Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma MedDRA version: 21.1 Level: PT Classification code 10065430 Term: HER-2 positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Seattle Genetics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Double-Blinded Phase: Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH) or fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) methodology Have received previous treatment with a taxane, trastuzumab, pertuzumab, and T-DM1 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 measurable or non-measureable disease assessable by RECIST 1.1 At least 18 years of age at time of consent Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 Have adequate hepatic function Have adequate baseline hematologic parameters Have creatinine clearance = 50 mL/min or, in patients = 45 kg in weight, a serum creatinine within institutional normal limits Have left ventricular ejection fraction (LVEF) = 50% If female of childbearing potential, must have a negative result of serum or urine pregnancy test. Women of childbearing potential and men with partners of childbearing potential must agree to use a highly effective birth control methods. CNS Inclusion – Based on screening contrast 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 a. Brain metastases previously treated with local therapy my either be stable since treatment or may have progressed since prior local CNS therapy. b. 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 enrol if all of the following criteria are met: i. Time since whole brain radiation therapy (WBRT) is = 21 days prior to first dose of treatment, time since stereotactic radiosurgery (SRS) is = 7 days prior to first dose of treatment, or time since surgical resection is = 28 days ii. Other sites of disease assessable by RECIST 1.1 are present c. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions Unblinded Phase: For patients who were randomized to the control arm and on the longterm follow-up period at the time of the 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 measurable or non-measurable disease assessable by RECIST 1.1 Have ECOG PS 0 or 1 Adequate hepatic function Adequate hematologic parameters Have creatinine clearance = 50 mL/min as calculated per institutional uidelines or, in patients = 45 kg in weight, serum creatinine within institutional normal limits Have LVEF = 50% as assessed by ECHO or MUGA scan documented within 6 weeks prior to the time of crossover consent If female of childbearing potential, must have a negative result of serum or urine pregnancy test. Women of childbearing potential and men with partners of childbearing potential must agree to use a highly effective birth control methods CNS Inclusion – Based on screening contrast 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 a. Brain metastases previ
Exclusion criteria
Exclusion criteria: Double-Blinded Phase: Have previously been treated with: a. 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 severe toxicity) b. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously. Have previously been treated with capecitabine (or other fluoropyrimidine [e.g., 5-fluorouracil]) for metastatic disease (except in cases where capecitabine was given for = 21 days and was discontinued for reasons other than disease progression or severe toxicity). Note patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible. Have previously been treated with capecitabine for metastatic disease. Note patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible. Have any toxicity related to prior cancer therapies that has not resolved to = Grade 1. Have clinically significant cardiopulmonary disease. Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease Are known to be positive for human immunodeficiency virus (HIV) Require therapy with warfarin or other coumarin derviatives Unable for any reason to undergo contrast MRI of the brain 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 discussed with medical monitor and approval for enrolment is given Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total dose of > 2mg dexamethasone. 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 19b Known or suspected leptomeningeal disease (LMD) Unblinded Phase: Discontinuation of study treatment due to an adverse event while on the double-blind phase of the study Have any toxicity related to prior cancer therapies that has not resolved to = Grade 1 Have clinically significant cardiopulmonary disease Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease Are known to be positive for HIV Require therapy with warfarin or other coumarin derivatives Unable for any reason to undergo contrast MRI of the brain CNS Exclusion – Based on crossover screening brain MRI, patients must not have any of the following: Any untreated brain lesions > 2.0 cm in size unless discussed with medical monitor and approval for enrolment is given Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total dose of > 2mg dexamethasone. 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 19b Known or suspected leptomeningeal disease (LMD) Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy - PFS in patients with brain metastases at baseline using RECIST 1.1, as determined by BICR - OS - Comparative health economics Safety - Adverse events (AEs) Pharmacokinetics - Plasma concentrations of tucatinib and metabolites;Timepoint(s) of evaluation of this end point: Efficacy - Time from randomization to documented disease progression (as determined by BICR per RECIST 1.1), or death from any cause, whichever occurs first OS - End of the study Safety - Time from randomization to 30 days of last dose. | — |
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab on progression-free survival (PFS) per RECIST 1.1 based on blinded independent central review (BICR);Secondary Objective: Double-Blinded Phase: To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab in patients with brain metastases at baseline using RECIST 1.1 based on BICR To assess the effects of tucatinib vs. placebo in combination with capecitabine and trastuzumab on OS To assess the health-related quality of life and health economics associated with tucatinib vs. placebo in combination with capecitabine and trastuzumab Safety Objective To assess the safety and tolerability of tucatinib in combination with capecitabine and trastuzumab Pharmacokinetic Objective To evaluate the pharmacokinetics of tucatinib and metabolite ONT-993 when administered in combination with capecitabine and trastuzumab Unblinded Phase: To assess the safety and tolerability of tucatinib in combination with capecitabine and trastuzumab To assess PFS per RECIST 1.1 by investigator To assess OS;Primary end point(s): Progression Free Survival;Timepoint(s) of evaluation of this end point: Time from randomization to documented disease progression (as determined by BICR per RECIST 1.1), or death from any cause, whichever occurs first | — |
Countries
Australia, Austria, Belgium, Canada, Czech Republic, Denmark, France, Germany, Israel, Italy, Portugal, Switzerland, United Kingdom, United States
Contacts
Public ContactSeattle Genetics Trial Information
Seattle Genetics Trial Information Support
Outcome results
None listed