Clinical Trials /

Trastuzumab and Pertuzumab or Bevacizumab With Combination Chemotherapy in Treating Patients With Stage II-III Breast Cancer

NCT01959490

Description:

This phase II trial studies how well trastuzumab and pertuzumab or bevacizumab with combination chemotherapy works in treating patients with stage II-III breast cancer. Monoclonal antibodies, such as trastuzumab, pertuzumab, and bevacizumab, can block tumor growth in different ways. Some block the ability of tumors to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as docetaxel, carboplatin, doxorubicin hydrochloride, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving trastuzumab and pertuzumab or a commercially marketed formulation of bevacizumab without modification with combination chemotherapy may kill more tumor cells.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trastuzumab and Pertuzumab or Bevacizumab With Combination Chemotherapy in Treating Patients With Stage II-III Breast Cancer
  • Official Title: Next Generation Sequencing to Evaluate Breast Cancer Subtypes and Genomic Predictors of Response to Therapy in the Preoperative Setting for Stage II-III Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: CASE14112
  • SECONDARY ID: NCI-2013-01422
  • SECONDARY ID: CASE 14112
  • SECONDARY ID: P30CA043703
  • NCT ID: NCT01959490

Conditions

  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer

Interventions

DrugSynonymsArms
trastuzumabanti-c-erB-2, Herceptin, MOAB HER2Cohort I (HER2 positive)
Pertuzumab2C4, PerjetaCohort I (HER2 positive)
docetaxelRP 56976, Taxotere, TXTCohort I (HER2 positive)
carboplatinCarboplat, CBDCA, JM-8, Paraplat, ParaplatinCohort I (HER2 positive)
doxorubicinADM, ADR, Adria, Adriamycin PFS, Adriamycin RDF, doxorubicin hydrochlorideCohort II (HER2 negative)
cyclophosphamideCPM, CTX, Cytoxan, Endoxan, EndoxanaCohort II (HER2 negative)
paclitaxelAnzatax, Asotax, TAX, TaxolCohort II (HER2 negative)
BevacizumabAvastinCohort II (HER2 negative)

Purpose

This phase II trial studies how well trastuzumab and pertuzumab or bevacizumab with combination chemotherapy works in treating patients with stage II-III breast cancer. Monoclonal antibodies, such as trastuzumab, pertuzumab, and bevacizumab, can block tumor growth in different ways. Some block the ability of tumors to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as docetaxel, carboplatin, doxorubicin hydrochloride, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving trastuzumab and pertuzumab or a commercially marketed formulation of bevacizumab without modification with combination chemotherapy may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if genomically derived 'molecular subtypes' predict pathological complete
      response to combination chemotherapy and targeted therapy for HER2 early stage breast cancer.

      SECONDARY OBJECTIVES:

      I. To explore the ability of trastuzumab or pertuzumab response signatures to predict pCR in
      HER2 positive tumors treated with brief exposure to trastuzumab or pertuzumab followed by
      combination chemotherapy.

      II. To explore the value of immune signatures as well as AKT and IGF signatures to predict
      pCR in HER2 tumors treated with brief exposure to trastuzumab and pertuzumab.

      III. To explore if comprehensive annotation of genomic alterations (mutations, copy number
      alternations, gene fusions, non-coding RNA and splice variants) can further sub-stratify
      subtype-based classifiers for prediction of response to targeted therapy in early stage
      breast cancer IV. To explore if circulating RNA expression levels are associated with
      treatment response V. To explore changes in cardiac function and identify early cardiac
      injury using strain echocardiograms and cardiac biomarkers during treatment VI. To explore
      immunohistochemisitry-based markers of response to treatment

      Objectives for Imaging Sub-Study: Secondary Objectives I. Evaluate the visualization of
      primary breast tumors using analog and digital PET with FDG and FLT. II. Evaluate the
      quantification of FDG-uptake in primary breast tumors using analog and digital PET with FDG
      and FLT. III. Compare the levels and changes in metabolic tumor activity from analog and
      digital FDG-PET/CT or FLT-PET/CT with clinical follow up and other procures include into CASE
      14112 (such as DCE-MRI, genetic testing, etc.)

      OUTLINE: Patients are assigned to 1 of 2 treatment cohorts based on HER2 status.

      COHORT I (HER2 positive): Patients receive trastuzumab intravenously (IV) over 30-60 minutes,
      and pertuzumab IV over 30-60 minutes, docetaxel IV, and carboplatin IV on day 1. Treatment
      repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable
      toxicity. As part of standard of care, each patient will receive three MRIs pre-treatment,
      before biopsy is taken, and before surgery. Ten additional patients will be added to cohort 1
      to take part in the imaging sub-study. These ten patients will follow the same procedure as
      the other participants in cohort I but will have a PET/CT in place of the DCE-MRI

      COHORT II (HER2 negative): Patients receive bevacizumab IV over 30-60 minutes on day 1 of
      weeks 1, 3, 5, 7, 9, and 11; doxorubicin IV and cyclophosphamide IV over 30-60 minutes on day
      1 of weeks 1, 3, 5, and 7; and paclitaxel IV over 3 hours on day 1 of weeks 9, 11, 13, and
      15. Prior to receiving paclitaxel patients will receive the anti-nausea medication

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort I (HER2 positive)ExperimentalPatients receive trastuzumab IV over 30-60 minutes and Pertuzumab IV over 30-60 minutes, docetaxel IV, and carboplatin IV on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
  • docetaxel
  • carboplatin
Cohort II (HER2 negative)ExperimentalPatients receive bevacizumab IV over 30-60 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11; doxorubicin IV and cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 3, 5, and 7; and paclitaxel IV over 3 hours on day 1 of weeks 9, 11, 13, and 15.
  • doxorubicin
  • cyclophosphamide
  • paclitaxel
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed adenocarcinoma of the breast, with sufficient tissue
             available for estrogen receptor (ER), progesterone receptor (PR), and HER 2 testing

               -  HER2 must be positive by IHC or ISH testing by laboratory standard.

          -  Needle biopsy or incisional biopsy

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

          -  Resectable disease-clinical stage I (T/0/N0miT1N0-N0mi), IIA-IIIA (T2 N0/T3N0 or T1-3
             N1-N2a) or unresectable disease - clinical stage IIIB/IIIC (T4 or T1-3 N2b-3); no
             evidence of metastatic disease

          -  No prior chemotherapy, hormonal therapy, or radiation therapy for this cancer

          -  Absolute neutrophil count (ANC) ≥1000/ul

          -  Platelet count ≥ 100,000/ul

          -  Hemoglobin ≥ 9 g/dl

          -  Serum creatinine ≤ 1.5 mg/dl or measured creatinine clearance of > 30 ml/min

          -  Total bilirubin ≤ upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) ≤ 2.5 x ULN

          -  Patients with multiple foci of invasive cancer in the same breast are eligible if any
             single lesion meets the above size criteria and all sampled lesions are histologically
             similar (whether radiographically detected lesions separate from the target lesion are
             sampled for histologic evaluation is left to the discretion of the treating
             physicians); the presence of ductal carcinoma in situ (DCIS) or lobular carcinoma in
             situ (LCIS) in either breast will not render a patient ineligible; patients with a
             small focus of invasive cancer detected the contralateral breast (clinical T1N0) are
             eligible, however only the histologic response in the breast containing the target
             lesions will be considered in determining the patient's pathologic response

          -  Measurable disease in the breast or axilla that measures at least 1 cm by either
             clinical or radiographic measurement

        Exclusion Criteria:

          -  Excisional biopsy

          -  Pregnant and lactating women are not eligible; all participants of reproductive age
             must have a negative serum pregnancy test at baseline and agree to use an effective
             barrier method of contraception during the entire period of treatment on the study

          -  Patients with New York Heart Association (NYHA) grade 2 or higher congestive heart
             failure, myocardial infarction within the last 6 months, unstable angina pectoris, or
             arterial thrombotic event with the past 12 months, uncontrolled hypertension (systolic
             blood pressure > 150 and/or diastolic blood pressure > 100 on antihypertensive
             medications; patients not on medication for high blood pressure who are found to have
             systolic blood pressure [SBP] > 150 and/or diastolic blood pressure [DBP] > 100 should
             have 3 documented episodes of elevated blood pressure before being considered
             'uncontrolled', if they have 3 documented episodes of elevated blood pressure, then
             can be started on antihypertensive medications; patients currently on antihypertensive
             medications with elevated blood pressures as defined above may have their medications
             adjusted; if patients have persistent [3 episodes] of high blood pressure despite
             medication adjustment they will be considered ineligible for study participation; each
             measured episode should be 24 hours apart), prior history of hypertensive crisis or
             hypertensive encephalopathy, uncontrolled or clinically significant arrhythmia, grade
             II or greater peripheral vascular disease or prior history of stroke or transient
             ischemic attack (TIA); patient must have a pretreatment multi gated acquisition scan
             (MUGA) scan or echocardiogram with left ventricular ejection fraction (LVEF) above
             lower limit of normal

          -  No non-breast malignancy within the past 5 years other than treated squamous or basal
             cell carcinoma of the skin or CIS of the cervix

          -  Patients known to be human immunodeficiency virus (HIV) positive are not eligible for
             the study given their potentially compromised immune systems and increased risk of
             treatment-related toxicity

          -  Advanced (T1N1-4/T2-3 N any) invasive cancer in the contralateral breast

          -  Any known history of cerebrovascular disease including TIA, stroke or subarachnoid
             hemorrhage

          -  Patients must not have a non-healing wound or fracture

          -  Patients with an abdominal fistula, gastrointestinal perforation, or intra-abdominal
             abscess within 6 months

          -  Patients must not have a bleeding diathesis, hereditary of acquired bleeding disorder
             or coagulopathy

          -  Patients on therapeutic doses of Coumadin or Lovenox are ineligible to participate in
             study

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to study enrollment or anticipation of need for major surgical procedure during
             the course of the study; core biopsy or other minor surgical procedure, for example
             placement of a vascular access device, are excluded from this requirement

          -  No known hypersensitivity to any component of bevacizumab
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:The number of patients with a pathological complete response (pCR) who received targeted therapy with trastuzumab and pertuzumab or bevacizumab predicted by genomically-derived molecular subtypes.
Time Frame:Up to 30 days
Safety Issue:
Description:Ninety five percent confidence intervals for the pCR rate each group will be calculated to determine if they include the hypothesized rates.

Secondary Outcome Measures

Measure:The number of HER2 positive patients with a pCR predicted by a trastuzumab and pertuzumab response signature
Time Frame:Up to 30 days
Safety Issue:
Description:
Measure:The number of HER2 negative patients with a pCR predicted by the TGF-B response signature
Time Frame:Up to 30 days
Safety Issue:
Description:
Measure:The number of HER2 positive patients with a pCR predicted by the AKT signature and IGF signature.
Time Frame:Up to 30 days
Safety Issue:
Description:
Measure:The number of patients with a pCR predicated by copy number alterations.
Time Frame:Up to 30 days
Safety Issue:
Description:
Measure:The number of patients with a pCR predicted by changes in texture on breast DCE-MRI after a two-week "run-in" treatment with trastuzumab, pertuzumab, or bevacizumab
Time Frame:At 2 weeks
Safety Issue:
Description:Determine if changes in regularity and entropy range predict pCR and in an exploratory fashion determine if specific texture features exist in each molecular subtype that predict pCR.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Case Comprehensive Cancer Center

Last Updated

August 3, 2017