Laboratory-Treated T Cells After Second-Line Chemotherapy in Treating Patients With HER2/Neu-Negative Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Giving laboratory-treated T cells after chemotherapy may be an effective treatment for breast cancer. PURPOSE: This phase II trial is studying how well giving laboratory-treated T cells after second-line chemotherapy works in treating patients with HER2/neu-negative metastatic breast cancer.

Detailed Description
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OBJECTIVES: To determine in a phase II trial whether Her2Bi armed ATC infused after ChemoT for patients with HER2 0-2+ MBC or locally advanced, unresectable breast cancer would improve median PFS by 2 months beyond the median PFS of 2 months estimated from published trials in a one stage design. To determine the overall survival (OS) of patients with HER2 0-2+ MBC and locally advanced, unresectable breast cancer who receive aATC infusion after ChemoT. To confirm the toxicity profile for Her2Bi armed ATC given after ChemoT for patients with HER2 0-2+ MBC. To measure functional and phenotypic changes in immune cell populations (blood and tumor sites, if accessible) as a consequence of armed ATC (tumor biopsies done at KCI only). Cytokine responses, phenotypic markers of differentiation, and anti-tumor cytotoxicity will be examined. OUTLINE: Patients receive second-line chemotherapy for 4 courses or 4 months. Beginning as early as 1.5 weeks and as late as 4 weeks after chemotherapy, the patients will receive the first infusion of anti-CD3 x anti-HER2/neu bispecific antibody-armed activated T-cells (ATC) IV over 30-60 minutes once a week for 3 weeks. Low dose granulocyte-macrophage colony stimulating factor (250 µg/m2/twice per week) will start 3 days before the first aATC infusion and end with the last dose of aATC. Patients who are already on the protocol will be given a choice to add GM-CSF to their treatment regimen (after reconsenting) or continue to their treatment without GM-CSF. Patients then receive a boost of anti-CD3 x anti-HER2/neu bispecific antibody-armed ATC at 12 weeks after the 3rd ATC infusion. Blood and tumor tissue samples may be collected periodically for biomarker and other analyses. After completion of study therapy, patients are followed up periodically for ≥ 2 years.

Official Title
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A Phase II Study of Anti-CD3 x Anti-HER2/Neu Armed Activated T Cells for Patients With HER2/Neu (0, 1+ or 2+) Metastatic Breast Cancers.

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: HER2Bi-armed activated T cells
* Drug: Cyclophosphamide
* Other: Laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion: Metastatic Breast Cancer. Histologically confirmed breast cancer with evidence of metastatic disease (need not be biopsy proven) or locally, advanced unresectable disease. Patients with 0-2+ HER2 expression as determined by immunohistochemistry staining and/or FISH ratio <2.0, with the above pathologic criteria will be eligible. Hormone Therapy. Patients on prior hormonal therapy are eligible. Hormonal therapy will be stopped 2 weeks prior to leukopheresis. Hormone therapy may be restarted after leukopheresis Patients may have received any number of prior lines of chemotherapy providing Leukopheresis is done when the lymphocyte count has recovered to ≥500 cells/mm3 and there are no residual chemotoxicities that would prevent leukopheresis. Patients who have received Radiotherapy are eligible providing Leukopheresis is done at least 4 weeks after radiation to the axial skeleton. Patients who have received prior biological agents are eligible. Patients with measurable and non-measurable disease are eligible. Age > or = to 18 years ECOG 0-1 or Karnofsky > or = to 70% Life expectancy > or = to 3 months Patients with treated brain metastases are eligible Required Laboratory Data Granulocytes > 1,200/mm3 Platelet count > 50,000/μl Hemoglobin ≥ 8 gm/dl BUN < 1.5 times normal Serum creatinine < 1.8 mg/dl Creatinine Cl ≥50 ml/mm (can be calculated utilizing the Cockcroft & Gault equation: Creatinine Clearance (mL/min) = {(140 - Age)} x Wt [kg] (x 0.85 if Female}/ {72 x SCr [mg/dL]} Bilirubin < 1.5 times normal ALT, AST and alkaline phosphatase < 5 times upper normal Negative HIV Negaitve Hepatitis B surface antigen Negative Hepatitis C serology LVEF ≥ 45% at rest (MUGA or ECHO) PFT-FEV1, DLCO, and FVC ≥ 50% of predicted Negative serum test for pregnancy, unless male, prior hysterectomy, tubal ligation, or postmenopausal. (Note: postmenopausal is defined as age>55 with amenorrhea for >1 year or age <55 years with amenorrhea for 2 years and FSH level within postmenopausal range of institutional parameters; patients requiring FSH level to determine menopausal status need not have this performed and may choose to proceed with serum pregnancy testing.) Exclusion Criteria Patients with HER2 overexpression by immunohistochemistry (IHC) or overamplification by FISH are not eligible and are defined as follows: IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.0. Patients with a history of another malignancy within 5 years of study entry are not eligible (except basal cell skin carcinoma and carcinoma-in-situ of the cervix). No serious medical or psychiatric illness which prevents informed consent or intensive treatment is allowed. Patients will be ineligible for treatment on this protocol if (prior to protocol entry): There is a history of a recent myocardial infarction (within one year) There is a history of a past myocardial infarction (more than one year ago) along with current coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by MUGA or ECHO) There is a current history of angina/coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by MUGA or ECHO) There is clinical evidence of congestive heart failure requiring medical management (irrespective of MUGA or ECHO results) Patients will be ineligible if there is recurrent pleural effusion or ascites requiring drainage (through thoracentesis, paracentesis, or indwelling device) more often than once every 4 weeks. Patients with clinical evidence of active CNS metastases are ineligible for therapy on this protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HER2Bi-armed activated T cells/Cyclophosphamide/biomarker<br>HER2Bi-armed activated T cells Immediately after pheresis, the lymphocytes are activated with soluble monoclonal anti-CD3 antibody, which cross-links the CD3 receptors on T cells and activates them. Cyclophosphamide After recovering from the last cycle of chemotherapy (approx. two-four weeks) patients will be re-staged. If there are no residual chemotherapy related toxicities, they will be given lymphodepleting chemotherapy consisting of one dose of Cyclophosphamide 1.0 gm/m2 on day -7. Appropriate anti-emetics will be given as pre-medications before the dose of Cyclophosphamide Laboratory biomarker analysis The association between the [18F]-FDG PET/CT assessments (percent changes from baseline in SUVpeak) and immunologic biomarker changes as well as tumor response will be explored. | Biological: HER2Bi-armed activated T cells<br>* Immediately after pheresis, the lymphocytes are activated with soluble monoclonal anti-CD3 antibody, which cross-links the CD3 receptors on T cells and activates them.<br>Drug: Cyclophosphamide<br>* After recovering from the last cycle of chemotherapy (approx. two-four weeks) patients will be re-staged. If there are no residual chemotherapy related toxicities, they will be given lymphodepleting chemotherapy consisting of one dose of Cyclophosphamide 1.0 gm/m2 on day -7. Appropriate anti-emetics will be given as pre-medications before the dose of Cyclophosphamide<br>Other: Laboratory biomarker analysis<br>* The association between the [18F]-FDG PET/CT assessments (percent changes from baseline in SUVpeak) and immunologic biomarker changes as well as tumor response will be explored.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participant Who Were Alive Without Progression at 4 Months | 26 evaluable patients will be accrued in this study. A single-arm, single-stage phase II design will be used. If ≥9 out of 26 patients have not progressed by the 4-month follow-up, we will declare that the treatment is effective on TTP. | At the 4-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) was defined as the time duration from the first infusion until death or last observation. | Followed until death or last observation (assessed up to 5 years), whichever occurs first | 
| Overall Response Rate | Complete and partial responses; Responses will be evaluated using standard RECIST 1.1 criteria. | Following chemotherapy, up to 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-negative breast cancer, stage IV breast cancer, recurrent breast cancer