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

NCT ID: NCT01959490

Last Updated: 2019-03-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-24
• Study Completion Date: 2017-03-29

Brief Summary

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 immunohistochemistry-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 positron emission tomography (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.

Conditions

Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Cohort 1P (HER2 positive)

Patients receive a run-in Pertuzumab treatment of 840 mg IV over 60 minutes on day -14 followed by 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.

Group Type: EXPERIMENTAL

trastuzumab

Intervention Type: BIOLOGICAL

Given IV

Pertuzumab

Intervention Type: BIOLOGICAL

Given IV

docetaxel

Intervention Type: DRUG

Given IV

carboplatin

Intervention Type: DRUG

Given IV

Cohort 1T (HER2 positive)

Patients receive a run-in Trastuzumab treatment of 8 mg/kg IV over 90 minutes on day -14 followed by 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.

Group Type: EXPERIMENTAL

trastuzumab

Intervention Type: BIOLOGICAL

Given IV

Pertuzumab

Intervention Type: BIOLOGICAL

Given IV

docetaxel

Intervention Type: DRUG

Given IV

carboplatin

Intervention Type: DRUG

Given IV

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.

Group Type: EXPERIMENTAL

doxorubicin

Intervention Type: DRUG

Given IV

cyclophosphamide

Intervention Type: DRUG

Given IV

paclitaxel

Intervention Type: DRUG

Given IV

Bevacizumab

Intervention Type: DRUG

Interventions

trastuzumab

Given IV

Intervention Type: BIOLOGICAL

Pertuzumab

Given IV

Intervention Type: BIOLOGICAL

docetaxel

Given IV

Intervention Type: DRUG

carboplatin

Given IV

Intervention Type: DRUG

doxorubicin

Given IV

Intervention Type: DRUG

cyclophosphamide

Given IV

Intervention Type: DRUG

paclitaxel

Given IV

Intervention Type: DRUG

Bevacizumab

Intervention Type: DRUG

Other Intervention Names

anti-c-erB-2; Herceptin; MOAB HER2; 2C4; Perjeta; RP 56976; Taxotere; TXT; Carboplat; CBDCA; JM-8; Paraplat; Paraplatin; ADM; ADR; Adria; Adriamycin PFS; Adriamycin RDF; doxorubicin hydrochloride; CPM; CTX; Cytoxan; Endoxan; Endoxana; Anzatax; Asotax; TAX; Taxol; Avastin

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Case Comprehensive Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Paula Silverman, MD

Role: PRINCIPAL_INVESTIGATOR

Case Comprehensive Cancer Center

Locations

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Cleveland, Ohio, United States

Countries

United States

Other Identifiers

NCI-2013-01422

Identifier Type: REGISTRY

Identifier Source: secondary_id

CASE 14112

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA043703

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CASE14112

Identifier Type: -

Identifier Source: org_study_id