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Tucatinib With Brain and/or Spinal XRT in Patients With HER2+ Metastatic Breast Cancer and LMD

Primary Purpose

HER2-positive Breast Cancer, LMD

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Tucatinib 150 MG
Trastuzumab
Capecitabine
Brain & Spinal Radiation
Sponsored by
Sunnybrook Health Sciences Centre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HER2-positive Breast Cancer focused on measuring HER2+, Breast Cancer, Leptomeningeal disease, Tucanitib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Phase 1 Men or women with HER2+ metastatic breast cancer. Evidence of LMD in the brain and/or spine Age 18+ at time of consent; ECOG ≤ 2; If applicable, the last dose of prior chemotherapy, immunotherapy, endocrine therapy therapy must have been completed 14 days prior to study enrollment. More than 14 days or 5 half-lives from the last dose of any experimental agent is required, whichever is greater; All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1 prior to enrollment, except for alopecia; neuropathy, must have resolved to ≤ Grade 2. Phase 2: Inclusion Criteria Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 2 weeks prior to starting systemic therapy on the study; Adequate hematologic, liver, and renal function within 2 weeks prior to phase 2 enrollment, as follows: Hemoglobin ≥ 9 g/dL ANC ≥ 1 x109/L Platelets ≥ 100 x109/L Total bilirubin ≤ 1.5 X upper limit of normal (ULN) AST and ALT ≤ 2.5X ULN International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN Creatinine clearance (CrCL) ≥ 50 mL/min Exclusion Criteria: Phase 1 Prior WBRT for brain metastases Prior therapy specifically directed at LMD Inability to comply with MRI-based surveillance of CNS disease. Inability to swallow pills or any significant gastrointestinal diseases such as inflammatory bowel disease. Presently known dihydropyrimidine dehydrogenase deficiency; Diagnosed with Hereditary fructose intolerance; Diagnosed with Gilbert's disease; Prior history of other cancer with evidence of disease within the last 5 years; Prior use of tucatinib at any time prior to enrollment. Phase 2: Currently pregnant or breastfeeding; Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of systemic therapy Myocardial infarction or unstable angina within 6 months prior to the first dose of systemic therapy. Blood product transfusions in order to meet eligibility criteria

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Tucatinib, Transtuzumab, Capecitabine

    Arm Description

    Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease.

    Outcomes

    Primary Outcome Measures

    Survival status from the start of XRT • Survival status from the start of XRT
    To assess overall survival (OS) from the start of XRT.

    Secondary Outcome Measures

    Time to CNS progression from the start of XRT
    To determine the time for CNS symptoms progresses from start of XRT in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Safety and tolerability (CTCAE v.5.0)
    To determine the safety & tolerability of systemic therapy (tucatinib, trastuzumab and capecitabine) in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Progression free survival from the start of XRT
    To determine progression from the start of XRT in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    CNS specific objective response (RANO-BM)
    To determine the CNS objective response in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Extracranial objective response (RECIST v1.1)
    To determine the extracranial objective response in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Neurologic-specific QoL (FACT-BR version 4)
    To determine the neurologic-specific QoL's in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Overall QoL (EORTC QLQ-C30 version 3)
    To determine the Overall QoL in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).

    Full Information

    First Posted
    August 18, 2023
    Last Updated
    August 24, 2023
    Sponsor
    Sunnybrook Health Sciences Centre
    Collaborators
    Seagen Inc., Viatris Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06016387
    Brief Title
    Tucatinib With Brain and/or Spinal XRT in Patients With HER2+ Metastatic Breast Cancer and LMD
    Official Title
    Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease: A Multi-centre Phase II, Single Arm Feasibility Study
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    October 5, 2023 (Anticipated)
    Primary Completion Date
    October 5, 2025 (Anticipated)
    Study Completion Date
    October 5, 2028 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Sunnybrook Health Sciences Centre
    Collaborators
    Seagen Inc., Viatris Inc.

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The proposed study will evaluate the safety and efficacy of XRT followed by systemic therapy among patients with HER2+ metastatic breast cancer and LMD
    Detailed Description
    Breast cancer is the most common cancer among women worldwide, and the second leading cause of brain metastases (BrM). Despite recent treatment advances, the prognosis of patients with breast cancer BrM remains poor, and the prognosis among those with leptomeningeal disease (LMD) is particularly dire with a median survival of only 2-4 months. Patients with HER2+ metastatic breast cancer have a high life-time risk of central nervous system (CNS) metastases, with an approximately 50% lifetime risk. Although the cause of death among patients with breast cancer BrM is challenging to ascertain, approximately 50% of patients with HER2+ BrM are thought to die from central nervous system (CNS) disease involvement. Among patients with LMD specifically, the cause of death is most commonly related to CNS disease. In an analysis of 430 patients (96 of whom had breast cancer) treated for LMD in the National Cancer Database between 2005 and 2014, those patients treated with chemotherapy plus radiotherapy had a longer median overall survival of 5 months (3.5 - 6.5 months) compared to patients treated with XRT or chemotherapy alone. In addition, a majority (n=18/26, 69%) of observational studies irrespective of primary tumor site have shown an "improvement or likely improvement" in survival with the use of XRT for LMD, either alone or in combination with systemic therapy. Hence, this proposed study will evaluate the safety and efficacy of XRT followed by systemic therapy (which is considered standard of care) among patients with HER2+ metastatic breast cancer and LMD.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    HER2-positive Breast Cancer, LMD
    Keywords
    HER2+, Breast Cancer, Leptomeningeal disease, Tucanitib

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    30 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Tucatinib, Transtuzumab, Capecitabine
    Arm Type
    Experimental
    Arm Description
    Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease.
    Intervention Type
    Drug
    Intervention Name(s)
    Tucatinib 150 MG
    Other Intervention Name(s)
    Tukysa
    Intervention Description
    Tucatinib is a potent, selective, adenosine triphosphate-competitive small-molecule inhibitor of the receptor tyrosine kinase HER2. The molecular formula for tubatinib is C26H24N8O2 and it has a molecular weight of 480.52 g/mol.
    Intervention Type
    Drug
    Intervention Name(s)
    Trastuzumab
    Intervention Description
    MYL-1401O contains the active substance trastuzumab, which is an IgG1 monoclonal antibody. The molecular size of the intact molecule is around 148 kDa. Each vial of MYL-1401O contains 150 mg of lyophilized proposed active biosimilar substance trastuzumab as well as 3.36 mg L-Histidine Hydrochloride, 2.16 mg L-Histidine, 115.2 mg sorbitol and 33.6 mg PEG-3350 (Macrogol 3350). Sorbitol and PEG-3350 substitute the α- trehalose dehydrate and polysorbate-20, which are used as excipients in the EU-approved and US-licensed Herceptin formulations.
    Intervention Type
    Drug
    Intervention Name(s)
    Capecitabine
    Intervention Description
    Capecitabine is a tumour-activated antineoplastic agent (antimetabolite). The molecular formula for capecitabine is C15H22FN3O6 and has a molecular weight of 359.35 g/mol.
    Intervention Type
    Radiation
    Intervention Name(s)
    Brain & Spinal Radiation
    Other Intervention Name(s)
    Brain & Spinal XRT
    Intervention Description
    Brain & Spinal XRT is a treatment for patients with HER2+ metastatic breast cancer and leptomeningeal disease,
    Primary Outcome Measure Information:
    Title
    Survival status from the start of XRT • Survival status from the start of XRT
    Description
    To assess overall survival (OS) from the start of XRT.
    Time Frame
    From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
    Secondary Outcome Measure Information:
    Title
    Time to CNS progression from the start of XRT
    Description
    To determine the time for CNS symptoms progresses from start of XRT in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Time Frame
    From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
    Title
    Safety and tolerability (CTCAE v.5.0)
    Description
    To determine the safety & tolerability of systemic therapy (tucatinib, trastuzumab and capecitabine) in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Time Frame
    From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
    Title
    Progression free survival from the start of XRT
    Description
    To determine progression from the start of XRT in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Time Frame
    From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
    Title
    CNS specific objective response (RANO-BM)
    Description
    To determine the CNS objective response in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Time Frame
    Every 6 weeks through study completion, an average of 5 years
    Title
    Extracranial objective response (RECIST v1.1)
    Description
    To determine the extracranial objective response in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Time Frame
    Every 6 weeks through study completion, an average of 5 years
    Title
    Neurologic-specific QoL (FACT-BR version 4)
    Description
    To determine the neurologic-specific QoL's in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Time Frame
    Pre-treatment, at the start of Cycle 3 (Cycle 3 Day 1, +/- 7 days) and at the Safety Visit
    Title
    Overall QoL (EORTC QLQ-C30 version 3)
    Description
    To determine the Overall QoL in the proposed patient population after completion of brain and/or spinal XRT. To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
    Time Frame
    Pre-treatment, at the start of Cycle 3 (Cycle 3 Day 1, +/- 7 days) and at the Safety Visit

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Phase 1 Men or women with HER2+ metastatic breast cancer. Evidence of LMD in the brain and/or spine Age 18+ at time of consent; ECOG ≤ 2; If applicable, the last dose of prior chemotherapy, immunotherapy, endocrine therapy therapy must have been completed 14 days prior to study enrollment. More than 14 days or 5 half-lives from the last dose of any experimental agent is required, whichever is greater; All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1 prior to enrollment, except for alopecia; neuropathy, must have resolved to ≤ Grade 2. Phase 2: Inclusion Criteria Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 2 weeks prior to starting systemic therapy on the study; Adequate hematologic, liver, and renal function within 2 weeks prior to phase 2 enrollment, as follows: Hemoglobin ≥ 9 g/dL ANC ≥ 1 x109/L Platelets ≥ 100 x109/L Total bilirubin ≤ 1.5 X upper limit of normal (ULN) AST and ALT ≤ 2.5X ULN International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN Creatinine clearance (CrCL) ≥ 50 mL/min Exclusion Criteria: Phase 1 Prior WBRT for brain metastases Prior therapy specifically directed at LMD Inability to comply with MRI-based surveillance of CNS disease. Inability to swallow pills or any significant gastrointestinal diseases such as inflammatory bowel disease. Presently known dihydropyrimidine dehydrogenase deficiency; Diagnosed with Hereditary fructose intolerance; Diagnosed with Gilbert's disease; Prior history of other cancer with evidence of disease within the last 5 years; Prior use of tucatinib at any time prior to enrollment. Phase 2: Currently pregnant or breastfeeding; Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of systemic therapy Myocardial infarction or unstable angina within 6 months prior to the first dose of systemic therapy. Blood product transfusions in order to meet eligibility criteria
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    CLIMB-LMD Project Manager
    Phone
    437-247-2617
    Email
    CLIMB-LMD@sunnybrook.ca
    First Name & Middle Initial & Last Name or Official Title & Degree
    Mariam Saleem
    Phone
    437-243-8968
    Email
    CLIMB-LMD@sunnybrook.ca

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    The Aggregate data will be presented and/or published. The IPD will not be available keeping patients privacy in mind.

    Learn more about this trial

    Tucatinib With Brain and/or Spinal XRT in Patients With HER2+ Metastatic Breast Cancer and LMD

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