Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL
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|ClinicalTrials.gov Identifier: NCT03016377|
Recruitment Status : Active, not recruiting
First Posted : January 10, 2017
Last Update Posted : December 20, 2019
The body has different ways of fighting infection and disease. No single way is effective at fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to try to create a more effective treatment. This investigational treatment is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration.
In previous studies, it has been shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying your genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells makes a piece of an antibody called anti-CD19. This antibody can flow through the blood and can find and stick to leukemia cells because these leukemia cells have a substance on their surface called CD19. Anti-CD19 antibodies have been used to treat people with leukemia but have not been strong enough to cure most patients. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood a piece of it is now joined to the surface of the T cells. Only the part of the antibody that sticks to the leukemia cells is attached to the T cells instead of the entire antibody. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown.
Preliminary results of giving ATLCAR.CD19 cells to leukemia patients have been encouraging; however, many subjects receiving this treatment have experienced unwanted side effects including neurotoxicity and/or cytokine release syndrome (also referred to as cytokine storm or an infusion reaction). Cytokines are small proteins that aract as e signals to other cells and are the way cells talk to one another. During cytokine release syndromesyndrome, too many cytokines are released and too many cells in your body react to their release. Symptoms resulting from cytokine release syndrome vary from flu-like symptoms to more severe side effects such as cardiac arrest, multi-system organ failure or death. We predict that about 50% of patients on this study will experience mild to severe cytokine release syndrome.
To help reduce cytokine release syndrome symptoms in future patients, a safety switch has been added to the ATLCAR.CD19 cells that can cause the cells to become dormant or "go to sleep". The safety switch is called inducible caspase 9 or iC9. The modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells.
The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and tolerable (there are not too many unwanted effects). If you experience severe cytokine release syndrome or moderate to severe cytokine release syndrome that does not get better once you are given standard treatments, you may be given a second study drug called rimiducid. Similar studies showed that rimiducid can to turn on the safety switch, iC9 in other therapies. Using rimiducid to activate the safety switch may be done in addition to treating you according to hospital guidelines and making all efforts to immediately attend to your cytokine release syndrome symptoms
|Condition or disease||Intervention/treatment||Phase|
|Acute Lymphoblastic Leukemia Immune System Diseases Immunoproliferative Disorders||Biological: iC9-CAR19 cells Drug: Rimiducid Drug: Cyclophosphamide Drug: Fludarabine||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Administration of Autologous CAR-T Cells Targeting the CD19 Antigen and Containing the Inducible caspase9 Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia|
|Actual Study Start Date :||March 22, 2018|
|Estimated Primary Completion Date :||November 2021|
|Estimated Study Completion Date :||October 2036|
Experimental: iC9-CAR19 cells
The 3+3 design in adult subjects and an independent study using 3+3 design in pediatric subjects. The starting dose of 5 x 10^5 transduced cells/kg will enroll 3 adult subjects in the initial cohort. If there are no dose limiting toxicities w/in 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x10^6 transduced cells/kg in adults. If there is toxicity in 1/3 patients in the initial cohort, the cohort will be expanded to enroll up to 6 adult patients. If the dose level 1 is determined to be above the tolerated cell dose, de-escalation would occur to dose level -1 where subjects would receive 1 x 10^5 transduced cells/kg. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before administration of iC9-CAR19 T cells.
Biological: iC9-CAR19 cells
Three dose levels are being evaluated: dose level -1 (1 x 10^5), dose level 1 (5 x 10^5), and dose level 2 ( 1x 10^6)
Other Name: CAR.CD19 T cells
Subjects who develop grade 4 CRS or grade 2/3 CRS that is unresponsive to standard of care interventions will be given Rimiducid at .4 mg/kg.
Other Name: AP1903
900 mg/m^2 IV over 1 hour on day 4 of lymphodepleting chemotherapy.
Other Name: Neosar
25 mg/m^2/day IV over 30 minutes administered for 3 consecutive days.
Other Name: Fludara
- Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells [ Time Frame: 4 weeks ]Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outline in Section 13.5 Management of Neurotoxicity/Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) for CAR-T Therapy in the protocol and CRS symptoms will be graded according to criteria outlined in Section 13.2 CRS Grading of the protocol.
- Identify recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in adult and pediatric subjects with relapsed or refractory CD19+ ALL. [ Time Frame: 4 weeks ]The recommended phase 2 dose of iC9-CAR19 cells will be determined based on 3+3 dose finding rules and the tolerability of iC9-CAR19 cells assessed by NCI-CTCAE criteria and CRS grading criteria outlined in Section 13.2 Appendix B: CRS Grading Criteria and Management Guideline. ICANS grading criteria outlined in section 13.5 of the protocol.
- Measure the survival of iC9-CAR19 T cells in vivo as assessed by quantitative polymerase chain reaction (PCR) and flow cytometry. [ Time Frame: 15 years ]Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.
- Determine the overall survival after infusion of iC9-CAR19 T cells [ Time Frame: 15 years ]Overall survival will be measured from the date of administration of iC9-CAR19 T cells to the date of death.
- Determine the Overall Response Rate (ORR) (Complete Response/Complete Response with incomplete recovery of counts) mediated by iC9-CAR19 T cell therapy using National Comprehensive Cancer Network Response Criteria (NCCN) for ALL. [ Time Frame: 15 years ]ORR (Complete Response/Complete Response with incomplete recovery of counts) to iC9-CAR19 T cell therapy will be determined using National Comprehensive Cancer Network Response Criteria (NCCN) for acute lymphoblastic leukemia. Assessment of minimal residual disease will be included as criterion of response (ie, the percentage of subjects who achieve CRm [defined as minimal residual disease negative complete response] by either flow cytometry or PCR analysis will be determined)
- Determine the event-free survival rate by measuring from the date of administration of iC9-CAR19 T cells to the date of signs and symptoms of treatment failure, relapse or death. [ Time Frame: 15 years ]Event free survival rate applies to all subjects and will be measured from the date of administration of iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from complete response or complete response with incomplete recovery of counts, or death from any cause; subjects not known to have any of these events are censored on the date they were last examined.
- Determine the relapse-free survival rate by measuring from the date of achievement of a remission until the date of relapse or death from any cause. [ Time Frame: 15 years ]Relapse-free survival rate will apply only to subjects achieving complete response or complete response with incomplete recovery of counts and measured from the date of achievement of a remission until the date of relapse or death from any cause; subjects not known to have relapsed or died at last follow-up are censored on the date they were last examined.
- Measure the patient reported symptoms in adult patients using selected symptoms from the NCI PRO-CTCAE [ Time Frame: 15 years ]The NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of 78 symptomatic treatment toxicities.
- Measure the patient reported physical functions in adult patients using PROMIS Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. [ Time Frame: 15 years ]PROMIS (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health
- Patient reported health-related quality of life in adult patients using the PROMIS Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. [ Time Frame: 15 years ]PROMIS (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03016377
|United States, North Carolina|
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill|
|Chapel Hill, North Carolina, United States, 27599|
|Principal Investigator:||Matthew Foster, MD||Assistant Professor Hematology-Oncology|