A Study of Tucatinib Plus Trastuzumab Deruxtecan in HER2+ Breast Cancer

Study Overview
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Brief Summary
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This trial studies how well the drug tucatinib works when given with trastuzumab deruxtecan (T-DXd). It will also look at what side effects happen when these drugs are given together. A side effect is anything a drug does besides treating cancer. Participants in this trial have HER2-positive (HER2+) breast cancer that has either spread to other parts of the body (metastatic) or cannot be removed completely with surgery (unresectable). All participants will get both tucatinib and T-DXd.

Official Title
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A Single Arm, Open Label Phase 2 Study of Tucatinib in Combination With Trastuzumab Deruxtecan in Subjects With Previously Treated Unresectable Locally-Advanced or Metastatic HER2+ Breast Cancer

Conditions
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HER2 Positive Breast Cancer

Intervention / Treatment
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* Drug: tucatinib
* Drug: trastuzumab deruxtecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Have confirmed HER2+ breast cancer, as defined by the current American Society of Clinical Oncology - College of American Pathologists (ASCO/CAP) guidelines, previously determined at a Clinical Laboratory Improvements Amendments (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory. History of prior treatment with a taxane and trastuzumab in the LA/M setting OR progressed within 6 months after neoadjuvant or adjuvant treatment, including a taxane and trastuzumab. Have progression of unresectable LA/M breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy Have measurable disease assessable by RECIST v1.1 Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 Have a life expectancy of at least 6 months, in the opinion of the investigator CNS Inclusion - Based on medical history and screening contrast brain magnetic resonance imaging (MRI), participants with a history of brain metastases must have one of the following: Untreated brain metastases not needing immediate local therapy. For participants with untreated central nervous system (CNS) lesions >2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment Previously treated brain metastases Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator Participants treated with CNS local therapy for newly identified or previously treated progressing lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met: Time since whole brain radiation therapy (WBRT) is ≥14 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is ≥7 days prior to first dose of study treatment, or time since surgical resection is ≥28 days Other sites of measurable disease by RECIST v1.1 are present Relevant records of any CNS treatment must be available Exclusion Criteria Have previously been treated with: Lapatinib or neratinib within 12 months of starting study treatment (except in cases where lapatinib or neratinib was given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity) Tucatinib or enrolled on a tucatinib clinical trial Any investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) (eg, afatinib) at any time previously Trastuzumab deruxtecan or another antibody-drug conjugate (ADC) consisting of an exatecan derivative Have received treatment with: Any systemic anti-cancer therapy (including hormonal therapy) or experimental agent ≤21 days of first dose of study treatment or are currently participating in another interventional clinical trial. An exception for the washout of hormonal therapies is gonadotropin releasing hormone (GnRH) agonists used for ovarian suppression in premenopausal women, which are permitted concomitant medications Treatment with non-CNS radiation ≤7 days prior to first dose of study treatment Major surgery <28 days of first dose of study treatment Have clinically significant cardiopulmonary disease (such as history of iterstitial lung disease (ILD)/pneumonitis that required systemic corticosteroids, or have current ILD/pneumonitis, or where suspected ILD /pneumonitis cannot be ruled out be imaging at screening) Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C infection. Participants who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks Presence of known chronic liver disease Active or uncontrolled clinically serious infection Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Tucatinib + trastuzumab deruxtecan | Drug: tucatinib<br>* 300 mg orally twice daily<br>* Other names: TUKYSA, ARRY-380, ONT-380;Drug: trastuzumab deruxtecan<br>* 5.4 mg/kg via intravenous (into the vein; IV) infusion on Day 1 of each of 21-day cycle<br>* Other names: T-DXd, Enhertu, DS-8201;|

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 (RECIST) version 1.1 according to investigator assessment | ORR is defined as the proportion of subjects with confirmed complete response (CR) or partial response (PR) per RECIST v1.1 | From start of treatment up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) per RECIST v1.1 according to investigator assessment | DOR is defined as the time from first documentation of objective response to the first documentation of disease progression per RECIST v1.1 or death from any cause, whichever occurs earlier | From start of treatment up to approximately 3 years | 
| Progression-free survival (PFS) per RECIST v1.1 according to investigator assessment | PFS is defined as the time from start of study treatment to first documentation of tumor progression or to death due to any cause, whichever comes first | From start of treatment up to approximately 3 years | 
| Disease control rate (DCR) per RECIST v1.1 according to investigator assessment | DCR is defined as the proportion of subjects with confirmed CR, PR or stable disease according to RECIST v1.1 | From start of treatment up to approximately 3 years | 
| Overall survival (OS) | OS is defined as the time from treatment initiation to death due to any cause | From start of treatment up to approximately 5 years | 
| Incidence of adverse events (AEs) | An AE is defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | From start of treatment up to approximately 3 years | 
| Incidence of laboratory abnormalities |  | From start of treatment up to approximately 3 years | 
| Incidence of dose modifications |  | From start of treatment up to approximately 3 years | 
| Incidence of treatment discontinuations |  | From start of treatment up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2+ breast cancer, Metastatic breast cancer, Stage IV breast cancer, Seattle Genetics