Cyclophosphamide Followed by Intravenous and Intraperitoneal Infusion of Autologous T Cells Genetically Engineered to Secrete IL-12 and to Target the MUC16ecto Antigen in Patients With Recurrent MUC16ecto+ Solid Tumors
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|ClinicalTrials.gov Identifier: NCT02498912|
Recruitment Status : Recruiting
First Posted : July 15, 2015
Last Update Posted : May 11, 2018
|Condition or disease||Intervention/treatment||Phase|
|Solid Tumors||Procedure: Production of Genetically-modified T cells Drug: Cyclophosphamide Device: IP Catheter Insertion Genetic: Infusion of 4H11-28z/fIL-12/EGFRt+ Genetically-modified T cells Drug: Fludarabine||Phase 1|
There are 2 phases to the study: the Screening Phase and the Intervention Phase. Only patients identified as eligible from the Screening Phase may enroll in the Intervention Phase.
Screening Phase: After signing Informed Consent 1 (Screening Informed Consent), the patient's MUC16ecto tumor expression will be determined as previously described. In order to be eligible for this protocol, the patient's ovarian, primary peritoneal or fallopian tube carcinoma must express the MUC16ecto protein detectable by IHC analysis of banked (paraffin embedded) or fresh biopsied tumor. After signing Informed Consent 1, approximately 2 weeks will elapse while the patient's banked tumor is tested for MUC16ecto expression. If a patient's tumor is found to express MUC16ecto, she will undergo leukapheresis for the collection of peripheral blood mononuclear cells (PBMC), which will be frozen for future use. The leukapheresis product will be stored until the end of the study in case future research tests related to this study are developed.
Intervention Phase: Patients must sign Informed Consent 2 (Intervention Informed Consent) before receiving treatment on the study before receiving treatment on the study.
Once the patient is eligible to receive the CAR+ T cells, the frozen leukapheresis product will be thawed and used to generate the 4H11-28z/fIL-12/EGFRt+ genetically-modified T cells. It is expected to take approximately 4-6 weeks to prepare the autologous CAR+ T cells.
On day 1-3 patients in cohorts V will receive conditioning chemotherapy with cyclophosphamide 750 mg/m^2 or 300 mg/m2 cyclophosphamide concurrent with 25-30 mg/m2 fludarabine 2-7 days prior to the initial infusion of autologous CAR+T cells. Patients will receive autologous CAR+T cells in 2 infusions, the first IV and the second IP, each comprising about half the total dose. The IV infusion will be given first. The patient will then be closely monitored. One to 3 days later if clinically stable, the patient will receive the remaining dose of CAR+T cells IP. Patients in cohort I or -I will not receive cyclophosphamide, but will receive the T cells in the same manner (approximately half IV, followed by close monitoring and then 1-3 days later, if the patient is clinically stable, the remaining cells will be administered IP).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Clinical Trial of Cyclophosphamide Followed by Intravenous and Intraperitoneal Infusion of Autologous T Cells Genetically Engineered to Secrete IL-12 and to Target the MUC16ecto Antigen in Patients With Recurrent MUC16ecto+ Solid Tumors|
|Actual Study Start Date :||August 2015|
|Estimated Primary Completion Date :||August 2019|
|Estimated Study Completion Date :||August 2019|
Experimental: Cyclophosphamide followed by Autologous T Cells
This is a standard phase I dose escalation trial. Cohorts of 3-6 patients will be infused with escalating doses of modified T cells to establish the maximum tolerated dose (MTD) of modified T cells. There are 4 planned dose levels: 3 x 10^5, 1 x 10^6, 3 x 10^6, and 1 x 10^7 4H11-28z/fIL-12/EGFRt+ T cells/kg (Table 1). Cohort I-IV will be treated escalating dose levels. Once the MTD of T cells is established, the next cohort will receive lymphodepleting cyclophosphamide dose of 750 mg/m^2 or a regimen of cyclophosphamide dose 300 mg/m2 x 3 days concurrent with fludarabine dose 25-30 mg/m2 x 3 days 2-7 days prior to starting the T cell infusion at one dose level below the MTD. If the MTD is not established after Cohort IV, Cohort V will receive conditioning chemotherapy 2-7 days prior to starting the T cell infusion at the same dose as Cohort III.
Procedure: Production of Genetically-modified T cells
Device: IP Catheter Insertion
Genetic: Infusion of 4H11-28z/fIL-12/EGFRt+ Genetically-modified T cells
fludarabine dose 25-30 mg/m2 x 3 days
- maximum tolerated dose (MTD) [ Time Frame: 2 years ]There are 4 planned dose levels of 4H11-28z/fIL-12/EGFRt+ T cells: 3 x 10^5, 1 x 10^6, 3 x 10^6, and 1 x10^6 4H11-28z/fIL-12/EGFRt+ T cells/kg. The first subject will be treated at dose level 1 (3 x 1054H11-28z/fIL-12/EGFRt+ T cells/kg). At least one week will elapse from the first patient's T cell infusions before the second patient is treated (on dose level 1) to allow for toxicity and safely assessment. 3 subjects will be enrolled in cohort I and followed for 30 days for safety assessments. If no DLT is observed after all three subjects have been observed for 30 days, a second cohort of 3 subjects will be enrolled at the same dose level (3 x 10^54H11-28z/fIL-12/EGFRt+ T cells/kg) with the addition of cyclophosphamide plus or minus fludarabine.
- evidence of anti-tumor activity [ Time Frame: 2 years ]which will be defined according to the RECIST criteria, version 1.1 and, in appropriate subjects, the immune-related Response Criteria (irRC) (80)
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02498912
|Contact: Roisin O'Cearbhaill, MD||646-888-4227|
|Contact: Jae Park, MD||212-639-4048|
|United States, New York|
|Memorial Sloan Kettering Cancer Center||Recruiting|
|New York, New York, United States, 10065|
|Contact: Roisin O'Cearbhaill, MD 646-888-4227|
|Contact: Jae Park, MD 212-639-4048|
|Principal Investigator: Roisin O'Cearbhaill, MD|
|Principal Investigator:||Roisin O'Cearbhaill, MD||Memorial Sloan Kettering Cancer Center|