung cancer (NSCLC).

Intervention: TAK-981

Phase 2, Cohort B: Cervical Cancer

TAK-981 intravenously administered as 60 minute-infusion in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study in participants with cervical cancer.

Intervention: TAK-981

Phase 2, Cohort C: MSS-CRC

Intervention: TAK-981

Phase 2, Cohort D: r/r DLBCL after CAR T-cells therapy

Intervention: TAK-981

Phase 2, Cohort E: r/r DLBCL without prior cellular therapy

Intervention: TAK-981

Phase 2, Cohort F: r/r Follicular Lymphoma

Intervention: TAK-981

Outcomes

Primary Outcomes

Phase 1: Number of Participants Reporting One or More Treatment Emergent Adverse Events (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)

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.

Phase 1: Number of Participants With Grade 3 or Higher 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)

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.

Phase 1: Duration of 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)

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.

Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)

Time Frame: Cycle 1 (Cycle length is equal to [=] 21 days)

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.

Phase 2: Overall Response Rate (ORR)

Time Frame: From the first dose of study drug until first disease progression (PD) or death, whichever occurred first (up to 11.2 months)

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.

Secondary Outcomes

Phase 1, Cmax: Maximum Observed Plasma Concentration for TAK-981(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(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(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(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(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(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, Vss: Volume of Distribution at Steady State for TAK-981(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(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)(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)(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)(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)(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)(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)(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(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(Cycle 1 Day 8 (Cycle length = 21 days))
Phase 1: Fold Change From Baseline in SUMO Pathway Inhibition in Blood Lymphocytes(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(Cycle 1 Day 8 (Cycle length = 21 days))
Phase 2: Number of Participants Reporting One or More TEAEs(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(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(From the first dose of study drug through 30 days after the last dose of study drug (up to 12.2 months))