A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer

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.

Inclusion Criteria

• Histologically confirmed HER2+ metastatic 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 LA/M breast cancer after last systemic therapy, or be intolerant of last systemic therapy
• Measurable or non-measurable disease assessable by RECIST v1.1
• Hormone receptor (estrogen receptor/progesterone receptor) status must be known prior to randomization
• ECOG performance status score of 0 or 1
• Life expectancy ≥6 months
• CNS Inclusion - Based on screening contrast brain magnetic resonance imaging (MRI), subjects 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
• Subjects treated with CNS local therapy for newly identified 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 21 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, neratinib, afatinib, trastuzumab deruxtecan (DS-8201a), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for <21 days and was discontinued for reasons other than disease progression or severe toxicity).
• Prior treatment with T-DM1
• Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS radiation, experimental agent or participation in another interventional clinical trial ≤3 weeks prior to first dose of study treatment
• Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
• Alopecia;
• Neuropathy, which must have resolved to ≤ Grade 2;
• Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely
• Clinically significant cardiopulmonary disease
• Myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
• Carrier of Hepatitis A or Hepatitis C or has other known chronic liver disease
• Positive for human immunodeficiency virus (HIV)
• Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of informed consent until 7 months following the last dose of study drug
• Unable to swallow pills or has significant gastrointestinal disease which would preclude the adequate oral absorption of medications
• Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study treatment
• CNS Exclusion - Based on screening contrast brain magnetic resonance imaging (MRI), subjects 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

This study is designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in subjects 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. Subjects 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, subjects 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, subjects in both arms of the study will continue to be followed for survival until study closure or withdrawal of consent.

Lead Organization
Seattle Genetics

Primary ID SGNTUC-016
Secondary IDs NCI-2019-03833
Clinicaltrials.gov ID NCT03975647