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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 (BRIDGET)

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ClinicalTrials.gov Identifier: NCT05323955
Recruitment Status : Recruiting
First Posted : April 12, 2022
Last Update Posted : June 6, 2024
Sponsor:
Collaborator:
Seagen Inc.
Information provided by (Responsible Party):
Carey Anders, M.D., Duke University

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.

Condition or disease Intervention/treatment Phase
Brain Metastases Human Epidermal Growth Factor 2 Positive Carcinoma of Breast Advanced Breast Cancer Drug: Trastuzumab Drug: Trastuzumab Emtansine (T-DM1) Drug: Pertuzumab Drug: Tucatinib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 23, 2023
Estimated Primary Completion Date : October 2026
Estimated Study Completion Date : October 2027


Arm Intervention/treatment
Experimental: 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

Drug: Trastuzumab
Administer per current package insert based on site standard of care guidelines
Other Name: Herceptin

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

Drug: Pertuzumab
Administer per current package insert based on site standard of care guidelines
Other Name: Perjeta

Drug: Tucatinib
300 mg orally twice daily (21 Day Cycle)
Other Name: Tukysa




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 3 years ]
    Evaluate the ability of tucatinib in combination with trastuzumab/pertuzumab or TDM-1 to prolong intracranial progression free survival (PFS) in patients compared to historical controls. PFS is defined as the time from the day of study treatment initiation until evidence of intracranial disease progression per RANO-BM or death from any cause.


Secondary Outcome Measures :
  1. Progression Free Survival by RECIST 1.1 [ Time Frame: 3 years ]
    Evaluate the progression free survival by RECIST 1.1 criteria. PFS is defined as time from the day of study treatment initiation until evidence of disease progression per RECIST v1.1 or death from any cause.

  2. Progression Free Survival of Extracranial Disease [ Time Frame: 3 years ]
    Evaluate PFS of extracranial disease. PFS is defined as time from the day of study treatment initiation until evidence of extracranial disease progression per RECIST v1.1 or death from any cause.

  3. Distant Versus Local Intracranial Progression Free Survival [ Time Frame: 3 years ]
    Evaluate distant versus local intracranial PFS.

  4. Site of First Progression [ Time Frame: 3 years ]
    Evaluate the site of first progression (CNS vs non-CNS). Site of first progression (CNS vs non-CNS) is defined by first site of progression on trial either within the central nervous system or extracranial disease as defined by investigator

  5. Overall Survival (OS) [ Time Frame: 3 years ]
    Evaluate OS. OS defined as day of study treatment initiation until death from any cause.

  6. Assess Adverse Events [ Time Frame: 2 months ]
    Evaluate the toxicity profile of agents in patients with brain metastases. Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 intracranial recurrence can enter upon initiation of maintenance trastuzumab/pertuzumab after chemotherapy if chemotherapy deemed necessary by treating oncologist and meeting other inclusion criteria.
  • 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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05323955


Contacts
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Contact: Carey Anders, MD 919-684-5301 carey.anders@duke.edu
Contact: Rae Richards 317-634-5842 ext 38 rrichards@hoosiercancer.org

Locations
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United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Sarah Sammons, MD    919-668-5247    sarahl_sammons@dfci.harvard.edu   
Contact: Hugh Meadows       hughw_meadows@dfci.harvard.edu   
United States, Michigan
University of Michigan Health System Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Munira Hussain    734-936-8349    hussain@med.umich.edu   
Principal Investigator: Aki Morikawa, MD         
United States, Missouri
Washington University in St. Louis Recruiting
Saint Louis, Missouri, United States, 63130
Contact: Samantha Ruzicka, LMSW    314-747-5209    ruzicka@wustl.edu   
Principal Investigator: Nusayba Bagegni, MD         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Carey Anders, MD    919-684-5301    dukebrain1@dm.duke.edu   
Contact: Kelly Moulton    919-684-5301    dukebrain1@dm.duke.edu   
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Jean Koutou Essan, MPH    614-293-5637    JeanMartial.KoutouEssan@osumc.edu   
Principal Investigator: Sasha Beyer, MD         
United States, Oregon
Providence Portland Medical Center Recruiting
Portland, Oregon, United States, 97213
Contact: Alison K Conlin, MD MPH    503-215-5696    alison.conlin@providence.org   
Contact: Larisa Lundgren    503-215-0610    larisa.lundgren@providence.org   
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Rashmi Murthy, MD MBE    713-563-8453    rmurthy1@mdanderson.org   
Contact: Jill Swartz-Gomez, RN CCRP    713-792-2768    jschwartzgomez@mdanderson.org   
Sponsors and Collaborators
Carey Anders, M.D.
Seagen Inc.
Investigators
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Principal Investigator: Carey Anders, MD Duke Cancer Institute
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Responsible Party: Carey Anders, M.D., Sponsor Investigator, Duke University
ClinicalTrials.gov Identifier: NCT05323955    
Other Study ID Numbers: Pro00109777
First Posted: April 12, 2022    Key Record Dates
Last Update Posted: June 6, 2024
Last Verified: June 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Carey Anders, M.D., Duke University:
Brain metastases
HER2+ breast cancer
Trastuzumab
Pertuzumab
T-DM1
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasm Metastasis
Brain Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Trastuzumab
Pertuzumab
Ado-Trastuzumab Emtansine
Maytansine
Tucatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunotoxins
Immunoconjugates
Immunologic Factors
Physiological Effects of Drugs