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A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02614794
Recruitment Status : Active, not recruiting
First Posted : November 25, 2015
Last Update Posted : October 7, 2019
Sponsor:
Information provided by (Responsible Party):
Seattle Genetics, Inc.

Tracking Information
First Submitted Date  ICMJE November 20, 2015
First Posted Date  ICMJE November 25, 2015
Last Update Posted Date October 7, 2019
Actual Study Start Date  ICMJE January 28, 2016
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 10, 2018)
Progression-free survival (PFS) per RECIST 1.1 based on blinded independent central review (BICR) [ Time Frame: 48 months ]
Defined as the time from randomization to documented disease progression or death from any cause, whichever occurs earlier
Original Primary Outcome Measures  ICMJE
 (submitted: November 23, 2015)
Progression-free survival (PFS) [CNS and non-CNS] based on independent central review [ Time Frame: 28 months ]
Change History Complete list of historical versions of study NCT02614794 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
  • Progression-free survival (PFS) in patients with baseline brain metastases per RECIST 1.1 based on BICR [ Time Frame: 48 months ]
  • Overall Survival (OS) [ Time Frame: 58 months ]
    Defined as time from randomization to death from any cause
  • PFS per RECIST 1.1 based on investigator assessment [ Time Frame: 58 months ]
  • Objective response rate (ORR) per RECIST 1.1 based on BICR [ Time Frame: 58 months ]
  • Duration of response (DOR) per RECIST 1.1 based on BICR [ Time Frame: 58 months ]
    Defined as time from first documented response to documented disease progression or death from any cause, whichever occurs earlier
  • Clinical benefit rate (CBR) [ Time Frame: 58 months ]
    As determined by BICR per RECIST 1.1
  • Incidence of adverse events (AEs) [ Time Frame: 58 months ]
    As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements
  • Incidence of health resources utilization [ Time Frame: 58 months ]
  • Quality of life as measured by EQ-5D-5L questionnaire [ Time Frame: 58 months ]
    Treatment and placebo group index values changes will be summarized
  • Pharmacokinetic (PK) measure: Ctrough [ Time Frame: Up to 16 weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 23, 2015)
  • Progression free survival (PFS) based on investigator assessment [ Time Frame: 28 months ]
  • Progression free survival (PFS) (CNS vs. non-CNS) [ Time Frame: 28 months ]
  • Time to CNS progression [ Time Frame: 28 months ]
  • Objective response rate (ORR) (CNS vs. non-CNS) (%) [ Time Frame: 28 months ]
  • Duration of response (CNS vs. non-CNS) [ Time Frame: 28 months ]
  • Clinical benefit rate in CNS (the percentage of patients who have achieved complete response, partial response and stable disease as assessed by the RANO-BM criteria) [ Time Frame: 28 months ]
    This is the rate of response assessment of metastatic disease in the Central Nervous System as assessed using the new RANO-BM criteria (Lancet; Vol 16; June 2015; pg 270-278)
  • Clinical benefit rate in non-CNS (the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease as assessed by the RECIST 1.1 criteria) [ Time Frame: 28 months ]
    This is the rate of response assessment of non-CNS metastatic disease as assessed using the RECIST 1.1 criteria
  • Overall survival (OS) [ Time Frame: 28 months ]
  • Safety and Tolerability of ONT-380 in combination with capecitabine and trastuzumab as assessed by comparison of adverse events [ Time Frame: 28 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer
Official Title  ICMJE 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
Brief Summary

This study is being done to see if tucatinib works better than placebo to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery. All patients in the study will get capecitabine and trastuzumab, two drugs that are often used to treat this cancer.

Patients in this study will be randomly assigned to get either tucatinib or placebo (a pill with no medicine). This is a blinded study, so neither patients nor their doctors will know whether a patient gets tucatinib or placebo.

Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills or placebo pills two times every day. They will swallow capecitabine pills two times a day during the first two weeks of each cycle. Patients will get trastuzumab injections from the study site staff on the first day of every cycle.

Detailed Description

This is a randomized, international, multi-center, double-blinded study in patients with progressive unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab and T-DM1. Patients will be randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab.

Stratification factors include presence or history of treated or untreated brain metastases or brain lesions of equivocal significance (yes/no), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1), and region of world (US vs. Canada vs. Rest of World).

No crossover from placebo to tucatinib will be allowed.

Safety 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. Left ventricular ejection fraction will be assessed by MUGA or ECHO at screening and once every 12 weeks thereafter.

Contrast brain MRI will be performed at baseline in all patients. Efficacy assessments (CT of chest, abdomen and pelvis at a minimum) utilize RECIST 1.1 and include patients with evaluable tumors defined as measurable target lesions and non-measurable non-target lesions. RECIST assessment is performed 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 brain metastases identified at baseline. All treatment decisions are made based upon investigator assessment. All patients undergo a repeat MRI of the brain within 30 days of the end of treatment unless previously performed at time of disease progression. Patients in both arms of the study will be followed for OS after completion of study treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE HER2 Positive Breast Cancer
Intervention  ICMJE
  • Drug: tucatinib
    300 mg orally twice daily
    Other Name: ONT-380, ARRY-380
  • Drug: capecitabine
    1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle
    Other Name: Xeloda
  • Drug: trastuzumab
    8 mg/kg intravenously (IV) on Day 1 of Cycle 1, followed by 6 mg/kg on Day1 of each 21-day cycle. In regions where approved, trastuzumab may be given at 600mg subcutaneously once every 3-weeks at either study initiation or crossing over from previous IV trastuzumab.
    Other Name: Herceptin, Herceptin Hycleta
  • Drug: placebo
    Oral dose twice daily
Study Arms  ICMJE
  • Experimental: Tucatinib in combination with capecitabine & trastuzumab
    Tucatinib + capecitabine + trastuzumab
    Interventions:
    • Drug: tucatinib
    • Drug: capecitabine
    • Drug: trastuzumab
  • Active Comparator: Placebo in combination with capecitabine & trastuzumab
    Placebo + capecitabine + trastuzumab
    Interventions:
    • Drug: capecitabine
    • Drug: trastuzumab
    • Drug: placebo
Publications * Murthy R, Borges VF, Conlin A, Chaves J, Chamberlain M, Gray T, Vo A, Hamilton E. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Jul;19(7):880-888. doi: 10.1016/S1470-2045(18)30256-0. Epub 2018 May 24.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 16, 2019)
612
Original Estimated Enrollment  ICMJE
 (submitted: November 23, 2015)
180
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology
  • Received previous treatment with trastuzumab, pertuzumab, and T-DM1
  • Progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy
  • Have measurable or non-measurable disease assessable by RECIST 1.1
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  • Adequate hepatic and renal function and hematologic parameters
  • Left ventricular ejection fraction (LVEF) ≥ 50%
  • CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:

    1. No evidence of brain metastases
    2. Untreated brain metastases not needing immediate local therapy
    3. Previously treated brain metastases not needing immediate local therapy

      1. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy
      2. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if the following criteria are met:

        • 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.
        • Other sites of disease assessable by RECIST 1.1 are present
      3. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions

Exclusion Criteria

  • Previously been treated with:

    1. lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for ≤ 21 days and was discontinued for reasons other than disease progression or toxicity)
    2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously
    3. capecitabine (or other fluoropyrimidine) for metastatic disease except in cases where capecitabine was given for < 21 days and was discontinued for reasons other than disease progression or toxicity. Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.
  • Clinically significant cardiopulmonary disease
  • Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease
  • Positive for human immunodeficiency virus (HIV)
  • Unable for any reason to undergo MRI of the brain
  • Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment
  • Have known dihydropyrimidine dehydrogenase deficiency (DPD)
  • CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:

    1. Any untreated brain lesions > 2.0 cm in size, unless approved by medical monitor
    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)
    3. Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria
    4. Known or suspected leptomeningeal disease (LMD)
    5. Poorly controlled seizures
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   Czechia,   Denmark,   France,   Germany,   Israel,   Italy,   Portugal,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02614794
Other Study ID Numbers  ICMJE ONT-380-206
2015-002801-12 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Seattle Genetics, Inc.
Study Sponsor  ICMJE Seattle Genetics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Jorge Ramos, DO Seattle Genetics, Inc.
Study Director: Corinna Palanca-Wessels, MD, PhD Seattle Genetics, Inc.
PRS Account Seattle Genetics, Inc.
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP