A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or 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 with ado-trastuzumab emtansine (T-DM1) works better than T-DM1 alone to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery. Patients in this study will be randomly assigned to get either tucatinib or placebo (a pill with no medicine). This is a blinded study, so neither patients nor their doctors will know whether a patient gets tucatinib or placebo. All patients in the study will get T-DM1, a drug that is often used to treat this cancer. Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills or placebo pills two times every day. Patients will get T-DM1 injections from the study site staff on the first day of every cycle.

Detailed Description
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This study is designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in participants with unresectable locally-advanced or metastatic HER2+ breast cancer who have had prior treatment with a taxane and trastuzumab in any setting. Prior pertuzumab treatment is permitted, but not required. Participants will be randomized in a 1:1 manner to receive 21-day cycles of either tucatinib or placebo in combination with T-DM1. While on study treatment, participants will be assessed for progression every 6 weeks for the first 24 weeks, and every 9 weeks thereafter, irrespective of dose holds or interruptions. Study treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. After completion of study treatment and after occurrence of disease progression, participants in both arms of the study will continue to be followed for survival until study closure or withdrawal of consent.

Official Title
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Randomized, Double-blind, Phase 3 Study of Tucatinib or Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Subjects With Unresectable Locally-advanced or Metastatic HER2+ Breast Cancer (HER2CLIMB-02)

Conditions
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HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: tucatinib
* Drug: placebo
* Drug: T-DM1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed HER2+ breast carcinoma as determined by a sponsor-designated central laboratory History of prior treatment with a taxane and trastuzumab in any setting, separately or in combination Have progression of unresectable locally advanced/metastatic breast cancer after last systemic therapy, or be intolerant of last systemic therapy Measurable or non-measurable disease assessable by RECIST v1.1 ECOG performance status score of 0 or 1 CNS Inclusion - Based on screening contrast brain magnetic resonance imaging (MRI), participants must have at least one of the following: (a) No evidence of brain metastases (b) Untreated brain metastases not needing immediate local therapy (c) 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 Participants treated with CNS local therapy for newly identified lesions or previously treated and progressing lesions may be eligible to enroll if all of the following criteria are met: (i) Time since SRS is at least 7 days prior to first dose of study treatment, time since WBRT is at least 14 days prior to first dose, or time since surgical resection is at least 28 days. (ii) Other sites of evaluable disease are present Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions Exclusion Criteria: Prior treatment with tucatinib, afatinib, trastuzumab deruxtecan (DS-8201a), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with lapatinib or neratinib within 12 months of starting study treatment (except in cases where they were given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity). Prior treatment with pyrotinib for recurrent of mBC (except in cases where pyrotinib was given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity). CNS Exclusion - Based on screening contrast brain magnetic resonance imaging (MRI), participants must not have any of the following: Any untreated brain lesions >2 cm in size Ongoing use of corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent). Any brain lesion thought to require immediate local therapy Known or concurrent leptomeningeal disease as documented by the investigator Poorly controlled generalized or complex partial seizures

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 + T-DM1<br>Tucatinib + T-DM1 | Drug: tucatinib<br>* 300mg given twice per day by mouth (orally)<br>* Other names: ONT-380;Drug: T-DM1<br>* 3.6 mg/kg given into the vein (IV; intravenously) every 21 days<br>* Other names: Kadcyla;|
| Active Comparator: Placebo + T-DM1<br>Placebo + T-DM1 | Drug: placebo<br>* Given twice per day orally<br>Drug: T-DM1<br>* 3.6 mg/kg given into the vein (IV; intravenously) every 21 days<br>* Other names: Kadcyla;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by investigator assessment | PFS per investigator is defined as the time from the date of randomization to the investigator assessment of disease progression according to RECIST v1.1 or death from any cause, whichever occurs first. | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | OS is defined as the time from randomization to death due to any cause. | Up to approximately 5 years | 
| PFS per RECIST v1.1 by blinded independent committee review (BICR) | PFS per BICR is defined as the time from the date of randomization to the centrally-reviewed documented disease progression according to RECIST v1.1 or death from any cause, whichever occurs first. | Up to approximately 5 years | 
| PFS per RECIST v1.1 by investigator assessment in participants with brain metastases at baseline (PFS.BM per investigator) | PFS.BM is defined as the time from the date of randomization in participants with brain metastases at baseline to the investigator assessment of disease progression according to RECIST v1.1 or death from any cause, whichever occurs first. | Up to approximately 5 years | 
| PFS.BM per RECIST v1.1 by BICR |  | Up to approximately 5 years | 
| Objective response rate (ORR) per RECIST v1.1 by investigator assessment | ORR is defined as the proportion of participants with complete response (CR) or partial response (PR) according to RECIST v1.1. | Up to approximately 3 years | 
| ORR per RECIST v1.1 by BICR |  | Up to approximately 3 years | 
| Overall survival in participants with brain metastases at baseline (OS.BM) | OS.BM is defined as the time from randomization to death due to any cause in participants with brain metastases at baseline. | Up to approximately 5 years | 
| Duration of response (DOR) per RECIST v1.1 by investigator assessment | DOR is defined as the time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of disease progression or death from any cause, whichever occurs earlier. | Up to approximately 5 years | 
| DOR per RECIST v1.1 by BICR |  | Up to approximately 5 years | 
| Clinical benefit rate (CBR) per RECIST v1.1 by investigator assessment | CBR is defined as the proportion of participants with stable disease (SD) or non-CR or non-PD for ≥6 months or best response of CR or PR according to RECIST v1.1. | Up to approximately 3 years | 
| CBR per RECIST v1.1 by BICR |  | Up to approximately 3 years | 
| Number of participants with adverse events (AEs) | An AE is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | Through 1 month following last dose; up to approximately 9 months overall per participant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seattle Genetics