Tucatinib + Abemaciclib + Herceptin for HER2+ MBC

This research study is a Phase Ib clinical trial, which tests the safety of an
investigational intervention and also tries to define the appropriate dose of the
investigational intervention to use for further studies. "Investigational" means that the
intervention is being studied. The U.S. Food and Drug Administration (FDA) has not approved
the combination of Tucatinib, Abemaciclib, and Trastuzumab as a treatment for any disease.

In this research study, the investigators are:

- Studying the combination of Tucatinib, Abemaciclib, Trastuzumab, and hormonal therapy.

- Tucatinib is a drug that inhibits human epidermal growth factor receptor 2 (HER-2)
protein, which is a protein expressed in the cancer cells. By inhibiting this protein,
tucatinib may help stop or reduce the growth of the tumor. The U.S. Food and Drug
Administration (FDA) has not approved Tucatinib as a treatment for any disease, but it
has been used in a research setting with humans for many years.

- Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDK inhibitors work to stop
cell growth. The FDA has not approved Abemaciclib for this specific disease, but it has
been approved for other uses.

- Trastuzumab is called a "targeted therapy" because it works by attaching itself to
specific receptors on the surface of breast cancer cells, known as HER2 receptors. When
Trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are
blocked and the cancer cell may be marked for destruction by your immune system. This
process allows trastuzumab to help slow or stop the growth of the breast cancer. The FDA
has approved Trastuzumab as a treatment for this disease.

- Exemestane, Letrozole, and Anastrozole belong to a class of drugs called aromatase
inhibitors. the participant and the physician will choose the most appropriate aromatase
inhibitor for them. These drugs act by lowering the amount of estrogen produced by the
body by blocking an enzyme called aromatase. Each of these drugs have been approved by
the FDA for this cancer and have been used in the treatment of metastatic ER-positive
breast cancer for many years.

- In this part of the research study the investigators are looking for the safest doses of
these drugs to give to participants at the same time.

- The overall goal of this study is to evaluate the safety and effectiveness of Tucatinib
in combination with Abemaciclib, Trastuzumab, and hormonal therapy for hormone
receptor-positive, HER2-positive Metastatic Breast Cancer

Inclusion Criteria:

Dose Escalation Cohort:

- At least one measurable or non-measurable metastasis by radiographic evaluation or
physical examination.

- Progressive breast cancer on most recent regimen

- Presence of CNS metastases allowed, but not required for participation in the dose
escalation cohort.

Expansion Cohort A:

- At least one measurable CNS metastasis per RANO-BM, defined as ≥ 10 mm in at least one
dimension.

- Unequivocal evidence of new and/or progressive brain metastases, and at least one of
the following scenarios:

- Treated with SRS or surgery with residual un-treated lesions remaining. Such
participants are eligible for immediate enrollment on this study providing that at
least one untreated lesion is measurable

- Participants who have had prior WBRT and/or SRS and then whose lesions have
subsequently progressed are also eligible. In this case, lesions which have been
treated with SRS may be considered as target lesions if there is unequivocal evidence,
in the opinion of the treating physician, of progression following SRS.

- Participants who have not previously been treated with cranial radiation (e.g.,
WBRT or SRS) are eligible to enter the study, but such participants must be
asymptomatic from their CNS metastases and not requiring corticosteroids for
symptom control.

- Both participants who present with systemic stable/absent or systemic progressive
disease are eligible, as long as they fulfill one of the above criteria.

Expansion Cohort B:

- New and/or progressive brain metastasis(es) with clinical indication for surgical
resection.

- Participants must have evaluable intracranial disease according to RANO-BM prior to
surgical resection. Should participants also have extracranial disease, it may be
evaluable according to RECIST 1.1

Expansion Cohort C:

-At least one measurable extracranial metastasis according to RECIST 1.1

All Cohorts:

- Pathologically confirmed Hormone Receptor (HR)-positive HER2-positive MBC by local
laboratory with the following requirements:

- To fulfill the requirement of HR-positive disease, the most recent biopsy
(primary tumor or metastatic lesion) of the breast cancer must express at least
one of the hormone receptors (estrogen receptor [ER] or progesterone receptor
[PR]) by immunohistochemistry (IHC). ER and PR assays are considered positive if
there are > 1% positive tumor nuclei in the sample.

- To fulfill the requirement of HER2-positive disease, the most recent biopsy
(primary tumor or metastatic lesion) of the breast cancer must demonstrate HER2
overexpression or amplification (immunohistochemistry of 3+ or HER2 gene
amplification by in situ hybridization with a ratio of HER2-gene signals to
centromere 17 signals ≥ 2.0 or average HER2 copy number ≥ 6.0 signals/cells).

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

- Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (echo) or multigated
acquisition (MUGA) scan within 3 months before initiation of study treatment. Patients
with a history of LVEF < 50% should have left ventricular ejection fraction (LVEF) ≥
50% by echocardiogram (echo) or multigated acquisition (MUGA) scan within the
screening window.

- Stable or decreasing corticosteroid dose for at least 7 days prior to initiation of
treatment.

- Concurrent administration of other anti-cancer therapy during the course of this study
is not allowed, except for hormonal therapy with one of the commercially available
aromatase inhibitors (AI) and the use of ovarian suppression in pre-menopausal
patients. Note that concurrent use of supportive care medications (e.g.
anti-resorptive agents, pain medications) is allowed. Pre-menopausal patients will
need to receive ovarian suppression with the use of one of the commercially available
GNRH agonists, per the choice of the treating physician.

- The subject is ≥18 years old.

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1.5 × 109/L

- Platelets ≥ 100 × 109/L

- Hemoglobin ≥ 8 g/dL

- Note: Patients may receive erythrocyte transfusions to achieve this hemoglobin level
at the discretion of the investigator. Initial treatment must not begin earlier than
the day after the erythrocyte transfusion.

- Total bilirubin ≤ 1.5 × ULN.

- Patients with Gilbert's syndrome with a total bilirubin ≤ 2.0 times ULN and
direct bilirubin within normal limits are permitted;

- AST(SGOT)/ALT(SGPT) ≤ 3.0 × institutional ULN.

- Albumin > 2.5mg/dL

- Serum creatinine ≤ 1.5 × ULN.

- Female subjects of childbearing potential must have a negative serum or urine
pregnancy test prior to initiating protocol therapy.

- The effects of tucatinib, abemaciclib, and trastuzumab on the developing human fetus
are unknown so women of child-bearing potential and men must agree to use adequate
contraception (barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation and 4 months after completion of tucatinib and
abemaciclib administration and 7 months after trastuzumab administration.

- The subject is capable of understanding and complying with the protocol and has signed
the informed consent document.

- Participant must be able to swallow and retain oral medication.

- Have discontinued all previous therapies for breast cancer (including chemotherapy,
radiotherapy, immunotherapy, and investigational therapy), except for trastuzumab, for
at least the following number of days prior to receiving study drug(s):

- 28 days for myelosuppressive agents given every 28-day schedule.

- 21 days for myelosuppressive agents given every 21-day schedule.

- 14 days for myelosuppressive agents given every 7-day schedule, or for oral
agents or for nonmyelosuppresive agents

- Patients must have recovered from the acute effects of therapy (until the toxicity
resolves to either baseline or at least Grade 1) except for residual alopecia or
peripheral neuropathy

Exclusion Criteria:

- Visceral crisis or impending visceral crisis at time of screening.

- CNS complications for whom urgent neurosurgical intervention is indicated (e.g.,
resection, shunt placement).

- Known leptomeningeal metastases [Defined as positive CSF cytology and/or unequivocal
radiological evidence of clinically significant leptomeningeal involvement. CSF
sampling is not required in the absence of suggestive symptoms to exclude
leptomeningeal involvement].

- Patients unable to undergo gadolinium contrast-enhanced MRI or receive IV gadolinium
contrast for any reason (e.g., due to pacemaker, ferromagnetic implants,
claustrophobia, extreme obesity, hypersensivity).

- Has received prior therapy with a CDK4/6 inhibitor.

- No washout is required for endocrine therapy. If a patient has been on ovarian
suppression for at least 28 days prior to study entry, ccontinuation of ovarian
suppression is permitted on protocol. Patients can receive a new form of endocrine
therapy with one of the commercially available AIs at the time of initiation of
protocol therapy.

- Subjects with a history of grade 3 or 4 allergic reactions attributed to compounds of
similar biologic composition to tucatinib and/or abemaciclib or any constituent of the
product(s).

- The subject has an uncontrolled intercurrent illness, including, but not limited to,
ongoing or active infection, uncontrolled hypertension, unstable angina pectoris,
uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association
Class III or IV, active ischemic heart disease, myocardial infarction within the
previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration
diagnosed within the previous 6 months, chronic liver or renal disease, or severe
malnutrition.

- The subject is pregnant or breast-feeding.1No active, second potentially
life-threatening cancer. Exceptions include non-melanoma skin cancers, curatively
treated in situ cancer of the cervix, DCIS, stage1/grade 1 endometrial carcinoma.

- Has had major surgery within 21 days before treatment initiation.

- Active infection requiring iv antibiotics at the time of treatment initiation.

- Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs,
resulting in dyspnea at rest.

- Known intolerance to trastuzumab.

- Patients may not be receiving concurrent therapy with strong inhibitors of CYP3A4 or
strong inhibitors or inducers of CYP2C8. Please refer to Appendix M for a list of
inhibitors and inducers. Please note that concurrent use of trimethoprim, a component
of Bactrim, is prohibited per protocol. Patients who require PCP prophylaxis will need
to switch to an alternative antibiotic (e.g. mepron)