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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 : April 11, 2019
Sponsor:
Collaborators:
Stanford University
Juno Therapeutics, Inc.
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE July 10, 2015
First Posted Date  ICMJE July 15, 2015
Last Update Posted Date April 11, 2019
Actual Study Start Date  ICMJE August 2015
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
maximum tolerated dose (MTD) [ Time Frame: 2 years ]
There are 5 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 x10^7 and 3 x10^7 4H11-28z/fIL-12/EGFRt+ T cells/kg. The first subject will be treated at dose level 1 (3 x 10^5 4H11-28z/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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 13, 2015)
maximum tolerated dose (MTD) [ Time Frame: 2 years ]
There are 4 planned dose levels of 4H11-28z/fIL-12/EFGRt+ T cells: 3 x 105, 1 x 106, 3 x 106, and 1 x106 4H11-28z/fIL-12/EFGRt+ T cells/kg. The first subject will be treated at dose level 1 (3 x 1054H11-28z/fIL-12/EFGRt+ 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 1054H11-28z/fIL-12/EFGRt+ T cells/kg) with the addition of cyclophosphamide.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 13, 2015)
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)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief Summary The purpose of this phase I study is to test the safety of different dose levels of specially prepared cells collected called "modified T cells". In the screening part of this study the tumor was found to have a protein called MUC16. This protein is present on about 70% of ovarian cancers. The investigators want to find a safe dose of modified T cells for patients with this type of cancer that has progressed after standard chemotherapy. We also want to find out what effects these modified T cells have on the patient and their cancer.
Detailed Description

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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
This is a standard phase I dose escalation trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumors
Intervention  ICMJE
  • 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
    Patients who do not have sufficient CAR T cells for the assigned dose cohort will be treated in the cohort for which cells are available.
  • Drug: Fludarabine
    fludarabine dose 25-30 mg/m2 x 3 days
Study Arms  ICMJE Experimental: Cyclophosphamide followed by Autologous T Cells
Cohorts of 3-6 pts will be infused with escalating doses of modified T cells to establish the MTD of modified T cells. There are 5 planned dose levels: 3 x 10^5, 1 x 10^6, 3 x 10^6, & 1 x 10^7 & 3 x 10^7 4H11-28z/fIL-12/EGFRt+ T cells/kg. Cohort I-IV & VI 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 MTD isn't 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. Pts in Cohort V received cyclophosphamide chemotherapy on Day 1 or cyclophosphamide concurrent with fludarabine on Day 1-3, followed 2 to 4 days later by T cell infusion. This cohort is closed to further accrual.
Interventions:
  • 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 13, 2015)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2020
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pathologically confirmed diagnosis of high-grade serous ovarian, primary peritoneal, or fallopian tube carcinoma
  • Presence of measurable recurrence, with RECIST measurable disease at the time of intervention consent
  • Patient's carcinoma must express the MUC16ecto antigen detectable by IHC analysis of banked (paraffin embedded) or freshly biopsied tumor
  • IHC evidence of MUC16ecto expression will be performed according to the technique and 0-5 scoring system described by Dharma et al (63)
  • Only MUC16ecto tumors with moderate to strong immunoreactive scores (3-5) will be considered positive
  • Patients must have had one prior platinum-based chemotherapeutic regimen for management of ovarian, primary peritoneal, or fallopian tube carcinoma and at least two prior chemotherapy regimens.
  • Patients are allowed to receive, but are not required to receive, up to 5 additional prior chemotherapy treatment regimens (including platinum-based chemotherapy). Prior hormonal therapy is allowed, does not count towards this prior regimen requirement, and must be discontinued at least one week prior to T cell infusion. Continuation of hormone replacement therapy is permitted
  • Patients are allowed to receive, but are not required to receive, biologic/targeted therapy as part of their primary treatment regimen. Patients are allowed to receive, but are not required to receive, up to 5 biologic/targeted therapies as part of their treatment regimen for recurrent disease (either alone or in combination with chemotherapy)
  • Karnofsky Performance Status score of 70% or greater
  • Life expectancy of at least 3 months
  • Adequate bone marrow, renal, and hepatic function:
  • Absolute neutrophil count (ANC) ≥ 1500/mm³
  • Platelets ≥ 100,000/mm³
  • Creatinine ≤ 1.5mg/dL or creatinine clearance > 60ml/min
  • ALT, AST, and total bilirubin all < 2.5 x the institutional upper limit of normal (ULN)
  • Adequate pulmonary and cardiac function: No clinical evidence of cardiopulmonary disease, which, in the opinion of the investigator, precludes enrollment
  • Age ≥18 years
  • No anti-cancer therapy (chemotherapy, biologic therapy, or immunotherapy) in the 3 weeks prior to the T cell infusion (and all hematologic effects have resolved). No prior immunotherapy with checkpoint blockade (i.e. PD1 inhibitor, PDL1 inhibitor or CTL4-antagonist or similar agent) in the 6 months prior to the T cell infusion (and all clinically significant related side-effects related must be resolved).

Exclusion Criteria:

  • Known active hepatitis B infection, known history of hepatitis C or HIV infection
  • Clinical or radiographic evidence of bowel obstruction, or need for parenteral hydration and/or nutrition
  • Known or suspected extensive abdominal adhesions.
  • Any of the following cardiac conditions:
  • Clinically significant heart disease (NYHA class III or IV) or symptomatic congestive heart failure
  • Myocardial infarction ≤6 months prior to enrollment
  • History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
  • History of severe non-ischemic cardiomyopathy with ejection fraction ≤20%
  • Active autoimmune disease (excluding autoimmune thyroid disease on a stable thyroid regimen). Such conditions include but are not limited to systemic lupus erythematous, rheumatoid arthritis, ulcerative colitis, Crohn's disease and temporal arteritis.
  • Known or suspected leptomeningeal disease; patients with metastases to the brain stem, midbrain, pons or medulla.
  • Known or suspected untreated brain metastases. Patients with Radiographically stable, asymptomatic previously irradiated lesions are eligible provided patient is ≥4weeks beyond completion of cranial irradiation and ≥ 3 weeks off of corticosteroid therapy at the time of study intervention.
  • Prior history of seizure disorder
  • Any concurrent active malignancies, defined as malignancies requiring any therapy other than expectant observation, since adverse events resulting from these malignancies or their treatment may confound our assessment of the safety of adoptive T cell therapy for ovarian cancer.
  • Prior radiotherapy to any portion of the abdominal cavity or pelvis
  • Current pregnancy or lactation
  • Any of the following within 28 days of first date of study treatment:
  • Serious uncontrolled medical illness or disorder that in the opinion of the treating physician would make the patient ineligible for the study
  • Active uncontrolled infection (with the exception of uncomplicated urinary tract infection)
  • Abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
  • Abdominal surgery (for reasons other than IP port placement)
  • Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Roisin O'Cearbhaill, MD 646-888-4227
Contact: Jae Park, MD 212-639-4048
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02498912
Other Study ID Numbers  ICMJE 15-014
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE
  • Stanford University
  • Juno Therapeutics, Inc.
Investigators  ICMJE
Principal Investigator: Roisin O'Cearbhaill, MD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP