Infusion of Autologous T Cells Engineered to Target FSH Receptor in Recurrent Ovarian Cancer

Study Overview
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Brief Summary
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The purpose of this first in human study is to evaluate the safety of treatment with autologous T cells genetically modified to express a CER (chimeric endocrine receptor) targeting the FSHR (follicle-stimulating hormone receptor) (FSHCER T cells), with or without conditioning chemotherapy, in participants with recurrent or persistent ovarian, fallopian tube, or primary peritoneal cancer.

Official Title
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A Phase I Clinical Trial of an Infusion of Autologous T Cells Genetically Engineered With a Chimeric Receptor to Target the Follicle-Stimulating Hormone Receptor in Patients With Recurrent Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Follicle Stimulating Hormone Receptor T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed diagnosis of high-grade (grade 2-3) epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube carcinoma (EOC), which are serous, endometrioid, clear cell, mucinous, mixed epithelial, or undifferentiated. The study does not include pure sarcoma, stromal, or germ-cell tumors. Tumors that are substantially high-grade carcinoma and have focal elements of lower grade tumors or sarcomatous elements (e.g., carcinosarcoma) are eligible. Have measurable disease or detectable (non-measurable) disease. Measurable disease is defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be ≥10 mm when measured by CT, MRI, or caliper measurement at clinical examination or ≥20 mm when measured by chest x-ray. Lymph nodes must be ≥15 mm in short axis when measured by CT or MRI. Detectable (non-measurable) disease is defined as not having measurable disease but having: Baseline values of CA-125 at least 2 × upper limit of normal AND EITHER Ascites and/or pleural effusion attributed to tumor OR Solid and/or cystic abnormalities on radiographic imaging consistent with recurrent disease that do not meet response evaluation criteria in solid tumors (RECIST) version 1.1 definitions for target lesions. Patient's carcinoma should express the FSHR antigen, detectable by PCR analysis of archival tumor sample Patients must have had 1 prior platinum-based chemotherapeutic regimen for the management of ovarian, primary peritoneal, or fallopian tube carcinoma and at least 2 prior chemotherapy regimens. Patients should be considered platinum- refractory (progression while on a prior platinum chemotherapy) or resistant (persistence or recurrence within 6 months after a prior platinum chemotherapy) and be deemed unlikely to have significant benefit from any standard therapies by the treating investigator. Patients with a known germline or somatic BRCA pathogenic mutation should have a prior PARP inhibitor and subsequent progression, unless they have a documented history of intolerance or inability to swallow oral medications Patients are allowed to receive, but are not required to receive, up to 6 additional prior chemotherapy treatment regimens (including platinum-based chemotherapy). Prior maintenance therapy with an agent when there has not been progression will not be a separate treatment regimen. Prior hormonal therapy is allowed, and when used alone, even as a therapeutic agent, it does not count toward this prior regimen requirement. Hormonal therapy must be discontinued at least 1 week before T-cell infusion. Continuation of hormone replacement therapy is permitted Patients are allowed to receive, but are not required to receive, biologic/targeted therapy alone or as part of their treatment regimens. When used as treatment after progression, these treatments will count as a separate therapy. ECOG status of 2 or better (or Karnofsky Performance Status score of ≥60%) Life expectancy of at least 3 months. Adequate bone marrow, renal, and hepatic function. No anticancer therapy (chemotherapy, biologic therapy, or immunotherapy) in the 3 weeks before the T-cell infusion (and all hematologic effects have resolved). No prior immunotherapy with checkpoint blockade (e.g., PD1 inhibitor, PDL1 inhibitor, or CTL4- antagonist or similar agent) in the 6 months before the T-cell infusion (and all clinically significant related side effects must be resolved). Patient agrees to undergo placement of either interventional radiologically placed or surgically placed peritoneal port (may be temporary or subcutaneous). Although it is anticipated that patients who are eligible for this study will not have childbearing potential, any patient the treating doctor or investigator deems to have childbearing potential must agree to an acceptable means of contraception from the time of screening to at least 6 months after T-cell infusion. 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 that would preclude port placement or infusion. Any of the following cardiac conditions: Clinically significant heart disease (New York Heart Association class 3 or 4) or symptomatic congestive heart failure. Myocardial infarction <6 months before enrollment. History of clinically significant ventricular arrhythmia or unexplained syncope that is not believed to be vasovagal in nature or due to dehydration. History of severe non-ischemic cardiomyopathy with ejection fraction <20%. Findings on baseline ECG or ECHO that, in the opinion of the patient's treating physician or investigator, would require medical intervention before anticancer therapy 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 and 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 >4 weeks beyond completion of cranial irradiation and >3 weeks off of corticosteroid therapy at the time of study intervention. Prior history of clinically significant seizure disorder (e.g., not including childhood febrile seizures). Any concurrent active malignancies, defined as malignancies requiring any therapy other than expectant observation, because adverse events (AEs) 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 lactation or pregnancy 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 intraabdominal abscess. Abdominal surgery (for reasons other than IP port placement). Any other issue which, in the opinion of the treating physician or principal investigator, would make the patient ineligible for the study.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intraperitoneal treatment- Dose Level 1<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 1 x 10^5. Intraperitoneal: Infusion will be administered through a thin membrane of the abdominal cavity. | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intravenous treatment - Dose Level 1<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 1 x 10^5 by Intravenous (IV). | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intraperitoneal treatment- Dose Level 2<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 3 x 10^5. Intraperitoneal: Infusion will be administered through a thin membrane of the abdominal cavity. | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intravenous treatment - Dose Level 2<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 3 x 10^5 by Intravenous (IV). | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intraperitoneal treatment- Dose Level 3<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 1 x 10^6. Intraperitoneal: Infusion will be administered through a thin membrane of the abdominal cavity. | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intravenous treatment - Dose Level 3<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 1 x 10^6 by Intravenous (IV). | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intraperitoneal treatment- Dose Level 4<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 3 x 10^6. Intraperitoneal: Infusion will be administered through a thin membrane of the abdominal cavity. | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intravenous treatment - Dose Level 4<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 3 x 10^6 by Intravenous (IV). | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intraperitoneal treatment- Dose Level 5<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 1 x 10^7. Intraperitoneal: Infusion will be administered through a thin membrane of the abdominal cavity. | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|
| Experimental: Intravenous treatment - Dose Level 5<br>Participants will receive one infusion of Follicle-Stimulating Hormone Receptor T (FSHCER T) cells at a dose of 1 x 10^7 by Intravenous (IV). | Drug: Follicle Stimulating Hormone Receptor T Cells<br>* Participants will receive an infusion of autologous t cells genetically modified ex vivo to express the FSHR-specific 4-1BB/CD3ζ CER.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of FSHCER T Cells | Participants will receive escalating doses of FSHCER T Cells to determine the Maximum Tolerated Dose (MTD). MTD is defined as the the highest dose of t cells that does not cause unacceptable side effects. | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | The duration of response is measured from the time measurement criteria are met for immune complete response or immune partial response (whichever is first recorded) until the first date that progressive disease (immune related progressive disease -irPD) is objectively documented (taking as reference for PD the smallest measurements recorded [nadir] since the treatment started). | Up to 15 years | 
| Duration of Stable Disease | Stable Disease is measured from the start of the treatment until the criteria for confirmed progressive disease are met. | Up to 15 years | 
| Overall Survival | Overall survival defined as the time from initial date of treatment to date of death. | Up to 15 years |