Patient case: 56-year-old female with breast cancer; genetic feature: ERBB2

Clinical trial: Phase 2 Study of Tucatinib vs Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer

Summary: The purpose of this study is to assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab on progression-free survival (PFS) per RECIST 1.1 based on independent central review.

Detailed description: A randomized, international, multi-center, double-blinded study in patients with pretreated unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with a taxane, trastuzumab, pertuzumab and T-DM1. Patients will be randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab.
  Stratification factors include presence or history of treated or untreated brain metastases (yes/no), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (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. Cardiac ejection fraction will be assessed by MUGA/ECHO at screening and once every 12 weeks thereafter.
  Brain MRI will be performed at baseline in all patients. Efficacy assessments utilize RECIST 1.1 and should include measurement of all known sites of metastatic or locally advanced unresectable disease 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. All treatment decisions will be made based upon investigator assessment of radiologic scans. All patients will undergo a repeat MRI of the brain within 30 days of the end of treatment. Patients in both arms of the study will continue to be followed for OS after completion of study treatment.

Eligibility: Inclusion Criteria
  Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by fluorescence in situ hybridization (FISH) and/or 3+ staining by immunohistochemistry (IHC)
  Have received previous treatment with a taxane, trastuzumab, pertuzumab, and T-DM1
  Have 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
  Be at least 18 years of age at time of consent
  Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1
  Have adequate hepatic and renal function
  Have left ventricular ejection fraction (LVEF) ≥ 50%
  CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:
  No evidence of brain metastases
  Untreated brain metastases not needing immediate local therapy
  Previously treated brain metastases
  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 initial MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met:
  i. 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
  ii. Other sites of evaluable disease are present
  c. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
  Exclusion Criteria
  Have previously been treated with:
  1. lapatinib within 12 months of starting study treatment or
  2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously
  Have previously been treated with capecitabine for metastatic disease. Note: Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.
  Have clinically significant cardiac disease
  Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease
  Are known to be positive for human immunodeficiency virus (HIV)
  Unable for any reason to undergo MRI of the brain
  CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:
  Any untreated brain metastases > 2.0 cm in size, unless discussed with medical monitor
  Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)
  Any lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening MRI may still be eligible for the study based on criteria described under CNS inclusion criteria
  Known or concurrent leptomeningeal disease (LMD)

Relevance to patient case: definitely relevant