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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Neoplasms, Lymphoma, Hematologic Neoplasms

Intervention / Treatment
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* Drug: TAK-981


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Relapsed/refractory DLBCL that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic therapy and has not received prior cellular therapy. At least one prior line of therapy must have included a CD20-targeted therapy (cohort E). Relapsed/refractory FL that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic therapy. At least 1 prior line of therapy must have included a CD20-targeted therapy (cohort F). In Phase 2 only, have at least 1 radiologically measurable lesion based on RECIST v1.1 for participants with solid tumors or Lugano criteria for lymphoma. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Note: In Phase 2 stage 1, have an additional lesion for pretreatment and on-treatment biopsy. In Phase 2 stage 1, willing to consent to mandatory pretreatment and on-treatment tumor biopsy. Note: For fresh tumor biopsies, the lesion must be accessible for a biopsy procedure as assessed by the investigator. Is willing to provide archival tumor tissue sample, if available. Adequate bone marrow reserve and renal and hepatic function. Recovered to Grade 1 or baseline or established as sequelae from all toxic effects of previous therapy (except alopecia, neuropathy, or autoimmune endocrinopathies with stable endocrine replacement therapy, bone marrow parameters [any of Grade 1 or 2 permitted if directly related to bone marrow involvement). Consented to undergo serial skin punch biopsies (dose escalation only). Suitable venous access for safe drug administration and the study-required PK and pharmacodynamics sampling. Women of childbearing potential participating in this study should avoid becoming pregnant, and male participants should avoid impregnating a female partner. Nonsterilized female participants of reproductive age and male participants should use effective methods of contraception through defined periods during and after study treatment as specified below. Female participants must meet 1 of the following: Postmenopausal for at least 1 year before the screening visit, or Surgically sterile, or If they are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception at the same time, from the time of signing of the informed consent form (ICF) through 6 months after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) Male participants, even if surgically sterilized (that is, status post vasectomy) must agree to 1 of the following: Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) 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. 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. Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and inducers of cytochrome P-450 3A4/5 (CYP3A4/5) or are strong permeability glycoprotein (P-gp) inhibitors. To participate in this study, participants should discontinue use of such agents for at least 2 weeks (1 week for CYP3A4/5 and P-gp inhibitors) before receiving a dose of TAK-981. Participant requires the use of drugs known to prolong QTc interval (during Phase 1 only). History of allogeneic tissue or solid organ transplant. 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. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1, Dose Escalation Cohort: TAK-981<br>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<br>* Intravenous infusion.<br>|
| Experimental: Phase 2, Cohort A: Nonsquamous NSCLC<br>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<br>* Intravenous infusion.<br>|
| Experimental: Phase 2, Cohort B: Cervical Cancer<br>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<br>* Intravenous infusion.<br>|
| Experimental: Phase 2, Cohort C: MSS-CRC<br>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<br>* Intravenous infusion.<br>|
| Experimental: Phase 2, Cohort D: r/r DLBCL after CAR T-cells therapy<br>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<br>* Intravenous infusion.<br>|
| Experimental: Phase 2, Cohort E: r/r DLBCL without prior cellular therapy<br>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<br>* Intravenous infusion.<br>|
| Experimental: Phase 2, Cohort F: r/r Follicular Lymphoma<br>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<br>* Intravenous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants Reporting one or More Treatment Emergent Adverse Events (TEAEs) |  | Up to 48 months | 
| Phase 1: Number of Participants Based on Severity of TEAEs | Severity grade will be 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 will be assessed by American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria. | Up to 48 months | 
| Phase 1: Number of Participants With Clinically Significant Laboratory Values |  | Up to 48 months | 
| Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) |  | Up to Cycle 1 (Cycle length is equal to [=] 21 days) | 
| Phase 2: Overall Response Rate (ORR) | ORR is defined as percentage of participants who achieve complete response (CR) and partial response (PR), as determined by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) for participants with solid tumors or Lugano classification for lymphoma. | From the first dose until best response is achieved (up to 48 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1, Cmax: Maximum Observed Plasma Concentration for TAK-981 |  | Cycle 1 Day 1: Up to 48 hours post dose; Cycle 1 Day 8: 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: Up to 48 hours post dose; Cycle 1 Day 8: Up to 24 hours post dose (Cycle length =21 days) | 
| Phase 1, AUClast: 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: Up to 48 hours post dose; Cycle 1 Day 8: Up to 24 hours post dose (Cycle length =21 days) | 
| Phase 1, AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981 |  | Cycle 1 Day 1: Up to 48 hours post dose; Cycle 1 Day 8: Up to 24 hours post dose (Cycle length =21 days) | 
| Phase 1, Terminal Disposition Phase Half-life (t1/2z) for TAK-981 |  | Cycle 1 Day 1: Up to 48 hours post dose; Cycle 1 Day 8: Up to 24 hours post dose (Cycle length =21 days) | 
| Phase 1, Total Clearance (CL) After Intravenous Administration for TAK-981 |  | Cycle 1 Day 1: Up to 48 hours post dose; Cycle 1 Day 8: Up to 24 hours post dose (Cycle length =21 days) | 
| Phase 1, Volume of Distribution at Steady State After Intravenous Administration (Vss) for TAK-981 |  | Cycle 1 Day 1: Up to 48 hours post dose; Cycle 1 Day 8: Up to 24 hours post dose (Cycle length =21 days) | 
| Phase 1: ORR | ORR is defined as percentage of participants who achieve CR and PR through the study (approximately 48 months), as determined by the investigator according to the RECIST V1.1 for participants with solid tumors or Lugano classification for lymphoma. | From the first dose until best response is achieved (up to 48 months) | 
| Phase 1 and Phase 2: Disease Control Rate (DCR) | DCR is defined as the percentage of participants who achieve stable disease (SD) or better (determined by the investigator according to RECIST v1.1 criteria for solid tumors or Lugano classification for lymphoma) greater than (>) 6 weeks during the study in the response-evaluable population. | From the first dose until best response is achieved (up to 48 months) | 
| Phase 1 and Phase 2: Duration of Response (DOR) | DOR is the time from the date of first documentation of a PR or better to the date of first documentation of progressive disease for responders (PR or better) and will be determined by the investigator according to RECIST v1.1 for participants with solid tumors or Lugano classification for lymphoma. | From the time of 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 (up to 48 months) | 
| Phase 1 and Phase 2: Time to Progression (TTP) | TTP is defined as the time from the date of the first dose administration to the date of first documented progressive disease and will be determined by the investigator according to RECIST v1.1 for participants with solid tumors or Lugano classification for lymphoma. | From the date of first study drug administration to the date of first documented PD (up to 48 months) | 
| Phase 1 and Phase 2: Time to Response (TTR) | TTR is defined as the time from the date of first study drug administration to the date of first documented PR or better by the investigator for responders according to RECIST v1.1 for participants with solid tumors or Lugano classification for lymphoma. | From the date of first study drug administration to the date of first documented PR or better (up to 48 months) | 
| Phase 1 and Phase 2: Progression-free Survival (PFS) | PFS is defined as the time from the date of the first dose administration to the date of first documentation of progressive disease or death due to any cause, whichever occurs first and will be determined by the investigator according to RECIST v1.1 for participants with solid tumors or Lugano classification for lymphoma. | 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 (up to 48 months) | 
| Phase 1: Number of Participants With TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation and SUMO Pathway Inhibition in Skin/Blood |  | Up to 48 months | 
| Phase 2: Number of Participants Reporting one or More TEAEs |  | Up to 48 months | 
| Phase 2: Number of Participants Based on Severity of TEAEs | Severity grade will be evaluated as per the NCI CTCAE Version 5.0, except for CRS, which will be assessed by ASTCT consensus grading criteria. | Up to 48 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. | From the date of first study drug administration to the date of death (up to 48 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy