Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs Placebo in Combination With Capecitabine and Trastuzumab in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma
This study is being done to see if tucatinib works better than placebo 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. All patients in the study will get capecitabine and trastuzumab, two drugs that are often used to treat this cancer. 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. Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills or placebo pills two times every day. They will swallow capecitabine pills two times a day during the first two weeks of each cycle. Patients will get trastuzumab injections from the study site staff on the first day of every cycle.
Stratification factors include presence or history of treated or untreated brain metastases or brain lesions of equivocal significance (yes/no), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1), and region of world (US vs. Canada vs. Rest of World).
No crossover from placebo to tucatinib will be allowed.
Safety assessments will be performed at a minimum of once every three weeks throughout study treatment and 30 days after the last dose of study drugs. Laboratory assessments will be performed locally at sites. Left ventricular ejection fraction will be assessed by MUGA or ECHO at screening and once every 12 weeks thereafter.
Contrast brain MRI will be performed at baseline in all patients. Efficacy assessments (CT of chest, abdomen and pelvis at a minimum) utilize RECIST 1.1 and include patients with evaluable tumors defined as measurable target lesions and non-measurable non-target lesions. RECIST assessment is performed at baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat MRI of the brain will be required on this same schedule only in those patients with brain metastases identified at baseline. All treatment decisions are made based upon investigator assessment. All patients undergo a repeat MRI of the brain within 30 days of the end of treatment unless previously performed at time of disease progression. Patients in both arms of the study will be followed for OS after completion of study treatment.
18 Years and up
Accepting Healthy Volunteers?
- Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology
- Received previous treatment with trastuzumab, pertuzumab, and T-DM1
- Progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy
- Have measurable or non-measurable disease assessable by RECIST 1.1
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Adequate hepatic and renal function and hematologic parameters
- Left ventricular ejection fraction (LVEF) ≥ 50%
- CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:
1. No evidence of brain metastases
2. Untreated brain metastases not needing immediate local therapy
3. Previously treated brain metastases not needing immediate local therapy
1. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy
2. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if the following criteria are met:
- Time since whole brain radiation therapy (WBRT) is ≥ 21 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 disease assessable by RECIST 1.1 are present
3. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
- Previously been treated with:
1. 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 toxicity)
2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously
3. capecitabine (or other fluoropyrimidine) for metastatic disease except in cases where capecitabine was given for < 21 days and was discontinued for reasons other than disease progression or toxicity. Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.
- Clinically significant cardiopulmonary disease
- Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease
- Positive for human immunodeficiency virus (HIV)
- Unable for any reason to undergo MRI of the brain
- Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment
- Have known dihydropyrimidine dehydrogenase deficiency (DPD)
- CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:
1. Any untreated brain lesions > 2.0 cm in size, unless approved by medical monitor
2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)
3. Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria
4. Known or suspected leptomeningeal disease (LMD)
5. Poorly controlled seizures