A Study of Tucatinib (MK-7119) in Combination With Trastuzumab and Capecitabine in Participants With Previously Treated Locally Advanced Unresectable or Metastatic Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Breast Carcinoma (MK-7119-001)

Study Overview
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Brief Summary
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The goal of this study is to evaluate the efficacy and safety of tucatinib in combination with trastuzumab and capecitabine in participants with unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with taxane anti-cancer agent, trastuzumab, pertuzumab and trastuzumab emtansine (T-DM1). The primary hypothesis is that the confirmed objective response rate (cORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as determined by independent central review (ICR) for the combination of tucatinib, trastuzumab and capecitabine, is greater than 20%.

Official Title
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A Phase 2 Open-label, Single Arm Study of MK-7119 in Combination With Trastuzumab and Capecitabine in Participants With Previously Treated Locally Advanced Unresectable or Metastatic HER2+ Breast Carcinoma

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Tucatinib
* Biological: Trastuzumab
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically confirmed HER2+ breast carcinoma Has received previous treatment with taxane anti-cancer agent, trastuzumab, pertuzumab, and T-DM1 with the exception of when the use of taxanes is contraindicated or judged not to be the best treatment at the investigator's discretion Has radiographically and/or histologically confirmed disease progression on last systemic anticancer treatment Has adequate organ function Female participant is not pregnant or breastfeeding and is not a woman of childbearing potential (WOCBP) or is a WOCBP and using contraception or abstinent from heterosexual intercourse during the intervention period and for at least 30 days after receiving the last dose of tucatinib, 80 days after receiving the last dose of trastuzumab, or 180 days after receiving the last dose of capecitabine, whichever occurs last and agrees to not donate eggs during this period Male participants refrain from donating sperm and are either abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 7 days after receiving the last dose of tucatinib and 90 days after receiving the last dose of capecitabine, whichever occurs last Previously treated brain metastasis is stable or progressed, provided there is no clinical indication for immediate re-treatment Exclusion Criteria: Has been previously treated with lapatinib within 12 months of starting study treatment Has been previously treated with neratinib, afatinib, tucatinib or capecitabine Has a history of exposure to doxorubicin, epirubicin, mitoxantrone, idarubicin, liposomal doxorubicin Has had treatment with any systemic anti-cancer therapy including hormonal therapy, non-central nervous system (CNS) radiation or experimental agent ≤3 weeks before first dose of study treatment Has any toxicity related to prior cancer therapies that has not resolved with the exception of alopecia, congestive heart failure, anemia Has clinically significant cardiopulmonary disease Has known myocardial infarction or unstable angina within 6 months prior to the first dose of study treatment Has any uncontrolled viral, bacterial or fungal infection within 14 days prior to the first dose of study treatment Is positive for Hepatitis B, Hepatitis C or has known chronic liver disease Is known to be positive for human immunodeficiency virus (HIV) Has evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment Has ongoing use of systemic corticosteroids for control of symptoms of brain metastases Has any brain lesion thought to require immediate local therapy Has known or suspected leptomeningeal disease (LMD) Has poorly controlled generalized or complex partial seizures or manifest neurologic progression due to brain metastases

Ages Eligible for Study
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Minimum Age: 20 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tucatinib + Trastuzumab + Capecitabine<br>Participants will receive tucatinib plus trastuzumab plus capecitabine. Tucatinib 300 mg will be administered orally twice daily (BID). Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg maintenance dose thereafter, will be administered intravenously (IV) on Day 1 of each 21-day cycle. Capecitabine 1000 mg/m^2 will be administered orally BID on Days 1-14 of each 21-day cycle. Tucatinib, trastuzumab and capecitabine treatment will continue until unacceptable toxicity, disease progression, death, withdrawal of consent or study closure. | Drug: Tucatinib<br>* Tucatinib 300 mg administered BID via oral tablet<br>* Other names: Tukysa;Biological: Trastuzumab<br>* Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg maintenance dose, administered via IV infusion<br>* Other names: Herceptin Hylecta;Drug: Capecitabine<br>* Capecitabine 1000 mg/m^2 administered BID via oral tablet<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (cORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), as Determined by Independent Central Review (ICR) | cORR is defined as the percentage of participants who have a confirmed Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) per RECIST v1.1. The percentage of participants who experience a confirmed CR or PR as determined by ICR based on RECIST v1.1 will be presented. | Up to  21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cORR per RECIST v1.1, as Determined by Investigator Assessment (INV) | cORR is defined as the percentage of participants who have a confirmed CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) per RECIST v1.1. The percentage of participants who experience a confirmed CR or PR as determined by INV based on RECIST v1.1 will be presented. | Up to  92 months | 
| Duration of Response (DOR) per RECIST v1.1, as Determined by ICR | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) per RECIST v1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST v1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The DOR as determined by ICR based on RECIST v1.1 will be presented. | Up to  92 months | 
| DOR per RECIST v1.1, as Determined by INV | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) per RECIST v1.1, DOR is defined as the time from first documented evidence of CR or PR until PD or death due to any cause, whichever occurs first. Per RECIST v1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The DOR as determined by INV based on RECIST v1.1 will be presented. | Up to  92 months | 
| Progression-free Survival (PFS) per RECIST v1.1, as Determined by ICR | PFS is defined as the time from randomization to the first documented PD or death due to any cause, whichever occurs first. Per RECIST v1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as determined by ICR based on RECIST v1.1 will be presented. | Up to  92 months | 
| PFS per RECIST v1.1, as Determined by INV | PFS is defined as the time from randomization to the first documented PD or death due to any cause, whichever occurs first. Per RECIST v1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as determined by INV based on RECIST v1.1 will be presented. | Up to  92 months | 
| Overall Survival (OS) | OS is defined as the time from start of study treatment to death due to any cause. | Up to  92 months | 
| Number of Participants Who Experience One or More Adverse Events (AEs) | An AE is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. The number of participants who experience one or more AEs will be presented. | Up to  92 months | 
| Number of Participants who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE will be presented. | Up to  92 months |