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

NCT ID: NCT05323955

Last Updated: 2025-06-17

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-23
• Study Completion Date: 2026-07-31

Brief Summary

Patients with advanced HER2+ breast cancer on maintenance trastuzumab/pertuzumab or T-DM1 with 1st or 2nd intracranial disease event (brain metastases) and stable extracranial disease will be enrolled. They will receive local therapy with stereotactic radiosurgery ± surgical resection if indicated followed by enrollment. Patients will continue standard of care trastuzumab/pertuzumab or T-DM1 with the addition of tucatinib. Hormone receptor positive patients requiring endocrine therapy should continue. Study treatment will continue until disease progression or intolerable side effects. Patients on trial with extracranial disease progression with stable intracranial disease should continue tucatinib into next line of therapy.

Detailed Description

Patients with advanced HER2+ breast cancer on either (1) first-line trastuzumab/pertuzumab OR (2) second-line T-DM1 in the metastatic setting OR (3) adjuvant trastuzumab-based therapy or T-DM1 with isolated intracranial recurrence will be included. Patients with de novo metastatic disease and brain metastases or isolated intracranial recurrence can enter upon initiation of maintenance trastuzumab/pertuzumab after chemotherapy if deemed necessary by treating oncologist and meeting other inclusion criteria. Patients with 1st or 2nd intracranial disease event (brain metastases) and stable extracranial disease will be enrolled. Third intracranial progression would be considered if > 12 month interval between second and third intracranial progression. They will receive local therapy with stereotactic radiosurgery ± surgical resection followed by enrollment. Patients will continue standard of care treatment trastuzumab/pertuzumab or T-DM1 with the addition of tucatinib. Hormone receptor-positive patients requiring endocrine therapy should continue.

Study treatment will continue until intercranial disease progression or intolerable side effects. Patients with extracranial disease progression while on trial with stable intracranial disease should continue tucatinib into the next line of therapy as described in protocol. If a subject continues tucatinib into the next line therapy they are still considered on study treatment and will be monitored according to the protocol. Cycles will continue consecutively and not restart. Once the subject comes off tucatinib they are considered off study treatment and will enter the follow up period.

Conditions

Brain Metastases; Human Epidermal Growth Factor 2 Positive Carcinoma of Breast; Advanced Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental Group

Trastuzumab/pertuzumab + tucatinib or T-DM1 + tucatinib

300mg of tucatinib taken orally twice a day. Taken on Days 1-21 of a 21 Day cycle (3 Weeks).

Trastuzumab/Biosimilar administered per current package insert based on site standard of care guidelines

Pertuzumab or Biosimilar administered per current package insert based on site standard of care guidelines

Trastuzumab Emtansine (T-DM1) administered per current package insert based on site standard of care guidelines

Group Type: EXPERIMENTAL

Trastuzumab

Intervention Type: DRUG

Administer per current package insert based on site standard of care guidelines

Trastuzumab Emtansine (T-DM1)

Intervention Type: DRUG

Administer per current package insert based on site standard of care guidelines

Pertuzumab

Intervention Type: DRUG

Administer per current package insert based on site standard of care guidelines

Tucatinib

Intervention Type: DRUG

300 mg orally twice daily (21 Day Cycle)

Interventions

Trastuzumab

Administer per current package insert based on site standard of care guidelines

Intervention Type: DRUG

Trastuzumab Emtansine (T-DM1)

Administer per current package insert based on site standard of care guidelines

Intervention Type: DRUG

Pertuzumab

Administer per current package insert based on site standard of care guidelines

Intervention Type: DRUG

Tucatinib

300 mg orally twice daily (21 Day Cycle)

Intervention Type: DRUG

Other Intervention Names

Herceptin; Perjeta; Tukysa

Eligibility Criteria

Inclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Carey Anders, M.D.

OTHER

Sponsor Role: lead

Responsible Party

Carey Anders, M.D.

Sponsor Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Carey Anders, MD

Role: PRINCIPAL_INVESTIGATOR

Duke Cancer Institute

Locations

University of California San Francisco

San Francisco, California, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan Health System

Ann Arbor, Michigan, United States

Washington University in St. Louis

St Louis, Missouri, United States

Duke University Medical Center

Durham, North Carolina, United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Providence Portland Medical Center

Portland, Oregon, United States

MD Anderson Cancer Center

Houston, Texas, United States

Countries

United States

Other Identifiers

Pro00109777

Identifier Type: -

Identifier Source: org_study_id