Clinical Trials /

A Breast Cancer Genome Guided Therapy Study

NCT03979508

Description:

The primary purpose of this study is to evaluate abemaciclib, a CDK4/6 inhibitor, in patients with triple negative breast cancer (TNBC) who have residual disease following neoadjuvant chemotherapy, but prior to surgery. The goal is to assess the novel mechanisms by which abemaciclib may activate the immune system and decrease the likelihood of metastases in triple negative breast cancer.

Related Conditions:
  • Benign Breast Neoplasm
  • Breast Lobular Carcinoma In Situ
  • Ductal Carcinoma In Situ
  • Invasive Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Breast Cancer Genome Guided Therapy Study
  • Official Title: Window Trial of Abemaciclib for Surgically Resectable, Chemotherapy-Resistant, Triple Negative Breast Cancer (a BEAUTY Study*)

Clinical Trial IDs

  • ORG STUDY ID: MC1734
  • SECONDARY ID: NCI-2019-03567
  • SECONDARY ID: MC1734
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03979508

Conditions

  • 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

Interventions

DrugSynonymsArms
AbemaciclibLY-2835219, LY2835219, VerzenioTreatment (abemaciclib)

Purpose

The primary purpose of this study is to evaluate abemaciclib, a CDK4/6 inhibitor, in patients with triple negative breast cancer (TNBC) who have residual disease following neoadjuvant chemotherapy, but prior to surgery. The goal is to assess the novel mechanisms by which abemaciclib may activate the immune system and decrease the likelihood of metastases in triple negative breast cancer.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (abemaciclib)ExperimentalPatients 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.
  • Abemaciclib

Eligibility 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 60 days
Safety Issue:
Description: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.
Measure:Changes in vimentin expression
Time Frame:Up to 60 days
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

February 24, 2020