The purpose of this study is 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 independent central review.
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 (HER2CLIMB)
This is a Phase 2 randomized, international, multi-center, double-blinded study of tucatinib or placebo in combination with capecitabine and trastuzumab in patients with pretreated unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with a taxane, trastuzumab, pertuzumab and T-DM1. After signing informed consent and meeting all eligibility criteria patients will be randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab.
Randomization will be made using a dynamic hierarchical randomization schema. Stratification factors will include presence or history of treated or untreated brain metastases (yes/no), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 vs. 1), and region of world (US vs Canada vs Rest of World). Stratification for presence of brain metastases will be based upon medical history and investigator assessment of screening MRI. Patients who have a documented history of prior brain metastases or unequivocal presence of CNS lesions on screening MRI will be considered a "Yes" for stratification purposes, and subsequent efficacy assessments. Patients with no prior history of brain metastases and lesions of equivocal significance on screening MRI will also be considered a "Yes" for purposes of stratification and follow-up.
Treatment will be administered in cycles of 21 days each. Tucatinib or placebo will be given PO BID. Capecitabine will be given at 1000 mg/m2 PO BID on Days 1-14 of each 21-day cycle. Trastuzumab will be given as a loading dose of 8 mg/kg IV followed by 6 mg/kg once every 21 days, except in specific circumstances where it may be given weekly to compensate for modifications in treatment schedule. Dose modifications of tucatinib or placebo and capecitabine will be allowed. Dose holding or discontinuation of tucatinib or placebo, capecitabine, and trastuzumab will also be allowed as needed for patient safety. Patients who discontinue either capecitabine or trastuzumab (but not both) may remain on study treatment. Patients who discontinue tucatinib or placebo, or both capecitabine and trastuzumab will not be allowed to remain on study treatment.
Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. After discontinuing study treatment, patients may receive further care as determined by their physician. In the absence of clear evidence of clinical progression, development of CNS symptoms, or radiographic changes thought to pose potential immediate risk to patient, all efforts should be made to continue treatment until unequivocal evidence of radiologic or clinical progression occurs, as defined in RECIST 1.1. No crossover from placebo to tucatinib will be allowed.
Patients will be assessed throughout the study for safety. Safety assessments including physical exam, collection of adverse events (AEs), and laboratory 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. Cardiac ejection fraction will be assessed by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO) at screening and once every 12 weeks thereafter.
Brain MRI will be performed at baseline in all patients regardless of prior history of brain metastases. Efficacy assessments will include measurement of all known sites of metastatic or locally advanced unresectable disease (including at a minimum the chest, abdomen, and pelvis) by high quality spiral computed tomography (CT), positron emission tomography (PET)/CT (if high quality CT scan included) and/or MRI scan as appropriate, as well as appropriate imaging of any other known sites of disease (e.g. bone scans) 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 prior history of brain metastases, brain metastases found at screening, or brain lesions of equivocal significance found at screening. Brain MRI may also be performed in patients without known brain metastases if there is clinical suspicion of new brain lesions. Additional imaging such as nuclear medicine bone scan or other unscheduled scans may be performed at the discretion of the investigator. Treatment decisions will be made based upon investigator assessment of radiologic scans. All patients will undergo a repeat MRI of the brain within 30 days of the end of treatment, unless an MRI of the brain has already been performed within 30 days or prior documentation of progression in the brain on study. Patients in both arms of the study will continue to be followed for OS after completion of study treatment.
HER2 Positive Breast Cancer Tucatinib Capecitabine Trastuzumab Xeloda Herceptin Breast Cancer ARRY-380 ONT-380
Open to people ages 18 years and up
Patients must meet the following criteria to be eligible for the study:
Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by fluorescence in situ hybridization (FISH) and/or 3+ staining by immunohistochemistry(IHC)
a. Tissue blocks or slides must be submitted to confirm HER2 positivity(FISH-positive or IHC 3+) by a sponsor-designated central laboratory prior to randomization. Centrally confirmed HER2 results (either IHC or FISH) from a previous study can be used to determine eligibility for this study with approval from the sponsor.
Patients must be willing and able to comply with study procedures.
Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:
Patients treated with CNS local therapy for newly identified lesions found on initial MRI performed during screening for this study may be eligible to enroll if all of 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 evaluable disease are present c. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
Patients will be excluded from the study for any of the following reasons:
Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
Have clinically significant cardiac disease such as:
Have evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment.
Based on screening brain MRI, patients must not have any of the following:
We will not share your information with anyone other than the team in charge of this study. Submitting your contact information does not obligate you to participate in research.
The study team should get back to you in a few business days.
You will also receive an email with next steps. Check your junk/spam folder if needed.
If you do not hear from the study team, please call 888-689-8273 and tell them you’re interested in study number NCT02614794.
© 2017 The Regents of the University of California