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

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

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.

There are two parts to this study. The first part of the study is already complete. Patients were randomly assigned to get either tucatinib or placebo (a pill with no medicine). Since this part was "blinded," neither patients nor their doctors knew whether a patient got tucatinib or placebo.

The second part of the study is called the Unblinded Phase. In this part of the study, participants and their doctors know which drugs are being given. Participants who used to get or are currently getting placebo may be able to start taking tucatinib instead.

Each treatment cycle lasts 21 days. Patients will swallow tucatinib 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.

Study Overview

• Status: Completed
• Conditions: HER2 Positive Breast Cancer
• Intervention / Treatment: Drug: tucatinib; Drug: capecitabine; Drug: trastuzumab; Drug: placebo

Detailed Description

This is a randomized, international, multi-center study in patients with progressive unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab and T-DM1. There are two phases to this trial: the Double-blind Phase and the Unblinded Phase. In the Double-blind phase, participants were randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab. In the Unblinded Phase, patients on placebo may be offered tucatinib.

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).

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.

For the blinded phase, contrast brain MRI was performed at baseline. Efficacy assessments (CT of chest, abdomen and pelvis at a minimum) utilized RECIST 1.1 and included patients with evaluable tumors defined as measurable target lesions and non-measurable non-target lesions. RECIST assessment was performed at baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat MRI of the brain was required on this same schedule only in those patients with brain metastases identified at baseline. All treatment decisions were made based upon investigator assessment. All patients underwent a repeat MRI of the brain within 30 days of the end of treatment unless previously performed at time of disease progression.

For the unblinded phase, RECIST assessments will be performed per standard clinical practice as determined by investigator with a maximum interval of 12 weeks.

• Study Type: Interventional
• Enrollment (Actual): 612
• Phase: Phase 2

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Contacts and Locations

Study Locations

• Australia
  • Heidelberg, Australia, 3084
    • Austin Hospital
  • Malvern, Australia, 3144
    • Cabrini Education and Research Precinct
  • Melbourne, Australia, 3000
    • Peter MacCallum Cancer Centre
  • Nedlands, Australia, 6009
    • Breast Cancer Research Centre
  • North Sydney, Australia, 2060
    • Mater Hospital
  • South Brisbane, Australia, 4101
    • Icon Cancer Care South Brisbane
  • South Brisbane, Australia, 4101
    • Mater Health Services
  • St Albans, Australia, 3021
    • Sunshine Hospital
  • Westmead, Australia, 2145
    • Westmead Hospital
• Austria
  • Graz, Austria, 8036
    • LKH- Universitat Klinikum Graz
  • Innsbruck, Austria, 6020
    • Medizinische Universitat Innsbruck
  • Linz, Austria, 4010
    • KH d. Barmherzigen Schwestern Linz
  • Salzburg, Austria, 5020
    • LKH Salzburg, Universitatsklinikum der PMU
• Belgium
  • Brasschaat, Belgium, 2930
    • AZ Klina
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint Luc
  • Charleroi, Belgium, 6000
    • Grand Hopital de Charleroi
  • Libramont, Belgium, 6800
    • Centre Hospitalier de l'Ardenne
  • Namur, Belgium, 5000
    • CHU UCL Namur-Site de Saint Elisabeth
• Canada
  • Calgary, Canada, T2N 4N2
    • Tom Baker Cancer Centre
  • Edmonton, Canada, T6G 1Z2
    • University of Alberta / Cross Cancer Institute
  • Halifax, Canada, B3H 2Y9
    • Queen Elizabeth II Health Sciences Centre
  • Montreal, Canada, H3T 1E2
    • Jewish General Hospital
  • Quebec, Canada, G1S 4L8
    • Hopital du Saint-Sacrement, CHU de Quebec-Universite Laval
  • Regina, Canada, S4T7T1
    • Allan Blair Cancer Centre
  • Saskatoon, Canada, S7N 4H4
    • Saskatoon Cancer Centre
  • St John's, Canada, A1B 3V6
    • H. Bliss Murphy Cancer Centre
  • Toronto, Canada, M4N 3M5
    • Sunnybrook Health Sciences Centre
  • Toronto, Canada, M5G 2M9
    • University Health Network, Princess Margaret Hospital
  • Vancouver, Canada, V5Z 4E6
    • British Columbia Cancer Agency - Vancouver Centre
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Fakultni nemocnice Hradec Kralove-oddeleni klinicke hematologie
  • Olomouc, Czechia, 77520
    • Fakultni Nemocnice Olomouc (Fnol) - Onkologicka Klinika
• Denmark
  • Aalborg, Denmark, 9100
    • Aalborg Universitetshospital
  • Copenhagen, Denmark, DK 2100
    • Rigs Hospiltalet
  • Herlev, Denmark, 2730
    • Herlev Hospital
  • Odense C, Denmark, 5000
    • Odense University Hospital
  • Vejle, Denmark, 7100
    • Sygehus Lillebaelt - Vejle Sygehus
• France
  • Besancon cedex, France, 25030
    • University Hospital of Besancon
  • Le Mans, France, 72000
    • Clinique Victor Hugo
  • Lyon, France, 69373
    • Centre Leon Berard - Centre regional de lutte contre le cancer Rhone-Alpes
  • Marseille, France, 13273
    • Institut Paoli Calmettes
  • Paris, France, 75005
    • Institute Curie - Centre de Lutte Contre Le Cancer CLCC de Paris
  • Pierre Bénite Cedex, France, 69495
    • Centre Hospitalier Lyon Sud
  • REIMS Cedex, France, 51056
    • Institut Jean Godinot
  • Rennes Cedex, France, 35042
    • Centre Eugene Marquis
  • Strasbourg, France, 67200
    • Hôpitaux Universitaires de Strasbourg
  • TOURS Cedex 09, France, 37044
    • CHU Tours - Hopital Bretonneau
  • Toulouse Cedex 9, France, 31059
    • Institut Claudius Regaud
• Germany
  • Berlin, Germany, 10117
    • Charite Universitatsmedizin Berlin
  • Essen, Germany, 45136
    • Kliniken Essen-Mitte - Evang. Huyssens-Stiftung
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf (UKE) - Onkologisches Zentrum - Interdisziplinaere Klinik und Poliklinik fuer Stammzelltransplantation
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein
  • Koblenz, Germany, 56068
    • InVO- Institut fUr Versorgungsforschung in der onkologie GbR
  • Köln, Germany, 50937
    • Universitätsklinikum Köln
  • Munchen, Germany, 80639
    • HOPE- Onkologisches Zentrum Rotkreuzklinikum
  • Offenbach am Main, Germany, 63069
    • Sana Klinikum Offenbach GmbH
• Israel
  • Haifa, Israel, 31096
    • Rambam Health Corp.
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center
  • Kfar Saba, Israel, 44281
    • Meir Medical Center
  • Petach Tikva, Israel, 49414
    • Rabin Medical Center
  • Rehovot, Israel, 76100
    • Kaplan Medical Center
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
  • Tel Hashomer, Israel, 52621
    • Sheba Medical Center
• Italy
  • Bologna, Italy, 40138
    • Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi
  • Bolzano, Italy, 39100
    • Ospedale di Bolzano
  • Brindisi, Italy, 72100
    • Presido Ospedaliero- Senatore Antonio Perrino
  • Carpi, Italy, 41012
    • Ospedale Ramazzini di Carpi
  • Genova, Italy, 16132
    • Ospedale Policlinico San Martino
  • Milano, Italy, 20141
    • Istituto Europeo di Oncologia
  • Pavia, Italy, 27100
    • IRCSS Policlinico San Matteo
  • Terni, Italy, 05100
    • Azienda Ospedaliera S. Maria di Terni
  • Torrette, Italy, 60126
    • A.O.U. - Ospedali Riuniti di Ancona
• Portugal
  • Lisboa, Portugal, 1998-018
    • Hospital Cuf Descobertas R. Mario Botas Parque das Nacoes
  • Porto, Portugal, 4099-001
    • Centro Hospitalar do Porto - Hospital Santo Antonio
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial de Barcelona
  • Caceres, Spain, 10002
    • Hospital San Pedro de Alcantara
  • Leon, Spain, 24008
    • Complejo Asistencial Universitario de León
  • Madrid, Spain, 28041
    • Hospital Universitario 12 De Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Palma de Mallorca, Spain, 07010
    • Hospital Son Espases
  • Santiago de Compostela, Spain, 15706
    • Hospital Clinico Univ De Santiago De Compostela
  • Valencia, Spain, 46015
    • Hospital Arnau de Vilanova
  • Zaragoza, Spain, 50009
    • Hospital Clinico Universitario Lozano Blesa de Zaragoza
• Switzerland
  • Bellinzona, Switzerland, 6500
    • Institute of Oncology of Southern Switzerland
• United Kingdom
  • Colchester, United Kingdom, C04 5JL
    • Colchester Hospital University NHS Foundation Trust
  • London, United Kingdom, W1G 6AD
    • Sarah Cannon Research Institute UK
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Northwood, United Kingdom, HA6 2RN
    • Mount Vernon Hospital, UK
  • Nottingham, United Kingdom, NG5 1PD
    • Nottingham University Hospitals NHS Trust
  • Peterborough, United Kingdom, PE3 9GZ
    • Peterborough City Hospital
  • Sheffield, United Kingdom, S10 2SJ
    • Weston Park Hospital- UK
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden Hospital (Surrey)
  • Truro, United Kingdom, TR1 3LQ
    • Royal Cornwall Hospitals NHS Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
    • Mobile, Alabama, United States, 36604
      • University of South Alabama - Mitchell Cancer Institute
  • Arizona
    • Goodyear, Arizona, United States, 85338
      • Cancer Treatment Centers of America - Phoenix
    • Phoenix, Arizona, United States, 85016
      • Arizona Oncology Associates, PC - HAL
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope National Medical Center
    • Los Angeles, California, United States, 90095
      • TRIO - Central Regulatory Office
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center / David Geffen School of Medicine
    • Redondo Beach, California, United States, 90277
      • Torrance Memorial Physician Network - TRIO
    • San Francisco, California, United States, 94134
      • University of California at San Francisco
    • San Marcos, California, United States, 92078
      • Kaiser Permanente San Marcos Medical Offices
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corporation TRIO
    • Vallejo, California, United States, 94589
      • Kaiser Permanente Medical Center Northern California
  • Colorado
    • Aurora, Colorado, United States, 80045-0510
      • University of Colorado Hospital / University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Lombardi Cancer Center / Georgetown University Medical Center
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists - South Region
    • Hollywood, Florida, United States, 33021
      • Memorial Regional Hospital TRIO
    • Jacksonville, Florida, United States, 32207
      • Baptist MD Anderson Cancer Center
    • Miami, Florida, United States, 33136
      • University of Miami
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center / Florida
    • Orlando, Florida, United States, 32806
      • Orlando Health, Inc. TRIO
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists - North Region
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute
    • West Palm Beach, Florida, United States, 33401
      • Florida Cancer Specialists - East West Palm Beach, FL (SCRI)
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute / Emory University School of Medicine
    • Augusta, Georgia, United States, 30912
      • Augusta University
    • Newnan, Georgia, United States, 30265
      • Cancer Treatment Centers of America
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637-1470
      • University Of Chicago
    • Niles, Illinois, United States, 60714
      • Illinois Cancer Specialists / Advocate Lutheran General Hospital
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Rockville, Maryland, United States, 20850
      • Maryland Oncology Hematology, P.A.
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute
  • Missouri
    • Kansas City, Missouri, United States, 64113
      • Saint Luke's Cancer Institute LLC
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Nebraska Cancer Specialists
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center/ Norris Cotton Cancer Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10003
      • Mount Sinai Beth Israel
    • New York, New York, United States, 10016
      • New York University (NYU) Cancer Institute
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center / University of North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27834
      • Leo W. Jenkins Cancer Services / Brody School of Medicine East Carolina University
  • Ohio
    • Columbus, Ohio, United States, 43210
      • James Cancer Hospital / Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health and Science University
    • Tualatin, Oregon, United States, 97062
      • Northwest Cancer Specialists, P.C.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania / Perelman Center for Advanced Medicine
    • Philadelphia, Pennsylvania, United States, 19124
      • Cancer Treatment Centers of America / Eastern Regional Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina/Hollings Cancer Center
    • Charleston, South Carolina, United States, 29414
      • Roper St. Francis Healthcare
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Wellmont Cancer Institute
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology - Nashville
    • Nashville, Tennessee, United States, 37204
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology - Austin Midtown
    • Dallas, Texas, United States, 75203
      • Texas Oncology Methodist
    • Denton, Texas, United States, 76210
      • Texas Oncology - Denton South
    • Fort Worth, Texas, United States, 76104
      • The Center for Cancer and Blood Disorders: Fortworth
    • Houston, Texas, United States, 77030-4095
      • MD Anderson Cancer Center / University of Texas
    • Houston, Texas, United States, 77024
      • Texas Oncology - Houston Memorial City
    • Houston, Texas, United States, 77030
      • Baylor Clinic
    • Lubbock, Texas, United States, 79410
      • Joe Arrington Cancer Research and Treatment Center
    • Paris, Texas, United States, 75460
      • Paris Regional Medical Center / US Oncology
    • Plano, Texas, United States, 75075
      • Texas Oncology - Plano East
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78212
      • Texas Oncology - San Antonio Medical Center Northeast
    • The Woodlands, Texas, United States, 77380
      • US Oncology Central Regulatory
    • Webster, Texas, United States, 77598
      • Texas Oncology - Deke Slayton Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists, PC
    • Winchester, Virginia, United States, 22601
      • Shenandoah Oncology P.C.
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute
    • Seattle, Washington, United States, 98109-1023
      • Seattle Cancer Care Alliance / University of Washington
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Carbone Cancer Center / University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Double-blind Phase 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:

     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 disease assessable by RECIST 1.1 are present

  4. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions

Double-blind Phase 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 Unblinded Phase Crossover Inclusion Criteria - Participants who were randomized to the control arm (placebo + trastuzumab + capecitabine) must meet the following criteria to be eligible to crossover to the experimental arm.
• Have measurable or non-measurable disease assessable by RECIST 1.1
• For patients who were randomized to the control arm and on the long-term follow-up period at the time of crossover screening: 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.
• Have an ECOG Performance Status of 0 or 1
• Have a life expectancy of at least 6 months
• Have 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:

  i. No evidence of brain metastases ii. Untreated brain metastases not needing immediate local therapy iii. Previously treated brain metastases not needing immediate local therapy

• Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy

• 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:

  1. 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.
  2. Other sites of disease assessable by RECIST 1.1 are present Unblinded Phase Crossover Exclusion Criteria - Participants who were randomized to the control arm (placebo + trastuzumab + capecitabine) will be excluded from the crossover to the experimental arm for any of the following reasons.
• Discontinuation of study treatment due to an adverse event while on the double-blind phase of the study. If the adverse event leading to discontinuation of study treatment has resolved, the patient may be allowed to crossover with approval from the medical monitor.

• History of exposure to the following cumulative doses of anthracyclines:

  • Doxorubicin > 360 mg/m^2
  • Epirubicin > 720 mg/m^2
  • Mitoxantrone > 120 mg/m^2
  • Idarubicin > 90 mg/m^2
  • Liposomal doxorubicin > 550 mg/m^2

• History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or biologically similar to tucatinib

  o Exceptions for Grade 1 or 2 infusion related reactions to trastuzumab that were successfully managed, or known allergy to one of the excipients in the study drugs

• Have received treatment with any systemic anti-cancer therapy, non-CNS radiation, or experimental agent within 3 weeks prior to start of crossover therapy

• Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:

  • Alopecia and neuropathy (must have resolved to ≤ Grade 2)
  • CHF (must have been ≤ Grade 1 in severity at the time of occurrence and must have resolved completely)
  • Anemia (must have resolved to ≤ Grade 2)
• Have clinically significant cardiopulmonary disease
• Have known myocardial infarction or unstable angina within 6 months prior to start of crossover therapy
• Require therapy with warfarin or other coumarin derivatives
• Inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications
• Have used a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor or have used a strong CYP2C8 or CYP34A inducer within 5 days prior to start of the crossover (tucatinib) treatment.
• Known dihydropyrimidine dehydrogenase deficiency
• Unable to undergo contract MRI of the brain
• Have evidence within 2 years prior to start of crossover therapy of another malignancy that required systemic treatment
• CNS Exclusion:

• CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:

  • Any untreated brain lesions > 2.0 cm in size, unless approved by medical monitor
  • Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)
  • 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
  • Known or suspected leptomeningeal disease (LMD)
  • Poorly controlled seizures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tucatinib in combination with capecitabine & trastuzumab; Tucatinib + capecitabine + trastuzumab	Drug: tucatinib; 300 mg orally twice daily; Other Names: ONT-380, ARRY-380; Drug: capecitabine; 1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle; Other Names: 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 Names: Herceptin, Herceptin Hycleta
Active Comparator: Placebo in combination with capecitabine & trastuzumab; Placebo + capecitabine + trastuzumab	Drug: capecitabine; 1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle; Other Names: 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 Names: Herceptin, Herceptin Hycleta; Drug: placebo; Oral dose twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Per RECIST 1.1 as Determined by Blinded Independent Central Review (BICR)	Defined as the time from the date of randomization to the date of documented disease progression.	34.6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS in Patients With Brain Metastases at Baseline Using RECIST 1.1 as Determined by BICR	Defined as the time from the date of randomization to the date of documented disease progression.	34.6 months
Confirmed Objective Response Rate (ORR) Per RECIST 1.1 as Determined by BICR	Defined as achieving a best overall response of confirmed complete response (CR) or confirmed partial response (PR).	34.6 months
ORR Per RECIST 1.1 as Determined by Investigator Assessment	Defined as achieving a best overall response of confirmed CR or confirmed PR.	34.6 months
Duration of Response (DOR) Per RECIST 1.1 as Determined by BICR	Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.	24.6 months
DOR Per RECIST 1.1 as Determined by Investigator Assessment	Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.	33.2 months
Clinical Benefit Rate (CBR) as Determined by BICR Per RECIST 1.1	Clinical benefit was defined as achieving stable disease (SD) or non-complete response (CR)/non-progressive disease (PD) for at least 6 months or a best overall response of confirmed CR or confirmed partial response (PR).	34.6 months
CBR Per RECIST 1.1 as Determined by Investigator Assessment	Clinical benefit was defined as achieving stable disease (SD) or non-CR/non-PD for at least 6 months or a best overall response of confirmed CR or confirmed PR.	34.6 months
Frequency of Dose Modifications		35.1 months
Incidence of Health Resources Utilization	Cumulative incidence of health resource utilization, including length of stay, hospitalizations, and ER visits using the EQ-5D-5L questionnaire.	36.1 months
Pharmacokinetic Measure: Ctrough of Tucatinib	Individual plasma tucatinib concentrations at each sampling time	3.5 months
Pharmacokinetic Measure: ONT-993	Individual plasma primary metabolite concentrations at each sampling time	3.5 months
Overall Survival (OS) at Time of Primary Analysis	Defined as time from randomization to death from any cause	35.9 months
PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Primary Analysis	Defined as the time from the date of randomization to the date of documented disease progression	34.6 months
Incidence of Adverse Events (AEs) at Time of Primary Analysis	As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.	36.1 months
Overall Survival (OS) at Time of Final Analysis	Defined as time from randomization to death from any cause	Up to 60.1 months
PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Final Analysis	Defined as the time from the date of randomization to the date of documented disease progression	Up to 58.0 months
Incidence of Adverse Events (AEs) at Time of Final Analysis	As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.	Up to 60.1 months
Frequency of Dose Modifications at Time of Final Analysis		Up to 60.1 months

Collaborators and Investigators

• Sponsor: Seagen Inc.
• Investigators: Study Director: Jorge Ramos, DO, Seagen Inc.; Study Director: Corinna Palanca-Wessels, MD, PhD, Seagen Inc.

Publications and helpful links

General Publications

• Mueller V, Wardley A, Paplomata E, Hamilton E, Zelnak A, Fehrenbacher L, Jakobsen E, Curtit E, Boyle F, Harder Brix E, Brenner A, Crouzet L, Ferrario C, Munoz-Mateu M, Arkenau HT, Iqbal N, Aithal S, Block M, Cold S, Cancel M, Hahn O, Poosarla T, Stringer-Reasor E, Colleoni M, Cameron D, Curigliano G, Siadak M, DeBusk K, Ramos J, Feng W, Gelmon K. Preservation of quality of life in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with tucatinib or placebo when added to trastuzumab and capecitabine (HER2CLIMB trial). Eur J Cancer. 2021 Aug;153:223-233. doi: 10.1016/j.ejca.2021.05.025. Epub 2021 Jun 29.
• Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. doi: 10.1200/JCO.20.00775. Epub 2020 May 29.
• Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Muller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. doi: 10.1056/NEJMoa1914609. Epub 2019 Dec 11. Erratum In: N Engl J Med. 2020 Feb 6;382(6):586.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2016
• Primary Completion (Actual): September 4, 2019
• Study Completion (Actual): August 11, 2022

Study Registration Dates

• First Submitted: November 20, 2015
• First Submitted That Met QC Criteria: November 23, 2015
• First Posted (Estimated): November 25, 2015

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: July 26, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Breast Cancer; Capecitabine; Xeloda; Breast Carcinoma; Metastatic Breast Cancer; Seattle Genetics; Trastuzumab; Herceptin; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Tucatinib; ONT-380; HER-2 Positive Breast Cancer; ARRY-380; HER2 Positive Breast Carcinoma; HER2 Positive Locally Advanced Breast Cancer; HER-2 Positive Breast Carcinoma; HER-2 Positive Locally Advanced Breast Cancer; Metastatic Malignant Neoplasm in the Brain; Brain Metastases in Breast Cancer; Asymptomatic Brain Metastases in Breast Cancer; Low Symptomatic Brain Metastases in Breast Cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Trastuzumab; Capecitabine; Tucatinib
• Other Study ID Numbers: ONT-380-206; 2015-002801-12 (EudraCT Number)