Targeted T Cells After Neoadjuvant Chemotherapy in Treating Women With Stage II or III Breast Cancer Undergoing Surgery

<p>DISEASE CHARACTERISTICS:</p><ul><li><p>Diagnosis of adenocarcinoma of the breast by core-needle biopsy</p><ul><li>Palpable primary breast tumor measuring ≥ 2.0 cm on physical exam or imaging</li><li>Stage II or III disease</li><li>HER2-negative disease by IHC or FISH (0-2+)</li><li>cN0 or cN1 disease allowed (no ipsilateral cN2a, cN2b, or cN3 disease)</li><li>Operable disease</li></ul></li><li><p>Patients with either skeletal pain or alkaline phosphatase (ALP) that is &gt; upper limit of normal (ULN) but ≤ 2.5 times ULN are eligible provided bone scans do not demonstrate metastatic disease</p><ul><li>Suspicious findings on bone scan must be confirmed to be benign by x-ray, MRI, or biopsy</li></ul></li><li>No other definitive clinical or radiologic evidence of metastatic disease</li><li>No synchronous bilateral breast cancer (invasive or ductal carcinoma in situ [DCIS])</li><li><p>No prior invasive breast cancer</p><ul><li>DCIS and LCIS allowed</li></ul></li><li>Estrogen receptor-negative (&lt; 10% by IHC) and progesterone receptor-negative (&lt; 10% by IHC) disease</li></ul><p>PATIENT CHARACTERISTICS:</p><ul><li>Menopausal status not specified</li><li>ECOG performance status 0-1</li><li>ANC ≥ 1,200&#x2F;mm^3</li><li>Platelet count ≥ 100,000&#x2F;mm^3</li><li>Hemoglobin ≥ 10 g&#x2F;dL</li><li>Total bilirubin ≤ ULN (unless the patient has a grade 1 bilirubin elevation [&gt; ULN to 1.5 times ULN] resulting from Gilbert disease or similar syndrome due to slow conjugation of bilirubin)</li><li>ALP ≤ 2.5 times ULN*</li><li>AST ≤ 1.5 times ULN* NOTE: *ALP and AST may not both be &gt; ULN.
Patients with AST or ALP &gt; ULN must not have demonstrable metastatic disease on liver imaging.</li><li>Serum creatinine ≤ ULN</li><li>Not pregnant or nursing</li><li>Fertile patients must use effective non-hormonal contraception during and for ≥ 3 months after completion of study treatment</li><li>Sufficient material in pre-treatment core biopsy for correlative studies</li><li>No history of invasive breast cancer (history of DCIS or lobular carcinoma in situ allowed)</li><li>No other malignancies except for carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin unless the patient is considered to be disease-free for ≥ 5 years before randomization and is deemed by her physician to be at low risk for recurrence</li><li><p>No cardiac disease that would preclude the use of anthracyclines, including any of the following:</p><ul><li>Angina pectoris requiring antianginal medication</li><li>History of documented congestive heart failure</li><li>Serious cardiac arrhythmia requiring medication</li><li>Sever conduction abnormality</li><li>Valvular disease with documented cardiac function compromise</li><li>Uncontrolled hypertension defined as BP &gt; 140&#x2F;90 mm Hg on antihypertensive therapy (patients with hypertension that is well-controlled on medication are eligible)</li></ul></li><li>No history of myocardial infraction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function</li><li>No symptomatic peripheral vascular disease</li><li>No sensory or motor neuropathy ≥ grade 2, as defined by the NCI&#x27;s CTCAE v3.0</li><li>No other nonmalignant systemic disease (e.g., cardiovascular, renal, hepatic, etc.) that would preclude treatment with any of the treatment regimens or would prevent required follow-up</li><li>No psychiatric or addictive disorders or other conditions that, in the opinion of the investigators, would preclude the patient from complying with study treatment</li></ul><p>PRIOR CONCURRENT THERAPY:</p><ul><li>No prior anthracyclines or taxanes for any malignancy</li><li>No prior treatment for this cancer, including radiotherapy, chemotherapy, biotherapy, and&#x2F;or hormonal therapy</li><li>More than 30 days since prior investigational agents</li><li>At least 1 week since prior and no concurrent sex hormone therapy (e.g., birth control pills, hormonal replacement therapy)</li><li><p>No concurrent steroids except for adrenal failure, septic shock, pulmonary toxicity, or hormones administered for non-disease-related conditions (e.g., insulin for diabetes)</p><ul><li>Hydrocortisone for severe adverse reactions related to HER2Bi-armed activated T cells allowed</li></ul></li></ul>

<p>DISEASE CHARACTERISTICS:</p><ul><li><p>Diagnosis of adenocarcinoma of the breast by core-needle biopsy</p><ul><li>Palpable primary breast tumor measuring ≥ 2.0 cm on physical exam or imaging</li><li>Stage II or III disease</li><li>HER2-negative disease by IHC or FISH (0-2+)</li><li>cN0 or cN1 disease allowed (no ipsilateral cN2a, cN2b, or cN3 disease)</li><li>Operable disease</li></ul></li><li><p>Patients with either skeletal pain or alkaline phosphatase (ALP) that is &gt; upper limit of normal (ULN) but ≤ 2.5 times ULN are eligible provided bone scans do not demonstrate metastatic disease</p><ul><li>Suspicious findings on bone scan must be confirmed to be benign by x-ray, MRI, or biopsy</li></ul></li><li>No other definitive clinical or radiologic evidence of metastatic disease</li><li>No synchronous bilateral breast cancer (invasive or ductal carcinoma in situ [DCIS])</li><li><p>No prior invasive breast cancer</p><ul><li>DCIS and lobular carcinoma in situ (LCIS) allowed</li></ul></li><li>Estrogen receptor-negative (&lt; 10% by IHC) and progesterone receptor-negative (&lt; 10% by IHC) disease</li></ul><p>PATIENT CHARACTERISTICS:</p><ul><li>Menopausal status not specified</li><li>ECOG performance status 0-1</li><li>ANC ≥ 1,200&#x2F;mm^3</li><li>Platelet count ≥ 100,000&#x2F;mm^3</li><li>Hemoglobin ≥ 10 g&#x2F;dL</li><li>Total bilirubin ≤ ULN (unless the patient has a grade 1 bilirubin elevation [&gt; ULN to 1.5 times ULN] resulting from Gilbert disease or similar syndrome due to slow conjugation of bilirubin)</li><li>ALP ≤ 2.5 times ULN*</li><li>AST ≤ 1.5 times ULN* NOTE: *ALP and AST may not both be &gt; ULN.
Patients with AST or ALP &gt; ULN must not have demonstrable metastatic disease on liver imaging.</li><li>Serum creatinine ≤ ULN</li><li>Not pregnant or nursing</li><li>Fertile patients must use effective non-hormonal contraception during and for ≥ 3 months after completion of study treatment</li><li>Sufficient material in pre-treatment core biopsy for correlative studies</li><li>No history of invasive breast cancer (history of DCIS or LCIS allowed)</li><li>No other malignancies except for carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin unless the patient is considered to be disease-free for ≥ 5 years before randomization and is deemed by her physician to be at low risk for recurrence</li><li><p>No cardiac disease that would preclude the use of anthracyclines, including any of the following:</p><ul><li>Angina pectoris requiring antianginal medication</li><li>History of documented congestive heart failure</li><li>Serious cardiac arrhythmia requiring medication</li><li>Sever conduction abnormality</li><li>Valvular disease with documented cardiac function compromise</li><li>Uncontrolled hypertension defined as BP &gt; 140&#x2F;90 mm Hg on antihypertensive therapy (patients with hypertension that is well-controlled on medication are eligible)</li></ul></li><li>No history of myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function</li><li>No symptomatic peripheral vascular disease</li><li>No sensory or motor neuropathy ≥ grade 2, as defined by the NCI&#x27;s CTCAE v3.0</li><li>No other nonmalignant systemic disease (e.g., cardiovascular, renal, hepatic, etc.) that would preclude treatment with any of the treatment regimens or would prevent required follow-up</li><li>No psychiatric or addictive disorders or other conditions that, in the opinion of the investigators, would preclude the patient from complying with study treatment</li></ul><p>PRIOR CONCURRENT THERAPY:</p><ul><li>No prior anthracyclines or taxanes for any malignancy</li><li>No prior treatment for this cancer, including radiotherapy, chemotherapy, biotherapy, and&#x2F;or hormonal therapy</li><li>More than 30 days since prior investigational agents</li><li>At least 1 week since prior and no concurrent sex hormone therapy (e.g., birth control pills, hormonal replacement therapy)</li><li><p>No concurrent steroids except for adrenal failure, septic shock, pulmonary toxicity, or hormones administered for non-disease-related conditions (e.g., insulin for diabetes)</p><ul><li>Hydrocortisone for severe adverse reactions related to HER2Bi-armed activated T cells allowed</li></ul></li></ul>

2010-08-03

2010-09-16

2010-08-04

2010-09-17

<p>OBJECTIVES:</p><ul><li>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.</li><li>To investigate the association between pCR and clinical responses (disease-free survival and overall survival).</li><li>To determine if HER2Bi-armed ATCs administered after neoadjuvant chemotherapy will modulate the cytotoxicity of lymphocytes in the blood and tumor-infiltrating lymphocytes.</li><li>To determine if there is an association between systemic and tumor site anti-tumor responses.</li><li>To determine if HER2Bi-armed ATCs administration 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.</li><li>To investigate the association between the observed changes in numbers and proportion of CD44^hi&#x2F;CD24^lo, CD133, aldehyde dehydrogenase activity (ALDH1)-positive cells and the pCR.</li></ul><p>OUTLINE: This is a multicenter study.</p><ul><li>Neoadjuvant chemotherapy: Patients receive doxorubicin hydrochloride and cyclophosphamide every 2 weeks for 4 doses.
Patients then receive paclitaxel once a week for 12 doses.</li><li>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.</li><li>Surgery: Approximately 2 weeks after the last dose of HER2Bi-armed ATCs, patients undergo standard surgery.</li></ul><p>Tissue and blood samples are collected periodically for correlative immune function tests.</p><p>After completion of study treatment, patients are followed up every 8 weeks for 48 weeks and then every 3 months thereafter.</p>

<p>OBJECTIVES:</p><ul><li>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.</li><li>To investigate the association between pCR and clinical responses (disease-free survival and overall survival).</li><li>To determine if HER2Bi-armed ATCs administered after neoadjuvant chemotherapy will modulate the cytotoxicity of lymphocytes in the blood and tumor-infiltrating lymphocytes.</li><li>To determine if there is an association between systemic and tumor site anti-tumor responses.</li><li>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.</li><li>To investigate the association between the observed changes in numbers and proportion of CD44^hi&#x2F;CD24^lo, CD133, aldehyde dehydrogenase activity (ALDH1)-positive cells and the pCR.</li></ul><p>OUTLINE: This is a multicenter study.</p><ul><li>Neoadjuvant chemotherapy: Patients receive doxorubicin hydrochloride and cyclophosphamide every 2 weeks for 4 doses.
Patients then receive paclitaxel once a week for 12 doses.</li><li>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.</li><li>Surgery: Approximately 2 weeks after the last dose of HER2Bi-armed ATCs, patients undergo standard surgery.</li></ul><p>Tissue and blood samples are collected periodically for correlative immune function tests.</p><p>After completion of study treatment, patients are followed up every 8 weeks for 48 weeks and then every 3 months thereafter.</p>