CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer
- Conditions
- Pancreatic CancerOvarian CancerLung CancerCervical CancerMesothelioma
- Interventions
- Biological: Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL)
- Registration Number
- NCT01583686
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 15
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/Phase I Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) 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. 1/Phase I Aldesleukin 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. 2/Phase II Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) 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 1/Phase I Fludarabine 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. 1/Phase I Cyclophosphamide 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. 2/Phase II Fludarabine 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 2/Phase II Cyclophosphamide 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 2/Phase II Aldesleukin 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
- Primary Outcome Measures
Name Time Method Number of Patients With Objective Tumor Regression 3.5 mos. 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.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) 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. 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.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States