Laboratory Treated T Cells After Chemotherapy in Treating Patients With HER2-Negative Stage II-III Breast Cancer That Can Be Removed By Surgery

This study is currently recruiting participants.
Verified September 2013 by Barbara Ann Karmanos Cancer Institute
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Lawrence Lum, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier:
NCT01658969
First received: March 8, 2012
Last updated: September 6, 2013
Last verified: September 2013
  Purpose

This phase II trial studies how well giving laboratory treated T cells after chemotherapy works in treating patients with HER2-negative stage II-III breast cancer that can be removed by surgery. 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 paclitaxel, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or 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


Condition Intervention Phase
Ductal Breast Carcinoma in Situ
Lobular Breast Carcinoma in Situ
Male Breast Cancer
Stage II Breast Cancer
Stage IIIA Breast Cancer
Drug: Doxorubicin
Drug: Cyclophosphamide
Drug: Paclitaxel
Drug: Docetaxel
Biological: HER2Bi-armed activated T cells
Other: laboratory biomarker analysis
Procedure: therapeutic conventional surgery
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Anti-CD3 x Anti-HER2/Neu (Her2Bi) Armed Activated T Cells (ATC) After Neoadjuvant Chemo in Pts.With HER2/Neu (0-2+)-Negative Stage II-III Breast Cancers

Resource links provided by NLM:


Further study details as provided by Barbara Ann Karmanos Cancer Institute:

Primary Outcome Measures:
  • pCR defined as absence of all invasive tumor in both breast and axilla [ Time Frame: Up to 12 months post-surgery ] [ Designated as safety issue: No ]
    Estimated with as binomial proportion and 95% confidence interval. Estimates will be computed for both response-evaluable and for the entire study cohort. The association between measures of immune function using rank correlation methods will be estimated.


Secondary Outcome Measures:
  • Overall survival (OS) [ Time Frame: At 1 month post-aATC dose; and then at 3, 6, and 12 months post-surgery (optional) ] [ Designated as safety issue: No ]
  • Recurrence-free Survival (RFS), where an event is defined as recurrence of disease or death [ Time Frame: At 1 month post-aATC dose; and then at 3, 6, and 12 months post-surgery (optional) ] [ Designated as safety issue: No ]

Estimated Enrollment: 48
Study Start Date: July 2010
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Doxorubicin, Cyclophosphamide, Paclitaxel & Docetaxel

Doxorubicin (usually 60 mg/m2)via IV,Dose Dense AC->T Concomitantly w/cyclophosphamide; given every 2 wks for 4 cycles with appropriate G-CSF support

Cyclophosphamide(usually 600 mg/m2)via IV, Dose Dense AC->T Concomitantly w/doxorubicin; given every 2 wks for 4 cycles with appropriate G-CSF support

Docetaxel (usually 75 mg/m2)via IV, Concomitantly with doxorubicin + cyclophoshamide; every 3 wks for 6 cycles with appropriate G-CSF support, except no G-CSF will be given following the last cycle of therapy

Cyclophosphamide(500 mg/m2)via IV, Concomitantly w/docetaxel + doxorubicin; every 3 weeks for 6 cycles with appropriate G-CSF support, except no G-CSF will be given following the last cycle of therapy

Doxorubicin (usually 50 mg/m2)via IV, Concomitantly with docetaxel + cyclophoshamide; every 3 wks for 6 cycles with appropriate G-CSF support, except no G-CSF will be given following the last cycle of therapy

Drug: Doxorubicin
Doxorubicin (usually 60 mg/m2)administered via IV,Dose Dense AC->T Concomitantly with cyclophosphamide; given every 2 weeks for 4 cycles with appropriate G-CSF support
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
  • Rubex
Drug: Cyclophosphamide
Cyclophosphamide(usually 600 mg/m2)administered via IV, Dose Dense AC->T Concomitantly with doxorubicin; given every 2 weeks for 4 cycles with appropriate G-CSF support
Other Names:
  • Cytoxan
  • CPM
  • CTX
  • Endoxan
  • Endoxana
Drug: Paclitaxel
Administered IV, 2-3 weeks after doxorubicin + cyclophosphamide, usually 175 mg/m2 every 2 weeks for 4 cycles with appropriate GCSF support, except no G-CSF will be given following the last cycle of therapy or paclitaxel (usually 80 mg/m2) every week for 12 weeks
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
  • Onxal™
Drug: Docetaxel
Docetaxel (usually 75 mg/m2)administered via IV, Concomitantly with doxorubicin + cyclophoshamide; every 3 weeks for 6 cycles with appropriate G-CSF support, except no G-CSF will be administered following the last cycle of therapy
Other Names:
  • RP 56976
  • Taxotere
  • TXT
Biological: HER2Bi-armed activated T cells
Four (4) infusions of 20 billion armed ATC given once per week for 4 weeks
Other: laboratory biomarker analysis
Correlative studies
Procedure: therapeutic conventional surgery
Approximately 2 weeks after infusions of HER2Bi-armed activated T cells
Drug: Cyclophosphamide
Cyclophosphamide(500 mg/m2)administered via IV, Concomitantly with docetaxel + doxorubicin; every 3 weeks for 6 cycles with appropriate G-CSF support, except no G-CSF will be administered following the last cycle of therapy
Other Names:
  • CPM
  • CTX
  • Endoxan
  • Endoxana
  • Cytoxan®
  • Neosar®
Drug: Doxorubicin
Doxorubicin (usually 50 mg/m2) administered via IV, Concomitantly with docetaxel + cyclophoshamide; every 3 weeks for 6 cycles with appropriate G-CSF support, except no G-CSF will be administered following the last cycle of therapy

Detailed Description:

OBJECTIVES:

I. To determine, in a phase II clinical trial of women with stage II-III human epidermal growth factor receptor (HER)2-negative breast cancer, if a regimen of neoadjuvant chemotherapy (chemoT) followed by immunotherapy (IT) improves the complete pathologic response (pCR) rate at the time of surgery. IT will consist of 4 infusions of 20 x 10^9 Her2Bi-armed activated T cells (ATC) (aATC) given once per week for 4 weeks. The association between pCR and clinical responses (disease free survival [DFS] and overall survival [OS]) will be investigated.

II. To determine if aATC infusions following neoadjuvant chemoT will modulate the cytotoxicity of lymphocytes in the blood and tumor infiltrating lymphocytes (TIL) and if there is an association between systemic and tumor site anti-tumor responses. The immune measures will be done pre-IT, prior to infusion #3 (midpoint of IT), 2 weeks after IT (prior to surgery), and 1 month after surgery.

III. To determine if aATC infusions after neoadjuvant chemoT decreases the frequency and colony forming ability of the putative breast cancer stem cells (CSC) in the tumor tissue at the time of surgery, compared to those obtained in the tumor biopsy after chemoT. 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 will be investigated.

OUTLINE:

NEOADJUVANT CHEMOTHERAPY: Patients receive dose-dense AC->T regimen comprising doxorubicin hydrochloride intravenously (IV) and cyclophosphamide IV once every 2 weeks for 4 courses followed by paclitaxel IV once every 2 weeks for 4 courses or paclitaxel IV once weekly for 12 weeks. Or, patients receive TAC regimen comprising docetaxel IV, doxorubicin hydrochloride IV, and cyclophosphamide IV once every 3 weeks for 6 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY: Beginning 3-6 days after the last dose of chemotherapy, patients receive Her2Bi-armed activated T cells IV over 5-30 minutes once weekly for 4 weeks.

SURGERY: Patients then undergo surgical resection of the breast 2 weeks later.

After completion of study treatment, patients may be followed up at 1, 3, 6, and 12 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Signed and dated IRB-approved consent form
  • Patients may be male or female.
  • 18 years of age or older. Women of reproductive potential must agree to use an effective nonhormonal method of contraception during therapy.
  • 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 IHC (0-2+) and FISH
  • (HER2/CEP17 amplification ratio <2.0) for whom definitive surgical treatment after "third
  • generation" neoadjuvant chemoT (see section 4.3.1) is planned. ER or PR receptors 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.
  • At the time of registration:
  • Absolute neutrophil count (ANC) must be ≥ 1200/mm3.
  • Platelet count must be ≥ 100,000/mm3.
  • Hemoglobin must be ≥ 9.0 mg/dL.

There must be evidence of adequate hepatic function by these criteria:

  • Total bilirubin must be ≤ the 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
  • AST/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, 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, CT, or MRI), abdominal/pelvis imaging (CT or MRI), and bone imaging (bone scan or 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.
    • Left Ventricular Ejection Fraction (LVEF) ≥ 50 % (by MUGA or echocardiography)

Exclusion Criteria:

Patients with any of the following conditions will be ineligible for this study:

  • 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 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 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 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 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 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01658969

Locations
United States, Michigan
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Lawrence Lum    313-576-8326    luml@karmanos.org   
Principal Investigator: Lawrence Lum, M.D.         
Sub-Investigator: Zaid Al-Kadhimi, M.D.         
Sub-Investigator: Rouba Ali-Fehmi, M.D.         
Sub-Investigator: Lydia Choi, M.D.         
Sub-Investigator: Abhinav Deol, M.D.         
Sub-Investigator: Neb Duric, M.D.         
Sub-Investigator: Lawrence Flaherty, M.D.         
Sub-Investigator: David Gorski, M.D.         
Sub-Investigator: Sayeh Lavasani, M.D.         
Sub-Investigator: Michael Simon, M.D.         
Sub-Investigator: Archana Thakur, M.D.         
Sponsors and Collaborators
Barbara Ann Karmanos Cancer Institute
Investigators
Principal Investigator: Lawrence Lum Barbara Ann Karmanos Cancer Institute
  More Information

No publications provided

Responsible Party: Lawrence Lum, Principal Investigator, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier: NCT01658969     History of Changes
Other Study ID Numbers: 2010-056, NCI-2011-02634, R01CA140314
Study First Received: March 8, 2012
Last Updated: September 6, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Barbara Ann Karmanos Cancer Institute:
HER2-negative breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Carcinoma
Carcinoma in Situ
Carcinoma, Intraductal, Noninfiltrating
Carcinoma, Ductal, Breast
Carcinoma, Lobular
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Adenocarcinoma
Neoplasms, Ductal, Lobular, and Medullary
Carcinoma, Ductal
Cyclophosphamide
Docetaxel
Doxorubicin
Paclitaxel
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on April 17, 2014