A Study of TAK-676 With Pembrolizumab After Radiation Therapy to Treat a Number of Cancers

Study Overview
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Brief Summary
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In this study, adults with non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC) and squamous-cell carcinoma of the head and neck (SCCHN) will be treated with TAK-676 and pembrolizumab following radiotherapy. The main aims of this study are to check if people are improving after treatment with TAK-676, getting side effects from these combined treatments, and how much TAK-676 people with these cancers can receive without getting unacceptable side effects from it. Participants will receive radiotherapy, then at least 40 hours later will receive pembrolizumab followed by TAK-676 slowly through a vein (infusion). Participants will receive an infusion of pembrolizumab at the same dose every 3 weeks. Different small groups of participants will receive lower to higher doses of TAK-676 on specific days of a 21-day cycle. This study will be happening at sites in North America.

Detailed Description
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The drug being tested in this study is called TAK-676. This study will evaluate the safety, tolerability and preliminary antitumor activity of TAK-676 with pembrolizumab following radiation therapy in the treatment of advanced NSCLC, TNBC or SCCHN that has progressed on checkpoint inhibitors (CPIs) and will estimate the maximum tolerated dose (MTD) and determine the recommended phase 2 dose (RP2D) of this combination. The study will enroll approximately 65 participants. Participants will be assigned to dose escalating cohorts based on Bayesian Optimal Interval (BOIN) design. The starting dose of TAK-676 will be 0.2 mg and the subsequent dosing will be initiated based on the available safety and tolerability data from the previous cohort. This multi-center trial will be conducted in the United States. There will be many clinic visits. The number of visits will depend on the number of cycles of treatment. Participants will attend an end of treatment (EOT) visit 30 days after receiving their last dose of study drug or before the start of subsequent systemic anticancer therapy, whichever occurs first. They might continue to have check-ups every 12 weeks if they left the study for a reason apart from their cancer getting worse.

Official Title
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An Open-label, Phase 1, Dose-escalation Study to Evaluate the Safety and Preliminary Antitumor Activity of TAK-676 With Pembrolizumab Following Radiation Therapy in the Treatment of Non-small-cell Lung Cancer, Triple-negative Breast Cancer, or Squamous-cell Carcinoma of the Head and Neck That Has Progressed on Checkpoint Inhibitors

Conditions
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Squamous Cell Carcinoma of Head and Neck, Carcinoma, Non-Small-Cell Lung, Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: TAK-676
* Radiation: Image-guided radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Participants must have at least 2 measurable lesions (i.e. ≥10 mm longest diameter for extranodal lesions, ≥15 mm short axis for lymph nodes), with at least one inside and at least one other outside of the radiation field. The tumor outside the radiation field must be accessible for biopsy, and the participant must consent to tumor biopsy at screening and during treatment. Participants must have pathologically confirmed (cytological diagnosis is adequate) advanced or metastatic NSCLC, TNBC, or SCCHN who have: Received or been offered all established standard of care (SOC) treatment options for which they are eligible; and Progressed on CPIs in a prior line of therapy. Adequate bone marrow, renal and hepatic functions. Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan within 4 weeks before receiving the first dose of study drug. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI CTCAE, V5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy. Exclusion Criteria: History of any serious cardiac or cerebrovascular conditions in the last 6 months, including uncontrolled congestive heart disease, unstable angina, myocardial infarction, hypertension greater than or equal to (≥) 160/100 millimeter of mercury (mmHg) in spite of optimal therapy, cardiac arrhythmias, pericardial effusion, cardiomyopathy, or symptomatic stroke. Chronic, stable atrial fibrillation on stable anticoagulation therapy, including low molecular weight heparin, will be allowed. History of brain metastasis unless: Clinically stable, (that is, treatment completed ≥4 weeks prior) following prior surgery, whole-brain radiation, or stereotactic radiosurgery, AND Off corticosteroids. Known history of uncontrolled autoimmune disorders, human immunodeficiency virus (HIV) infection, or other relevant congenital or acquired immunodeficiencies. Chronic, active hepatitis (example, participants with known hepatitis B surface antigen seropositive and/or detectable hepatitis C virus [HCV]-ribonucleic acid [RNA]). Treatment with any investigational products and systemic anticancer drugs (including vascular endothelial growth factor (VEGF) inhibitors), within 14 days or 5 half-lives, whichever is shorter, before Cycle 1 Day 1 (C1D1) of study drugs. Prior radiation to lesions chosen for biopsy or response assessment. Prior radiation to lesions other than those chosen for radiation therapy or biopsy in the current protocol within 4 weeks of C1D1 of study drug(s). Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of start of radiation therapy, 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). Receipt of live attenuated vaccine (example, tuberculosis Bacillus Calmette-guerin [BCG] vaccine, oral polio vaccine, measles, rotavirus, yellow fiver) within 28 days of C1D1 of study drug(s). Recipients of allogeneic or autologous stem cell transplantation or organ transplantation. Ongoing Grade ≥2 infection or participants with Grade ≥2 fever of malignant origin. Fridericia's corrected QT interval (QTcF) >450 milliseconds (msec) (males) or >475 msec (females) on a 12-lead electrocardiogram (ECG) during the screening period. Grade ≥2 hypotension (that is, hypotension for which nonurgent intervention is required) at screening or during C1D1 pre-dose assessment. Oxygen saturation less than (<) 92% on room air at screening or during C1D1 predose assessment. Use of medications that are known clinical organic anion transporting polypeptide 1B1 (OATP1B1) and/or OATP1B3 inhibitors, concurrently or within 14 days of C1D1 of study drugs. Current smoker. Vaping within 90 days of C1D1 of study drugs. Current diagnosis of pneumonitis, interstitial lung disease, severe chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, other restrictive lung diseases, acute pulmonary embolism, or Grade ≥2 pleural effusion or ascites not controlled by tap or requiring indwelling catheters. Treated with other stimulator of interferon genes (STING) agonists/antagonist and toll-like receptors agonists within the past 6 months.

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination Dose Escalation Phase: Radiation + Pembrolizumab + TAK-676<br>Participants will receive image-guided radiation therapy between Day -8 and Day -2. Participants will then receive pembrolizumab 200 milligram (mg), infusion, intravenously (IV), once on Day 1 of Cycle 1 and then every 3 weeks in each 21-day treatment cycle, followed by TAK-676 infusion with escalating doses (0.2 mg and above), IV, once on Days 1, 8, 15 in each 21-day treatment cycle until disease progression, intolerance to pembrolizumab or TAK-676 or withdrawal of consent, whichever occurs first. | Drug: Pembrolizumab<br>* IV infusion.<br>Drug: TAK-676<br>* IV infusion.<br>Radiation: Image-guided radiation therapy<br>* Radiation therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Based on TEAEs Severity | AE: any untoward medical occurrence in participants administered with pharmaceutical product that does not necessarily have a causal relationship with this treatment. TEAE: any AE either reported for the first time or worsening of a pre-existing event after the first dose of study drug is considered treatment emergent. Severity grade is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Grade 1: Mild (asymptomatic/mild symptoms; clinical/diagnostic observations only; intervention not indicated); Grade 2: Moderate (minimal, local/noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living [ADL]); Grade 3: Severe (severe/medically significant but not immediately life-threatening hospitalization/prolongation of hospitalization indicated; disabling; limiting self-care ADL); Grade 4: Life-threatening consequences, urgent intervention indicated; Grade 5: Death related to AE. | From first dose of study drug administration up to 30 months | 
| Number of Participants with Dose-limiting Toxicities (DLTs) | A DLT is defined as any TEAE that occur during Cycle 1 and is considered by investigator to be at least possibly related to TAK-676 in combination with pembrolizumab. TEAEs meeting DLT definitions occurring in later cycles will be considered in the determination of RP2D of TAK-676. DLTs will be assessed based on NCI CTCAE version 5.0. | Up to 30 months | 
| Number of Participants Reporting One or More Treatment Emergent Serious Adverse events (TESAEs) | TEAE: any AE either reported for the first time or worsening of a pre-existing event after the first dose of study drug is considered treatment emergent. An SAE is defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is a medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization | From first dose of study drug administration up to 30 months | 
| Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE: any AE either reported for the first time or worsening of a pre-existing event after the first dose of study drug is considered treatment emergent. | From first dose of study drug administration up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Assessed by Investigator as per RECIST v1.1 | ORR will be defined as the percentage of participants who achieve confirmed complete response (cCR) or confirmed partial response (cPR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version1.1 (RECIST, V1.1). | Up to 30 months | 
| Duration of Response (DOR) For all Tumor Lesions Assessed by Investigator as per RECIST v1.1 | DOR will be defined as 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 stable disease (SD) or better. Evaluation will be determined by the investigator according to RECIST, V1.1. | From date of first documentation of cPR or better to the date of first documentation of progressive disease (PD) (up to 30 months) | 
| Time to Response (TTR) For all Tumor Lesions Assessed by Investigator as per RECIST v1.1 | TTR will be defined as the time from the date of first dose administration to the date of first documented cPR or better as determined by the investigator according to RECIST, V1.1. | From the date of first dose administration to the date of first documented cPR or better (Up to 30 months) | 
| Overall Response Rate Assessed by Investigator as per Modified Intratumoral Immunotherapy RECIST (modified itRECIST) | ORR will be defined as the percentage of participants who achieve confirmed complete response (cCR) or confirmed partial response (cPR) as determined by the investigator according to Modified itRECIST. | Up to 30 months | 
| Overall Response Rate For Tumors Within the Radiation Field (ORRirradiated) | ORRirradiated will be defined as the percentage of participants who achieve cCRirradiated or cPRirradiated in the tumor lesions lying within the radiation field as determined by the investigator according to modified itRECIST. | Up to 30 months | 
| Overall Response Rate For Tumors Outside the Radiation Field (ORRnonirradiated) | ORRnonirradiated will be defined as the percentage of participants who achieve cCRnonirradiated or cPRnonirradiated in the tumor lesions lying outside of the radiation field as determined by the investigator according to modified itRECIST. | Up to 30 months | 
| Duration of Response (DOR) For Tumors Within the Radiation Field (DORirradiated) | DORirradiated for tumor lesions lying within radiation field will be defined as the time from the date of first documentation of a cPRirradiated or better to the date of first documentation of irradiated PD in those lesions for irradiated responders (cPRirradiated or better). Irradiated responders without documentation of irradiated PD will be censored at the date of last response assessment that is irradiated SD or better. Evaluation will be determined by the investigator according to modified itRECIST. | From date of first documentation of cPRirradiated or better to the date of first documentation of irradiated PD (up to 30 months) | 
| Duration of Response (DOR) For Tumors Outside the Radiation Field (DORnonirradiated) | DORnonirradiated for tumor lesions lying outside of the radiation field will be defined as time from the date of first documentation of a cPRnonirradiated or better to the date of first documentation of nonirradiated PD in those lesions for nonirradiated responders (cPRnonirradiated or better). Nonirradiated responders without documentation of nonirradiated PD will be censored at the date of last response assessment that is nonirradiated SD or better. Evaluation will be determined by the investigator according to modified itRECIST. | From date of first documentation of cPRnonirradiated or better to the date of first documentation of nonirradiated PD (up to 30 months) | 
| Time to Response (TTR) For Tumors Within the Radiation Field (TTRirradiated) | TTRirradiated in the tumor lesions lying within the radiation field will be defined as the time from the date of first dose administration to the date of first documented cPRirradiated or better as determined by the investigator according to modified itRECIST. | From the date of first dose administration to the date of first documented cPRirradiated or better (up to 30 months) | 
| Time to Response (TTR) For Tumors Outside the Radiation Field (TTRnonirradiated) | TTRnonirradiated in the tumor lesions lying outside of the radiation field will be defined as the time from the date of first dose administration to the date of first documented cPRnonirradiated or better during the study in response-evaluable population as determined by the investigator according to modified itRECIST. | From the date of first dose administration to the date of first documented cPRnonirradiated or better (up to 30 months) | 
| Number of Participants with Increase in T-Cell Infiltration in Tumor Evaluated by Immunohistochemistry | Participants with the increase in T-cell infiltration levels between the pretreatment and on-treatment tumor biopsies will be reported. | Up to approximately 30 months | 

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