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Trial record 5 of 5 for:    OAS2

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

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ClinicalTrials.gov Identifier: NCT03979508
Recruitment Status : Not yet recruiting
First Posted : June 7, 2019
Last Update Posted : June 7, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE June 5, 2019
First Posted Date  ICMJE June 7, 2019
Last Update Posted Date June 7, 2019
Estimated Study Start Date  ICMJE August 1, 2019
Estimated Primary Completion Date July 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
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 [ Time Frame: Up to 21 days ]
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 point estimate for the rate of conversion from a post NAC CD8/FOXP3 ratio < 1.6 to a post-abemaciclib CD8/FOXP3 ratio >=1.6 is calculated as the proportion of eligible patients whose post-abemaciclib CD8/FOXP3 ratio >=1.6 among the eligible patients whose began abemaciclib treatment after a post NAC finding of a residual tumor CD8/FOXP3 ratio >=1.6. 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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
  • Incidence of adverse events [ Time Frame: Up to 60 days ]
    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.
  • Changes in vimentin expression [ Time Frame: Up to 60 days ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 5, 2019)
  • Changes in mitoses [ Time Frame: Up to 60 days ]
    Examined graphically overall and by triple negative breast cancer (TNBC) subtypes.
  • Changes in nuclear pleomorphism [ Time Frame: Up to 60 days ]
    Examined graphically overall and by TNBC subtypes.
  • Changes in tubule formation [ Time Frame: Up to 60 days ]
    Examined graphically overall and by TNBC subtypes.
  • Changes in tumor Ki-67 [ Time Frame: Up to 60 days ]
    Examined graphically overall and by TNBC subtypes.
  • Changes in serum tyrosine kinase inhibitor (TKI) [ Time Frame: Up to 60 days ]
    Examined graphically overall and by TNBC subtypes.
  • Changes in SNAIL [ Time Frame: Up to 60 days ]
    Examined graphically overall and by TNBC subtypes.
  • Changes in SLUG [ Time Frame: Up to 60 days ]
    Examined graphically overall and by TNBC subtypes.
  • Changes in E-Cadherin [ Time Frame: Up to 60 days ]
    Examined graphically overall and by TNBC subtypes.
  • Changes in tumor-infiltrating lymphocytes [ Time Frame: Up to 60 days ]
    Examined graphically overall and by TNBC subtypes.
  • Effect of abemaciclib on tumor ribonucleic acid (RNA)-sequencing (seq) data [ Time Frame: Up to 60 days ]
    The Gene set enrichment analysis (GSEA) method will be used to determine whether an a priori set of genes are over-represented in the differential expression analysis of the pre- and post- drug response phenotypes. CIBERSORT will be used to estimate the cell composition from RNA transcriptomic data (e.g. immune cell populations).
  • Effect of abemaciclib on the phenotype of peripheral blood mononuclear cells (PBMC) [ Time Frame: Up to 60 days ]
  • Effect of abemaciclib on formalin-fixed paraffin-embedded (FFPE) tumor sections (imaging mass cytometry (HyperionTM system) [ Time Frame: Up to 60 days ]
    Examination of genes directly involved in tumor cell antigen presentation (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 (IRFs, OAS2), genes involved in double strand (ds)RNA response (DDX58, DHX58), genes encoding interferons, including type 3 IFNs (IFNL1, IFNL2, IFNL3), genes indicating a cytotoxic T cell response (PRF1, GZMB), and regulatory T cell (Treg)-specific transcription factor genes (FOXP3, IKZF2).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Abemaciclib in Treating Patients With Surgically Resectable, Chemotherapy Resistant, Triple Negative Breast Cancer
Official Title  ICMJE Window Trial of Abemaciclib for Surgically Resectable, Chemotherapy-Resistant, Triple Negative Breast Cancer (a BEAUTY Study*)
Brief Summary This phase II trial studies how well abemaciclib works in treating patients with triple negative breast cancer that can be removed by surgery 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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Anatomic Stage I Breast Cancer AJCC v8
  • Anatomic Stage IA Breast Cancer AJCC v8
  • Anatomic Stage IB 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
  • 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
  • Breast Fibrocystic Change
  • Ductal Breast Carcinoma In Situ
  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Invasive Breast Carcinoma
  • Lobular Breast Carcinoma In Situ
  • Progesterone Receptor Negative
  • 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 Carcinoma
Intervention  ICMJE
  • Drug: Abemaciclib
    Given PO
    Other Names:
    • LY-2835219
    • LY2835219
    • Verzenio
  • Procedure: Therapeutic Conventional Surgery
    Undergo standard of care surgical resection
Study Arms  ICMJE 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.
Interventions:
  • Drug: Abemaciclib
  • Procedure: Therapeutic Conventional Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 5, 2019)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2022
Estimated Primary Completion Date July 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 magnetic resonance imaging (MRI) or other institutional standard 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: Any of the following prior therapies:

    • Chemotherapy =< 21 days prior to registration.

      • Note: Neoadjuvant chemotherapy (NAC) must be completed >= 14 days prior to registration.
  • 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).
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03979508
Other Study ID Numbers  ICMJE MC1734
NCI-2019-03567 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1734 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Matthew P Goetz Mayo Clinic
PRS Account Mayo Clinic
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP