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About
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 alone, or in combination with pembrolizumab. Abemaciclib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Full 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 regimen without the addition of pembrolizumab (Cohort A).
II. To examine the effects of abemaciclib on the CD8/FOXP3 ratio in chemotherapy resistant TNBC patients following a neoadjuvant chemotherapy regimen with the addition of pembrolizumab (Cohort B).
SECONDARY OBJECTIVES for Cohort A and Cohort B Independently:
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 for Cohort A and Cohort B Independently:
I. To evaluate the effect of abemaciclib on tumor ribonucleic acid (RNA) expression.
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 cohorts.
COHORT A: Patients receive a neoadjuvant chemotherapy regimen without pembrolizumab.
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.
COHORT B: Patients receive a neoadjuvant chemotherapy regimen in combination with pembrolizumab.
GROUP 3: Patients undergo standard of care surgical resection.
GROUP 4: 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 4 are followed up within 30-60 days.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Women of age >=18 years
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.
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: Cohort A: CLOSED TO PRE-REGISTRATION and REGISTRATION as of protocol amendment 6 (04/14/2023) 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)
AC or EC or FEC followed by docetaxel or paclitaxel
Docetaxel in combination with doxorubicin and cyclophosphamide (TAC)
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: Cohort B: Neoadjuvant chemotherapy (NAC) with one of the following regimens in combination with pembrolizumab that was not discontinued early due to intolerability with less than 50% of planned treatment given due to disease progression or patient request:
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: COHORT B GROUP 4 ONLY: The following laboratory values obtained after completion of NAC but =< 14 days prior to registration:
REGISTRATION: COHORT B GROUP 4 ONLY: Absolute neutrophil count (ANC) >= 1500/mm^3.
REGISTRATION: COHORT B GROUP 4 ONLY: Platelets (PLT) >= 100,000/mm^3.
REGISTRATION: COHORT B GROUP 4 ONLY: Hemoglobin (HgB) >= 8.0 g/dL.
REGISTRATION: COHORT B GROUP 4 ONLY: Total bilirubin =< 1.5 x upper limit of normal (ULN).
REGISTRATION: COHORT B GROUP 4 ONLY: Aspartate transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT) =< 3 x ULN.
REGISTRATION: COHORT B GROUP 4 ONLY: Alanine transaminase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 3 x ULN.
REGISTRATION: COHORT B GROUP 4 ONLY: Serum creatinine =< 1.5 x ULN.
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.
PRE-REGISTRATION: Prior treatment with CDK 4/6 inhibitors (e.g. palbociclib, ribociclib, abemaciclib, etc.)
PRE-REGISTRATION: Prior treatment with 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 =< 3 years prior to registration.
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:
REGISTRATION: COHORT B GROUP 4: 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:
REGISTRATION: COHORT B GROUP 4: Failure to recover to grade 1 or lower from effects of neoadjuvant chemotherapy.
REGISTRATION: COHORT B GROUP 4: Concurrent use of strong and moderate inducers and/or strong inhibitors of cytochrome P450 3A =< 7 days prior to registration.
REGISTRATION: COHORT B GROUP 4: Known infections as follows (NOTE: Screening is not required for enrollment):
REGISTRATION: COHORT B GROUP 4: Concurrent use of chemotherapy, radiotherapy, immunotherapy, or other components of neoadjuvant treatment.
Primary purpose
Allocation
Interventional model
Masking
200 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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