A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors

A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors

An Open-label, Dose Escalation and Expansion, Phase 1a/1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-500, a Novel Stimulator of Interferon Genes Agonist, as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Select Locally Advanced or Metastatic Solid Tumors

This study is about TAK-500, given either alone or with pembrolizumab, in adults with select locally advanced or metastatic solid tumors. The aims of the study are: to assess the safety profile of TAK-500 when given alone and when given with pembrolizumab. to assess the effects of TAK-500, when given alone and when given with pembrolizumab, on adults with locally advanced or metastatic solid tumors. Participants may receive TAK-500 for up to 1 year. Participants may continue with their treatment if they have continuing benefit and if this is approved by their study doctor. Participants who are receiving TAK-500 either alone or with pembrolizumab will continue with their treatment until their disease progresses or until they or their study doctor decide they should stop this treatment.

The drug being tested in this study is called TAK-500. The study will evaluate the safety, tolerability, antitumor activity, pharmacokinetics (PK), and pharmacodynamics of TAK-500 when used as a single agent (SA) and in combination with pembrolizumab in participants with locally advanced or metastatic solid tumors. The study will be conducted in 2 phases: Dose Escalation and Dose Expansion Phase. The study will enroll approximately 118 participants (approximately 84 in the Dose Escalation Phase and approximately 34 in Dose Expansion Phase). The dose escalation phase will determine the recommended dose of TAK-500 along with the combination agents for the dose expansion phase. All the participants will be assigned to one of the 3 cohorts: TAK-500 Single Agent (SA) (dosed Q3W or Q2W) Dose Escalation: TAK-500 (dosed Q3W or Q2W) + Pembrolizumab (dosed Q3W) Dose Expansion: TAK-500 (dosed Q3W and/or Q2W) + Pembrolizumab (dosed Q3W) This multi-center trial will be conducted in the United States. Participants with demonstrated clinical benefit may continue treatment beyond 1 year if approved by the sponsor.

Pancreatic Cancer, Hepatocellular Cancer, Mesothelioma, Breast Cancer, Gastric Cancer, Esophageal Cancer, Nasopharyngeal Cancer, Kidney Cancer, Squamous Cell Cancer of Head and Neck (SCCHN), Non-small Cell Lung Cancer (NSCLC), Non-squamous

TAK-500 dose escalation starting at 8 microgram per kilogram (mcg/kg), infusion, intravenously, once on Day 1 of each 21-day treatment cycle (once every 3 weeks, Q3W) or once on Day 1, 15 and 29 of each 42-day treatment cycle (every 2 weeks, Q2W), for up to 1 year.

TAK-500, infusion, intravenously, once on Day 1 of each 21-day treatment cycle (once every 3 weeks, Q3W) or once on Day 1, 15 and 29 of each 42-day treatment cycle (once every 2 weeks, Q2W), for up to 1 year, along with pembrolizumab 200 milligram (mg) infusion, intravenously, once on Day 1 of each 21-day treatment cycle or on Days 1 and 22 in a 42-day cycle (Q3W) for up to 1 year. The exact starting dose of TAK-500 will be determined from the results of the TAK-500 SA arm dose escalation.

TAK-500, infusion, intravenously, once on Days 1 and 22 (Q3W), or once on Days 1, 15, and 29, in a 42-day treatment cycle (once every 2 weeks, Q2W) with pembrolizumab 200 mg infusion, intravenously, once on Days 1 and 22, in a 42-day treatment cycle (Q3W) for up to 1 year. The dose of TAK-500 for the Dose Expansion arm will be based on the results of the TAK-500 in combination with pembrolizumab Dose Escalation arm.

TEAE Grades will be evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

DLT will be defined as any of the TEAEs that occur during Cycle 1 and are considered by the investigator to be at least possibly related to TAK-500 as a SA or in combination with pembrolizumab. Toxicity will be evaluated according to NCI CTCAE version 5.0.

Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations

Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1 and Cycle 4 Day 1: pre-infusion and at multiple time points (up to 21 days) post-infusion (Cycle length=21 days)

Cycle 1 Day 1, and Cycle 2 Day 1: pre-infusion and at multiple time points (up to 21 days) post-infusion (Cycle length=21 days)

Cycle 1 Day 1, and Cycle 2 Day 1: pre-infusion and at multiple time points (up to 21 days) post-infusion (Cycle length=21 days)

Cycle 1 Day 1, and Cycle 2 Day 1: pre-infusion and at multiple time points (up to 21 days) post-infusion (Cycle length=21 days)

Cycle 1 Day 1, and Cycle 2 Day 1: pre-infusion and at multiple time points (up to 21 days) post-infusion (Cycle length=21 days)

Cycle 1 Day 1, and Cycle 2 Day 1: pre-infusion and at multiple time points (up to 21 days) post-infusion (Cycle length=21 days)

ORR is defined as the percentage of participants who achieve cPR or cCR (determined by the investigator) during the study in the response-evaluable population. ORR will be assessed as per RECIST Version 1.1. CR: defined as disappearance of all target and non- target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than <10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. cPR or cCR is defined as a PR or CR that is confirmed with additional imaging 6 weeks after initial response.

DCR is defined as the percentage of participants who achieve cCR + cPR + stable disease (SD) or better (determined by the investigator) greater than (>) 6 weeks during the study in the response-evaluable population. DCR will be assessed as per RECIST Version 1.1. CR: disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: at least a 20% increase in the sum of diameters of target lesions.

DOR is defined as the time from the date of first documentation of a cPR or better to the date of first documentation of PD for responders (cPR or better). Responders without documentation of PD will be censored at the date of last response assessment that is SD or better. DOR will be assessed as per RECIST Version 1.1. PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: at least a 20% increase in the sum of diameters of target lesions.

TTR is defined as the time from the date of first dose administration to the date of first documented cPR or better (determined by the investigator) in the safety population. TTR will be assessed as per RECIST Version 1.1. PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.

PFS is defined as the time from date of study treatment to the first documented PD based on RECIST v.1.1, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of diameters of target lesions.

Measurement of changes in tumor immune cell infiltration will be measured by immunohistochemistry or in-situ hybridization on fresh tumor biopsies taken pre and post treatment (up to 23 days after first administration of TAK-500) for each participant.

Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Individuals with the following pathologically confirmed (cytological diagnosis is adequate) select locally advanced or metastatic solid tumors, whose disease has progressed on or are intolerant to all standard therapy: gastroesophageal (esophageal, gastroesophageal junction, and gastric) adenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma (HCC), nonsquamous non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), mesothelioma, triple-negative breast cancer (TNBC), renal clear cell carcinoma (RCC) and nasopharyngeal carcinoma (NPC). Participants who are intolerant to all standard therapies are those who have developed clinical or laboratory abnormalities that prevent continued drug administration as evaluated by the principal investigator at the time of screening. Must have at least 1 RECIST version 1.1 measurable lesion. Adequate bone marrow, renal, and hepatic functions, as determined by the following laboratory parameters: Absolute neutrophil count (ANC) greater than or equal to (>=) 1000/microliter (mcL), platelet count >=75,000/mcL, and hemoglobin >= 8.0 grams per deciliter (g/dL) without growth factor support for ANC or transfusion support for platelets within 14 days before the first study treatment dose. Total bilirubin <=1.5 times the institutional upper limit of normal (ULN). For participants with Gilbert's disease or HCC, <=3 milligrams per deciliter (mg/dL). Serum alanine aminotransferase and aspartate aminotransferase <=3.0*ULN or <=5.0*ULN with liver metastases or HCC. Albumin >=3.0 g/dL. Calculated creatinine clearance using the Cockcroft-Gault formula >=30 mL/minute. Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or multiple gated acquisition scan (MUGA) within 4 weeks before receiving the first dose of study drug. For participants with HCC only: Child-Pugh score less than or equal to 7 (Child-Pugh A or B7). Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy. Previously treated with fully human/humanized antineoplastic monoclonal antibodies must not have received treatment with such antibodies for at least 4 weeks or the time period equal to the dosing interval, whichever is shorter. No washout period is required for prior treatment with pembrolizumab or other anti-programmed cell death protein 1 (PD-1) antibodies, although the first study dose of these drugs must not occur at an interval less than standard of care (that is, 3 weeks for 200 mg of IV pembrolizumab). Exclusion Criteria: History of any of the following <=6 months before first dose of study drug(s): congestive heart failure New York Heart Association Grade III or IV, unstable angina, myocardial infarction, persistent hypertension >=160/100 millimeters of mercury (mmHg) despite optimal medical therapy, ongoing cardiac arrhythmias of Grade >2 (including atrial flutter/fibrillation or intermittent ventricular tachycardia), other ongoing serious cardiac conditions (example, Grade 3 pericardial effusion or Grade 3 restrictive cardiomyopathy), or symptomatic cerebrovascular events. Chronic, stable atrial fibrillation on stable anticoagulation therapy, including low molecular-weight heparin, is allowed. QT interval with Fridericia correction method >450 milliseconds (men) or >475 milliseconds (women) on a 12- lead ECG during the screening period. Grade >=2 hypotension (that is, hypotension for which nonurgent intervention is required) at screening or during C1D1 predose assessment. Oxygen saturation <92% on room air at screening or during C1D1 predose assessment. Treatment with other STING agonists/antagonists, Toll-like receptor agonists or CCR2 agonist/antagonist within the past 6 months. Active vaping within 90 days of C1D1 of study drug(s). Active smoking. Active diagnosis of pneumonitis, interstitial lung disease, severe chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, other restrictive lung diseases, acute pulmonary embolism, or Grade >=2 pleural effusion not controlled by tap or requiring indwelling catheters. Grade >=2 fever of malignant origin. Chronic, active hepatitis (example, participants with known hepatitis B surface antigen seropositive and/or detectable hepatitis C virus [HCV] RNA). History of hepatic encephalopathy. Prior or current clinically significant ascites, as measured by physical examination, that requires active paracentesis for control. Treatment with any investigational products or other anticancer therapy (including chemotherapy, targeted agents, and immunotherapy), within 14 days or 5 half-lives, whichever is shorter, before C1D1 of study drug(s). Radiation therapy within 14 days (42 days for radiation to the lungs) and/or systemic treatment with radionuclides within 42 days before C1D1 of study drug(s). Participants with clinically relevant ongoing pulmonary complications from prior radiation therapy are not eligible. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 14 days of C1D1 of study drug(s), with the following exceptions: Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids. Physiological doses of replacement steroid therapy (example, for adrenal insufficiency), not to exceed the equivalent of 10 mg prednisone daily. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation. Additional criteria specific for participants in TAK-500 and pembrolizumab combination arm only: Contraindication to the administration of a pembrolizumab or prior intolerance to pembrolizumab or other anti-PD-1 or anti-programmed cell death protein ligand 1 antibody. History of intolerance to any component of the study treatment agents or known serious or severe hypersensitivity reaction to any of the study drugs or their excipients. (Pembrolizumab is formulated with L-histidine, polysorbate 80, and sucrose

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 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.