Ensayos clínicos

Inclusion Criteria:

• Have confirmed HER2+ breast cancer, as defined by the current American Society of Clinical Oncology - College of American Pathologists (ASCO/CAP) guidelines, previously determined at a Clinical Laboratory Improvements Amendments (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory.
• History of prior treatment with a taxane and trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab)
• Have disease progression of unresectable LA/M breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy.
• Have measurable disease assessable by RECIST v1.1.
• Be at least 18 years of age at time of consent.
• Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1.
• Have a life expectancy of at least 6 months, in the opinion of the investigator.
• Have adequate hepatic function as defined by the following:
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN).
  • Exception: Subjects with known history of Gilbert’s Syndrome who have a direct bilirubin ≤ 1.5 x ULN in addition to a normal  aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are eligible b. Transaminases (AST and ALT) ≤ 3 x ULN (≤ 5 x ULN if liver metastases are present).
• Have adequate baseline hematologic parameters as defined by:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^3 /µL;
  • Platelet count ≥100 x 10^3 /µL;
  • Hemoglobin ≥ 9 g/dL;
  • In subjects transfused before study entry, transfusion must be ≥ 14 days prior to start of therapy to establish adequate hematologic parameters independent from transfusion support.
• Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73 m^2 using the Modification of Diet in Renal Disease (MDRD) study equation.
• International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN, unless on medication known to alter INR and PTT/aPTT.
• Have left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment.
• For subjects of childbearing potential, the following stipulations apply:
  • Must have a negative serum or urine pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to starting study treatment.  A subject with a false positive result and documented verification that the subject is not pregnant is eligible for participation;
  • Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of study drug;
  • Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 7 months after the final dose of study drug;
• If sexually active in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study drug.
• For subjects who can father children, the following stipulations apply:
  • Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 4 months after the final study drug;
  • If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control starting at time of informed consent and continuing throughout the study and for at least 4 months after the final dose of study drug;
  • If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 2 contraception options starting at time of informed consent and continuing throughout the study and for at least 4 months after the final dose of study drug administration.
• Subject must provide signed informed consent per a consent document that has been approved by an institutional review board or independent ethics committee (IRB/IEC) prior to initiation of any study-related tests or procedures that are not part of standard of care for the patient’s disease.
• Subjects must be willing and able to comply with study procedures.

CNS Inclusion:

• Based on medical history and screening contrast brain magnetic resonance imaging (MRI), subjects with a history of brain metastases must have one of the following:
  • Untreated brain metastases not needing immediate local therapy. For subjects with untreated central nervous system (CNS) lesions > 2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment.
• Previously treated brain metastases:
  • Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator;
  • Subjects treated with CNS local therapy for newly identified or previously treated progressing lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met:
  • Time since whole brain radiation therapy (WBRT) is ≥ 14 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 measurable disease by RECIST v1.1 are present;
  • Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions.

Exclusion Criteria:

• Have previously been treated with:
  • Lapatinib or neratinib within 12 months of starting study treatment (except in cases where lapatinib or neratinib was given for ≤ 21 days and was discontinued for reasons other than disease progression or severe toxicity); 
  • Tucatinib or enrolled on a tucatinib clinical trial;
  • Any investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) (e.g., afatinib) at any time previously;
  • T-DXd or another antibody-drug conjugate (ADC) consisting of an exatecan derivative.
• 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 (e.g., Doxil, Caelyx, Myocet) > 550 mg/m^2.
• History of allergic reactions to trastuzumab or compounds chemically or biologically similar to tucatinib or T-DXd, except for Grade 1 or 2 infusion-related reactions (IRRs) 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 (including hormonal therapy) or experimental agent ≤ 21 days of first dose of study treatment or are currently participating in another interventional clinical trial. An exception for the washout of hormonal therapies is gonadotropin releasing hormone (GnRH) agonists used for ovarian suppression in premenopausal women, which are permitted concomitant medications;
  • Treatment with non-CNS radiation ≤ 7 days prior to first dose of study treatmentl
  • Major surgery < 28 days of first dose of study treatment.
• Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
  • Alopecia;
  • Neuropathy, which must have resolved to ≤ Grade 2;
  • Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely;
  • Anemia, which must have resolved to ≤ Grade 2.
• Have clinically significant cardiopulmonary disease such as:
  • Ventricular arrhythmia requiring therapy;
  • Symptomatic hypertension or uncontrolled hypertension as determined by investigator;
  • Any history of symptomatic CHF;
  • Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or above) due to complications of advanced malignancy;
  • Hypoxia requiring supplementary oxygen therapy;
  • Have had a history of interstitial lung disease (ILD)/pneumonitis (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, or radiation pneumonitis) that required systemic corticosteroids, or has current ILD/pneumonitis, or where suspected ILD/ pneumonitis cannot be ruled out by imaging at screening.
• Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment.
• Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C infection. Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
• Presence of known chronic liver disease.
• Subjects known to be positive for human immunodeficiency virus (HIV) are excluded if they meet any of the following criteria:
  • CD4+ T-cell count of < 350 cells/µL;
  • Detectable HIV viral load;
  • History of an op  the past 12 months;
  • On stable antiretroviral therapy for < 4 weeks.
• Active or uncontrolled clinically serious infection.
• Are pregnant, breastfeeding, or planning a pregnancy.
• Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications.
• Have used a strong cytochrome P450 (CYP) 2C8 inhibitor within 5 elimination half-lives of the inhibitor, or have used a strong CYP3A4 or moderate/strong CYP2C8 inducer within 5 days prior to first dose of study treatment.
• Unable for any reason to undergo contrast MRI of the brain.
• Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures.
• History of malignancy other than breast cancer within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS of ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

CNS Exclusion:

• Based on medical history and screening contrast brain MRI, subjects must not have any of the following (listed in criteria 18–22):
  • Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor and approval for enrollment is given.
• Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent). However, subjects on a chronic stable dose of ≤ 2 mg total daily dose of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical monitor.
• Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to subject (e.g., brain stem lesions). Subjects 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 18b.
• Known or suspected leptomeningeal disease (LMD) as documented by the investigator.
• Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases.
• Have ongoing ≥ Grade 2 diarrhea of any etiology.

Eligibility last updated 1/25/22. Questions regarding updates should be directed to the study team contact.