Clinical trial NCT00232505: Cetuximab + / - Carboplatin for Estrogen Receptor-Negative, Progesterone Receptor-Negative Metastatic Breast Cancer
Official title: Phase II Trial of Cetuximab Alone and in Combination With Carboplatin in ER-Negative, PR-Negative, HER-2 Nonoverexpressing Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: recurrent breast cancer
stage IV breast cancer
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Bristol-Myers Squibb
name: Avon Foundation
name: National Center for Research Resources (NCRR)
First posted: 2005-10-04
Enrollment: 112
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving cetuximab together with carboplatin is more effective than giving cetuximab alone in treating metastatic breast cancer.

PURPOSE: This randomized phase II trial is studying cetuximab and carboplatin to see how well they work compared with cetuximab alone in treating women with estrogen receptor-negative (ER-), progesterone receptor-negative (PR-) metastatic breast cancer.

Detailed description: OBJECTIVES:

Primary

* Compare the overall response rate in women with estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor 2 (HER2)-nonoverexpressing metastatic breast cancer treated with cetuximab with vs without carboplatin.

Secondary

* Compare the time to disease progression in patients treated with these regimens.
* Correlate downstream effects of epidermal growth factor receptor (EGFR) inhibitor on Mitogen-activated protein kinases (MAPK), Protein kinase B (AKT), monoclonal antibody Ki-67 (Ki67), and EGFR-dependent signaling, proliferation, and apoptosis with toxicity and response in patients with accessible tumors treated with these regimens.
* Determine the changes in biomarkers and gene expression in circulating tumor cells during treatment.
* Compare the overall survival rate in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive cetuximab IV over 60-120 minutes once a week.
* Arm II: Patients receive cetuximab as in arm I and carboplatin IV on days 1, 8, and 15.

In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients not responding to treatment in arm I may cross over to arm II.

Blood samples are collected periodically throughout study for correlative biomarker analysis by Immunohistochemistry (IHC) and gene expression analysis.

After completion of study treatment, patients are followed every 4 months.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed breast cancer

  * Metastatic (stage IV) disease
* Measurable disease by RECIST criteria

  * Irradiated lesions are not considered measurable disease
* Central nervous system (CNS) metastases allowed if disease is stable (no evidence of progression) ≥ 3 months after local therapy
* No lesions identifiable only by positron emission tomography (PET) scan
* HER2 nonoverexpressing disease by IHC (0 or 1) or non-gene amplified by Fluorescence In Situ Hybridization (FISH)

  * HER2 2+ by IHC allowed
* Hormone receptor status:

  * Estrogen receptor-negative and progesterone receptor-negative tumor

Inclusion Criteria

* At least 18 years of age
* Metastatic breast cancer (Stage IV) with measurable disease by RECIST criteria
* No more than three prior chemotherapy regimens either in the adjuvant or metastatic setting.
* Histologically documented (either primary or metastatic site) breast cancer that is estrogen receptor- (ER-) negative, PR-negative, and HER-2 nonoverexpressing by immunohistochemistry (0,1) or non-gene amplified by FISH performed upon the primary tumor or metastatic lesion. HER-2 2+ by immunohistochemistry is usually negative by FISH, and this confirmatory test should be performed when possible, however may participate if fulfill other criteria.
* Completion of prior chemotherapy at least 3 weeks prior to study entry.
* Patients may have received therapy (ies) in the adjuvant or metastatic setting, however must have discontinued prior to entry. Patients may receive concurrent bisphosphonates, however if taking bisphosphonates, bone lesions may not be used for progression or response.
* Radiation therapy must be completed at least 2 weeks prior to study entry, and radiated lesions may not serve as measurable disease.
* Patients may have CNS metastases if stable (no evidence of progression) \> 3 months after local therapy.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and life expectancy of at least 6 months.
* Adequate organ function defined as:absolute neutrophil count (ANC) \> 1500/mm3, plts \> 100,000/mm3, creatinine clearance \>50 mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) (or ≤5 x ULN in case of liver metastases); total bilirubin ≤1.5 mg/dL.
* Tissue block available for EGFR studies is recommended, although will not exclude patients from participating.
* Pregnant or lactating women will be excluded. Women of child bearing potential must have documented negative pregnancy test within two weeks of study entry and agree to acceptable birth control during the duration of the study therapy.
* Signed written informed consent.

Exclusion Criteria

* Lesions identifiable only by PET.
* More than three prior chemotherapy regimens (including adjuvant). Sequential regimens such as doxorubicin and cyclophosphamide followed by paclitaxel (AC-paclitaxel) are considered one regimen.
* Prior therapy which specifically and directly targets the EGFR pathway with therapeutic intent.
* Prior platinum agent for metastatic disease. If platinum agent was used adjuvantly, the patient must have had at least 12 months disease-free interval prior to relapse.
* Prior severe infusion reaction to a monoclonal antibody.
* Major medical conditions that might affect study participation (uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection).
* Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy that is either symptomatic or asymptomatic but with decreased ejection fraction \<45%
* Other significant comorbid condition which the investigator feels might compromise effective and safe participation in the study.
* Inability to comply with the requirements of the study.

Primary outcomes:
measure: Overall Disease Response Rate
timeFrame: 5 years
Secondary outcomes:
measure: Overall Survival
timeFrame: Every four months until death of any cause or end of data collection up to 40 months
measure: Progression-Free Survival
timeFrame: Every four months until progression, death of any cause, or end of data collection up to 40 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
state: Alabama
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Washington, D.C.
country: United States
facility: Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
state: District of Columbia
city: Washington, D.C.
country: United States
facility: Washington Cancer Institute at Washington Hospital Center
state: District of Columbia
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Raleigh
country: United States
facility: Rex Cancer Center at Rex Hospital
state: North Carolina
city: Houston
country: United States
facility: M. D. Anderson Cancer Center at University of Texas
state: Texas
city: Houston
country: United States
facility: Baylor University Medical Center - Houston
state: Texas
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Lisa A. Carey, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, Liu MC, Storniolo AM, Rimawi MF, Forero-Torres A, Wolff AC, Hobday TJ, Ivanova A, Chiu WK, Ferraro M, Burrows E, Bernard PS, Hoadley KA, Perou CM, Winer EP. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol. 2012 Jul 20;30(21):2615-23. doi: 10.1200/JCO.2010.34.5579. Epub 2012 Jun 4.
citation: Oliveras-Ferraros C, Vazquez-Martin A, Lopez-Bonet E, Martin-Castillo B, Del Barco S, Brunet J, Menendez JA. Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: new prospects in the treatment of triple-negative/basal-like breast cancer. Int J Oncol. 2008 Dec;33(6):1165-76.