A Study of TAK-981 Given With Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors

NCT ID: NCT04381650

Last Updated: 2025-12-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 161 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-17
• Study Completion Date: 2024-10-29

Brief Summary

TAK-981 is being tested in combination with pembrolizumab to treat participants who have select advanced or metastatic solid tumors.

The study aims are to evaluate the safety, tolerability, and preliminary efficacy of TAK-981 in combination with pembrolizumab.

Participants will be on this combination treatment for 21-day cycles. They will continue with this treatment for up to 24 months or until participants meet any discontinuation criteria.

Detailed Description

The drug being tested in this study is called TAK-981. TAK-981 is being tested to treat people who have select advanced or metastatic solid tumors. The study will include a dose escalation phase and a dose expansion phase.

The study will enroll approximately 231 participants, approximately 32 participants in the dose escalation phase 1 and approximately 76 to 199 participants in the 8 cohorts of dose expansion phase 2. Participants will receive escalating doses of TAK-981 and fixed dose of pembrolizumab until recommended phase 2 dose (RP2D) is determined:

• Dose Escalation: TAK-981 + Pembrolizumab (Fixed Dose)

Once Phase 2 doses are identified, participants of select advanced or metastatic solid tumors will receive TAK-981 in below defined cohorts in the expansion phase 2:

• Dose Expansion Phase: Cohort A: Non-squamous Non-small Cell Lung Cancer (NSCLC)
• Dose Expansion Phase: Cohort B: Cervical Cancer
• Dose Expansion Phase: Cohort C: Microsatellite Stable Colorectal Cancer (MSS-CRC)
• Dose Expansion Phase: Cohort D: Cutaneous Melanoma
• Dose Expansion Phase: Cohort E: Squamous NSCLC
• Dose Expansion Phase: Cohort F: Checkpoint Inhibitors (CPI) Refractory Squamous or Nonsquamous NSCLC

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 60 months. Participants will make multiple visits to the clinic, and progression-free survival follow-up for maximum up to 12 months after last dose of study drug.

Conditions

Advanced or Metastatic Solid Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Escalation: TAK-981 40 mg + Pembrolizumab

Participants received TAK-981 40 mg, intravenous (IV) infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until the recommended Phase 2 dose (RP2D) was determined (for a maximum of 24 months).

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Escalation: TAK-981 60 mg + Pembrolizumab

Participants received TAK-981 60 mg, intravenous (IV) infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until the RP2D was determined (for a maximum of 24 months).

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Escalation: TAK-981 90 mg + Pembrolizumab

Participants received TAK-981 90 mg, intravenous (IV) infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until the RP2D was determined (for a maximum of 24 months).

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Escalation: TAK-981 120 mg + Pembrolizumab

Participants received TAK-981 120 mg, intravenous (IV) infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until the RP2D was determined (for a maximum of 24 months).

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Expansion: Cohort A: Non-squamous NSCLC TAK-981 90 mg

Participants with non-squamous non-small cell lung cancer (NSCLC) received TAK-981 as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Expansion: Cohort A: Non-squamous NSCLC TAK-981 120 mg

Participants with NSCLC received TAK-981 as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Expansion Phase: Cohort B: Cervical Cancer

Participants with cervical cancer received TAK-981 as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Expansion Phase: Cohort C: MSS-CRC

Participants with microsatellite stable colorectal cancer (MSS-CRC) received TAK-981 as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Expansion Phase: Cohort D: Cutaneous Melanoma

Participants with cutaneous melanoma received TAK-981 as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Expansion Phase: Cohort E: Squamous NSCLC

Participants with squamous NSCLC received TAK-981 as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Dose Expansion Phase: Cohort F: CPI Refractory Squamous or Nonsquamous NSCLC

Participants with checkpoint inhibitors (CPI) refractory squamous or non-squamous NSCLC received TAK-981 as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Group Type: EXPERIMENTAL

TAK-981

Intervention Type: DRUG

TAK-981 IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab IV infusion.

Interventions

TAK-981

TAK-981 IV infusion.

Intervention Type: DRUG

Pembrolizumab

Pembrolizumab IV infusion.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Has a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed below that is incurable: Note: Prior neoadjuvant or adjuvant therapy included in initial treatment may not be considered first- or later-line standard of care treatment unless such treatments were completed less than 12 months prior to the current tumor recurrence.

A. Non-squamous NSCLC for which prior standard first-line treatment containing an anti-programmed cell death protein 1/programmed cell death protein 1 ligand (PD-1/PD-L1) checkpoint inhibitor (CPI) alone or in combination has failed and that has progressed on no more than 1 prior systemic therapy. In Phase 2, participants with nonsquamous NSCLC must have not received more than 1 prior systemic therapy and must not have presented with disease progression during the first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy.

Note: In Phase 1, participants with nonsquamous NSCLC and known driver mutations/genomic aberrations (e.g., 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. In Phase 2, participants with driver mutations are not eligible.

B. CPI-naive cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix) participants for whom prior standard first-line treatment has failed and who have received no more than 1 prior systemic line of therapy for recurrent or Stage IVB cervical cancer. 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 (e.g., weekly cisplatin) is not counted as a systemic chemotherapy regimen.

C. CPI-naïve microsatellite stable-colorectal cancer (MSS-CRC) participants for whom prior standard first-line treatment has failed and who have progressed on no more than 3 chemotherapy regimens.

Note: Participants must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens if indicated.

D. Unresectable Stage III or Stage IV cutaneous melanoma that has not received prior therapy in the metastatic setting.

Note: Participants with acral melanoma are not eligible. Participants who have presented with disease relapse after ≥6 months of the last dose of CPI or BRAF-mitogen-activated protein kinase kinase (MEK) inhibitor in the adjuvant setting are eligible.

E. Squamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed. Participant must have not received more than 1 prior systemic therapy and must not have presented with disease progression during the first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy.

F. Squamous or nonsquamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed within 6 months from the initiation of the CPI. Participants must not have received more than 1 prior systemic therapy in the metastatic setting.

Note: Participants with driver mutations are not eligible.

2. Has at least 1 radiologically measurable lesion based on RECIST, Version 1.1. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

3. Has a performance status of 0 or 1 on the Eastern Cooperative Group Oncology (ECOG) Performance Scale.

4. Has left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.

5. Has recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela. Note: Has a neuropathy ≤Grade 2, any grade alopecia, or autoimmune endocrinopathies with stable replacement therapy are permitted.

6. Demonstrate adequate organ function as described below:

A. Platelet count ≥75.0 × 10^9/L. B. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L. C. Hemoglobin ≥85 g/L (red blood cell [RBC] transfusion allowed ≥14 days before assessment).

D. Calculated creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula.

E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) ≤3.0 times the upper limit of normal (ULN), <5.0 times the ULN if liver enzyme elevations are due to liver metastases; bilirubin ≤1.5 times the ULN. Participants with Gilbert's syndrome may have a bilirubin level >1.5 times the ULN, per discussion between the investigator and the medical monitor.

Exclusion Criteria

1. History of uncontrolled brain metastasis (evidence of progression by imaging over a period of 4 weeks and/or neurologic symptoms that have not returned to baseline). Participant with treated brain metastases are allowed provided they are radiologically stable, without evidence of progression for at least 4 weeks by repeat imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. Note: For asymptomatic participants, screening brain imaging is not required.

2. Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the participant is not on active anticancer therapy.

3. Major surgery ≤14 days from the first dose of study drug and not recovered fully from any complications from surgery.

4. History of immune-related AEs related to treatment with immune CPIs that required treatment discontinuation.

5. Receiving or requires the continued use of medications that are known to be strong or moderate inhibitors and inducers of cytochrome P-450 (CYP) 3A4/5 and strong P-glycoprotein (Pgp) inhibitors.

6. Baseline prolongation of the QT interval corrected using Fridericia's formula (QTcF) (e.g., repeated demonstration of QTcF interval >480 milliseconds (ms), history of congenital long QT syndrome, or torsades de pointes).

7. Has a history of autoimmune disease requiring systemic immunosuppressive therapy with daily doses of prednisone >10 mg/day or equivalent doses, or any other form of immunosuppressive therapy. Hormone replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for thyroid, adrenal or pituitary insufficiency) for endocrinopathies are not considered prohibited forms of systemic treatment of an autoimmune disease.

8. Has a history of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.

9. Has an evidence of active, non-infectious pneumonitis.

10. Has a history of allogeneic tissue or solid organ transplant.

11. Has an active infection requiring systemic therapy.

12. Has a known history of human immunodeficiency virus (HIV) infection or any other relevant congenital or acquired immunodeficiency.

13. Has a known hepatitis B virus 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.

14. 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, uncontrolled hypertension despite appropriate medical therapy, ongoing symptomatic cardiac arrhythmias >Grade 2, pulmonary embolism or symptomatic cerebrovascular events, or any other serious cardiac condition (e.g., pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.

15. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda Development Center Americas, Inc.

INDUSTRY

Sponsor Role: collaborator

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

HonorHealth

Scottsdale, Arizona, United States

University of California Irvine Medical Center

Orange, California, United States

Stanford Cancer Institute (SCI)

Stanford, California, United States

Yale Cancer Center

New Haven, Connecticut, United States

Georgia Cancer Center at Augusta University

Augusta, Georgia, United States

The Center for Cancer and Blood Disorders - PPDS

Bethesda, Maryland, United States

Morristown Medical Center

Morristown, New Jersey, United States

Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

Montefiore Einstein Cancer Center - BRANY - PPDS

The Bronx, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

University of Oklahoma Peggy and Charles Stephenson Cancer Center

Oklahoma City, Oklahoma, United States

Providence Cancer Institute, Franz Clinic

Portland, Oregon, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

START South Texas Accelerated Research Therapeutics

San Antonio, Texas, United States

University of Virginia Health System

Charlottesville, Virginia, United States

Virginia Cancer Specialists (Fairfax) - USOR

Fairfax, Virginia, United States

Instituto de Oncologia Do Parana

Curitiba, Paraná, Brazil

ONCOSITE Centro de Pesquisa Clinica Em Oncologia

Ijuí, Rio Grande do Sul, Brazil

Hospital de Clinicas de Porto Alegre (HCPA) - PPDS

Porto Alegre, Rio Grande do Sul, Brazil

Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)

Porto Alegre, Rio Grande do Sul, Brazil

Fundacao Pio XII Hospital de Cancer de Barretos

Barretos, São Paulo, Brazil

Hospital de Base Da Faculdade de Medicina de Sao Jose Do Rio Preto

São José do Rio Preto, São Paulo, Brazil

Cetus Hospital Dia Oncologia

Belo Horizonte, , Brazil

INCA Instituto Nacional de Cancer

Rio de Janeiro, , Brazil

Instituto Do Cancer Do Estado de Sao Paulo Octavio Frias de Oliveira

Rio de Janeiro, , Brazil

Sun Yat-Sen University Cancer Center

Guangzhou, Guangdong, China

Union Hospital Tongji Medical College Huazhong University of Science and Technology

Wuhan, Hubei, China

The First Affiliated Hospital, Zhejiang University School of Medicine - PPDS

Hangzhou, Zhejiang, China

Klinicki bolnicki centar Zagreb

Zagreb, City of Zagreb, Croatia

Clinical Hospital Centre Osijek

Osijek, , Croatia

General Hospital Pula

Pula, , Croatia

University Hospital Centre Split

Split, , Croatia

National Cancer Center East

Kashiwa-Shi, Chiba, Japan

National Cancer Center Hospital

Chuo-Ku, Tokyo, Japan

The Cancer Institute Hospital of Japanese Foundation For Cancer Research

Chuo-Ku, Tokyo, Japan

Pauls Stradins Clinical University Hospital

Riga, , Latvia

Riga East Clinical University Hospital Latvian Oncology Center

Riga, , Latvia

Hospital of Lithuanian University of Health Sciences Kaunas Clinics

Kaunas, Kaunas County, Lithuania

Hospital of Lithuanian University of Health Sciences Kauno klinikos

Kaunas, Kaunas County, Lithuania

National Cancer Institute

Vilnius, Vilnius County, Lithuania

Uniwersyteckie Centrum Kliniczne-Ul. Smoluchowskiego 17

Gdansk, Pomeranian Voivodeship, Poland

Centrum Onkologii im. Prof. Franciszka Lukaszczyka w Bydgoszczy

Bydgoszcz, , Poland

Instytut Medyczny Santa Familia Sp. z o. o.

Lodz, , Poland

Specjalistyczna Praktyka Lekarska Slawomir Mandziuk

Lublin, , Poland

Warminsko-Mazurskie Centrum Chorob Pluc w Olsztynie

Olsztyn, , Poland

Med-Polonia Sp. z o.o.

Poznan, , Poland

Centrum Terapii Wspolczesnej

Lodz, Łódź Voivodeship, Poland

Kantonsspital Muensterlingen

Münsterlingen, Thurgau (de), Switzerland

Kantonsspital Winterthur

Winterthur, Zurich (de), Switzerland

Universitaetsspital Bern - Inselspital

Bern, , Switzerland

Countries

United States; Brazil; China; Croatia; Japan; Latvia; Lithuania; Poland; Switzerland

References

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.

Reference Type: DERIVED

PMID: 35226739 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.takeda.com/study-detail/5f6b603d4db2bf003ab4a3a5?idFilter=%5B%22TAK-981-1502%22%5D

To obtain more information about this study, click this link.

Other Identifiers

2020-004325-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

jRCT2031210417

Identifier Type: REGISTRY

Identifier Source: secondary_id

TAK-981-1502

Identifier Type: -

Identifier Source: org_study_id