A Study of TAK-981 in People With Advanced Solid Tumors or Cancers in the Immune System

NCT03648372 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: TAK-981-1002U1111-1214-45372020-003947-27
• Study Type: interventional
• Target: 109
• Locations: 1 country
• Sites: 8

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.

Conditions

Neoplasms; Lymphoma; Hematologic Neoplasms

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (5)

• 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.

  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.

  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.

  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.

  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.

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

Secondary Outcomes (21)

• 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)

Study Arms (7)

Phase 1, Dose Escalation Cohort: TAK-981

EXPERIMENTAL

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.

Drug: TAK-981

Phase 2, Cohort A: Nonsquamous NSCLC

EXPERIMENTAL

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).

Drug: TAK-981

Phase 2, Cohort B: Cervical Cancer

EXPERIMENTAL

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.

Drug: TAK-981

Phase 2, Cohort C: MSS-CRC

EXPERIMENTAL

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 microsatellite-stable colorectal cancer (MSS-CRC).

Drug: TAK-981

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

EXPERIMENTAL

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 relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after prior chimeric antigen receptor (CAR) T-cells therapy.

Drug: TAK-981

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

EXPERIMENTAL

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 relapsed/refractory DLBCL that have not received prior cellular therapy.

Drug: TAK-981

Phase 2, Cohort F: r/r Follicular Lymphoma

EXPERIMENTAL

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 relapsed/refractory follicular lymphoma (FL).

Drug: TAK-981

Interventions

TAK-981 DRUG

Intravenous infusion.

Phase 1, Dose Escalation Cohort: TAK-981; Phase 2, Cohort A: Nonsquamous NSCLC; Phase 2, Cohort B: Cervical Cancer; Phase 2, Cohort C: MSS-CRC; Phase 2, Cohort D: r/r DLBCL after CAR T-cells therapy; Phase 2, Cohort E: r/r DLBCL without prior cellular therapy; Phase 2, Cohort F: r/r Follicular Lymphoma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult male or female participants ≥18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• 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).
• Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric-type adenocarcinoma, clear-cell carcinoma, and mesonephric carcinoma. Histologic confirmation of the original primary tumor is required via pathology report.
• Note: First-line treatment must have consisted of platinum-containing doublet. Chemotherapy administered concurrently with primary radiation (example- weekly cisplatin) is not counted as a systemic chemotherapy regimen.
• o CPI-naïve MSS-CRC participants who have progressed on no more than 3 chemotherapy regimens (cohort C).
• Note: Participants must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens if indicated.
• Relapsed/refractory DLBCL progressed or relapsed after prior CAR T cell therapy that has received approval by a health authority for the treatment of DLBCL (cohort D).

You may not qualify if:

• 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.
• History of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
• Has evidence of active, noninfectious pneumonitis.
• Have a significant active infection.
• Known history of human immunodeficiency virus (HIV) infection or any other relevant congenital or acquired immunodeficiency.
• Known hepatitis B virus (HBV) surface antigen seropositive or detectable hepatitis C infection viral load. Note: Participants who have positive hepatitis B core antibody or hepatitis B surface antigen antibody can be enrolled but must have an undetectable hepatitis B viral load.

Sponsors & Collaborators

• Takeda: lead

Study Sites (8)

University of California San Diego Moores Cancer Center

La Jolla, California, 92093, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

HealthPartners Cancer Care Center - Regions Hospital

Saint Paul, Minnesota, 55101, United States

Location

University Hospitals Seidman Cancer Center

Cleveland, Ohio, 44106, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Froedtert and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Nakamura A, Grossman S, Song K, Xega K, Zhang Y, Cvet D, Berger A, Shapiro G, Huszar D. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation. Blood. 2022 May 5;139(18):2770-2781. doi: 10.1182/blood.2021014267.

  PMID: 35226739 DERIVED

Related Links

• To obtain more information on the study, click here/on this link

MeSH Terms

Conditions

Neoplasms; Lymphoma; Hematologic Neoplasms

Interventions

TAK-981

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms by Site; Hematologic Diseases

Limitations and Caveats

The study was terminated early due to enrollment challenges.

Results Point of Contact

• Title: Study Director
• Organization: Takeda

TrialDisclosures@takeda.com

+1-877-825-3327

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 24, 2018
• First Posted: August 27, 2018
• Study Start: October 1, 2018
• Primary Completion: November 22, 2023
• Study Completion: December 14, 2023
• Last Updated: November 19, 2024
• Results First Posted: November 19, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

US (8)