Abemaciclib in Treating Patients With Surgically Resectable Chemotherapy Resistant Triple Negative Breast Cancer

  • STATUS
    Recruiting
  • End date
    Jul 31, 2022
  • participants needed
    100
  • sponsor
    Mayo Clinic
Updated on 5 September 2021
paclitaxel
metastases
cancer
total bilirubin
cyclophosphamide
absolute neutrophil count
estrogen
carcinoma
breast cancer
fluorouracil
progesterone
residual tumor
doxorubicin
metastasis
neutrophil count
carboplatin
immunohistochemistry
HER2
carcinoma in situ
lobular carcinoma
docetaxel
triple negative breast cancer
progesterone receptor
erbb2
estrogen receptor
abemaciclib
invasive breast cancer
anthracycline
epirubicin
5-fluorouracil
ductal carcinoma in situ
therapeutic conventional surgery
lobular carcinoma in situ
breast disease
dcis

Summary

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.

Description

PRIMARY OBJECTIVE:

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 formalin-fixed 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 are assigned to 1 of 2 groups.

GROUP 1: Patients undergo standard of care surgical resection.

GROUP 2: 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 in group 2 are followed up within 30-60 days.

Details
Condition Ductal Carcinoma In Situ, Fibrocystic Disease of Breast, Estrogen Receptor Negative, Progesterone Receptor Negative, Invasive Breast Carcinoma, Lobular Breast Carcinoma in Situ, Invasive Breast Cancer, Ductal Carcinoma In Situ (DCIS), Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Fibrocystic Breast Disease, HER2/Neu Negative, Triple-Negative Breast Carcinoma, HER2/Neu Negative, Triple-Negative Breast Carcinoma, HER2/Neu Negative, Triple-Negative Breast Carcinoma, Triple Negative Breast Carcinoma, HER2/Neu Negative, HER2/Neu Negative, HER2/Neu Negative, HER2/Neu Negative, dcis, Breast Lobular Carcinoma In Situ
Treatment therapeutic conventional surgery, Abemaciclib
Clinical Study IdentifierNCT03979508
SponsorMayo Clinic
Last Modified on5 September 2021

Eligibility

Yes No Not Sure

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
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
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
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
Docetaxel in combination with cyclophosphamide (TC) (for patients who are not candidates for anthracyclines)
Carboplatin or cisplatin in combination with a taxane (paclitaxel, docetaxel, or nab-paclitaxel) (for patients who are not candidates for anthracyclines)
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: GROUP 2 ONLY: Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained after completion of NAC but =< 14 days prior to registration)
REGISTRATION: GROUP 2 ONLY: Platelets (PLT) >= 100,000/mm^3 (obtained after completion of NAC but =< 14 days prior to registration)
REGISTRATION: GROUP 2 ONLY: Hemoglobin (HgB) >= 8.0 g/dL (obtained after completion of NAC but =< 14 days prior to registration)
REGISTRATION: GROUP 2 ONLY: Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained after completion of NAC but =< 14 days prior to registration)
REGISTRATION: GROUP 2 ONLY: Aspartate transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT) =< 3 x ULN (obtained after completion of NAC but =< 14 days prior to registration)
REGISTRATION: GROUP 2 ONLY: Alanine transaminase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 3 x ULN (obtained after completion of NAC but =< 14 days prior to registration)
REGISTRATION: GROUP 2 ONLY: Serum creatinine =< 1.5 x ULN (obtained after completion of NAC but =< 14 days prior to registration)
REGISTRATION: GROUP 2 ONLY: 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
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: Other active malignancy =< 3 years prior to registration
PRE-REGISTRATION: Biopsy proven stage IV breast cancer
PRE-REGISTRATION: History of any of the following conditions
Syncope of cardiovascular etiology
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)
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
Pregnant persons
Nursing persons
Persons of childbearing potential who are unwilling to employ adequate contraception
REGISTRATION: GROUP 2 ONLY: 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
Exceptions: Residual alopecia and grade 2 peripheral neuropathy are allowed
REGISTRATION: GROUP 2 ONLY: Failure to recover to grade 1 or lower from effects of neoadjuvant chemotherapy
Active fungal infection (requiring intravenous or oral antifungal treatment)
Active systemic bacterial infection requiring intravenous antibiotics
Detectable viral infections (e.g. known human immunodeficiency virus [HIV], known active hepatitis B or C)
REGISTRATION: GROUP 2 ONLY: Concurrent use of strong and moderate inducers and/or strong inhibitors of cytochrome P450 3A =< 7 days prior to registration
REGISTRATION: GROUP 2 ONLY: Known infections as follows (NOTE: Screening is not required for enrollment)
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