|Phase II||Biomarker/Laboratory analysis, Treatment||Active||18 and over||NCI, Other||CDR0000675211|
P30CA022453, WSU-2010-056, 2010-056, NCT01147016
RATIONALE: Treating a patient's T cells in the laboratory may help the T cells kill more tumor cells when they are put back in the body. Drugs used in chemotherapy, such as 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 combination chemotherapy followed by laboratory-treated T cells before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
PURPOSE: This phase II clinical trial is studying how well giving laboratory-treated T cells after chemotherapy works in treating women with stage II or stage III breast cancer undergoing surgery.
Further Study Information
- To determine, in a phase II clinical trial of women with stage II-III triple-negative breast cancer, if a regimen of neoadjuvant chemotherapy followed by HER2Bi-armed activated T cells (ATCs) improves the pathologic complete response (pCR) rate at the time of surgery.
- To investigate the association between pCR and clinical responses (disease-free survival and overall survival).
- To determine if HER2Bi-armed ATCs administered after neoadjuvant chemotherapy will modulate the cytotoxicity of lymphocytes in the blood and tumor-infiltrating lymphocytes.
- To determine if there is an association between systemic and tumor site anti-tumor responses.
- To determine if HER2Bi-armed ATCs administered after neoadjuvant chemotherapy decreases the frequency and colony-forming ability of the putative breast cancer stem cells in the tumor tissue at the time of surgery compared to that obtained in the tumor biopsy after chemotherapy.
- To investigate the association between the observed changes in numbers and proportion of CD44^hi/CD24^lo, CD133, aldehyde dehydrogenase activity (ALDH1)-positive cells and the pCR.
OUTLINE: This is a multicenter study.
- Neoadjuvant chemotherapy: Patients receive doxorubicin hydrochloride and cyclophosphamide every 2 weeks for 4 doses. Patients then receive paclitaxel once a week for 12 doses.
- Neoadjuvant immunotherapy: Beginning 3-6 days after the last dose of chemotherapy, patients receive autologous HER2Bi-armed activated T cells (ATCs) IV over 30-60 minutes once a week for 4 weeks.
- Surgery: Approximately 2 weeks after the last dose of HER2Bi-armed ATCs, patients undergo standard surgery.
Tissue and blood samples are collected periodically for correlative immune function tests.
After completion of study treatment, patients are followed up every 8 weeks for 48 weeks and then every 3 months thereafter.
- Signed and dated institutional review board (IRB)-approved consent form
- Women of reproductive potential must agree to use an effective nonhormonal method of contraception during therapy
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and/or Karnofsky PS of >= 70%
- Diagnosis of invasive adenocarcinoma of the breast made by core needle biopsy
- Palpable primary breast tumor measuring >= 2.0 cm on physical exam or imaging
- Patients with stage II-IIIA breast cancer that is HER2-negative by immunohistochemistry (IHC) (0-2+) or fluorescence in situ hybridization (FISH) (HER2/chromosome enumeration probe [CEP]17 amplification ratio < 2.2) for whom definitive surgical treatment after "third generation" neoadjuvant chemoT is planned; Patients with HER2 (3+) cancer by IHC that also demonstrate a FISH ratio <2.2 are also eligible. Estrogen receptor (ER) or progesterone receptor (PR) status can be positive or negative; the receptor status needs to be recorded
- Patients may have lymph node positive or negative disease, as long as they have clinical stage II or IIIA breast cancer; patients may have the lymph nodes assessed by any method deemed appropriate by the treating physicians, including pre-neoadjuvant therapy sentinel lymph node biopsy
- Patients must discontinue sex hormone therapy prior to registration, e.g. birth control pills, hormonal replacement therapy
- Absolute neutrophil count (ANC) must be >= 1200/mm^3
- Platelet count must be >= 100,000/mm^3
- Hemoglobin must be >= 9.0 mg/dL
- Total bilirubin must be =< the upper limit of normal (ULN) for the lab unless the patient has a grade 1 bilirubin elevation (> ULN to 1.5 x ULN) resulting from Gilbert's disease or similar syndrome due to slow conjugation of bilirubin; and
- Alkaline phosphatase must be =< 2.5 x ULN for the lab
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) must be =< 1.5 x ULN for the lab
- Alkaline phosphatase and AST/ALT may not both be > the ULN; for example, if the alkaline phosphatase is > the ULN but =< 2.5 x ULN, then the AST/ALT must be =< the ULN; if the AST/ALT is > the ULN but =< 1.5 x ULN, then the alkaline phosphatase must be =< ULN
- Patients with either skeletal pain or alkaline phosphatase that is > ULN must have a bone scan showing they do not have metastatic disease; suspicious findings on bone scan must be confirmed as benign by x-ray, magnetic resonance imaging (MRI), or biopsy
- Patients with AST/ALT or alkaline phosphatase > ULN must have liver imaging that does not demonstrate metastatic disease
- Patients with AST/ALT > ULN must have negative hepatitis studies
- Patients with stage II disease and clinical suspicion for metastatic disease based on reported symptoms, physical examination findings, or laboratory abnormalities must have staging studies demonstrating no evidence of metastatic disease (with exception of axillary lymph nodes or mammary nodes); patients with stage IIIA disease must have staging studies demonstrating no evidence of metastatic disease (with exception of axillary lymph nodes or mammary nodes), even if asymptomatic with normal physical examination and laboratory values; such staging studies must include: chest imaging (chest X-ray, computed tomography [CT], or MRI), abdominal/pelvis imaging (CT or MRI), and bone imaging (bone scan or positron emission tomography [PET]-scan); abnormalities that are indeterminate and too small to biopsy should be followed with further imaging, as appropriate, but do not exclude patients from the study; abnormalities that are suspicious and large enough to biopsy exclude patients from the study, unless a biopsy is performed and is negative for metastatic disease
- Serum creatinine =< 1.5 x ULN for the lab
- Pre-entry core biopsy with sufficient material for correlative studies
- Left Ventricular Ejection Fraction (LVEF) >= 50 % (by multigated acquisition scan [MUGA] or echocardiography)
- Tumor determined to be HER2-positive by immunohistochemistry (3+) or by fluorescent in situ hybridization (HER2/CEP17 amplification ratio >= 2.0)
- Tumors clinically staged as T4 or N3
- Definitive evidence of metastatic disease with exception of axillary lymph nodes or mammary nodes
- Synchronous bilateral breast cancer (invasive or ducal carcinoma in situ [DCIS])
- Treatment including radiation therapy, chemoT, biotherapy, and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry
- Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible if this therapy is discontinued 1 week prior to registration)
- Prior history of invasive breast cancer (Patients with a history of DCIS or lobular carcinoma in situ [LCIS] are eligible)
- Prior therapy with anthracyclines for any malignancy
- Other malignancies unless the patient is considered to be disease-free for 5 or more years prior to randomization and is deemed by the physician to be at low risk for recurrence; patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell or squamous cell carcinoma of the skin
- Known cardiac disease that would preclude the use of anthracyclines; this includes:
- Angina pectoris that requires the use of anti-anginal medication
- History of documented congestive heart failure
- Serious cardiac arrhythmia requiring medication
- Severe conduction abnormality
- Valvular disease with documented cardiac function compromise; and
- Uncontrolled hypertension defined as blood pressure (BP) that is consistently > 150/90 on antihypertensive therapy at the time of registration (Patients with hypertension that is well controlled on medication are eligible)
- History of myocardial infarction (MI) documented by elevated cardiac enzymes with persistent regional wall motion abnormality on assessment of left ventricular (LV) function (Patients with history of MI must have an echo instead of/in addition to a MUGA to evaluate LV wall motion)
- Symptomatic peripheral vascular disease
- Sensory/motor neuropathy >= grade 2, as defined by the National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0)
- Other non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude treatment with any of the treatment regimens or would prevent required follow-up
- Chronic ongoing steroid use at the time of registration for any condition (such as asthma, rheumatoid arthritis, etc)
- Administration of any investigational agents within 30 days before study entry
- Pregnancy or lactation at the time of registration
- Psychiatric or addictive disorders or other conditions that in the opinion of the investigators would preclude the patient from complying with the study protocol.
Minor changes from these guidelines will be allowed at the discretion of the research team under special circumstances. The reasons for exceptions will be documented
Trial Lead Organizations/Sponsors
Barbara Ann Karmanos Cancer InstituteNational Cancer Institute
|Lawrence Lum, M.D.||Principal Investigator|
|Barbara Ann Karmanos Cancer Institute|
|Clinical Trials Office - Barbara Ann Karmanos Cancer Institute||Ph: 800-527-6266|
|Rouba Ali-Fehmi, M.D.||Sub-Investigator|
|Lydia Choi, M.D.||Principal Investigator|
|Abhinav Deol, M.D.||Sub-Investigator|
|Neb Duric, Ph.D.||Sub-Investigator|
|Lawrence E. Flaherty||Sub-Investigator|
|David Gorski, M.D., Ph.D.||Sub-Investigator|
|Sayeh Lavasani, M.D.||Sub-Investigator|
|Michael Simon, M.D., MPH||Sub-Investigator|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01147016
Information obtained from ClinicalTrials.gov on April 16, 2013
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