Preventing brain metastases in advanced HER2+ breast cancer patients

Secondary BRain Metastases Prevention After Isolated Intracranial Progression on Trastuzumab/Pertuzumab or T-DM1 in Patients With aDvanced Human Epidermal Growth Factor Receptor 2+ brEast Cancer With the Addition of Tucatinib

This study is testing if adding a new drug called tucatinib to local brain treatment can help people with advanced HER2+ breast cancer avoid more brain tumors while keeping their other cancer under control.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 48 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Duke University (Academic / other)
• Drugs / interventions: trastuzumab, pertuzumab, Lapatinib, neratinib, afatinib, tucatinib, chemotherapy, radiation
• Locations: 8 sites (San Francisco, California and 7 other locations)
• Trial ID: NCT05323955 on ClinicalTrials.gov

What this trial studies

This clinical trial focuses on patients with advanced HER2+ breast cancer who have experienced isolated intracranial progression while on standard treatments like trastuzumab/pertuzumab or T-DM1. Participants will receive local therapy, such as stereotactic radiosurgery, followed by the addition of tucatinib to their ongoing treatment regimen. The study aims to evaluate the effectiveness of this combination in preventing further brain metastases while maintaining stable extracranial disease. Treatment will continue until disease progression or intolerable side effects occur.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with advanced HER2+ breast cancer and a history of brain metastases who are currently receiving trastuzumab/pertuzumab or T-DM1.

Not a fit: Patients with HER2-negative breast cancer or those without brain metastases may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly reduce the incidence of brain metastases in patients with advanced HER2+ breast cancer.

How similar studies have performed: Other studies have shown promise in using targeted therapies like tucatinib in similar patient populations, indicating potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

* Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
* Age ≥ 18 years at the time of consent.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
* Locally advanced/unresectable or metastatic breast cancer with presence of brain metastases (Stage IV).
* Histologically confirmed HER2+ breast carcinoma by ASCO-CAP guidelines, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology on most recent biopsy (primary tissue).
* Currently receiving: (1) first-line trastuzumab/pertuzumab with or without endocrine therapy OR (2) second-line T-DM1 in the metastatic setting OR (3) adjuvant trastuzumab-based therapy or T-DM1 with isolated intracranial recurrence. Patients with de novo metastatic disease and brain metastases or isolated metastatic disease to the brain can enroll at time of initiation of trastuzumab/pertuzumab. Induction taxane therapy is not required and need to administer can be determined by the treating physician. Patients on trastuzumab alone are allowed if pertuzumab not tolerated.
* Systemic disease otherwise stable per RECIST 1.1 or no evidence of extracranial disease.
* Adequate hepatic and renal function and hematologic parameters:

  * Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
  * Platelets ≥ 100 × 109/L
  * Hemoglobin ≥ 9 g/dL
  * Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
  * Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present)
  * Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min as calculated using the Cockcroft-Gault (CG) equation
  * Left ventricular ejection fraction (LVEF) ≥ 50%.
* Central nervous system inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have ALL of the following:

  * Adequate local therapy to existing brain lesions ≥ 5mm including surgical resection and/or stereotactic radiosurgery
  * Limited to first or second intracranial progression. Third intracranial progression would be considered if \> 12 month interval between second and third intracranial progression.
  * Time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of study treatment.
  * Time since surgical resection is ≥ 14 days prior to first dose of study treatment.
  * Time since local therapy \< 12 weeks. Patients with de novo metastastic breast cancer presenting with brain metastases may enter following cessation of chemotherapy if within 24 weeks of local therapy to the brain and brain metastases have remained stable based on brain MRI.
  * Prior radiation is required within 12 weeks of enrollment to at least 1 brain lesion. Other brain lesions under 5mm do not require treatment.

NOTE: Relevant records of any CNS treatment including radiation must be available to allow for classification of target and non-target lesions

* Females of childbearing potential must have a negative serum pregnancy test at screening. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
* Females of childbearing potential and males must be willing to abstain from heterosexual intercourse or to use contraception as outlined in the protocol.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

* Previously been treated with: Lapatinib, neratinib, afatinib, tucatinib or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously (patients treated with adjuvant neratinib allowed if relapse \> 12 months after last dose).
* Clinically significant cardiopulmonary disease.
* Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including:

  * tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and TB testing in line with local practice),
  * hepatitis B (known positive HBV surface antigen (HBsAg) result),
  * hepatitis C, or
  * human immunodeficiency virus (positive HIV 1/2 antibodies)

NOTE: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be allowed if they are stable and have been on treatment for ≥ 4 weeks prior to first dose of study drug(s). Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy. Testing not required.

* Unable for any reason to undergo MRI of the brain
* Use of a strong cytochrome P450 (CYP)2C8 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. See protocol.
* Central nervous system exclusion - Based on screening brain MRI, patients must not have any of the following:

  * Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \> 2 mg of dexamethasone (or equivalent)
  * Diffuse leptomeningeal disease or positive CSF cytology; however, discreet dural-based metastases are allowed
  * Poorly controlled seizures. Defined as seizures that continue to occur despite optimal anticonvulsant medications based on investigator discretion.
  * History of whole brain radiation therapy
  * Any untreated brain lesions ≥ 5 mm
* Active infection requiring intravenous systemic therapy.
* Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
* Patients with a prior or concurrent malignancy within last 3 years whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen, per treating physician discretion, are not eligible for this trial.
* Treatment with any investigational drug within 30 days prior to registration.

Where this trial is running

San Francisco, California and 7 other locations

• University of California San Francisco — San Francisco, California, United States (Recruiting)
• Dana Farber Cancer Institute — Boston, Massachusetts, United States (Recruiting)
• University of Michigan Health System — Ann Arbor, Michigan, United States (Recruiting)
• Washington University in St. Louis — St. Louis, Missouri, United States (Recruiting)
• Duke University Medical Center — Durham, North Carolina, United States (Recruiting)
• Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States (Recruiting)
• Providence Portland Medical Center — Portland, Oregon, United States (Recruiting)
• MD Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Carey Anders, MD — Duke Cancer Institute
• Study coordinator: Carey Anders, MD

Conditions Brain Metastases; Human Epidermal Growth Factor 2 Positive Carcinoma of Breast; Advanced Breast Cancer; Brain metastases; HER2+ breast cancer; Trastuzumab; Pertuzumab; T-DM1