T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery

Exclusion Criteria

• •Patients who are receiving any other investigational agents.
• •Patients unable to speak or understand English, since they cannot complete neurocognitive evaluation.
• •Patients with known leptomeningeal metastatic disease.
• •Patients with major symptoms or impairments related to brain metastases, such as aphasia or severe confusion, will be excluded per principal investigator (PI) discretion when those symptoms preclude proper neurocognitive evaluation during the study treatment.
• •Patients who have received previous treatment with T-DM1 and had systemic progression of disease while on it, are ineligible. Patients receiving treatment with T- DM1 whose only site of disease progression was brain are allowed to enroll in this trial.
• •Patients who have received chemotherapy in the previous 3 weeks (6 weeks for nitrosoureas or mitomycin).
• •Hepatitis B virus (HBV), Hepatitis B surface antigen positive (HBs Ag positive) or hepatitis C virus (HCV) (anti-HCV positive) patients are ineligible because of potential reactivation of hepatitis virus with temozolomide use.
• •Grade greater than or equal to 3 peripheral neuropathy according to (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
• •Cerebral Vascular Accident (CVA) or Transitory Ischemic Attack (TIA) in the year before enrollment, or presence of residual symptoms from CVA that happened more than a year before.
• •Pulmonary Embolism (PE) in the 3 months before enrollment. Anticoagulation is permitted.
• •Impaired cardiac function or clinically significant cardiac disease including the following:
• •* New York Heart Association grade III or IV congestive heart failure.
• •* Myocardial infarction within the last 12 months.
• •Subjects with impaired left ventricular ejection fraction (LVEF) (\<50%).
• •Patients with inability to complete brain MRI studies with contrast.
• •Patients with breast tissue expanders must have those removed before enrollment.
• •History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or T-DM1. Patients who are tolerating TDM1 successfully with pre-medications and slower infusion will be allowed.
• •Patients receiving medications that are strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers are ineligible. In vitro studies indicate that DM1, the cytotoxic component of T-DM1, is metabolized mainly by CYP3A4 and to a lesser extent by cytochrome P450 3A5 (CYP3A5). Concomitant use of strong CYP3A4 inhibitors with T-DM1 should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. Lists including medications and substances known or with the potential to interact with CYP3A4 isoenzymes are provided in Appendix B.
• •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, that would limit compliance with study requirements.
• •Pregnant women are excluded from this study because temozolomide is an alkylating agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide and/or T-DM1, breastfeeding should be discontinued if the mother is treated with either of those agents. These potential risks may also apply to other agents used in this study.
• •human immunodeficiency virus (HIV)-positive patients are excluded because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
• •Patients with any other concomitant invasive malignancies are ineligible. Prior invasive cancers treated with curative intent, and with no evidence of recurrent disease, may be eligible after principal investigator (PI) evaluation. Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible.
• •Patients who are receiving any other investigational agents.
• •Patients unable to speak or understand English, since they cannot complete neurocognitive evaluation.
• •Patients with known leptomeningeal metastatic disease.
• •Patients previously treated with whole brain radiation therapy (WBRT).
• •Patients with major symptoms or impairments related to brain metastases, such as aphasia or severe confusion, will be excluded per PI discretion when those symptoms preclude proper neurocognitive evaluation during the study treatment.
• •Patients who have received previous treatment with T-DM1 and had systemic progression of disease while on it, are ineligible. Patients receiving treatment with T- DM1 whose only site of disease progression was brain are allowed to enroll in this trial.
• •Patients who have received chemotherapy in the previous 3 weeks (6 weeks for nitrosoureas or mitomycin).
• •HBV (HBs Ag positive) or HCV (anti-HCV positive) patients are ineligible because of potential reactivation of hepatitis virus with temozolomide use.
• •Grade greater than or equal to 3 peripheral neuropathy according to (NCI CTCAE) version 4.0.
• •Cerebral Vascular Accident (CVA) or Transitory Ischemic Attack (TIA) in the year before enrollment, or presence of residual symptoms from CVA that happened more than a year before.
• •Pulmonary Embolism (PE) in the 3 months before enrollment. Anticoagulation is permitted.
• •Impaired cardiac function or clinically significant cardiac disease including the following:
• •* New York Heart Association grade III or IV congestive heart failure.
• •* Myocardial infarction within the last 12 months.
• •* Subjects with impaired LVEF (\<50%).
• •* Patients with inability to complete brain MRI studies with contrast.
• •* Patients with breast tissue expanders must have those removed before enrollment.
• •* History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or T-DM1. Patients who are tolerating TDM1 successfully with pre-medications and slower infusion will be allowed.
• •Patients receiving medications that are strong CYP3A4 inhibitors or inducers are ineligible. In vitro studies indicate that DM1, the cytotoxic component of T-DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors with T-DM1 should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. Lists including medications and substances known or with the potential to interact with CYP3A4 isoenzymes are provided in Appendix B.
• •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, that would limit compliance with study requirements.
• •Pregnant women are excluded from this study because temozolomide is an alkylating agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide and/or T-DM1, breastfeeding should be discontinued if the mother is treated with either of those agents. These potential risks may also apply to other agents used in this study.
• •HIV-positive patients are excluded because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
• •Patients with any other concomitant invasive malignancies are ineligible. Prior invasive cancers treated with curative intent, and with no evidence of recurrent disease, may be eligible after PI evaluation.