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Trial record 1 of 1 for:    NCT02614794
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Phase 2 Study of Tucatinib vs Placebo in Combination With Capecitabine & Trastuzumab in Patients With Metastatic HER2+ Breast Cancer (HER2CLIMB)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2016 by Cascadian Therapeutics Inc.
Sponsor:
Information provided by (Responsible Party):
Cascadian Therapeutics Inc.
ClinicalTrials.gov Identifier:
NCT02614794
First received: November 20, 2015
Last updated: December 23, 2016
Last verified: December 2016
  Purpose
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.

Condition Intervention Phase
HER2 Positive Breast Cancer
Drug: Tucatinib
Drug: Capecitabine
Drug: Trastuzumab
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Cascadian Therapeutics Inc.:

Primary Outcome Measures:
  • Progression-free survival (PFS) per RECIST 1.1 based on independent central review [ Time Frame: 42 months ]

Secondary Outcome Measures:
  • Progression free survival (PFS) per RECIST 1.1 based on investigator assessment [ Time Frame: 42 months ]
  • Objective response rate (ORR) per RECIST 1.1 based on independent central review [ Time Frame: 42 months ]
  • Duration of response (DOR) per RECIST 1.1 based on independent central review [ Time Frame: 42 months ]
  • Clinical benefit rate (CBR) [SD for ≥ 6 months, best response, CR or partial response (PR)] per RECIST 1.1 based on independent central review [ Time Frame: 42 months ]
  • Effect of tucatinib in combination with capecitabine and trastuzumab on patients with brain metastases at baseline per RECIST 1.1 based on independent central review [ Time Frame: 42 months ]
  • Effect of tucatinib in combination with capecitabine and trastuzumab on overall survival (OS) [ Time Frame: 52 months ]
  • Safety and Tolerability of tucatinib in combination with capecitabine and trastuzumab as assessed by comparison of adverse events [ Time Frame: 42 months ]

Estimated Enrollment: 480
Study Start Date: December 2015
Estimated Study Completion Date: January 2021
Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tucatinib in combination with capecitabine & trastuzumab
Tucatinib in combination with capecitabine & trastuzumab
Drug: Tucatinib
Treatment will be administered in cycles of 21 days each. Tucatinib 300 mg or placebo will be given orally twice daily (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 intravenously (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.
Other Name: ONT-380
Drug: Capecitabine
Treatment will be administered in cycles of 21 days each. Tucatinib 300 mg or placebo will be given orally twice daily (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 intravenously (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.
Other Name: Xeloda
Drug: Trastuzumab
Treatment will be administered in cycles of 21 days each. Tucatinib 300 mg or placebo will be given orally twice daily (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 intravenously (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.
Other Name: Herceptin
Active Comparator: Placebo in combination with capecitabine & trastuzumab
Placebo in combination with capecitabine & trastuzumab
Drug: Capecitabine
Treatment will be administered in cycles of 21 days each. Tucatinib 300 mg or placebo will be given orally twice daily (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 intravenously (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.
Other Name: Xeloda
Drug: Trastuzumab
Treatment will be administered in cycles of 21 days each. Tucatinib 300 mg or placebo will be given orally twice daily (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 intravenously (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.
Other Name: Herceptin
Drug: Placebo
Treatment will be administered in cycles of 21 days each. Tucatinib 300 mg or placebo will be given orally twice daily (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 intravenously (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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

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:

    1. 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
    2. 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)
  9. Have adequate baseline hematological parameters as defined by:

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 103/µL
    2. Platelet count ≥ 100 x 103/µL
    3. Hemoglobin ≥ 9 g/dL
  10. Have creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines
  11. 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.)
  12. 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
  13. 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.
  14. 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.
  15. 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.
  16. 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:

  17. No evidence of brain metastases
  18. 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.
  19. Previously treated brain metastases

    1. 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.
    2. 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

Exclusion Criteria

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

  1. Have previously been treated with:

    1. lapatinib within 12 months of starting study treatment or
    2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously.
  2. 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.
  3. History of exposure to the following cumulative doses of anthracyclines:

    1. Doxorubicin > 360 mg/m2
    2. Epirubicin > 720 mg/m2
    3. Mitoxantrone > 120 mg/m2
    4. Idarubicin > 90 mg/m2
    5. Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) > 550 mg/m2
  4. 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
  5. 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
  6. 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
  7. 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
  8. Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
  9. Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease
  10. Are known to be positive for human immunodeficiency virus (HIV)
  11. Are pregnant, breastfeeding, or planning a pregnancy
  12. Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed)
  13. Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications
  14. 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
  15. Have known dihydropyrimidine dehydrogenase deficiency
  16. Unable for any reason to undergo MRI of the brain
  17. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
  18. 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:

  19. Any untreated brain metastases > 2.0 cm in size, unless discussed with medical monitor and approval for enrollment is given
  20. 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
  21. 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
  22. Known or concurrent leptomeningeal disease (LMD) as documented by the investigator
  23. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02614794

  Show 54 Study Locations
Sponsors and Collaborators
Cascadian Therapeutics Inc.
Investigators
Study Director: Luke Walker, MD Cascadian Therapeutics Inc.
  More Information

Responsible Party: Cascadian Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT02614794     History of Changes
Other Study ID Numbers: ONT-380-206
Study First Received: November 20, 2015
Last Updated: December 23, 2016

Keywords provided by Cascadian Therapeutics Inc.:
Tucatinib
Capecitabine
Trastuzumab
Xeloda
Herceptin
Breast Cancer
ARRY-380
ONT-380

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Trastuzumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on March 30, 2017