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

A Phase 1b/2 Study of TAK-981 Plus Pembrolizumab to Evaluate the Safety, Tolerability, and Antitumor Activity of the Combination in Patients With Select Advanced or Metastatic Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Advanced or Metastatic Solid Tumors
• Intervention / Treatment: Drug: TAK-981; Drug: Pembrolizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Belo Horizonte, Brazil, 30110-140
    • Cetus Hospital Dia Oncologia
  • Rio de Janeiro, Brazil, 20941-150
    • Instituto Do Cancer Do Estado de Sao Paulo Octavio Frias de Oliveira
  • Rio de Janeiro, Brazil, 20230-230
    • Inca Instituto Nacional de Cancer
  • Paraná
    • Curitiba, Paraná, Brazil, 80530-010
      • Instituto de Oncologia do Parana
  • Rio Grande do Sul
    • Ijuí, Rio Grande do Sul, Brazil, 98700-000
      • ONCOSITE Centro de Pesquisa Clínica Em Oncologia
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
    • Porto Alegre, Rio Grande do Sul, Brazil, 90610-000
      • Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)
  • São Paulo
    • Barretos, São Paulo, Brazil, 14784-370
      • Fundacao Pio Xii Hospital de Cancer de Barretos
    • São José do Rio Preto, São Paulo, Brazil, 15090-000
      • Hospital de Base da Faculdade de Medicina de São José do Rio Preto
• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-sen University Cancer Center
  • Hubei
    • Wuhan, Hubei, China
      • Union Hospital Tongji Medical College Huazhong University of Science and Technology
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • The First Affiliated Hospital, Zhejiang University School of Medicine - PPDS
• Croatia
  • Osijek, Croatia, 31000
    • Clinical Hospital Centre Osijek
  • Pula, Croatia, 52100
    • General Hospital Pula
  • Split, Croatia, 21000
    • University Hospital Centre Split
  • City of Zagreb
    • Zagreb, City of Zagreb, Croatia, 10000
      • Klinicki bolnicki centar Zagreb
• Japan
  • Chiba
    • Kashiwa-Shi, Chiba, Japan, 277-0882
      • National Cancer Center East
  • Tokyo
    • Chuo-Ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
    • Chuo-Ku, Tokyo, Japan, 104-0045
      • The Cancer Institute Hospital of Japanese Foundation for Cancer Research
• Latvia
  • Riga, Latvia, LV-1002
    • Pauls Stradins Clinical University Hospital
  • Riga, Latvia, LV-1079
    • Riga East Clinical University Hospital Latvian Oncology Center
• Lithuania
  • Kaunas County
    • Kaunas, Kaunas County, Lithuania, LT-50161
      • Hospital of Lithuanian University of Health Sciences Kaunas Clinics
    • Kaunas, Kaunas County, Lithuania, LT-50161
      • Hospital of Lithuanian University of Health Sciences Kauno klinikos
  • Vilnius County
    • Vilnius, Vilnius County, Lithuania, LT-08660
      • National Cancer Institute
• Poland
  • Bydgoszcz, Poland, 85-796
    • Centrum Onkologii im. Prof. Franciszka Lukaszczyka w Bydgoszczy
  • Lodz, Poland, 90-302
    • Instytut Medyczny Santa Familia Sp. z o. o.
  • Lublin, Poland, 20-362
    • Specjalistyczna Praktyka Lekarska Slawomir Mandziuk
  • Olsztyn, Poland, 10-357
    • Warminsko-Mazurskie Centrum Chorob Pluc w Olsztynie
  • Poznan, Poland, 60-569
    • Med-Polonia Sp. z o.o.
  • Pomeranian Voivodeship
    • Gdansk, Pomeranian Voivodeship, Poland, 80-214
      • Uniwersyteckie Centrum Kliniczne-Ul. Smoluchowskiego 17
  • Łódź Voivodeship
    • Lodz, Łódź Voivodeship, Poland, 90-242
      • Centrum Terapii Wspolczesnej
• Switzerland
  • Bern, Switzerland, 3010
    • Universitaetsspital Bern - Inselspital
  • Thurgau (de)
    • Münsterlingen, Thurgau (de), Switzerland, 8596
      • Kantonsspital Muensterlingen
  • Zurich (de)
    • Winterthur, Zurich (de), Switzerland, 8400
      • Kantonsspital Winterthur
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • HonorHealth
  • California
    • Orange, California, United States, 92868
      • University of California Irvine Medical Center
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute (SCI)
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Cancer Center
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Cancer Center at Augusta University
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • The Center for Cancer and Blood Disorders - PPDS
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Cancer Institute Of New Jersey
  • New York
    • The Bronx, New York, United States, 10461
      • Montefiore Einstein Cancer Center - BRANY - PPDS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina at Chapel Hill
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Peggy and Charles Stephenson Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Cancer Institute, Franz Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Hillman Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • San Antonio, Texas, United States, 78229
      • START South Texas Accelerated Research Therapeutics
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists (Fairfax) - USOR

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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).	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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).	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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).	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.
Experimental: 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.	Drug: TAK-981; TAK-981 IV infusion.; Drug: Pembrolizumab; Pembrolizumab IV infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 except cytokine release syndrome (CRS), which was graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS.	Up to approximately 24 months
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)	DLTs were evaluated according to NCI CTCAE Version 5.0 except CRS, which was graded according to ASTCT Consensus Grading for CRS.	Up to Cycle 1 (each cycle was of 21 days)
Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (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 NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT Consensus Grading for CRS.	Up to approximately 24 months
Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs)	An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.	Up to approximately 24 months
Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation	An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.	Up to approximately 24 months
Phase 1: Number of Participants With Clinically Significant Laboratory Values	Laboratory parameters included clinical chemistry, hematology, and urinalysis. Participants with at least 1 Grade 3 or 4 Lab Abnormalities were reported.	Up to approximately 24 months
Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1	ORR is defined as the percentage of participants who achieve Complete Response (CR) and Partial Response (PR) (determined by the investigator) during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.	Up to approximately 25 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981		Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981		Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981		Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981		Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981		Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981		Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981		Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Phases 1 and 2: Disease Control Rate (DCR)	DCR is defined as the percentage of participants who achieved stable disease (SD) or better (CR + PR + SD determined by the investigator) >6 weeks during the trial in the response-evaluable population.	Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Durable Response Rate (DRR)	DRR is defined as the rate of objective responses (CR + PR) maintained for at least 6 months initiating at any time within 12 months of commencing therapy.	Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Duration of Response (DOR)	DOR is defined as a time from the time of first documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study.	Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Progression-free Survival (PFS)	PFS is defined as 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, through the end of the study.	Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Time to Response (TTR)	TTR is defined as time from the date of the first dose administration to the date of first documented PR or better.	Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phases 1 and 2: Time to Progression (TTP)	TTP is defined as the from the date of the first dose administration to the date of the first documentation of PD as defined by standard disease criteria.	Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Phase 2: Overall Survival (OS)	OS is defined as the time from the date of the first dose administration to the date of death. Participants without documentation of death at the time of analysis were censored at the date last known to be alive.	Up to approximately 25 months
Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes	The level of TAK-981-SUMO adduct formation was evaluated by flow cytometry as the percentage of adduct formed in peripheral blood lymphocytes. Fold change from baseline was calculated as: Post-treatment value / Baseline value. Positive change denotes improvement.	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)
Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes	SUMO pathway inhibition in blood was evaluated by flow cytometry in peripheral blood lymphocytes with an antibody recognizing SUMO 2/3 chains. Fold change from baseline was calculated as: Post-treatment value / Baseline value.	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 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs)	An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. AEs were evaluated according to NCI CTCAE, Version 5.0 except CRS, which was graded according to ASTCT Consensus Grading for CRS.	Up to approximately 25 months
Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)	An 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 NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT Consensus Grading for CRS.	Up to approximately 25 months
Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation	An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.	Up to approximately 25 months

Collaborators and Investigators

• Sponsor: Takeda
• Collaborators: Takeda Development Center Americas, Inc.
• Investigators: Study Director: Medical Director, Takeda

Publications and helpful links

General Publications

• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2020
• Primary Completion (Actual): October 29, 2024
• Study Completion (Actual): October 29, 2024

Study Registration Dates

• First Submitted: May 6, 2020
• First Submitted That Met QC Criteria: May 6, 2020
• First Posted (Actual): May 11, 2020

Study Record Updates

• Last Update Posted (Actual): December 10, 2025
• Last Update Submitted That Met QC Criteria: November 24, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab; TAK-981
• Other Study ID Numbers: TAK-981-1502; 2020-004325-23 (EudraCT Number); jRCT2031210417 (Registry Identifier: jRCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No