Clinical Trials /

Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD

NCT03501979

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: UAB 1794
  • NCT ID: NCT03501979

Conditions

  • Metastatic Breast Cancer
  • Leptomeningeal Disease

Interventions

DrugSynonymsArms
TucatinibONT-380Tucatinib + Trastuzumab + Capecitabine
TrastuzumabTucatinib + Trastuzumab + Capecitabine
CapecitabineTucatinib + Trastuzumab + Capecitabine

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Tucatinib + Trastuzumab + CapecitabineExperimentalTucatinib 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.
  • Tucatinib
  • Trastuzumab
  • Capecitabine

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:

               1. Contrast-enhanced MRI Note: If patient has implants in place that are MRI
                  incompatible, these must be removed prior to enrollment.

               2. 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.

               3. Evaluation by medical oncologist at baseline and at every cycle (required)

               4. 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.

          -  Prior treatment allowances are as follows:

               1. >14 days since last dose of any previous endocrine therapy, chemotherapy,
                  trastuzumab or other antibody-based therapy. NOTE: If patients have been
                  previously receiving trastuzumab on a weekly basis (at a dose of 2mg/kg), only a
                  7 day washout will be required.

               2. >14 days or five half-lives since previous treatment with any experimental agent,
                  whichever is greater

               3. Cumulative dose of doxorubicin >360 mg/m2 or previous treatment with another
                  anthracycline with cumulative dose equivalent to >360 mg/m2 doxorubicin is not
                  allowed.

               4. Patients must not have received any therapy specifically directed at LMD,
                  including prior systemic or intrathecal therapy for LMD.

               5. Radiotherapy:

                    -  Patients must not have received radiotherapy to the neuroaxis following
                       diagnosis of LMD for the purpose of treating LMD, and may not receive

                         -  radiotherapy to the neuroaxis concurrently with the study drug;

                    -  Patients must not have received whole brain radiotherapy for parenchymal
                       metastases within the last 2 weeks (14 days) or focal CNS radiotherapy
                       within 1 week (7 days) prior to first dose of study drug. Note: Radiation
                       for the purpose of palliation in the setting of a painful bone or dural
                       metastasis can be allowed at the discretion of the treating physicians.

          -  All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with
             the following exceptions: alopecia; neuropathy, which must have resolved to ≤ Grade 2;
             and CHF, which must have been ≤ Grade 1 in severity at the time of occurrence, and
             must have resolved completely. Must be without significant systemic illness (e.g.
             infection unresponsive to treatment after 7 days)

          -  Adequate hematologic, liver, and renal function, as follows:

               1. Hemoglobin ≥ 9 g/dL

               2. ANC ≥ 1000 cells/μL

               3. Platelets ≥ 100,000/μ

               4. Total bilirubin ≤ 1.5 X upper limit of normal (ULN), unless a known history of
                  Gilbert's disease (≤ 3 X ULN)

               5. Transaminases (AST/SGOT and ALT/SGPT) ≤ 2.5X ULN (< 5 X ULN if liver metastases
                  are present)

               6. International normalized ratio (INR) and activated partial thromboplastin time
                  (aPTT) ≤ 1.5 X ULN

               7. Creatinine clearance (CrCL) ≥ 50 mL/min

          -  Left ventricular ejection fraction (LVEF) must be within institutional limits of
             normal as assessed by ECHO or MUGA documented within 4 weeks prior to enrollment on
             the study.

          -  Able to understand the study requirements and document informed consent indicating
             his/her awareness of the investigational nature and the risks of this study.

        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

          -  Previous treatment with tucatinib

          -  Previous treatment with capecitabine within 12 months prior to study registration

          -  Prior history of other cancer (except non melanoma skin, cervical intraepithelial
             neoplasia) with evidence of disease within the last 5 years.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:From date of study enrollment until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 3 years
Safety Issue:
Description:Length of subject survival after starting study treatment. A Gehan-like trial design with an interim futility analysis will be used.

Secondary Outcome Measures

Measure:Number of adverse events
Time Frame:Baseline up to 3 years or until disease progression or unacceptable toxicity or death.
Safety Issue:
Description:Adverse event reporting will be graded following the National Cancer Institute of Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Subjects who receive at least one dose of the drug combination will be evaluable for toxicity from the time of the first dose.
Measure:Progression free survival
Time Frame:Baseline to 12 weeks
Safety Issue:
Description:From the start of treatment to 12 weeks
Measure:Objective response in the central nervous system (CNS)
Time Frame:Baseline up to 3 years
Safety Issue:
Description:Data from subjects who have received at least one cycle of therapy and disease re-evaluation for CNS tumors by imaging, cytopathology, and clinical evaluation will be accumulated until disease progression.
Measure:Clinical benefit rate (CBR) in CNS
Time Frame:Baseline to 3 years
Safety Issue:
Description:The overall survival from the combination therapy is compared to the historical control. Clinical benefit is observed with a ratio of successes and corresponding confidence interval.
Measure:Objective response in extra-CNS disease
Time Frame:Baseline up to 3 years
Safety Issue:
Description:Data from subjects who have received at least one cycle of therapy and disease re-evaluation for extra-CNS tumors by imaging, cytopathology, and clinical evaluation will be accumulated until disease progression. Extra-CNS response will be classified per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Measure:Clinical benefit rate (CBR) in extra-CNS disease
Time Frame:Baseline to 3 years
Safety Issue:
Description:The overall survival from the combination therapy is compared to the historical control. Clinical benefit is observed with a ratio of successes and corresponding confidence interval.
Measure:Symptom Burden
Time Frame:Beginning at baseline and every 21 days until the end of study up to three years
Safety Issue:
Description:The M.D. Anderson Symptom Inventory Brain Tumor (MDASI -BT) module questionnaire will collect data at each study time point and evaluate changes of symptom burden.
Measure:Quality of Life
Time Frame:Beginning at baseline and every 42 days until the end of study up to three years
Safety Issue:
Description:The Linear Analog Scale Assessment Quality of Life will be used to evaluate changes in the quality of life at restaging visits.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Alabama at Birmingham

Trial Keywords

  • HER2+
  • metastatic breast cancer
  • leptomeningeal disease
  • tucatinib
  • trastuzumab
  • capecitabine

Last Updated

April 17, 2018