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Eligibility
for people ages 18 years and up
Location
at San Francisco, California and other locations
Dates
study started
estimated completion:
Principal Investigator

Description

Summary

The purpose of this study is to assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab on progression-free survival (PFS) per RECIST 1.1 based on independent central review.

Official Title

Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs Placebo in Combination With Capecitabine and Trastuzumab in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma (HER2CLIMB)

Details

This is a Phase 2 randomized, international, multi-center, double-blinded study of tucatinib or placebo in combination with capecitabine and trastuzumab in patients with pretreated unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with a taxane, trastuzumab, pertuzumab and T-DM1. After signing informed consent and meeting all eligibility criteria patients will be randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab.

Randomization will be made using a dynamic hierarchical randomization schema. Stratification factors will include presence or history of treated or untreated brain metastases (yes/no), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 vs. 1), and region of world (US vs Canada vs Rest of World). Stratification for presence of brain metastases will be based upon medical history and investigator assessment of screening MRI. Patients who have a documented history of prior brain metastases or unequivocal presence of CNS lesions on screening MRI will be considered a "Yes" for stratification purposes, and subsequent efficacy assessments. Patients with no prior history of brain metastases and lesions of equivocal significance on screening MRI will also be considered a "Yes" for purposes of stratification and follow-up.

Treatment will be administered in cycles of 21 days each. Tucatinib or placebo will be given PO BID. Capecitabine will be given at 1000 mg/m2 PO BID on Days 1-14 of each 21-day cycle. Trastuzumab will be given as a loading dose of 8 mg/kg IV followed by 6 mg/kg once every 21 days, except in specific circumstances where it may be given weekly to compensate for modifications in treatment schedule. Dose modifications of tucatinib or placebo and capecitabine will be allowed. Dose holding or discontinuation of tucatinib or placebo, capecitabine, and trastuzumab will also be allowed as needed for patient safety. Patients who discontinue either capecitabine or trastuzumab (but not both) may remain on study treatment. Patients who discontinue tucatinib or placebo, or both capecitabine and trastuzumab will not be allowed to remain on study treatment.

Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. After discontinuing study treatment, patients may receive further care as determined by their physician. In the absence of clear evidence of clinical progression, development of CNS symptoms, or radiographic changes thought to pose potential immediate risk to patient, all efforts should be made to continue treatment until unequivocal evidence of radiologic or clinical progression occurs, as defined in RECIST 1.1. No crossover from placebo to tucatinib will be allowed.

Patients will be assessed throughout the study for safety. Safety assessments including physical exam, collection of adverse events (AEs), and laboratory assessments will be performed at a minimum of once every three weeks throughout study treatment and 30 days after the last dose of study drugs. Laboratory assessments will be performed locally at sites. Cardiac ejection fraction will be assessed by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO) at screening and once every 12 weeks thereafter.

Brain MRI will be performed at baseline in all patients regardless of prior history of brain metastases. Efficacy assessments will include measurement of all known sites of metastatic or locally advanced unresectable disease (including at a minimum the chest, abdomen, and pelvis) by high quality spiral computed tomography (CT), positron emission tomography (PET)/CT (if high quality CT scan included) and/or MRI scan as appropriate, as well as appropriate imaging of any other known sites of disease (e.g. bone scans) at baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat MRI of the brain will be required on this same schedule only in those patients with prior history of brain metastases, brain metastases found at screening, or brain lesions of equivocal significance found at screening. Brain MRI may also be performed in patients without known brain metastases if there is clinical suspicion of new brain lesions. Additional imaging such as nuclear medicine bone scan or other unscheduled scans may be performed at the discretion of the investigator. Treatment decisions will be made based upon investigator assessment of radiologic scans. All patients will undergo a repeat MRI of the brain within 30 days of the end of treatment, unless an MRI of the brain has already been performed within 30 days or prior documentation of progression in the brain on study. Patients in both arms of the study will continue to be followed for OS after completion of study treatment.

Keywords

HER2 Positive Breast Cancer Tucatinib Capecitabine Trastuzumab Xeloda Herceptin Breast Cancer ARRY-380 ONT-380

Eligibility

You can join if…

Open to people ages 18 years and up

Patients must meet the following criteria to be eligible for the study:

  1. Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by fluorescence in situ hybridization (FISH) and/or 3+ staining by immunohistochemistry(IHC)

    a. Tissue blocks or slides must be submitted to confirm HER2 positivity(FISH-positive or IHC 3+) by a sponsor-designated central laboratory prior to randomization. Centrally confirmed HER2 results (either IHC or FISH) from a previous study can be used to determine eligibility for this study with approval from the sponsor.

  2. Have received previous treatment with a taxane, trastuzumab, pertuzumab, and T-DM1
  3. Have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy
  4. Have measurable or non-measureable disease assessable by RECIST 1.1
  5. Be at least 18 years of age at time of consent
  6. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1
  7. Have a life expectancy of at least 6 months, in the opinion of the investigator
  8. Have adequate hepatic function as defined by the following:
  9. Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients with known Gilbert's disease, who may enroll if the conjugated bilirubin is ≤1.5 X ULN
  10. Transaminases [aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)] ≤ 2.5 X ULN (≤ 5 X ULN if liver metastases are present)
  11. Have adequate baseline hematological parameters as defined by:
  12. Absolute neutrophil count (ANC) ≥ 1.5 x 103/µL
  13. Platelet count ≥ 100 x 103/µL
  14. Hemoglobin ≥ 9 g/dL
  15. Have creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines
  16. International normalized ratio (INR) and activated partial thromboplastin time (aPTT)≤ 1.5 X ULN unless on medication known to alter INR and aPTT. (Note: Warfarin and other coumarin derivatives are prohibited.)
  17. Have left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram(ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment
  18. If female of childbearing potential, must have a negative result of serum pregnancy test performed within 7 days prior to first dose of study treatment. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
  19. Women of childbearing potential (as defined above) and men with partners of childbearing potential must agree to use a highly effective birth control method,i.e. methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral,intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device;intrauterine hormone-releasing system; bilateral tubal occlusion/ligation;vasectomized partner; or sexual abstinence. Male patients with partners of childbearing potential must use barrier contraception. All study patients should practice effective contraception, as described above, starting from the signing of informed consent until 7 months after the last dose of study medication or investigational medicinal product.
  20. Patient must provide signed informed consent per a consent document that has been approved by an institutional review board or independent ethics committee (IRB/IEC)prior to initiation of any study-related tests or procedures that are not part of standard-of-care for the patient's disease.
  21. Patients must be willing and able to comply with study procedures.

    CNS Inclusion

    Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:

  22. No evidence of brain metastases
  23. Untreated brain metastases not needing immediate local therapy. For patients with untreated CNS lesions> 2.0 cm on screening MRI, discussion with and approval from the medical monitor is required prior to enrollment.
  24. Previously treated brain metastases
  25. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator.
  26. Patients treated with CNS local therapy for newly identified lesions found on initial MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met:

    i. Time since whole brain radiation therapy (WBRT) is> 21 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is> 7 days prior to first dose of study treatment, or time since surgical resection is> 28 days ii.Other sites of evaluable disease are present c. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions

You CAN'T join if...

Patients will be excluded from the study for any of the following reasons:

  1. Have previously been treated with:
  2. lapatinib within 12 months of starting study treatment or
  3. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously.
  4. Have previously been treated with capecitabine for metastatic disease. Note: Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.
  5. History of exposure to the following cumulative doses of anthracyclines:
  6. Doxorubicin> 360 mg/m2
  7. Epirubicin> 720 mg/m2
  8. Mitoxantrone> 120 mg/m2
  9. Idarubicin> 90 mg/m2
  10. Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet)> 550 mg/m2
  11. Have history of allergic reactions to trastuzumab, capecitabine, or tucatinib (or compounds chemically or biologically similar), except for Grade 1 or 2 infusion related reactions to trastuzumab that were successfully managed
  12. Have received treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS radiation, or experimental agent ≤ 3 weeks of first dose of study treatment
  13. Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:

    • alopecia and neuropathy, which must have resolved to ≤ Grade 2; and
    • congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely
  14. Have clinically significant cardiac disease such as:

    • ventricular arrhythmia requiring therapy,
    • uncontrolled hypertension (defined as persistent systolic blood pressure> 150 mm Hg and/or diastolic blood pressure> 100 mm Hg on antihypertensive medications), or
    • any history of symptomatic CHF
  15. Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
  16. Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease
  17. Are known to be positive for human immunodeficiency virus (HIV)
  18. Are pregnant, breastfeeding, or planning a pregnancy
  19. Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed)
  20. Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications
  21. Have used a strong CYP3A4 inducer or inhibitor, or strong CYP2C8 inducer or inhibitor within 3 elimination half-lives of the inhibitor or inducer prior to first dose of study treatment
  22. Have known dihydropyrimidine dehydrogenase deficiency
  23. Unable for any reason to undergo MRI of the brain
  24. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
  25. Have evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment.

    CNS Exclusion

Based on screening brain MRI, patients must not have any of the following:

  1. Any untreated brain metastases> 2.0 cm in size, unless discussed with medical monitor and approval for enrollment is given
  2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of> 2 mg of dexamethasone (or equivalent). However, patients on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical monitor
  3. Any lesion thought to require immediate local therapy, including (but not limited to)a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g. brain stem lesions). Patients who undergo local treatment for such lesions identified by screening MRI may still be eligible for the study based on criteria described under CNS inclusion criteria 19b
  4. Known or concurrent leptomeningeal disease (LMD) as documented by the investigator
  5. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy

Locations

  • University of California, Los Angeles accepting new patients
    Los Angeles, California, 90095, USA

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Cascadian Therapeutics Inc.
ID
NCT02614794
Phase
Phase 2
Lead Scientist
Amy Chien
Study Type
Interventional
Last Updated
December 2016
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