Breast Cancer Clinical Trial
A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer
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.
Full 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.
Eligibility 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:
No evidence of brain metastases
Untreated brain metastases not needing immediate local therapy
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:
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
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:
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)
neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously
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:
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 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:
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 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
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There are 172 Locations for this study
Birmingham Alabama, 35249, United States
Mobile Alabama, 36604, United States
Goodyear Arizona, 85338, United States
Phoenix Arizona, 85016, United States
Duarte California, 91010, United States
Los Angeles California, 90095, United States
Los Angeles California, 90095, United States
Redondo Beach California, 90277, United States
San Francisco California, 94134, United States
San Marcos California, 92078, United States
Santa Maria California, 93454, United States
Vallejo California, 94589, United States
Aurora Colorado, 80045, United States
New Haven Connecticut, 06520, United States
Washington District of Columbia, 20007, United States
Fort Myers Florida, 33901, United States
Hollywood Florida, 33021, United States
Jacksonville Florida, 32207, United States
Miami Beach Florida, 33140, United States
Miami Florida, 33136, United States
Orlando Florida, 32806, United States
Saint Petersburg Florida, 33705, United States
Tampa Florida, 33612, United States
West Palm Beach Florida, 33401, United States
Atlanta Georgia, 30322, United States
Atlanta Georgia, 30342, United States
Augusta Georgia, 30912, United States
Newnan Georgia, 30265, United States
Chicago Illinois, 60612, United States
Chicago Illinois, 60637, United States
Niles Illinois, 60714, United States
Urbana Illinois, 61801, United States
Westwood Kansas, 66205, United States
Baltimore Maryland, 21201, United States
Rockville Maryland, 20850, United States
Boston Massachusetts, 02215, United States
Detroit Michigan, 48202, United States
Royal Oak Michigan, 48073, United States
Minneapolis Minnesota, 55407, United States
Kansas City Missouri, 64113, United States
Omaha Nebraska, 68130, United States
Lebanon New Hampshire, 03756, United States
Hackensack New Jersey, 07601, United States
Bronx New York, 10467, United States
New York New York, 10003, United States
New York New York, 10016, United States
Stony Brook New York, 11794, United States
Chapel Hill North Carolina, 27599, United States
Durham North Carolina, 27710, United States
Greenville North Carolina, 27834, United States
Columbus Ohio, 43210, United States
Portland Oregon, 97213, United States
Portland Oregon, 97239, United States
Tualatin Oregon, 97062, United States
Philadelphia Pennsylvania, 19104, United States
Philadelphia Pennsylvania, 19124, United States
Charleston South Carolina, 29414, United States
Charleston South Carolina, 29425, United States
Kingsport Tennessee, 37660, United States
Nashville Tennessee, 37203, United States
Nashville Tennessee, 37204, United States
Austin Texas, 78705, United States
Dallas Texas, 75203, United States
Denton Texas, 76210, United States
Fort Worth Texas, 76104, United States
Houston Texas, 77024, United States
Houston Texas, 77030, United States
Houston Texas, 77030, United States
Lubbock Texas, 79410, United States
Paris Texas, 75460, United States
Plano Texas, 75075, United States
San Antonio Texas, 78212, United States
San Antonio Texas, 78229, United States
The Woodlands Texas, 77380, United States
Webster Texas, 77598, United States
Salt Lake City Utah, 84112, United States
Fairfax Virginia, 22031, United States
Winchester Virginia, 22601, United States
Seattle Washington, 98104, United States
Seattle Washington, 98109, United States
Madison Wisconsin, 53792, United States
Heidelberg , 3084, Australia
Malvern , 3144, Australia
Melbourne , 3000, Australia
Nedlands , 6009, Australia
North Sydney , 2060, Australia
South Brisbane , 4101, Australia
South Brisbane , 4101, Australia
St Albans , 3021, Australia
Westmead , 2145, Australia
Graz , 8036, Austria
Innsbruck , 6020, Austria
Linz , 4010, Austria
Salzburg , 5020, Austria
Brasschaat , 2930, Belgium
Brussels , 1200, Belgium
Charleroi , 6000, Belgium
Libramont , 6800, Belgium
Namur , 5000, Belgium
Calgary , T2N 4, Canada
Edmonton , T6G 1, Canada
Halifax , B3H 2, Canada
Montreal , H3T 1, Canada
Quebec , G1S 4, Canada
Regina , S4T7T, Canada
Saskatoon , S7N 4, Canada
St John's , A1B 3, Canada
Toronto , M4N 3, Canada
Toronto , M5G 2, Canada
Vancouver , V5Z 4, Canada
Hradec Kralove , 500 0, Czechia
Olomouc , 77520, Czechia
Aalborg , 9100, Denmark
Copenhagen , DK 21, Denmark
Herlev , 2730, Denmark
Odense C , 5000, Denmark
Vejle , 7100, Denmark
Besancon cedex , 25030, France
Le Mans , 72000, France
Lyon , 69373, France
Marseille , 13273, France
Paris , 75005, France
Pierre Bénite Cedex , 69495, France
REIMS Cedex , 51056, France
Rennes Cedex , 35042, France
Strasbourg , 67200, France
Toulouse Cedex 9 , 31059, France
TOURS Cedex 09 , 37044, France
Berlin , 10117, Germany
Essen , 45136, Germany
Hamburg , 20246, Germany
Hannover , 30625, Germany
Kiel , 24105, Germany
Koblenz , 56068, Germany
Köln , 50937, Germany
Munchen , 80639, Germany
Offenbach am Main , 63069, Germany
Haifa , 31096, Israel
Jerusalem , 91120, Israel
Kfar Saba , 44281, Israel
Petach Tikva , 49414, Israel
Rehovot , 76100, Israel
Tel Aviv , 64239, Israel
Tel Hashomer , 52621, Israel
Bologna , 40138, Italy
Bolzano , 39100, Italy
Brindisi , 72100, Italy
Carpi , 41012, Italy
Genova , 16132, Italy
Milano , 20141, Italy
Pavia , 27100, Italy
Terni , 05100, Italy
Torrette , 60126, Italy
Lisboa , 1998-, Portugal
Porto , 4099-, Portugal
Barcelona , 08035, Spain
Barcelona , 08036, Spain
Caceres , 10002, Spain
Leon , 24008, Spain
Madrid , 28007, Spain
Madrid , 28041, Spain
Palma de Mallorca , 07010, Spain
Santiago de Compostela , 15706, Spain
Valencia , 46015, Spain
Zaragoza , 50009, Spain
Bellinzona , 6500, Switzerland
Colchester , C04 5, United Kingdom
London , SW3 6, United Kingdom
London , W1G 6, United Kingdom
Manchester , M20 4, United Kingdom
Northwood , HA6 2, United Kingdom
Nottingham , NG5 1, United Kingdom
Peterborough , PE3 9, United Kingdom
Sheffield , S10 2, United Kingdom
Sutton , SM2 5, United Kingdom
Truro , TR1 3, United Kingdom
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