Treating Cancer With Anti-mesothelin Modified Lymphocytes
- A possible new procedure for treating people with advanced cancer uses blood cells known as peripheral blood cells. Once these cells are modified and grown in a laboratory, they can be used to target and destroy cancer cells. Some cells can be modified to target a protein called mesothelin that is found on some types of cancer cells. By blocking mesothelin, it is expected that these cells will help shrink existing tumors. However, it is possible that the cells will not have this effect. Researchers want to try this therapy on people who have advanced cancer that has not responded to standard treatments.
- To test the safety and effectiveness of anti-mesothelin modified cells for advanced cancer.
- Individuals at greater than or equal to 18 years of age and less than or equal to 66 years of age with advanced cancer that involves mesothelin and has not responded to standard treatments.
- Participants will be screened with a physical exam and medical history. They will also have imaging studies before starting treatment. Blood and urine samples will be collected.
- Participants will have leukapheresis to collect peripheral blood cells. These cells will be modified for the treatment.
- Participants will have chemotherapy to prepare the immune system to receive the modified cells. The chemotherapy will take place for 1 week before the cell infusion.
- Participants will receive their modified cells as an infusion. They will also receive interleukin-2 to help boost their immune system response. The interleukin-2 will be given every 8 hours for up to 15 doses.
- Participants will recover from the infusion treatment in the hospital for at least 2 weeks.
- The results of the treatment will be monitored with frequent follow-up blood tests and imaging studies.
Biological: Anti-mesothelin CAR
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-mesothelin Gene Engineered Lymphocytes|
- Determine a safe dose of administration and determine if this approach will result in an objective tumor regression. [ Time Frame: approximately 6 years ] [ Designated as safety issue: Yes ]
|Study Start Date:||March 2012|
|Estimated Study Completion Date:||December 2019|
|Estimated Primary Completion Date:||March 2019 (Final data collection date for primary outcome measure)|
Experimental: Single Arm
Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of anti-mesothelin CAR engineered PBL plus low dose IV aldesleukin.
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.Biological: Anti-mesothelin CAR
Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of anti-mesothelin CAR engineered PBL. On day 0, cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).Drug: Cycolphosphamide
Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.Drug: Aldesleukin
Aldesleukin (based on total body weight) 72,000 IU/kg IV over a period of 15 minutes approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).
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- 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 IFN-gamma with high specificity.
- 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.
-Determine the in vivo survival of CAR gene-engineered cells.
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.
- PBMC obtained by leukapheresis will be cultured in order to stimulate T-cell growth.
- Transduction is initiated by exposure of approximately 108 to 5 X 108 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 IV aldesleukin
- Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has 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 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01583686
|Contact: June Kryk, R.N.||(301) email@example.com|
|Contact: Steven A Rosenberg, M.D.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center 866-820-4505 email@example.com|
|Principal Investigator:||Steven A Rosenberg, M.D.||National Cancer Institute (NCI)|