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

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ClinicalTrials.gov Identifier: NCT02614794
Recruitment Status : Recruiting
First Posted : November 25, 2015
Last Update Posted : December 12, 2018
Sponsor:
Information provided by (Responsible Party):
Seattle Genetics, Inc.

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.


Condition or disease Intervention/treatment Phase
HER2 Positive Breast Cancer Drug: tucatinib Drug: capecitabine Drug: trastuzumab Drug: placebo Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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
Study Start Date : December 2015
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Tucatinib in combination with capecitabine & trastuzumab
Tucatinib + capecitabine + trastuzumab
Drug: tucatinib
300 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

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 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

Drug: placebo
Oral dose twice daily




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Progression-free survival (PFS) in patients with baseline brain metastases per RECIST 1.1 based on BICR [ Time Frame: 48 months ]
  2. Overall Survival (OS) per RECIST 1.1 based on BICR [ Time Frame: 58 months ]
    Defined as time from randomization to death from any cause

  3. PFS per RECIST 1.1 based on investigator assessment [ Time Frame: 58 months ]
  4. Objective response rate (ORR) per RECIST 1.1 based on BICR [ Time Frame: 58 months ]
  5. 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

  6. Clinical benefit rate (CBR) [ Time Frame: 58 months ]
    As determined by BICR per RECIST 1.1

  7. Incidence of adverse events (AEs) [ Time Frame: 48 months ]
    As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements

  8. Incidence of health resources utilization [ Time Frame: 58 months ]
  9. Quality of life as measured by EQ-5D-5L questionnaire [ Time Frame: 58 months ]
    Treatment and placebo group index values changes will be summarized

  10. Pharmacokinetic (PK) measure: Ctrough [ Time Frame: Up to 16 weeks ]
  11. PK measure: Cmax [ Time Frame: Up to 16 weeks ]


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

Inclusion Criteria

  • Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH) 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
  • 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) 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02614794


Contacts
Contact: Seattle Genetics Trial Information Support 866-333-7436 clinicaltrials@seagen.com

  Show 171 Study Locations
Sponsors and Collaborators
Seattle Genetics, Inc.
Investigators
Study Director: Jorge Ramos, DO Seattle Genetics, Inc.
Study Director: Corinna Palanca-Wessels, MD, PhD Seattle Genetics, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Seattle Genetics, Inc.
ClinicalTrials.gov Identifier: NCT02614794     History of Changes
Other Study ID Numbers: ONT-380-206
2015-002801-12 ( EudraCT Number )
First Posted: November 25, 2015    Key Record Dates
Last Update Posted: December 12, 2018
Last Verified: December 2018

Keywords provided by Seattle Genetics, Inc.:
Tucatinib
Capecitabine
Trastuzumab
Xeloda
Herceptin
Breast Cancer
ARRY-380
ONT-380
HER2 Positive Breast Carcinoma
HER2 Positive Locally Advanced Breast Cancer
HER-2 Positive Breast Cancer
HER-2 Positive Breast Carcinoma
HER-2 Positive Locally Advanced Breast Cancer
Recurrent Breast Carcinoma
Stage IV Breast Cancer
Metastatic Breast Cancer
Breast Carcinoma
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:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Trastuzumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents