Biomarkers in Women Receiving Chemotherapy and Celecoxib for Stage II or Stage III Breast Cancer That Can Be Removed by Surgery

• ClinicalTrials.gov Identifier: NCT00665457
• Recruitment Status: Terminated
• First Posted: April 23, 2008
• Results First Posted: July 10, 2018
• Last Update Posted: July 10, 2018
• Sponsor: University of Nebraska
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Elizabeth Reed, MD, University of Nebraska

Study Description

Brief Summary:

RATIONALE: Studying samples of blood and tumor tissue from patients with cancer in the laboratory may help doctors learn more about changes that occur in DNA and identify biomarkers related to cancer.

PURPOSE: This phase II clinical trial is studying biomarkers and side effects in women receiving chemotherapy and celecoxib for stage II or stage III breast cancer that can be removed by surgery.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Biological: filgrastim; Drug: capecitabine; Drug: celecoxib; Drug: cyclophosphamide; Drug: docetaxel; Drug: doxorubicin hydrochloride; Genetic: gene expression analysis; Genetic: polymorphism analysis; Genetic: protein expression analysis; Genetic: reverse transcriptase-polymerase chain reaction; Other: imaging biomarker analysis; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Other: pharmacogenomic studies; Procedure: dynamic contrast-enhanced magnetic resonance imaging; Procedure: needle biopsy; Procedure: neoadjuvant therapy; Procedure: radiomammography; Procedure: ultrasound imaging	Phase 2

Detailed Description:

OBJECTIVES:

• To determine the safety and efficacy of four courses of neoadjuvant chemotherapy comprising docetaxel, capecitabine, and celecoxib followed by doxorubicin hydrochloride, cyclophosphamide, and celecoxib for the treatment of women with resectable stage II or III breast cancer.
• To determine the mRNA and protein levels of thyraidylate synthase (TS), thymidine phosphylase (TP), vascular endothelial growth factor (VEGF), Multi-Drug Resistance Protein 1 (MDR-1), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-2 (MMP-2) in tumor tissue prior to and following treatment.
• To correlate baseline expression of TS, TP, VEGF, MDR, COX-2, and MMP-2 to tumor response measured by physical exam, breast MRI, breast ultrasound, mammography, and pathologic response.
• To determine if polymorphisms in the genes that encode those proteins also correlate with outcome, if a correlation is found between specific molecular markers and clinical outcome.

OUTLINE:

• Neoadjuvant chemotherapy: Patients receive docetaxel IV over 1 hour on days 1, 8, and 15, oral capecitabine twice daily on days 1-14, and oral celecoxib twice daily on days 1-21. Courses repeat every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients then receive doxorubicin hydrochloride IV and cyclophosphamide IV once daily on day 1, oral celecoxib twice daily on days 1-14, and filgrastim subcutaneously once daily on days 3-10. Courses repeat every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Celecoxib is stopped one week prior to surgery.

• Surgery: Patients undergo definitive surgery (either modified radical mastectomy or lumpectomy combined with axillary node dissection). Patients may also undergo adjuvant radiotherapy and hormonal therapy at the discretion of multidisciplinary breast team.

Blood is collected at baseline and examined for genetic polymorphisms associated with functional changes in proteins. Tumor tissue is obtained by needle biopsy at baseline, before the second course of docetaxel/capecitabine/celecoxib, and at surgical resection. Molecular markers and protein expression are assessed by immunohistochemistry using fluorescence-image analysis and real-time reverse-transcriptase PCR.

Patients undergo imaging comprising dynamic MRI, ultrasound, and mammogram at baseline and after the first and second 4 courses of chemotherapy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Neoadjuvant Therapy and Biomarker Analysis of Stage II and III Breast Cancer With Docetaxel/Capecitabine and Celecoxib Followed by Doxorubicin/Cyclophosphamide and Celecoxib
• Study Start Date: April 2004
• Actual Primary Completion Date: July 2009
• Actual Study Completion Date: July 2009

Arms and Interventions

Arm

Intervention/treatment

Experimental: Celecoxib; •Neoadjuvant chemotherapy: Patients receive docetaxel IV over 1 hour on days 1, 8, and 15, oral capecitabine twice daily on days 1-14, and oral celecoxib twice daily on days 1-21. Courses repeat every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin hydrochloride IV and cyclophosphamide IV once daily on day 1, oral celecoxib twice daily on days 1-14, and filgrastim subcutaneously once daily on days 3-10. Courses repeat every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Celecoxib is stopped one week prior to surgery. •Surgery: Patients undergo definitive surgery (either modified radical mastectomy or lumpectomy combined with axillary node dissection). Patients may also undergo adjuvant radiotherapy and hormonal therapy at the discretion of multidisciplinary breast team.

Biological: filgrastim; Drug: capecitabine; Drug: celecoxib; Drug: cyclophosphamide; Drug: docetaxel; Drug: doxorubicin hydrochloride; Genetic: gene expression analysis; Genetic: polymorphism analysis; Genetic: protein expression analysis; Genetic: reverse transcriptase-polymerase chain reaction; Other: imaging biomarker analysis; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Other: pharmacogenomic studies; Procedure: dynamic contrast-enhanced magnetic resonance imaging; Procedure: needle biopsy; Procedure: neoadjuvant therapy; Procedure: radiomammography; Procedure: ultrasound imaging

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Grade 4 Adverse Events [ Time Frame: every 3 weeks X 4, then every 2 weeks X4 ]
   Grading of adverse events was determine by the principal investigator according to NCI common toxicity criteria (CTC version 3.0). Safety analysis is based on any participant experiencing a grade 4 AE.
2. Participants Who Experienced Pathologic Complete Response, Progression-free and Overall Survival, and Time to Treatment Failure [ Time Frame: 20 weeks ]
   CTEP RECIST guidelines are defined as followed: Pathologic complete response is no signs of residual malignancy cells at the primary site and axillary lymph nodes are seen with histologic examination. Progression-free survival is defined as from the first date of therapy until the first notation of clinical progression or relapse. Overall survival is defined as from the first date of therapy until the date of death. Time to treatment failure is defined as from the first date of therapy until the date the patient is removed from study for any reason.

Eligibility Criteria

• Ages Eligible for Study: 19 Years to 120 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

DISEASE CHARACTERISTICS:

• Pathologic evidence of invasive breast cancer

  • Stage II-III disease
  • Resectable disease
• Must have a primary tumor estimated by mammogram, ultrasound or palpation to be ≥ 3 cm and/or palpable axillary nodes > 1 cm for whom neoadjuvant chemotherapy is appropriate
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status 0-1
• Absolute granulocyte count > 2,000/mm^3
• Platelet count > 100,000/mm^3
• Serum bilirubin < 1.5 times upper limit of normal (ULN)
• Serum creatinine < 1.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study therapy
• No allergies to sulfa medication, aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs)

• No uncontrolled concurrent illness that might jeopardize the patient's ability to receive the chemotherapy program outlined in this protocol, including any of the following:

  • Active infection requiring intravenous antibiotics
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Serious, uncontrolled cardiac arrhythmia
• No other prior malignancy except for adequately treated basal cell or squamous cell skin cancer, noninvasive carcinomas, or other cancers from which the patient has been disease-free for at least 5 years

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiation therapy for ipsilateral breast cancer.
• At least 2 weeks since prior treatment with cyclooxygenase (COX)-2 inhibitors
• No concurrent sorivudine or brivudine to treat herpes simplex or herpes zoster viral infections
• No concurrent participation in another therapeutic clinical trial

Contacts and Locations

Sponsors and Collaborators

University of Nebraska

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Elizabeth C. Reed, MD; University of Nebraska

More Information

• Responsible Party: Elizabeth Reed, MD, Principal Investigator, University of Nebraska
• ClinicalTrials.gov Identifier: NCT00665457
• Other Study ID Numbers: 085-04; P30CA036727 ( U.S. NIH Grant/Contract ); UNMC-08504
• First Posted: April 23, 2008
• Results First Posted: July 10, 2018
• Last Update Posted: July 10, 2018
• Last Verified: June 2018

Keywords provided by Elizabeth Reed, MD, University of Nebraska:

stage II breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Celecoxib; Cyclophosphamide; Docetaxel; Doxorubicin; Liposomal doxorubicin; Capecitabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Anti-Inflammatory Agents, Non-Steroidal