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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

Phase 2
18 Years
Open (Enrolling)
Ductal Breast Carcinoma in Situ, Lobular Breast Carcinoma in Situ, Male Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer

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Trial Information

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


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


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.

Inclusion 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

- (HER2/CEP17 amplification ratio <2.0) for whom definitive surgical treatment after

- 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

- 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

- 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

- preclude treatment with any of the treatment regimens or would prevent required

- Chronic ongoing steroid use at the time of registration for any condition (such as

- 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.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

pCR defined as absence of all invasive tumor in both breast and axilla

Outcome Description:

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.

Outcome Time Frame:

Up to 12 months post-surgery

Safety Issue:


Principal Investigator

Lawrence Lum

Investigator Role:

Principal Investigator

Investigator Affiliation:

Barbara Ann Karmanos Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

July 2010

Completion Date:

November 2015

Related Keywords:

  • Ductal Breast Carcinoma in Situ
  • Lobular Breast Carcinoma in Situ
  • Male Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • HER2-negative breast cancer
  • Breast Neoplasms
  • Carcinoma
  • Carcinoma in Situ
  • Carcinoma, Intraductal, Noninfiltrating
  • Carcinoma, Ductal, Breast
  • Carcinoma, Lobular
  • Breast Neoplasms, Male



Barbara Ann Karmanos Cancer Institute Detroit, Michigan  48201