Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03696784|
Recruitment Status : Recruiting
First Posted : October 5, 2018
Last Update Posted : April 22, 2019
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 subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome and neurotoxocity. In this study, to help reduce cytokine release syndrome and/or neurotoxicity 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 and or neurotoxicity 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 and/or neurotoxicity. 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 and/or neurotoxicity, but still allows the remaining iC9-CAR19 cells to effectively fight the lymphoma.
The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable in patients with relapsed/refractory B-cell lymphoma.
|Condition or disease||Intervention/treatment||Phase|
|Lymphoma Lymphoma, B-Cell Immune System Diseases Immunoproliferative Disorders Lymphatic Diseases||Biological: iC9-CAR19 T cells Drug: Bendamustine Drug: Fludarabine Drug: AP1903||Phase 1|
This study is a phase I dose finding trial to determine if chimeric antigen receptor T (CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9 safety switch can be safely administered to adult subjects with relapsed or refractory B-cell Lymphoma. The safety of iC9-CAR19 cells will be investigated using the 3+3 design. The starting dose of 1 x 106 transduced cells/kg (dose level 1) will enroll at least 3 subjects in the initial cohort. If there are no dose limiting toxicities (DLTs) within 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 2 x 106 transduced cells/kg. If there is toxicity in 1/3 subjects in the initial cohort, the cohort will be expanded to enroll up to 6 subjects. During iC9-CAR19 T cell dose exploration, AP1903 (0.4 mg/kg), a dimerizing agent that is designed to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop grade 4 cytokine release syndrome (CRS) or grade ≥3 CRS that is unresponsive to standard of care interventions, and to subjects who develop grade ≥3 CAR-T-cell-related encephalopathy syndrome (CRES) or grade 2 CRES that does not improve to grade ≤1 within 72 hours with standard of care interventions.
Peripheral blood, up to 300 mL (in up to 3 collections) will be obtained from subjects for cell procurement. In subjects with low T-cell count (CD3 count as assayed by flow cytometry less than 200/μL) in the peripheral blood, a leukopheresis may be performed to isolate sufficient T cells. The parameters for pheresis will be up to 2 blood volumes
Subjects will receive a "pre-conditioning" cytoreductive regimen of bendamustine 70 mg/m2/day administered IV followed by an IV dose of fludarabine 30 mg/m2/day administered over 3 consecutive days. These agents will be administered per institutional guidelines. Prophylaxis (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine chemotherapy will be provided per institutional guideline
Administration of iC9-CAR19 T cells
Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9-CAR19 T cells within 2 - 14 days after completing the lymphodepleting chemotherapy regimen. We will administer iC9-CAR19 post lymphodepletion at dose levels specified in the table in section 4.1. A recently published trial in refractory DLBCL established that a dose of 2 x 106 CAR19+ T cells/kg was safe and associated with significant in vivo expansion and we anticipate similar results with iC9-CAR19+ T cells.
Duration of Therapy
Therapy in this study involves 1 infusion of iC9-CAR19 cells.
Duration of Follow-up
Subjects who receive a cell infusion will be followed for up to 15 years for replication-competent retrovirus evaluation or until death, whichever occurs first. Subjects who are removed from study and do not receive the cellular therapy product due to unacceptable adverse events will be followed until resolution or stabilization of the adverse event.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Study of Autologous Activated T-cells Targeting the CD19 Antigen and Containing the Inducible Caspase 9 Safety Switch in Subjects With Relapsed/Refractory B-cell Lymphoma|
|Actual Study Start Date :||March 12, 2019|
|Estimated Primary Completion Date :||October 30, 2019|
|Estimated Study Completion Date :||October 30, 2033|
Experimental: Single Arm iC9.CAR19 T cells
The safety of iC9-CAR19 cells will be investigated using the 3+3 design. Dose level (DL) Dose (#transduced cells/kg)
-1 1 x 10^5
Lymphodepleting chemotherapy of IV bendamustine 70 mg/m2 and IV fludarabine 30 mg/m2/day for 3 consecutive days will be given within 2-14 days prior to cell infusion.
AP1903 (0.4 mg/kg), a dimerizing agent to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop severe cytokine release syndrome (CRS) or CAR-T-cell-related encephalopathy syndrome (CRES) according to the protocol.
Biological: iC9-CAR19 T cells
iC9-CAR19 T cells will be given by a licensed healthcare provider via intravenous injection over 5-10 minutes through either a peripheral or a central line.
70mg/m2 IV given as a daily infusion for 3 days per institutional guidelines 2 - 14 days prior to the T cell infusion.
30 mg/m2 given as a daily infusion for 3 days per institutional guidelines 2 - 14 days prior to the T cell infusion
Other Name: Fludara
Subjects who develop Grade 4 CRS or grade ≥3 CRS that is unresponsive to standard of care interventions (i.e., does not resolve to grade 0 - 1 within 24 hours after 2 doses of tocilizumab, with sum of doses ≥12mg/kg) and subjects who develop grade ≥3 CRES or grade 2 CRES that does not improve to grade ≤1 within 72 hours with standard of care interventions will receive 0.4 mg/kg of AP1903 as an IV infusion over 2 hrs.
Other Name: Rimiducid
- 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 a recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in subjects with relapsed or refractory B-cell lymphoma [ 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, Cytokine release syndrome (CRS) grading criteria, and CAR‑T‑cell-related encephalopathy syndrome (CRES) per CAR-T-cell therapy-associated toxicity (CARTOX-10). In the CARTOX-10, one point is assigned for each of the following tasks that is performed correctly (normal cognitive function is defined by an overall score of 10): orientation to year, month, city, hospital, and President/Prime Minister of country of residence (total of 5 points); name three objects — for example, point to clock, pen, button (maximum of 3 points); write a standard sentence, for example, 'our national bird is the bald eagle' (1 point); count backwards from 100 in tens (1 point).
- Survival of iC9-CAR19 T cells in vivo [ 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.
- Overall response rate (ORR) mediated by autologous iC9-CAR19 T cells administered to subjects with relapsed or refractory B-cell lymphoma. [ Time Frame: 15 years ]ORR (Complete Response (CR)) to iC9-CAR19 T cell therapy will be determined using the revised Lugano criteria. CR= no new lesions; normal bone marrow; Target nodes/nodal masses must regress to ≤ 1.5 cm in LDi; no extralymphatic sites of disease; and/or a PET-CT score of 1, 2, or 3* with or without a residual mass.
- Overall survival (OS) in subjects with relapsed or refractory B-cell lymphoma following infusion of iC9-CAR19 T cells. [ Time Frame: 15 years ]OS will be measured from the date of administration of iC9-CAR19 T cells to the date of death. Subjects who have not died by the analysis data cut-off date will be censored at their last date of contact.
- Progression free survival (PFS) in subjects with relapsed or refractory B-cell lymphoma following infusion of iC9-CAR19 T cells [ Time Frame: 15 years ]
PFS is defined from day of iC9-CAR19 T cell infusion to the date of disease progression per the Lugano criteria or death as a result of any cause. Subjects who do not meet criteria for progression by the analysis data cut-off date will be censored at their last evaluable disease assessment date.
Progression is defined as PET-CT score 4 or 5 with an increase in intensity of uptake from baseline and/or New FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment; An individual node/lesion must be abnormal with:
Longest diameter (LDi) > 1.5 centimeter (cm) and Increase by ≥ 50% from nadir and an increase in LDi or Shortest Diameter from nadir 0.5 cm for lesions ≤ 2 cm 1.0 cm for lesions > 2 cm
- Duration of response (DOR) in subjects with relapsed or refractory B-cell lymphoma who experience an objective response following infusion of iC9-CAR19 T cells. [ Time Frame: 15 years ]DOR is defined for subjects who experience an objective response as the date of first objective response to disease progression per the Lugano criteria, or death as a result of any cause. Subjects who do not meet criteria for progression or death by the analysis cut-off date will be censored at their last evaluable disease assessment date.
- Change in patient-reported symptoms [ Time Frame: 1 year ]Patient reported symptoms will be measured using selected symptoms from the NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE). The PRO-CTCAE is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of symptomatic treatment toxicities. Each of the symptom terms included in the PRO-CTCAE is assessed relative to one or more distinct attributes, including presence/absence, frequency, severity, and/or interference with usual or daily activities. Responses are provided on a 5-point Likert scale: Frequency item: How OFTEN did you have? (Never / Rarely / Occasionally / Frequently / Almost constantly); Severity item: What was the SEVERITY of your at its WORST? (None / Mild / Moderate / Severe / Very severe);Interference item: How much did INTERFERE with your usual or daily activities? (Not at all / A little bit / Somewhat / Quite a bit / Very much)
- Change in physical function [ Time Frame: 1 year ]The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a v1.0. assesses one's ability to carry out activities that require physical actions, ranging from self-care (activities of daily living) to more complex activities that require a combination of skills, often within a social context. "Physical Function" is inclusive of the term "disability" and includes the full spectrum of physical functioning from severe impairment to exceptional physical abilities. Each question has five response options ranging in value from one to five, resulting in a total score (T-score) from 0 to 100. A higher PROMIS T-score represents more of the concept being measured. For positively-worded concepts like Physical Function, a T-score of 60 is one SD better than average. By comparison, a Physical Function T-score of 40 is one SD worse than average.
- Change in health related quality of life [ Time Frame: 1 year ]The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health measures assess an individual's physical, mental, and social health. The measures are generic, rather than disease-specific, and often use an "In General" item context as it is intended to globally reflect individuals' assessment of their health. Each question has five response options ranging in value from one to five, which are summed into T-score values for physical and mental health. A higher PROMIS T-score represents more of the concept being measured. Thus, a person who has T- scores of 60 for the Global Physical Health or Global Mental Health scales is one standard deviation better (more healthy) than the general population.
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): NCT03696784
|Contact: Catherine Chengemail@example.com|
|Contact: Spencer Laingfirstname.lastname@example.org|
|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 email@example.com|
|Contact: Spencer Laing 919-962-8618 firstname.lastname@example.org|
|Principal Investigator: Grover Natalie, MD|
|Principal Investigator:||Natalie Grover, MD||UNC Lineberger Comprehensive Cancer Center|