Activated T-cell Therapy, Low-Dose Aldesleukin, and Sargramostim in Treating Patients With Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That is Stage III-IV, Refractory, or Recurrent

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of activated T-cell therapy when given together with low-dose aldesleukin and sargramostim in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that is stage III-IV, has not responded to previous treatment, or has come back. Activated T cells that have been coated with bi-specific antibodies, such as anti-cluster of differentiation (CD)3 and anti-human epidermal growth factor receptor 2 (HER2), may stimulate the immune system in different ways and stop tumor cells from growing. Aldesleukin may stimulate white blood cells to kill tumor cells. Colony-stimulating factors, such as sargramostim, may increase the production of blood cells. Giving activated T-cell therapy with low-dose aldesleukin and sargramostim may be a better treatment for ovarian, fallopian tube, or primary peritoneal cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Perform a phase I clinical trial consisting of dose-escalation/de-escalation of intraperitoneal (IP) infusions of anti-CD3 x anti-HER2/neu (HER2Bi) armed anti-CD3 activated T cells (aATC) in women with high risk or recurrent ovarian cancer to determine the maximum tolerated dose (MTD) for IP injections in combination with a fixed intravenous (IV) dose of 10 x 10^9 (± 20%) aATC once a week. II. To clearly define the toxicity profile of IP and IV HER2Bi aATC at the MTD or technically feasible dose in patients with ovarian cancer. SECONDARY OBJECTIVES: I. Evaluate clinical responses, time to progression, and overall survival. II. Evaluate phenotype, cytokine profiles and interferon (IFN)-gamma enzyme-linked immunosorbent spots (ELISPOTS), cytotoxicity and antibodies directed at laboratory ovarian cancer cell lines. III. Monitor cancer antigen (CA)125 or tumor markers, and antibody responses to mouse proteins (human anti-mouse antibodies [HAMA]). IV. The migration of armed ATC out of the peritoneal and serum cytokine levels induced by IP or IV armed ATC infusion will be assessed by studying the appearance of armed ATC at various time points (0, 4, 8, 12, 24, 48, 72, and 96 hours after IP infusion) in the blood after IP infusions by performing flow cytometry to detect anti-CD3 (OKT3) x anti-Her2 (Herceptin®) bi-specific antibody (BiAb) on the surface of aATC. OUTLINE: This is a dose-escalation study of IP infused HER2Bi-armed activated T cells. Patients receive HER2Bi-aATC IV over 5-15 minutes and IP within 3-4 days of IV dose weekly for 4 weeks. Patients also receive low-dose aldesleukin subcutaneously (SC) daily and sargramostim SC twice weekly beginning 3 days before the first HER2Bi-aATC infusions infusion and ending 7 days after the last HER2Bi-aATC infusion. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 1 and 3 months, and then every 6 months.

Official Title
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Treatment of High Risk or Recurrent Ovarian Cancer With Anti-CD3 x Anti-HER2 Bispecific Antibody Armed Activated T Cells (BATs), Low Dose IL-2, and GM-CSF (Phase I).

Conditions
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Malignant Ovarian Clear Cell Tumor, Malignant Ovarian Serous Tumor, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Stage IIIA Fallopian Tube Cancer, Stage IIIA Ovarian Cancer, Stage IIIA Primary Peritoneal Cancer, Stage IIIB Fallopian Tube Cancer, Stage IIIB Ovarian Cancer, Stage IIIB Primary Peritoneal Cancer, Stage IIIC Fallopian Tube Cancer, Stage IIIC Ovarian Cancer, Stage IIIC Primary Peritoneal Cancer, Stage IV Fallopian Tube Cancer, Stage IV Ovarian Cancer, Stage IV Primary Peritoneal Cancer

Intervention / Treatment
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* Biological: Aldesleukin
* Biological: HER2Bi-Armed Activated T Cells
* Other: Laboratory Biomarker Analysis
* Biological: Sargramostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented, epithelial ovarian, fallopian tube, or primary peritoneal, high grade serous or clear cell carcinoma are eligible; all patients must have a confirmed pathology; stage 3 and 4 initial disease with response to primary surgery and neo/adjuvant chemotherapy, platinum refractory disease, and patients with recurrent disease are candidates Patients meeting the above pathologic criteria will be eligible for therapy irrespective of their HER2/neu over expression status; immunohistochemical staining will be not be required for protocol entry but fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) studies for HER2/neu are preferred Chemotherapy: no limit to prior therapies; however, patients with multiple chemotherapy regimens will be screened for lymphocyte proliferation at investigator's discretion Herceptin: women who have been previously treated with Herceptin or other monoclonal antibody therapies are eligible for the trial Radiation therapy: patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease Patients may have no evidence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria or have measurable disease; CA-125 and other available markers will be obtained Karnofsky performance score of >= 70 is required or Eastern Cooperative Oncology Group (ECOG) score, performance status (PS) = 0-2 The patient must have a life expectancy of 3 months or more based on the judgment of the investigators; women who have rapidly progressive symptomatic disease affecting major organ systems such as the liver and lungs will be excluded Negative serum test for pregnancy in premenopausal women No previous or concurrent malignancy, other than curatively treated in situ squamous cell carcinoma of the cervix or basal cell carcinoma of the skin or non-active breast cancer Each patient must be aware of the nature of her disease process and must willingly consent to treatment after being informed of alternatives, potential benefits, side effects, and risks; eligibility testing that is considered standard of care may be done prior to informed consent but no immunotherapy related procedures or testing may occur without informed consent No serious medical or psychiatric illness which prevents informed consent or intensive treatment Patients will be ineligible for treatment on this protocol if: 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 (left ventricular ejection fraction [LVEF] < 45% by echocardiogram [ECHO]) There is a current history of angina/coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by ECHO) There is clinical evidence of congestive heart failure requiring medical management (irrespective of ECHO results) Patients who have persistently elevated systolic blood pressures (BPs) >= 145 or diastolic BPs >= 90 need to have their systolic or diastolic BP controlled with anti-hypertensive agents for at least 3 days prior to the initiation of cell therapy; patients already on anti-hypertensive agents will have their medicine adjusted based on the clinical judgment of the patient care team Patients with treated brain metastases (received definitive radiation and/or underwent surgical resection) are eligible for therapy on this protocol; patients with clinical evidence of active brain metastases are ineligible for therapy on this protocol Granulocytes >= 1,000/mm^3 Platelet count >= 50,000/ul Hemoglobin >= 8 gm/dl Blood urea nitrogen (BUN) =< 1.5 times normal Serum creatinine =< 1.8 mg/dl Creatinine clearance >= 60 ml/mm Bilirubin =< 2.0 times normal Serum glutamic oxaloacetic transaminase (SGOT) =< 2.0 times normal Human immunodeficiency virus (HIV) = negative LVEF >= 45% at rest (by ECHO) Pulmonary function tests (PFT)-forced expiratory volume in one second (FEV1), diffusing capacity of the lung for carbon monoxide (DLCO2), and forced vital capacity (FVC) >= 60% predicted value if clinically indicated Minor changes from the required initial laboratory data guidelines will be allowed at the discretion of the attending team under special circumstances; the reasons for exceptions must be documented prior to enrollment Appropriate slides of the primary lesion will be available for future review; if available, HER2/neu positivity will be recorded Peritoneal dialysis catheter implantation is identical to that from the Gynecologic Oncology Group (GOG) 252 Protocol and revised from the GOG Surgical Procedures Manual

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Treatment (aldesleukin, sargramostim, HER2Bi-aACT)<br>Patients receive HER2Bi-aATC IV over 5-15 minutes and IP within 3-4 days of IV dose weekly for 4 weeks. Patients also receive low-dose aldesleukin SC daily and sargramostim SC twice weekly beginning 3 days before the first HER2Bi-aATC infusions infusion and ending 7 days after the last HER2Bi-aATC infusion. Treatment continues in the absence of disease progression or unacceptable toxicity. | Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Biological: HER2Bi-Armed Activated T Cells<br>* Given IV and IP<br>* Other names: HER2Bi-Armed ATCs;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of IP injections in combination with the IV fixed dose of aATC determined by the incidence of dose-limiting toxicity (DLT) defined using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 |  | Up to 4 weeks | 
| Toxicity profile of IP and IV HER2Bi-aATC at the MTD or technically feasible dose graded using NCI CTCAE version 4.0 | Patients who received any armed ATC but not evaluable for DLT will be analyzed separately for the toxicity profile. The toxicity will be summarized with point and exact confidence intervals. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in cytokine profiles | Increases or decreases in the amount of cytokine produced from the pre immunotherapy baseline at any time point after immunotherapy will be considered as continuous outcomes. Paired t-test or Wilcoxon signed rank test will be used to compare the difference between baseline and after any time point of aATC treatment in proliferation, ELISPOTS, and the amount of cytokine produced. The data collected at all study time points after immunotherapy will be analyzed using mixed-effect model for longitudinal data adjusted for baseline measures. | Baseline to up to 12 months | 
| Changes in HAMA levels in serum samples | Sera from patients will be obtained before and after immunotherapy at the designated time points to determine if there is development of HAMA responses directed at OKT3 (mouse IgG2a antibody). Paired t-test or Wilcoxon signed rank test will be used to compare the difference between baseline and after any time point of aATC treatment in proliferation, ELISPOTS, and the amount of cytokine produced. The data collected at all study time points after immunotherapy will be analyzed using mixed-effect model for longitudinal data adjusted for baseline measures. | Baseline to up to 12 months | 
| Changes in phenotyping induced by immunotherapy in peripheral blood mononuclear cells (PBMC) | PBMC from the patients will be obtained before and after immunotherapy to determine if there changes induced by immunotherapy. Paired t-test or Wilcoxon signed rank test will be used to compare the difference between baseline and after any time point of aATC treatment in proliferation, ELISPOTS, and the amount of cytokine produced. The data collected at all study time points after immunotherapy will be analyzed using mixed-effect model for longitudinal data adjusted for baseline measures. | Baseline to up to 12 months | 
| Clinical response rate (including complete response, partial response, progressive disease, and stable disease) measured on the basis of CA-125 or RECIST-defined tumor measurements | Point and exact confidence interval estimates will be calculated for response rate. | Up to 12 months | 
| Increases in IFN-gamma ELISPOTS | Paired t-test or Wilcoxon signed rank test will be used to compare the difference between baseline and after any time point of aATC treatment in proliferation, ELISPOTS, and the amount of cytokine produced. The data collected at all study time points after immunotherapy will be analyzed using mixed-effect model for longitudinal data adjusted for baseline measures. | Baseline to up to 12 months | 
| Increases in the immunoglobulin G titer against selected ovarian cancer cell lines in serum samples | Sera from patients will be obtained before and after immunotherapy to determine if there are changes induced by immunotherapy. Paired t-test or Wilcoxon signed rank test will be used to compare the difference between baseline and after any time point of aATC treatment in proliferation, ELISPOTS, and the amount of cytokine produced. The data collected at all study time points after immunotherapy will be analyzed using mixed-effect model for longitudinal data adjusted for baseline measures. | Baseline to 4 weeks | 
| Overall survival | Will be estimated with the standard Kaplan-Meier method, from which summary statistics of interest (median, 6 month, 1-year rate, etc.) will be derived. Both point and 95% confidence interval estimates will be calculated. | From the beginning of immunotherapy to the time of death, assessed up to 12 months | 
| Progression free survival | Will be estimated with the standard Kaplan-Meier method, from which summary statistics of interest (median, 6 month, 1-year rate, etc.) will be derived. Both point and 95% confidence interval estimates will be calculated. | From the beginning of immunotherapy to progression or death, assessed up to 12 months |