A Phase II Non-randomized Study to Assess the Safety and Efficacy of the Combination of Tucatinib and Trastuzumab and Capecitabine for Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- Tucatinib
- Conditions
- Metastatic Breast Cancer
- Sponsor
- University of Alabama at Birmingham
- Enrollment
- 17
- Locations
- 9
- Primary Endpoint
- Length of Subject Survival After Starting Study Treatment
- Status
- Terminated
- Last Updated
- 8 months ago
Overview
Brief Summary
A phase 2 non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab with capecitabine for the treatment of leptomeningeal metastases in HER2-neu positive breast cancer.
Detailed Description
The purpose of this study is to evaluate a new treatment for patients with HER2+ metastatic breast cancer (MBC) with leptomeningeal disease (LMD). This is a rare and fast-growing form of cancer. Leptomeningeal disease refers to the seeding of tumor cells to the leptomeninges and dissemination in the cerebrospinal fluid. Currently, there are is no standard of care treatment for LMD. However, we think the combination therapy will be safe and well-tolerated and may also improve survival. Blood and spinal fluid samples will be collected to evaluate the effects on the body and the cancer, which will help provide greater understanding to therapy response in patients. The study has a two-stage design with the first stage including 15 subjects from up to ten institutions nationwide. If it advances to the second stage based on the number of successes, another 15 subjects will be enrolled.
Investigators
Erica Stringer-Reasor
Assistant Professor
University of Alabama at Birmingham
Eligibility Criteria
Inclusion Criteria
- •Men and women, age ≥18 years at time of consent
- •Histologically proven metastatic infiltrating carcinoma of the breast that is HER2 positive - Immunohistochemistry (IHC) 3+ and/or Fluorescence in situ hybridization (FISH) ratio \>2.0, or average HER2 copy number \>6.0 signals per cell or per current ASCO-CAP (American Society of Clinical Oncology - College of American Pathologists) or NCCN (National Comprehensive Cancer Network) guidelines. (NOTE: HER2 testing may be performed on primary and/or metastatic site; Any estrogen and progesterone \[ER/PR\] status is allowed.)
- •Evidence of leptomeningeal disease (LMD) as diagnosed by a) presence of malignant cells in CSF (+CSF cytology) and/or b) Magnetic Resonance Imaging (MRI) evidence of LMD, plus clinical signs and/or symptoms. NOTE: Measurable extra-CNS disease is not required. Note: Patients who have MRI evidence of focal LMD with negative cytology and no symptoms are not eligible for enrollment.
- •Karnofsky Performance Status ≥ 50 or Eastern Cooperative Oncology Group (ECOG) ≤ 3
- •Patient is able and willing to undergo study-required testing including:
- •Contrast-enhanced MRI Note: If patient has implants in place that are MRI incompatible, these must be removed prior to enrollment.
- •Placement of an Ommaya reservoir (ventricular access device). Note: This is mandatory for the first 15 patients enrolled onto the protocol (first stage). In the second stage, this is strongly recommended per protocol. If a patient cannot or chooses not to undergo Ommaya placement in the second stage, the patient will be allowed to enroll.
- •Evaluation by medical oncologist at baseline and at every cycle (required)
- •Evaluation by neurologist/neuro-oncologist at baseline and at every cycle (strongly recommended); if this is not possible at a site, a medical oncologist may per perform the protocol specified evaluations at each visit.
- •Patients who are on steroids due to CNS disease or LMD diagnosis should be on a stable dose for at least 5 days prior to registration.
Exclusion Criteria
- •Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures.
- •Patient is pregnant or is breastfeeding. Note: If female and of child-bearing potential (females who are not surgically sterile or who have had a period in the last 12 months), has negative pregnancy test within 21 days prior to treatment. If a sexually active male or a sexually active female of child- bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose.
- •History of allergic reactions to compounds of similar chemical or biological composition to capecitabine (Group A only), trastuzumab or tucatinib, except for a history of Grade 1 or Grade 2 infusion related reaction to trastuzumab, that has been successfully managed.
- •Known to be HIV positive, or a carrier for Hepatitis B and/or Hepatitis C (whether active disease or not)
- •Known liver disease, autoimmune hepatitis, or sclerosing cholangitis
- •Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications
- •Use of a strong CYP2C8/CYP3A4 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment.
- •Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy or congestive heart failure. Note: Patients with hypertension must have controlled disease defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg on antihypertensive medications.
- •Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug.
- •Patient with known dihydropyrimidine dehydrogenase deficiency
Arms & Interventions
Tucatinib + Trastuzumab + Capecitabine
Tucatinib will be taken orally at 300 mg twice a day starting with Cycle 1, Day 1. A cycle consists of 21 days. Capecitabine will be taken orally at 1000 mg/m2 twice a day on Days 1-14 starting with cycle 1. Trastuzumab is given intravenously as a loading dose of 8 mg/kg on Cycle 1, Day 1 and then at 6 mg/kg for all subsequent cycles.
Intervention: Tucatinib
Tucatinib + Trastuzumab + Capecitabine
Tucatinib will be taken orally at 300 mg twice a day starting with Cycle 1, Day 1. A cycle consists of 21 days. Capecitabine will be taken orally at 1000 mg/m2 twice a day on Days 1-14 starting with cycle 1. Trastuzumab is given intravenously as a loading dose of 8 mg/kg on Cycle 1, Day 1 and then at 6 mg/kg for all subsequent cycles.
Intervention: Trastuzumab
Tucatinib + Trastuzumab + Capecitabine
Tucatinib will be taken orally at 300 mg twice a day starting with Cycle 1, Day 1. A cycle consists of 21 days. Capecitabine will be taken orally at 1000 mg/m2 twice a day on Days 1-14 starting with cycle 1. Trastuzumab is given intravenously as a loading dose of 8 mg/kg on Cycle 1, Day 1 and then at 6 mg/kg for all subsequent cycles.
Intervention: Capecitabine
Outcomes
Primary Outcomes
Length of Subject Survival After Starting Study Treatment
Time Frame: Through study completions, an average of 2 years
Number of participants alive. A Gehan-like trial design with an interim futility analysis will be used.
Secondary Outcomes
- Number of Adverse Events(up to 28 months)
- Symptom Burden(Baseline, end of study (up to 28 months))
- Quality of Life Assessment(up to 28 months)
- Progression Free Survival(up to 12 months)
- Duration of Response in the Central Nervous System (CNS)(up to 28 months)
- Clinical Benefit Rate (CBR) in CNS(Baseline up to 28 months)
- Duration of Response in Extra-CNS Disease(up to 28 months)
- Clinical Benefit Rate (CBR) in Extra-CNS Disease(up to 28 months)