T-DM1 with or without Abemaciclib for the Treatment of HER2-Positive Metastatic Breast Cancer

Inclusion Criteria

• PHASE I: REGISTRATION: Age >= 18 years
• PHASE I: REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1 or 2
• PHASE I: REGISTRATION: Imaging or histologic evidence of progression of unresectable locally advanced or metastatic HER2-positive cancer that has progressed after at least one prior line of treatment in the metastatic setting * Note: HER2-positive breast cancer per American society of clinical oncology/College of American pathologists (ASCO-CAP) guidelines is required; one of the following must apply: 3+ by immunohistochemistry (IHC) or 2+ by IHC and in-situ hybridization (ISH) amplified
• PHASE I: REGISTRATION: Measurable or non-measurable disease
• PHASE I: REGISTRATION: There is no limit on the number of prior lines of chemotherapy, HER2-directed therapy or endocrine therapy
• PHASE I: REGISTRATION: Grade 0-1 peripheral neuropathy
• PHASE I: REGISTRATION: Absolute neutrophil count >= 1.5 x 10^9/L (obtained =< 14 days prior to registration)
• PHASE I: REGISTRATION: Platelet count >= 100,000/mm^3 (obtained =< 14 days prior to registration)
• PHASE I: REGISTRATION: Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)
• PHASE I: REGISTRATION: Creatinine =< 1.5 X upper limit of normal (ULN) (obtained =< 14 days prior to registration)
• PHASE I: REGISTRATION: Total bilirubin =< 1.5 x ULN (obtained =< 14 days prior to registration) (except in cases of known Gilbert’s syndrome where =< 2.0 x ULN is allowed and direct bilirubin within normal levels is permitted)
• PHASE I: REGISTRATION: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (obtained =< 14 days prior to registration) * NOTE: If liver metastases are present, AST and ALT =< 5 x ULN are acceptable
• PHASE I: REGISTRATION: Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 X ULN OR if patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulants (obtained =< 14 days prior to registration)
• PHASE I: REGISTRATION: Left ventricular ejection fraction (LVEF) >= 50% as determined by echocardiography or multiple-gated acquisition imaging =< 21 days prior to registration
• PHASE I: REGISTRATION: Able to swallow oral medication
• PHASE I: REGISTRATION: Able to provide written informed consent =<28 days prior to registration
• PHASE I: REGISTRATION: Willingness to provide mandatory blood specimens for correlative research
• PHASE I: REGISTRATION: Female subjects of childbearing potential should have a negative serum pregnancy =< 7 days prior to registration
• PHASE I: REGISTRATION: Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• PHASE I: REGISTRATION: Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• PHASE I: REGISTRATION: Negative pregnancy test ≤7 days prior to registration, for persons of childbearing potential only. * NOTE: A female of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of T-DM1 +/- abemaciclib and agree to use a highly effective contraception method during the treatment period and for 6 months following the last dose of T-DM1 +/- abemaciclib * Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom). Birth control must be used during the treatment period and continued for at least 6 months after the last dose of treatment with T-DM1 +/- abemaciclib * Cases of pregnancy that occur during maternal exposures to T-DM1+/-abemaciclib, or cases of pregnancy in female partners/spouses of male patients,should be reported. If a female patient is determined to be pregnant following T-DM1 +/- abemaciclib initiation, she must discontinue treatment immediately. Data on fetal outcome and breast-feeding are to be collected for regulatory reporting and drug safety evaluation
• PHASE II: PRE-REGISTRATION: Age >=18 years
• PHASE II: PRE-REGISTRATION: ECOG PS: 0 or 1
• PHASE II: PRE-REGISTRATION: Imaging or histologic evidence of unresectable locally advanced or metastatic Her2-positive cancer that has progressed after at least one prior line of treatment in the metastatic setting
• PHASE II: PRE-REGISTRATION: Agree to undergo a core biopsy of breast cancer tissue derived from a local, regional, or distant site for mandatory confirmation of ER+/ER-, PR and HER2 status * NOTE: If a single lesion is present, imaging must be completed after the lesion is biopsied and measurements must be taken from this image for disease evaluation by RECIST to be considered eligible for this trial. * NOTE: The phase II study requires a fresh biopsy for clinical and research purposes and archival tissue does not suffice. If the patient has already undergone a biopsy at the time of disease progression prior to enrolling on the trial, an additional research biopsy will still be required * Note: Histological confirmation of metastatic HER2-positive breast cancer per ASCO-CAP guidelines is required; one of the following must apply: 3+ by IHC or 2+ by IHC and ISH amplified
• PHASE II: PRE-REGISTRATION: One of the following must be true: * Progressed/relapsed during or within 12 months of completing neo-adjuvant treatment with a regimen containing a taxane, trastuzumab and pertuzumab * Progressed/relapsed during or within 12 months of completing adjuvant treatment with a regimen containing a taxane, trastuzumab and pertuzumab * Progressed/relapsed during metastatic treatment with a regimen containing a taxane, trastuzumab and pertuzumab * Progressed/relapsed > 12 months after receipt of adjuvant T-DM1
• PHASE II: PRE-REGISTRATION: Measurable disease as defined by RECIST criteria * NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease. Disease that is measurable by physical examination only is not eligible for Phase II portion of this trial
• PHASE II: PRE-REGISTRATION: Received 1 or 2 prior lines of chemotherapy alone, HER2-directed therapy alone, and/or chemotherapy with HER2-directed therapies in any disease setting. Any number of prior lines of endocrine therapy received in any disease setting
• PHASE II: PRE-REGISTRATION: Willingness to provide mandatory blood specimens for correlative research
• PHASE II: PRE-REGISTRATION: LVEF >= 50% as determined by echocardiography or multiple-gated acquisition imaging =< 21 days prior to pre-registration
• PHASE II: PRE-REGISTRATION: Able to swallow oral medications
• PHASE II: PRE-REGISTRATION: Able to provide written informed consent =< 28 days prior to pre-registration
• PHASE II: PRE-REGISTRATION: Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• PHASE II: PRE-REGISTRATION: Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• PHASE II: PRE-REGISTRATION: Prior therapy with T-DM1 is acceptable providing that all T-DM1-related toxicities have resolved, except for alopecia (any grade) or peripheral neuropathy (grade >= 1) * NOTE: All residual toxicities (except alopecia) should be at baseline or grade 1 (including peripheral neuropathy). ** NOTE: If indicated, patients can commence treatment with bisphosphonates of RANK-L inhibitors (e.g.,denosumab) any time prior to randomization. No washout period or treatment delay is required prior to commencing study treatment
• PHASE II: RANDOMIZATION: Absolute neutrophil count >= 1.5 x 10^9/L (obtained =< 14 days prior to registration)
• PHASE II: RANDOMIZATION: Platelet count >= 100,000/mm^3 (obtained =< 14 days prior to registration)
• PHASE II: RANDOMIZATION: Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to randomization)
• PHASE II: RANDOMIZATION: Creatinine =< 1.5 X ULN
• PHASE II: RANDOMIZATION: Total bilirubin =< 1.5 × ULN (except in cases of known Gilbert’s syndrome where =< 2.0 x ULN is allowed and direct bilirubin within normal levels is permitted) (obtained =< 14 days prior to registration)
• PHASE II: RANDOMIZATION: ALT and AST =< 2.5 x ULN NOTE: If liver metastases are present, AST and ALT =< 5 x ULN are acceptable
• PHASE II: RANDOMIZATION: PT/INR/PTT =< 1.5 X ULN OR if patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulants
• PHASE II: RANDOMIZATION: Negative pregnancy test =< 7 days prior to randomization, for persons of childbearing potential only * NOTE: A female of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of T-DM1 +/- abemaciclib and agree to use a highly effective contraception method during the treatment period and for 6 months following the last dose of T-DM1 +/- abemaciclib * Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom). Birth control must be used during the treatment period and continued for at least 6 months after the last dose of treatment with T-DM1 +/- abemaciclib * Cases of pregnancy that occur during maternal exposures to T-DM1+/- abemaciclib, or cases of pregnancy in female partners/spouses of male patients, should be reported. If a female patient is determined to be pregnant following T-DM1 +/- abemaciclib initiation, she must discontinue treatment immediately. Data on fetal outcome and breast-feeding are to be collected for regulatory reporting and drug safety evaluation

Exclusion Criteria

• PHASE I: REGISTRATION: Any of the following: * Surgery =< 21 days prior to registration * Chemotherapy, radiation therapy, immunology, and endocrine therapy =< 21 days prior to registration * Non-myelosuppressive agents (including Anti-Her2 therapy) =< 14 days prior to registration ** NOTE: Single fraction radiotherapy is allowed/exempt from this washout period ** NOTE: Must have fully recovered from the toxicities of therapy, except for alopecia or peripheral neuropathy
• PHASE I: REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens * NOTE: Examples include interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in Grade 2 or higher diarrhea
• PHASE I: REGISTRATION: Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy which interacts with the study drug(s)
• PHASE I: REGISTRATION: Uncontrolled intercurrent illness including, but not limited to: * ongoing or active infection * symptomatic congestive heart failure * unstable angina pectoris * cardiac arrhythmia
• PHASE I: REGISTRATION: Any of the following =< 14 days prior to registration: * Active bacterial infection (requiring intravenous [IV] antibiotics) * fungal infection * detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C)
• PHASE I: REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
• PHASE I: REGISTRATION: Other active non-breast malignancy =< 3 years prior to registrations. * EXCEPTIONS: Patients with a history of adequately treated cancers that are of very low risk of recurrence (i.e. papillary thyroid cancer treated with surgery, carcinoma in situ of the cervix, non-melanoma skin cancer) are eligible * NOTE: If there is a history of prior malignancy, the patient must not be receiving other specific anti-neoplastic treatment
• PHASE I: REGISTRATION: History of any of the following conditions: * syncope of cardiovascular etiology * ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation) * sudden cardiac arrest.
• PHASE I: REGISTRATION: History of myocardial infarction =< 6 months prior to registration or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• PHASE I: REGISTRATION: Received prior treatment with any CDK 4 and CDK 6 inhibitor (e.g. abemaciclib, ribociclib or palbociclib) or participated in any CDK 4 and CDK 6 inhibitor clinical trial for which treatment assignment is still blinded
• PHASE I: REGISTRATION: Received live virus vaccine =< 28 days prior to registration
• PHASE I: REGISTRATION: Currently taking and unable to discontinue medications that are moderate or strong inhibitors and/or inducers of CYP3A or CYP3A4 before registration
• PHASE I: REGISTRATION: Unstable or newly diagnosed brain metastases requiring local treatment * NOTE: Stable treated brain metastases allowed. Specifically, central nervous system metastasis are allowed provided they have been treated (i.e., surgery, radiation, and/or radiosurgery) >= 12 weeks prior to registration and have stable neurologic function, including no requirement for medication(s) to control symptoms for >= 2 weeks prior to registration * NOTE: Patients with known leptomeningeal disease are not eligible
• PHASE I: REGISTRATION: Persons who are pregnant, nursing, or of childbearing potential who are unwilling to employ adequate contraception are ineligible because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effect on the developing fetus and newborn are unknown
• PHASE II: PRE-REGISTRATION: Any of the following: * Surgery =< 21 days prior to pre-registration * Chemotherapy, radiation therapy, immunology, and endocrine therapy =< 21 days prior to pre-registration * Non-myelosuppressive agents (including Anti-Her2 therapy) =< 14 days prior to pre-registration * NOTE: Single fraction radiotherapy is allowed/exempt from this washout period * NOTE: Must have fully recovered from the toxicities of therapy, except for alopecia or peripheral neuropathy
• PHASE II: PRE-REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens * NOTE: Examples include interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea
• PHASE II: PRE-REGISTRATION: Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy which interacts with the study drug(s)
• PHASE II: PRE-REGISTRATION: Uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia
• PHASE II: PRE-REGISTRATION: Any of the following ≤14 days prior to pre-registration: * Active bacterial infection (requiring IV antibiotics) * fungal infection * detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C)
• PHASE II: PRE-REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
• PHASE II: PRE-REGISTRATION: Other active non-breast malignancy =< 3 years prior to pre-registrations * EXCEPTIONS: Patients with a history of adequately treated cancers that are of very low risk of recurrence (i.e. papillary thyroid cancer treated with surgery, carcinoma in situ of the cervix, non-melanoma skin cancer) are eligible * NOTE: If there is a history of prior malignancy, the patient must not be receiving other specific anti-neoplastic treatment
• PHASE II: PRE-REGISTRATION: History of any of the following conditions: * Syncope of cardiovascular etiology * Ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation) * Sudden cardiac arrest
• PHASE II: PRE-REGISTRATION: History of myocardial infarction =< 6 months prior to pre-registration or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• PHASE II: PRE-REGISTRATION: Received prior treatment with any CDK 4 and CDK 6 inhibitor (e.g. abemaciclib, ribociclib or palbociclib) or participated in any CDK 4 and CDK 6 inhibitor clinical trial for which treatment assignment is still blinded
• PHASE II: PRE-REGISTRATION: Received live virus vaccine =< 28 days prior to pre-registration
• PHASE II: PRE-REGISTRATION: Currently taking and unable to discontinue medications that are moderate or strong inhibitors and/or inducers of CYP3A or CYP3A4 before pre-registration
• PHASE II: PRE-REGISTRATION: Unstable or newly diagnosed brain metastases requiring local treatment * NOTE: Stable treated brain metastases allowed ** Specifically, central nervous system metastasis are allowed provided they have been treated (i.e., surgery, radiation, and/or radiosurgery) >= 12 weeks prior to pre-registration and have stable neurologic function, including no requirement for medication(s) to control symptoms for >= 2 weeks prior to pre-registration * NOTE: Patients with known leptomeningeal disease are not eligible
• PHASE II: PRE-REGISTRATION: Persons who are pregnant, nursing, or of childbearing potential who are unwilling to employ adequate contraception are ineligible because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown
• PHASE II: RANDOMIZATION: Unable to provide histological confirmation of metastatic or locally advanced HER2-positive breast cancer per ASCO CAP guidelines
• PHASE II: RANDOMIZATION: Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: * Pregnant persons * Nursing persons * Persons of childbearing potential who are unwilling to employ adequate contraception