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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Given SC
Given IV and IP
Correlative studies
Given SC
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
Time frame: 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.
Time frame: Up to 2 years
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: From the beginning of immunotherapy to progression or death, assessed up to 12 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.