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

Anatomic Stage III Breast Cancer AJCC v8 Clinical Trial

Official title:

Window Trial of Abemaciclib for Surgically Resectable, Chemotherapy-Resistant, Triple Negative Breast Cancer (a BEAUTY Study*)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03979508
• Other study ID #: MC1734
• Secondary ID: NCI-2019-03567MC
• Status: Recruiting
• Phase: Phase 2
• Start date: January 10, 2020
• Est. completion date: July 31, 2024

Study information

• Verified date: April 2024
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 alone, or in combination with pembrolizumab. 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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: July 31, 2024
• Est. primary completion date: July 31, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.
• Note: Benign breast disease, lobular carcinoma in situ (LCIS) or ductal carcinoma in situ (DCIS) in the ipsilateral or contralateral breast is allowed.
• Note: Additional ipsilateral or contralateral invasive breast cancer is allowed. The index lesion is the largest triple-negative, chemotherapy-resistant lesion.
• 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)
• 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)
• 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:

• 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)
• Docetaxel in combination with cyclophosphamide (TC)
• Carboplatin or cisplatin in combination with a taxane (paclitaxel, docetaxel, or nab-paclitaxel)
• 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.
• 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 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.
• 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: 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:

• Pregnant persons.
• Nursing persons.
• Persons of childbearing potential who are unwilling to employ adequate contraception.
• REGISTRATION: COHORT B GROUP 4: Failure to recover to grade 1 or lower from effects of neoadjuvant chemotherapy.
• Exceptions: Residual alopecia and grade 2 peripheral neuropathy are allowed.
• 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):

• 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).
• REGISTRATION: COHORT B GROUP 4: Concurrent use of chemotherapy, radiotherapy, immunotherapy, or other components of neoadjuvant treatment.
• NOTE: Patients must complete all elements of NAC =21 days prior to starting abemaciclib.

Related Conditions & MeSH terms

• Anatomic Stage I Breast Cancer AJCC v8
• Anatomic Stage II Breast Cancer AJCC v8
• Anatomic Stage III Breast Cancer AJCC v8
• Breast Carcinoma In Situ
• Breast Ductal Carcinoma In Situ
• Breast Fibrocystic Change
• Breast Lobular Carcinoma In Situ
• Breast Neoplasms
• Carcinoma
• Carcinoma in Situ
• Carcinoma, Ductal
• Carcinoma, Ductal, Breast
• Carcinoma, Intraductal, Noninfiltrating
• Carcinoma, Lobular
• Invasive Breast Carcinoma
• Prognostic Stage I Breast Cancer AJCC v8
• Prognostic Stage IA Breast Cancer AJCC v8
• Prognostic Stage IB 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
• 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
• Triple Negative Breast Neoplasms
• Triple-Negative Breast Carcinoma

Intervention

Drug:
• Abemaciclib
Given PO

Procedure:
• Therapeutic Conventional Surgery
Undergo standard of care surgical resection

Locations

Country	Name	City	State
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Mayo Clinic in Arizona	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Mayo Clinic

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in mitoses	Examined graphically overall and by triple negative breast cancer (TNBC) subtypes.	Up to 60 days
Other	Changes in nuclear pleomorphism	Examined graphically overall and by TNBC subtypes.	Up to 60 days
Other	Changes in tubule formation	Examined graphically overall and by TNBC subtypes.	Up to 60 days
Other	Changes in tumor Ki-67	Examined graphically overall and by TNBC subtypes.	Up to 60 days
Other	Changes in serum tyrosine kinase inhibitor (TKI)	Examined graphically overall and by TNBC subtypes.	Up to 60 days
Other	Changes in SNAIL	Examined graphically overall and by TNBC subtypes.	Up to 60 days
Other	Changes in SLUG	Examined graphically overall and by TNBC subtypes.	Up to 60 days
Other	Changes in E-Cadherin	Examined graphically overall and by TNBC subtypes.	Up to 60 days
Other	Changes in tumor-infiltrating lymphocytes	Examined graphically overall and by TNBC subtypes.	Up to 60 days
Other	Effect of abemaciclib on tumor ribonucleic acid (RNA)-sequencing (seq) data	Effect of abemaciclib on tumor RNA sequencing followed by standard and customized pathway and enrichment analysis (e.g., Gene set enrichment analysis (GSEA) and CIBERSORT methods). The GSEA method determines whether an a priori set of genes are over-represented in the differential expression analysis of the pre- and post- drug response phenotypes. Similarly, CIBERSORT estimates cell composition from RNA transcriptomic data (e.g. immune cell populations).	Up to 60 days
Other	Effect of abemaciclib on the phenotype of peripheral blood mononuclear cells (PBMC)	Will be assessed using mass cytometry (e.g,. CyTOF) to analyze a panel of 29 cell surface markers optimized for identification of human immune cell subsets, including the following targets: CD45, CD195 (CCR6), CD19, CD127, CD38, IgD, CD11c, CD16, CD194 (CCR4), CD123/IL-3R, TCRgd, CD185 (CXCR5), CD3, CD45RA, CD27, CD29, CD66b, CD183 (CXCR3), CD161, CD45RO, CD197 (CCR7), CD8a, CD25/IL-2R, CD20, HLA-DR, CD4, CD14, CD56/NCAM. Identification of specific immune cell subsets will be assessed using consensus clustering methods of predefined combination of markers.	Up to 60 days
Other	Effect of abemaciclib on formalin-fixed paraffin-embedded (FFPE) tumor sections	Will include (imaging mass cytometry multiplex quantitative RNA/protein immune-based profilings, such as Hyperion TM, Nanostring GeoMX, Codex, and may include the examination of genes directly involved in tumor cell antigen presentation (e.g. B2M, HLA-A, HLA-B, HLA-C, TAP1, TAP2, TAPBP), interferon-stimulated genes (ISGs) that regulate antigen presentation (e.g. STAT1, NLRC5) and other ISGs (e.g. IRFs, OAS2), genes involved in double strand RNA response (e.g. DDX58, DHX58), genes encoding interferons, including type 3 IFNs (e.g. IFNL1, IFNL2, IFNL3), genes indicating a cytotoxic T cell response (e.g. PRF1, GZMB), regulatory T cell-specific transcription factor genes (e.g., FOXP3, IKZF2)	Up to 60 days
Other	Change in in frequency of JAK-2 amplifications	The collection of JAK-2 will be used 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. A 95% binomial confidence for the difference in two independent proportions will be constructed for the difference in the percentage of patients with a post-abemaciclib CD8/FOXP3 ratio >= 1.6 among those with JAK-2 amplified TNBC and those with JAK-2 non-amplified TNBC.	Baseline up to time of surgery
Other	Change in microbiome with exposure to abemaciclib	The collection of microbiome information via stool collection will be used to generate descriptive analyses about the study population, as the total number of samples is expected to be insufficient for full statistical analysis. Will explore putative mechanistic connections underlying bacteria-drug interactions in all patients and attempt to identify the biomolecular features within the gut (stool) microbiome and its association with the pharmacokinetics and pharmacodynamics of abemaciclib.	Baseline up to prior to surgery
Primary	Proportion of patients who have a CD8/FOXP3 ratio < 1.6 in their residual tumors after neoadjuvant chemotherapy (NAC) that convert to CD8/FOXP3 ratio >= 1.6	A Simon optimum two stage phase II clinical trial design was chosen to test the null hypothesis that the rate of conversion to post-abemaciclib CD8/FOXP3 ratio of 1.6 or more is =< 5% against the alternative that rate of conversion to post-abemaciclib CD8/FOXP3 ratio of 1.6 or more is >= 20% with the target probability of a type I error and probability of a type II error set to 0.10. The probability of terminating after the first stage is 0.736, if the null hypothesis is true. A 90% confidence interval for this rate of conversion will be constructed using the Duffy-Santner approach taking into account the sequential nature of the study	Up to 21 days
Secondary	Incidence of adverse events	Adverse events will be monitored and graded with attribution assigned using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For each type of adverse event (AE) reported, the proportion of patients experiencing a grade 2 or worse level of that AE will be determined.	Up to 60 days
Secondary	Changes in vimentin expression	Vimentin expression will be evaluated by immunohistochemistry (IHC) with using 0, 1+, 2+ or 3+ scoring scheme. A point estimate of the proportion of eligible patients whose post-NAC residual tumor Vimentin expression levels were 2+ or 3+ and then fell to 0 or 1+ after abemaciclib among the eligible patients whose began abemaciclib treatment after a post NAC residual tumor Vimentin expression level finding of 2+ or 3+ will be calculated. A 90% confidence interval for this proportion will be constructed using one-sample binomial confidence for proportions.	Up to 60 days
Secondary	Impact of length of treatment	Association between amount of abemaciclib received and the change in CD8/FOXP3 ratio after abemaciclib will be explored graphically. A plot of the change in change in CD8/FOXP3 ratio after abemaciclib and days of treatment will be constructed to visually assess for trends. Also, the a 90% confidence interval for the difference in binomial proportions will be constructed to assess whether the proportion of patients whose post abemaciclib CD8/FOXP3 ratio >= 1.6 after completing 14-21 days of abemaciclib differs between those who discontinued abemaciclib the day prior to surgery and who discontinued abemaciclib 2 or more days prior to surgery. A 90% binomial confidence interval for the proportion of women who failed to complete 14-21 days of abemaciclib or underwent surgery or breast biopsy 2 or more days after last dose of abemaciclib among the eligible women who began abemaciclib treatment.	Up to 60 days