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Trial record 3 of 10 for:    tucatinib | breast cancer

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 : February 25, 2020
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.

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.


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

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 612 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Masking applied only during the Double-blind phase of the trial. The Unblinded Phase is open-label.
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
Actual Study Start Date : January 28, 2016
Actual Primary Completion Date : September 4, 2019
Estimated Study Completion Date : July 31, 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 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

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, Herceptin Hycleta

Drug: placebo
Oral dose twice daily




Primary Outcome Measures :
  1. Progression-free survival (PFS) per RECIST 1.1 as determined by blinded independent central review (BICR) (Double-blind Phase) [ 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 as determined by BICR (Double-blind Phase) [ Time Frame: 48 months ]
  2. Overall Survival (OS) [ Time Frame: 58 months ]
    Defined as time from randomization to death from any cause

  3. PFS per RECIST 1.1 as determined by investigator assessment [ Time Frame: 58 months ]
  4. Objective response rate (ORR) per RECIST 1.1 as determined by BICR (Double-blind Phase) [ Time Frame: 58 months ]
  5. ORR per RECIST 1.1 as determined by investigator assessment (Double-blind Phase) [ Time Frame: 58 months ]
  6. Duration of response (DOR) per RECIST 1.1 as determined by BICR (Double-blind Phase) [ Time Frame: 58 months ]
    Defined as time from first documented response to documented disease progression or death from any cause, whichever occurs earlier

  7. DOR per RECIST 1.1 as determined by investigator assessment (Double-blind Phase) [ Time Frame: 58 months ]
  8. Clinical benefit rate (CBR) as determined by BICR per RECIST 1.1 (Double-blind Phase) [ Time Frame: 58 months ]
  9. CBR per RECIST 1.1 as determined by investigator assessment (Double-blind Phase) [ Time Frame: 58 months ]
  10. Incidence of adverse events (AEs) [ Time Frame: 58 months ]
    As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements

  11. Frequency of dose modifications of tucatinib [ Time Frame: 58 months ]
    Dose modifications include dose holding, reductions, and discontinuations

  12. Frequency of dose modifications of trastuzumab [ Time Frame: 58 months ]
    Dose modifications include dose holding, reductions, and discontinuations

  13. Frequency of dose modifications of capecitabine [ Time Frame: 58 months ]
    Dose modifications include dose holding, reductions, and discontinuations

  14. Incidence of health resources utilization (Double-blind Phase) [ Time Frame: 58 months ]
  15. Quality of life as measured by EQ-5D-5L questionnaire (Double-blind Phase) [ Time Frame: 58 months ]
    Treatment and placebo group index values changes will be summarized

  16. Pharmacokinetic (PK) measure: Ctrough (Double-blind Phase) [ Time Frame: Up to 16 weeks ]


Information from the National Library of Medicine

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, Learn About Clinical Studies.


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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

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

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


Locations
Show Show 176 study locations
Sponsors and Collaborators
Seattle Genetics, Inc.
Investigators
Layout table for investigator information
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):
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Responsible Party: Seattle Genetics, Inc.
ClinicalTrials.gov Identifier: NCT02614794    
Other Study ID Numbers: ONT-380-206
2015-002801-12 ( EudraCT Number )
First Posted: November 25, 2015    Key Record Dates
Last Update Posted: February 25, 2020
Last Verified: February 2020
Keywords provided by Seattle Genetics, Inc.:
Tucatinib
Breast Cancer
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
Capecitabine
Trastuzumab
Xeloda
Herceptin
ARRY-380
ONT-380
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Trastuzumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological