A Study of Tucatinib or Placebo With Trastuzumab and Pertuzumab for Metastatic HER2+ Breast Cancer

Study Overview
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Brief Summary
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This study is being done to see if tucatinib works better than placebo when given with other drugs to treat participants with HER2-positive breast cancer. A placebo is a pill that looks the same as tucatinib but has no medicine in it. This study will also test what side effects happen when participants take this combination of drugs. A side effect is anything a drug does to the body besides treating your disease. Participants will have cancer that has spread in the body near where it started (locally advanced) and cannot be removed (unresectable) or has spread through the body (metastatic). In this study, all participants will get either tucatinib or placebo. Participants will be assigned randomly to a group. This is a blinded study, so patients and their doctors will not know which group a participant is in. All participants will also get trastuzumab and pertuzumab. These are 2 drugs used to treat this type of cancer.

Detailed Description
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Control arm: Placebo given orally twice daily plus trastuzumab and pertuzumab every 21 days Experimental arm: Tucatinib 300 mg given orally twice daily plus trastuzumab and pertuzumab every 21 days Trastuzumab and pertuzumab will be administered as follows: • Trastuzumab will be given intravenously (IV) at a dose of 6 mg/kg or subcutaneously (SC) at a fixed dose of 600 mg, once every 21 days. AND Pertuzumab will be given IV at 420 mg every 21 days. OR Fixed dose combination of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase will be given SC, once every 21 days, in lieu of trastuzumab and pertuzumab individually.

Official Title
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A Randomized, Double-blind, Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for Metastatic HER2+ Breast Cancer (HER2CLIMB-05)

Conditions
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HER2 Positive Breast Cancer

Intervention / Treatment
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* Drug: Tucatinib
* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Combination product: Trastuzumab + Pertuzumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Centrally confirmed HER2+ breast carcinoma according to the 2018 American Society of Clinical Oncologists (ASCO) College of American Pathologists (CAP) guidelines prior to randomization (defined as a 3+ score on immunohistochemistry (IHC) and/or 2+ IHC and concurrent positive by ISH). Have unresectable locally advanced or metastatic disease. If recurrent (after [neo]adjuvant therapy), must be at least 6 month treatment free from any trastuzumab and pertuzumab received in the early breast cancer setting for advanced HER2+ disease. Have received 4-8 cycles of pre-study induction therapy including only trastuzumab, pertuzumab, and taxane as first-line of therapy for the treatment of advanced breast cancer prior to study enrollment. Participants are eligible provided they are without evidence of disease progression following completion of induction therapy. Known hormone receptor status (per local guidelines; may be hormone receptor positive [HR+] or negative [HR-]) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 CNS Inclusion - Based on screening contrast-enhanced brain magnetic resonance imaging (MRI), participants may have any of the following: No evidence of brain metastases Untreated brain metastases which are asymptomatic not needing immediate local treatment and, if identified on prior brain imaging, without evidence of progression since starting first-line induction therapy with trastuzumab, pertuzumab, and taxane Previously treated brain metastases which are asymptomatic Brain metastases previously treated with local therapy must not have progressed since treatment Exclusion Criteria: Prior treatment with any tyrosine kinase inhibitor targeting HER2 and/or epidermal growth factor receptor (EGFR) including pyrotinib, lapatinib, tucatinib, neratinib, and afatinib (except neratinib if given in extended adjuvant setting and ≥ 12 months have elapsed since last neratinib dose prior to start of study drug) Unable to undergo contrast-enhanced MRI of the brain CNS Exclusion - Based on screening brain MRI and clinical assessment Symptomatic brain metastasis after CNS-directed local therapy Progression of brain metastases since starting first line trastuzumab, pertuzumab, and taxane Ongoing use of systemic corticosteroids at a total daily dose of >2 mg of dexamethasone (or equivalent) Any untreated brain lesion in an anatomic site which may pose risk to participant Known or suspected leptomeningeal disease (LMD) Poorly controlled (>1/week) seizures, or other persistent neurologic symptoms

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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tucatinib + trastuzumab + pertuzumab<br>Tucatinib + trastuzumab + pertuzumab | Drug: Tucatinib<br>* 300mg given by mouth (orally) twice daily<br>* Other names: TUKYSA, ONT-380, ARRY-380;Drug: Trastuzumab<br>* 6mg/kg given into the vein (IV; intravenously) or 600mg injected under the skin (SC; subcutaneous) every 21 days<br>* Other names: Herceptin, Herceptin Hylecta;Drug: Pertuzumab<br>* 420mg given by IV every 21 days<br>* Other names: Perjeta;Drug: Combination product: Trastuzumab + Pertuzumab<br>* 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase will be given by subcutaneous injection every 21 days. May be given in place of trastuzumab and pertuzumab individually.<br>* Other names: Phesgo;|
| Active Comparator: Placebo + trastuzumab + pertuzumab<br>Placebo + trastuzumab + pertuzumab | Drug: Trastuzumab<br>* 6mg/kg given into the vein (IV; intravenously) or 600mg injected under the skin (SC; subcutaneous) every 21 days<br>* Other names: Herceptin, Herceptin Hylecta;Drug: Pertuzumab<br>* 420mg given by IV every 21 days<br>* Other names: Perjeta;Drug: Combination product: Trastuzumab + Pertuzumab<br>* 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase will be given by subcutaneous injection every 21 days. May be given in place of trastuzumab and pertuzumab individually.<br>* Other names: Phesgo;Drug: Placebo<br>* Given orally twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | The time from the date of randomization to the investigator assessment of disease progression according to RECIST v1.1 or death from any cause | Up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The time from randomization to death from any cause. | Up to approximately 5 years | 
| PFS by blinded independent central review (BICR) per RECIST v1.1 | The time from the date of randomization to the documented disease progression assessed by BICR according to RECIST v1.1 or death from any cause | Up to approximately 3 years | 
| Time to deterioration of health-related quality of life (HRQoL) | Will be measured based on patient reported outcomes (PROs) according to the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ C30). | Up to approximately 3 years | 
| Central nervous system (CNS) PFS | The time from randomization to investigator assessed disease progression in brain (RECIST v1.1), or death from any cause | Up to approximately 3 years | 
| Incidence of adverse events (AEs) | 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. | Through 30 days after last study treatment, approximately 18 months | 
| Incidence of laboratory abnormalities | To be summarized using descriptive statistics. | Through 30 days after last study treatment, approximately 18 months | 
| Incidence of tucatinib dose alterations | To be summarized using descriptive statistics. | Through 30 days after last study treatment, approximately 18 months | 
| Incidence of trastuzumab dose alterations | To be summarized using descriptive statistics. | Through 30 days after last study treatment, approximately 18 months | 
| Incidence of pertuzumab dose alterations | To be summarized using descriptive statistics. | Through 30 days after last study treatment, approximately 18 months | 
| Maximum concentration (Cmax) | To be summarized using descriptive statistics. | Through 30 days after last study treatment, approximately 18 months | 
| Trough concentration (Ctrough) | To be summarized using descriptive statistics. | Through 30 days after last study treatment, approximately 18 months | 

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