A Breast Cancer Genome Guided Therapy Study
Keywords
Abstract
Description
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 the individual elements of tumor grade (mitoses, nuclear pleomorphism, and tubule formation).
IV. Within TNBC molecular subtypes (basal, mesenchymal, and LAR), to evaluate the effects of abemaciclib on tumor proliferation (as measured by tumor Ki-67 and serum tyrosine kinase inhibitor [TKI]).
V. Within TNBC molecular subtypes (basal, mesenchymal, and LAR), to evaluate the effects of abemaciclib on pDUB3 as well as tyrosine-protein kinase ITK/TSK (EMT) markers including SNAIL/SLUG, TWIST, and E-Cadherin as measured by immunohistochemistry (IHC).
VI. Within TNBC molecular subtypes (basal, mesenchymal, and LAR), to evaluate the effects of abemaciclib on quantification of tumor-infiltrating lymphocytes (as examined by hematoxylin and eosin staining method [H&E]).
EXPLORATORY OBJECTIVES:
I. To evaluate the effect of abemaciclib on tumor ribonucleic acid (RNA)-seq data using the gene set enrichment analysis (GSEA) and CIBERSORT methods.
II. Using the suspension mass cytometry (HeliosTM system) to evaluate the effects of abemaciclib on the phenotype of peripheral blood mononuclear cells (PBMC) as well as formalin-fixed paraffin-embedded (FFPE) tumor sections (imaging mass cytometry (HyperionTM system) which will include: a) genes directly involved in tumor cell antigen presentation (B2M, HLA-A, HLA-B, HLA-C, TAP1, TAP2, TAPBP); b) interferon-stimulated genes (ISGs) that regulate antigen presentation (e.g. STAT1, NLRC5) and other ISGs (IRFs, OAS2); c) genes involved in double strand (ds)RNA response (DDX58, DHX58); d) genes encoding interferons, including type 3 IFNs (IFNL1, IFNL2, IFNL3); e) genes indicating a cytotoxic T cell response (PRF1, GZMB); f) regulatory T cell (Treg)-specific transcription factor genes (FOXP3, IKZF2).
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.
After completion of study treatment, patients are followed up within 30-60 days.
Dates
| Last Verified: | 12/31/2019 |
| First Submitted: | 06/04/2019 |
| Estimated Enrollment Submitted: | 06/04/2019 |
| First Posted: | 06/06/2019 |
| Last Update Submitted: | 07/20/2020 |
| Last Update Posted: | 07/21/2020 |
| Actual Study Start Date: | 01/09/2020 |
| Estimated Primary Completion Date: | 07/30/2022 |
| Estimated Study Completion Date: | 07/30/2022 |
Condition or disease
Intervention/treatment
Drug: Treatment (abemaciclib)
Procedure: Treatment (abemaciclib)
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: Treatment (abemaciclib) Patients receive abemaciclib PO 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. | Drug: Treatment (abemaciclib) Given PO |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | Female |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: - PRE-REGISTRATION: Clinical T1-3, N0-3 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. 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 disease. - 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, 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 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 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). |
Outcome
Primary Outcome Measures
1. 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 [Up to 21 days]
Secondary Outcome Measures
1. Incidence of adverse events [Up to 60 days]
2. Changes in vimentin expression [Up to 60 days]
Other Outcome Measures
1. Changes in mitoses [Up to 60 days]
2. Changes in nuclear pleomorphism [Up to 60 days]
3. Changes in tubule formation [Up to 60 days]
4. Changes in tumor Ki-67 [Up to 60 days]
5. Changes in serum tyrosine kinase inhibitor (TKI) [Up to 60 days]
6. Changes in SNAIL [Up to 60 days]
7. Changes in SLUG [Up to 60 days]
8. Changes in E-Cadherin [Up to 60 days]
9. Changes in tumor-infiltrating lymphocytes [Up to 60 days]
10. Effect of abemaciclib on tumor ribonucleic acid (RNA)-sequencing (seq) data [Up to 60 days]
11. Effect of abemaciclib on the phenotype of peripheral blood mononuclear cells (PBMC) [Up to 60 days]
12. Effect of abemaciclib on formalin-fixed paraffin-embedded (FFPE) tumor sections (imaging mass cytometry (HyperionTM system) [Up to 60 days]
