Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia
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|ClinicalTrials.gov Identifier: NCT03016377|
Recruitment Status : Recruiting
First Posted : January 10, 2017
Last Update Posted : July 2, 2018
This research study combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to create a more effective treatment. The treatment being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration.
Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. 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 seem to 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 have shown that many subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome. In this study, to help reduce cytokine release syndrome symptoms, the ATLCAR.CD19 cells have a safety switch that when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject experiences moderate to severe cytokine release syndrome as a result of being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be given that reduces the severity of the cytokine release syndrome to mild, but still allows the remaining iC9-CAR19 cells to effectively fight the leukemia.
The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable and and later to determine an optimal dose of AP1903 to be given to subjects to alleviate severe cytokine release syndrome.
|Condition or disease||Intervention/treatment||Phase|
|Acute Lymphoblastic Leukemia Immune System Diseases Immunoproliferative Disorders||Biological: iC9-CAR19 cells Drug: AP1903 Drug: Cyclophosphamide Drug: Fludarabine||Phase 1|
Show Detailed Description
|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 AP1903 at .4 mg/kg.
Other Name: Rimiducid
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). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. CAR-T-cell-related encephalopathy (CRES) symptoms will be graded according to the criteria outline in Section 12.6 CRES Grading in the protocol and CRS symptoms will be graded according to criteria outlined in Section 12.2 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 12.2 Appendix B: CRS Grading Criteria and Management Guideline. CRES grading criteria outlined in section 12.6 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
|Contact: Catherine Cheng||(919) firstname.lastname@example.org|
|Contact: Spencer Laing||(919) email@example.com|
|United States, North Carolina|
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill||Recruiting|
|Chapel Hill, North Carolina, United States, 27599|
|Contact: Catherine Cheng 919-445-4208 firstname.lastname@example.org|
|Contact: Spencer Laing (919) 445-4208 email@example.com|
|Principal Investigator: Matthew Foster, MD|
|Principal Investigator:||Matthew Foster, MD||Assistant Professor Hematology-Oncology|