Abemaciclib and Niraparib Before Surgery for the Treatment of Hormone Receptor Positive HER2 Negative Breast Cancer
Abemaciclib and Niraparib Before Surgery for the Treatment of Hormone Receptor Positive HER2 Negative Breast Cancer
This phase I trial tests the side effects and best dose of abemaciclib and niraparib in
 treating patients with breast cancer that is positive for estrogen or progesterone receptors
 (hormone receptor positive [HR+]) and HER2 negative. Abemaciclib may stop the growth of tumor
 cells by blocking certain proteins called cyclin-dependent kinases, which are needed for cell
 growth. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as
 niraparib, can keep PARP from working so tumor cells can't repair themselves and grow. Giving
 abemaciclib and niraparib together before surgery may make the tumor smaller.
PRIMARY OBJECTIVES:

 I. To determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose of the
 combination of abemaciclib and niraparib tosylate monohydrate (niraparib).

 II. To assess safety and tolerability of the combination of abemaciclib and niraparib in
 early stage HR+ breast cancer.

 SECONDARY OBJECTIVES:

 I. To determine clinical response to treatment. II. To determine pathologic response to
 treatment. III. To determine feasibility of combination as determined by no delay to standard
 of care breast surgery.

 EXPLORATORY OBJECTIVE:

 I. To assess occurrence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia
 (AML) malignancy.

 OUTLINE: This is a phase 1 dose-escalation study of abemaciclib in combination with niraparib
 followed by a dose-expansion study.

 Patients receive abemaciclib orally (PO) twice daily (BID) and niraparib PO once daily (QD).
 Treatment repeats every 28 days for up to 2-4 cycles in the absence of disease progression or
 unacceptable toxicity. Patients who complete 4 cycles undergo standard of care mastectomy or
 lumpectomy. Patients demonstrating progressive disease after only 2 cycles are switched to
 receive standard of care chemotherapy prior to undergoing mastectomy or lumpectomy.

 Patients are followed up at 30 days after date of surgery, every 3 months for the first 6
 months, every 6 months for 2 years, then annually for up to 5 years from date of surgery.
Inclusion Criteria:

 -  Ability to understand and the willingness to sign a written informed consent document.

 -  Females (regardless of menopausal status), or males of all races and ethnic groups

 -  Biopsy proven estrogen receptor (ER) and/or progesterone receptor (PR) positive as
 defined as ER >= 1% and/or PR >= 1% by immunohistochemistry according to American
 Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
 for hormone receptor testing

 -  HER2 non-amplified per 2018 ASCO/CAP guidelines, defined as:

 -  Immunohistochemistry (IHC) score 0/1+, or

 -  IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to
 CEP17 < 2.0, and if reported, average HER2 gene copy number < 4 signals/cells; or

 -  ISH non-amplified with a ratio of HER2 to CEP17 < 2.0, and if reported, average
 HER2 gene copy number < 4 signals/cells

 -  Clinical T1-T3, any N, M0 invasive breast cancer, by American Joint Committee on
 Cancer (AJCC) 8th edition clinical staging with the goal being curative intent surgery
 to completely excise involved tumor in the breast and the draining lymph nodes

 -  Individuals with unilateral, multi-focal breast cancer (defined as more than one
 lesion of invasive breast cancer in the same breast separated from the dominant breast
 lesion by less than 5 cm of radiologically normal breast tissue) are eligible

 -  Participants must be planned for neoadjuvant chemotherapy

 -  Except for allowable endocrine therapy up to 4 weeks prior to study enrollment,
 participants must not have received prior anti-cancer therapy for the treatment of
 their breast cancer

 -  Participant must have disease that is amenable to biopsy, and agree to provide the
 required research biopsies at baseline, and 2 months after initiating study therapy

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

 -  The participant is able to swallow oral medications

 -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

 -  Platelets >= 100 x 10^9/L

 -  Hemoglobin >= 9 g/dL

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN). Participants with Gilbert's
 syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal
 limits are permitted

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN

 -  If a participant is a cancer survivor, they have undergone potentially curative
 therapy for all prior malignancies, with no evidence of recurrence > 5 years

 -  Female participants of childbearing potential (FOCBP) must have a negative serum or
 urine pregnancy test (per institutional standards) within 7 days prior to the start of
 study drugs

 -  FOCBP must agree to use highly-effective method(s) of contraception during the study
 and for 6 months after the last dose of study drugs

 -  FOCBP are those who have not been surgically sterilized or have not been free from
 menses for > 1 year without an alternative medical cause

 -  Male participants must agree to use an adequate method of contraception starting with
 the first dose of study therapy through at least 3 months after the last dose of study
 drugs

 -  Participant must agree to not donate blood during the study or for 90 days after the
 last dose of study treatment

 -  Participant receiving corticosteroids may continue as long as their dose is stable for
 least 4 weeks prior to initiating protocol therapy

 -  Participant must agree to not breastfeed during the study or for 30 days after the
 last dose of study treatment

 Exclusion Criteria:

 -  Prior history of malignancy within 5 years except for successfully treated cervical
 carcinoma in situ, lobular carcinoma in situ of the breast, or non-melanoma skin
 cancer

 -  Inflammatory breast cancer defined as clinically significant erythema of the breast
 and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau
 d'orange without erythema) is not eligible

 -  Participants that have undergone surgical axillary staging procedure prior to study
 entry

 -  Fine needle aspiration (FNA) or core needle biopsy of axillary node is permitted

 -  Bilateral breast cancer, provided tumors exhibit similar biomarkers (grade, ER/PR,
 HER2)

 -  Clinical or radiographic evidence of metastatic disease

 -  Isolated ipsilateral supraclavicular node involvement is permitted

 -  A prior history of ductal breast carcinoma in situ (DCIS) treated with
 contralateral mastectomy and not receiving endocrine therapy is eligible

 -  Breast implants are contraindicated only if the implant precludes the required
 research biopsies or interferes with palpating the breast lesion

 -  Prior treatment for this cancer including surgery, radiation therapy, chemotherapy,
 biotherapy, hormonal therapy or investigational agent prior to study entry

 -  Participants may have received up to 4 weeks of endocrine therapy prior to
 enrollment on trial

 -  Participants with myelodysplastic syndrome/acute myeloid leukemia or with features
 suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

 -  Contraindication to undergoing breast and/or axillary lymph node biopsy

 -  Contraindication to undergoing surgical resection

 -  Prior therapy with a PARP inhibitor

 -  Prior therapy with a CDK 4/6 inhibitor

 -  The patient has active systemic bacterial infection (requiring intravenous [IV]
 antibiotics at time of initiating study treatment), fungal infection, or detectable
 viral infection (such as known human immunodeficiency virus positivity or with known
 active hepatitis B or C [e.g., hepatitis B surface antigen positive]. Screening is not
 required for enrollment

 -  The patient has serious and/or uncontrolled preexisting medical condition(s) that, in
 the judgment of the investigator, would preclude participation in this study (for
 example, interstitial lung disease, severe dyspnea at rest or requiring oxygen
 therapy, severe renal impairment [e.g. estimated creatinine clearance < 30ml/min],
 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)

 -  Known history of pneumonitis or interstitial lung disease (ILD)

 -  Known history of deep vein thrombosis (DVT) or pulmonary embolism (PE)

 -  Participant must not have received a transfusion (platelets or red blood cells) =< 4
 weeks prior to initiating protocol therapy. Exceptions may be made at the discretion
 of the investigator for the treatment of clinical complications such as bleeding. In
 these cases, protocol therapy may start >= 7 days after transfusion

 -  Participant must not have received colony stimulating factors (e.g., granulocyte
 colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
 recombinant erythropoietin) within 4 weeks prior initiating protocol therapy

 -  The patient has a personal 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), or sudden
 cardiac arrest

 -  Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
 cardiac conditions, as judged by the investigator (e.g., unstable ischemia,
 uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's Correction
 Formula (QTcF) prolongation > 500 ms, electrolyte disturbances, etc.), or participants
 with congenital long QT syndrome

 -  Uncontrolled hypertension, or hypertension that cannot otherwise be clinically managed
 before initiating study therapy

 -  Psychiatric illness/social situations, or any condition that, in the opinion of the
 investigator, would: interfere with evaluation of study treatment or interpretation of
 participant safety or study results, or substantially increase risk of incurring
 adverse events (AEs), or compromise the ability of the patient to give written
 informed consent

 -  Participant must not have had major surgery =< 3 weeks prior to initiating protocol
 therapy and participant must have recovered from any surgical effects

 -  Hypersensitivity to any study agent, or its excipients, when administered alone

 -  Females who are pregnant or lactating

 -  Judgment by the investigator that the patient should not participate in the study if
 the patient is unlikely to comply with study procedures, restrictions and requirements