Abemaciclib in Treating Patients With Surgically Resectable, Chemotherapy Resistant, Triple Negative Breast Cancer
Abemaciclib in Treating Patients With Surgically Resectable, Chemotherapy Resistant, Triple Negative Breast Cancer
This phase II trial studies how well abemaciclib works in treating patients with triple
 negative breast cancer that can be removed by surgery (resectable) and does not respond to
 treatment with chemotherapy. Abemaciclib may stop the growth of cancer cells by blocking some
 of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:

 I. To examine the effects of abemaciclib on the CD8/FOXP3 ratio in chemotherapy resistant
 triple negative breast cancer (TNBC) patients following neoadjuvant chemotherapy.

 SECONDARY OBJECTIVES:

 I. Assess abemaciclib toxicities. II. To examine the effects of abemaciclib on the percentage
 of vimentin expressing invasive cancer cells.

 III. Within TNBC molecular subtypes (basal, mesenchymal, and luminal androgen receptor
 [LAR]), to evaluate the effects of abemaciclib on:

 IIIa. The individual elements of tumor grade (mitoses, nuclear pleomorphism, and tubule
 formation).

 IIIb. Tumor proliferation (as measured by tumor Ki-67 and serum tyrosine kinase inhibitor
 [TKI]).

 IIIc. pDUB3 as well as epithelial-mesenchymal transition (EMT) markers including SNAIL/SLUG,
 TWIST, and E-Cadherin as measured by immunohistochemistry (IHC).

 IIId. Quantification of tumor-infiltrating lymphocytes (as examined by hematoxylin and eosin
 [H&E]).

 EXPLORATORY OBJECTIVES:

 I. To evaluate the effect of abemaciclib on tumor ribonucleic acid (RNA)-seq data.

 II. To evaluate the effects of abemaciclib on the immune phenotype of peripheral blood
 mononuclear cells (PBMC), by evaluating expression of a panel of cell surface markers
 optimized of identification of human immune cell subpopulations.

 III. To evaluate the effects of abemaciclib on tumor-infiltrating immune cells in
 formalinfixed paraffin-embedded (FFPE) tumor sections, using multiplexed imaging technologies
 (e.g imaging mass cytometry, Nanostring digital spatial profiling [DSP] or CODEX) which will
 include:

 IIIa. Genes directly involved in tumor cell antigen presentation (e.g. B2M, HLA-A, HLA-B,
 HLA-C, TAP1, TAP2, TAPBP).

 IIIb. Interferon-stimulated genes (ISGs) that regulate antigen presentation (e.g. STAT1,
 NLRC5) and other ISGs (e.g. IRFs, OAS2).

 IIIc. Genes involved in double-strand ribonucleic acid (dsRNA) response (e.g. DDX58, DHX58).

 IIId. Genes encoding interferons, including type 3 IFNs (e.g. IFNL1, IFNL2, IFNL3).

 IIIe. Genes indicating a cytotoxic T cell response (e.g. PRF1, GZMB). IIIf. Regulatory T-cell
 (Treg)-specific transcription factor genes (e.g. FOXP3, IKZF2).

 IV. To assess the difference in the frequency of JAK-2 amplification among patients whose
 post-abemaciclib CD8/FOXP3 ratio >= 1.6 and that among patients whose post-abemaciclib
 CD8/FOXP3 ratio < 1.6.

 V. To generate organoids for future research. VI. To evaluate changes in the microbiome with
 exposure to abemaciclib.

 OUTLINE:

 Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-14 or days 1-21 in the
 absence of disease progression or unacceptable toxicity. Patients then undergo standard of
 care surgical resection no later than 12 weeks after the last dose of neoadjuvant
 chemotherapy.

 After completion of study treatment, patients are followed up within 30-60 days.
Inclusion Criteria:

 -  PRE-REGISTRATION: Clinical T1-4, N0-3, M0 breast cancer at diagnosis (prior to the
 start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC)
 staging version 8.

 -  Note: Benign breast disease, lobular carcinoma in situ (LCIS) or ductal carcinoma
 in situ (DCIS) in the contralateral breast is allowed.

 -  Note: Contralateral invasive breast cancer is allowed if disease is of clinically
 lower stage, and the higher stage lesion will be the study lesion for all
 biopsies and tissue samples.

 -  PRE-REGISTRATION: Histological confirmation of triple negative invasive breast cancer
 (defined as estrogen receptor [ER] =< 10%, progesterone receptor [PR] =< 10% and HER2
 not amplified by in situ hybridization [ISH] or immunohistochemistry [IHC] 0/1) at
 diagnosis.

 -  PRE-REGISTRATION: Neoadjuvant chemotherapy (NAC) with one of the following regimens
 that was not discontinued early due to intolerability with less than 50% of planned
 treatment given due to disease progression or patient request:

 -  Paclitaxel or docetaxel followed by one of the following: the combination of
 doxorubicin and cyclophosphamide (AC); the combination of epirubicin and
 cyclophosphamide (EC) or the combination of 5-fluorouracil, epirubicin and
 cyclophosphamide (FEC)

 -  Note: Carboplatin may be added to these regimens

 -  AC or EC or FEC followed by docetaxel or paclitaxel

 -  Note: Carboplatin may be added to these regimens

 -  Docetaxel in combination with doxorubicin and cyclophosphamide (TAC)

 -  PRE-REGISTRATION: Residual lesion/enhancement seen in the breast on breast imaging
 performed after completion of NAC.

 -  PRE-REGISTRATION: Able to swallow oral medication.

 -  PRE-REGISTRATION: Willing to undergo biopsy for research.

 -  PRE-REGISTRATION: Willing to provide tissue and blood samples for correlative research
 purposes.

 -  PRE-REGISTRATION: Willing to stop use of strong and moderate inducers and/or strong
 inhibitors of cytochrome P450 3A =< 7 days prior to registration.

 -  PRE-REGISTRATION: Provide written informed consent.

 -  REGISTRATION: Registration must occur =< 56 days after last dose of NAC.

 -  REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1,
 or 2.

 -  REGISTRATION: Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained after completion
 of NAC but =< 14 days prior to registration).

 -  REGISTRATION: Platelets (PLT) >= 100,000/mm^3 (obtained after completion of NAC but =<
 14 days prior to registration).

 -  REGISTRATION: Hemoglobin (HgB) >= 8.0 g/dL (obtained after completion of NAC but =< 14
 days prior to registration).

 -  REGISTRATION: Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained after
 completion of NAC but =< 14 days prior to registration).

 -  REGISTRATION: Aspartate transaminase (AST) serum glutamic oxaloacetic transaminase
 (SGOT) =< 3 x ULN (obtained after completion of NAC but =< 14 days prior to
 registration).

 -  REGISTRATION: Alanine transaminase (ALT) serum glutamate pyruvate transaminase (SGPT)
 =< 3 x ULN (obtained after completion of NAC but =< 14 days prior to registration).

 -  REGISTRATION: Serum creatinine =< 1.5 x ULN (obtained after completion of NAC but =<
 14 days prior to registration).

 -  REGISTRATION: Negative pregnancy test done =< 7 days prior to registration, for
 persons of childbearing potential only.

 Exclusion Criteria:

 -  PRE-REGISTRATION: History of deep venous thrombosis (DVT) or pulmonary embolisms (PE)
 =< 12 months prior to preregistration; OR Active DVT and/or PE requiring
 anti-coagulant therapy.

 -  NOTE: Patients who are on anti-coagulant therapy for maintenance are eligible as
 long as the DVT and/or PE was > 12 months prior to enrollment and there is no
 evidence for active thrombosis (either DVT or PE).

 -  NOTE: Patients on anticoagulation are eligible; however peri-biopsy and
 peri-surgical management of anticoagulation is per the institutional standard of
 care.

 -  PRE-REGISTRATION: Prior treatment with CDK 4/6 inhibitors (e.g. palbociclib,
 ribociclib, abemaciclib, etc.)

 -  PRE-REGISTRATION: Prior treatment with immunotherapy or radiation for this breast
 cancer.

 -  PRE-REGISTRATION: Prior incisional or excisional breast biopsy for this cancer.

 -  PRE-REGISTRATION: Any contraindications to pre-registration biopsy (such as bleeding
 diatheses, etc.).

 -  PRE-REGISTRATION: Receiving any investigational agent which would be considered as a
 treatment for the primary neoplasm.

 -  PRE-REGISTRATION: Other active malignancy =< 5 years prior to registration.

 -  EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.

 -  NOTE: If there is a history of prior malignancy, they must not be receiving
 another specific treatment for prior malignancy.

 -  PRE-REGISTRATION: Biopsy proven stage IV breast cancer.

 -  PRE-REGISTRATION: Serious pre-existing medical conditions that 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 < 30 ml/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).

 -  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.

 -  NOTE: Patients on anticoagulation are eligible; however peri-biopsy and
 peri-surgical management of anticoagulation is per the institutional standard of
 care.

 -  REGISTRATION: 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.

 -  REGISTRATION: Failure to recover to grade 1 or lower from effects of neoadjuvant
 chemotherapy.

 -  Exceptions: Residual alopecia and grade 2 peripheral neuropathy are allowed.

 -  REGISTRATION: Concurrent use of strong and moderate inducers and/or strong inhibitors
 of cytochrome P450 3A =< 7 days prior to registration.

 -  REGISTRATION: Known infections as follows (NOTE: Screening is not required for
 enrollment):

 -  Active systemic bacterial infection requiring intravenous antibiotics.

 -  Active fungal infection (requiring intravenous or oral antifungal treatment).

 -  Detectable viral infections (e.g. known human immunodeficiency virus [HIV], known
 active hepatitis B or C).