CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer

Study Overview
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Brief Summary
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Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with metastatic cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patients white blood cells with a retrovirus that has the gene for anti-mesothelin incorporated in the retrovirus. Objective: The purpose of this study is to determine a safe number of these cells to infuse and to see if these tumor fighting cells (anti-mesothelin cells) cause metastatic cancer tumors to shrink. Eligibility: - Adults age 18-70 with metastatic cancer expressing the mesothelin molecule. Design: Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-mesothelin cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-mesothelin cells, and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

Detailed Description
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Background: We have constructed a single retroviral vector that contains a chimeric T cell receptor (CAR) that recognizes mesothelin, which can be used to mediate genetic transfer of this CAR with high efficiency (> 50%) without the need to perform any selection. In co-cultures with mesothelin expressing cells, anti-mesothelin transduced T cells secreted significant amounts of interferon (IFN)-gamma with high specificity. Objectives: Primary Objectives: To evaluate the safety of the administration of anti-mesothelin CAR engineered peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning regimen, and aldesleukin. Determine if the administration anti-mesothelin CAR engineered peripheral blood lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer. Eligibility: Patients who are 18 years of age or older must have Metastatic or unresectable cancer that expresses mesothelin; Previously received and have been a non-responder to or recurred after standard care; Patients may not have: -Contraindications for low dose aldesleukin administration. Design: Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured in order to stimulate T-cell growth. Transduction is initiated by exposure of approximately 10^8 to 5 X 10^8 cells to retroviral vector supernatant containing the anti-mesothelin CAR. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo CAR gene-transduced PBMC plus low dose intravenous (IV) aldesleukin Patients will undergo complete evaluation of tumor with physical examination, Computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has stable disease (SD) or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will continue to be followed with this evaluation every 3-4 months until off study criteria are met. The study will be conducted using a Phase I/II optimal design. The protocol will proceed in a phase 1 dose escalation design. Once the maximum tolerated dose (MTD) has been determined, the study then would proceed to the phase II portion. Patients will be entered into two cohorts based on histology: cohort 1 will include patients with mesothelioma, and cohort 2 will include patients with other types of cancer that express mesothelin. For each of the 2 strata evaluated, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.

Official Title
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Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-mesothelin Gene Engineered Lymphocytes

Conditions
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Cervical Cancer, Pancreatic Cancer, Ovarian Cancer, Mesothelioma, Lung Cancer

Intervention / Treatment
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* Drug: Fludarabine
* Biological: Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL)
* Drug: Cyclophosphamide
* Drug: Aldesleukin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Metastatic or unresectable measurable cancers that express mesothelin. As in other protocols conducted by Dr. Hassan in the National Cancer Institute (NCI), epithelial mesotheliomas and pancreatic cancers do not need to be assessed for mesothelin expression since all of these tumors have been shown to express mesothelin. Other metastatic or unresectable cancers must be shown to expresses mesothelin as assessed by reverse transcription polymerase chain reaction (RT-PCR) or immunohistochemistry on tumor tissue. Bi-phasic mesotheliomas must express mesothelin on greater than 50% of the cells in the epithelial component. Diagnosis will be confirmed by the Laboratory of Pathology, NCI. Patients must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic or unresectable disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred. Greater than or equal to 18 years of age and less than or equal to 70 years of age. Willing to sign a durable power of attorney Able to understand and sign the Informed Consent Document Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment. Serology: Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.) Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be Hepatitis C virus ribonucleic acid (HCV RNA) negative. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Hematology: Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim. White blood cell (WBC) (> 3000/mm(3)). Platelet count greater than 100,000/mm(3). Hemoglobin greater than 8.0 g/dl. Chemistry: Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) less or equal to 2.5 times the upper limit of normal. Serum creatinine less than or equal to 1.6 mg/dl. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patient's toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo). Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less. Subject's must be co-enrolled in protocol 03-C-0277. EXCLUSION CRITERIA: Patients with sarcomatoid mesothelioma as mesothelin is not expressed in this type of mesothelioma. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Patients with known brain metastases. Patients receiving full dose anticoagulative therapy. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other major medical illnesses. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). Patients with diabetic retinopathy. Concurrent Systemic steroid therapy. History of severe immediate hypersensitivity reaction to any of the agents used in this study. History of coronary revascularization or ischemic symptoms. Documented left ventricular ejection fraction (LVEF) of less than or equal to 45% tested in patients with: Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block, chest pain, or ischemic heart disease Age greater than or equal to 65 years old Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with: A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years). Symptoms of respiratory dysfunction Patients who are receiving any other investigational agents.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Phase I<br>Non-myeloablative but lymphodepleting preparative regimen of cyclophosphamide and fludarabine plus anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) plus low dose aldesleukin. | Drug: Fludarabine<br>* Days -5 to Day -1: Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.<br>* Other names: Fludara;Biological: Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL)<br>* Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20 to 30 minutes.<br>Drug: Cyclophosphamide<br>* Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml 5% dextrose in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.<br>* Other names: Cytoxan;Drug: Aldesleukin<br>* Aldesleukin 72,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).<br>* Other names: Proleukin;|
| Experimental: 2/Phase II<br>Non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine + anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) + low-dose aldesleukin | Drug: Fludarabine<br>* Days -5 to Day -1: Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.<br>* Other names: Fludara;Biological: Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL)<br>* Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20 to 30 minutes.<br>Drug: Cyclophosphamide<br>* Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml 5% dextrose in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.<br>* Other names: Cytoxan;Drug: Aldesleukin<br>* Aldesleukin 72,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).<br>* Other names: Proleukin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Objective Tumor Regression | Objective tumor regression response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.0. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum LD. Progressive Disease (PD) is at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | 3.5 mos. | 
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 6 months and 17 days for Group A01, 16 months and 13 days for Group A02, 13 months and 3 days for Group A03, 10 months and 16 days for Group A04, and 11 months and 26 days for Group A05. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene Therapy, Mesothelioma, Pancreatic Cancer, Metastatic Cancer, Immunotherapy