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

NCT02498912 | Active Not Recruiting Phase 1

• 1 other identifier: 15-014
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Solid Tumors

Keywords

T Cells; Cyclophosphamide; MUC16ecto antigen; Intraperitoneal Infusion; Maximum Tolerated Dose (MTD); 15-014

Outcome Measures

Primary Outcomes (1)

• maximum tolerated dose (MTD)

  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.

  2 years

Secondary Outcomes (1)

• evidence of anti-tumor activity

  2 years

Study Arms (1)

Cyclophosphamide followed by Autologous T Cells

EXPERIMENTAL

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.

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

Interventions

Production of Genetically-modified T cells PROCEDURE

Cyclophosphamide followed by Autologous T Cells

Cyclophosphamide DRUG

Cyclophosphamide followed by Autologous T Cells

IP Catheter Insertion DEVICE

Cyclophosphamide followed by Autologous T Cells

Infusion of 4H11-28z/fIL-12/EGFRt+ Genetically-modified T cells GENETIC

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.

Cyclophosphamide followed by Autologous T Cells

Fludarabine DRUG

fludarabine dose 25-30 mg/m2 x 3 days

Cyclophosphamide followed by Autologous T Cells

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Stanford University: collaborator
• Juno Therapeutics, Inc., a Bristol-Myers Squibb Company: collaborator

Study Sites (1)

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Interventions

Cyclophosphamide; fludarabine

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Roisin O'Cearbhaill, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a standard phase I dose escalation trial.

Study Record Dates

• First Submitted: July 10, 2015
• First Posted: July 15, 2015
• Study Start: August 1, 2015
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: July 31, 2025

Record last verified: 2025-07

Locations

US (1)