Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma
- Conditions
- LymphomaLymphoma, B-CellImmune System DiseasesImmunoproliferative DisordersLymphatic Diseases
- Interventions
- Registration Number
- NCT03696784
- Lead Sponsor
- UNC Lineberger Comprehensive Cancer Center
- Brief Summary
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 neurotoxicity. 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, primary central nervous system lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
- Detailed Description
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, primary central nervous system lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). 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, rimiducid (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 Immune effector cell-associated neurotoxicity syndrome ( ICANS) that does not improve to grade ≤1 within 72 hours with standard of care interventions, and subjects with grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus. After the tolerable cell dose (TCD) of iC9-CAR19 T cells has been determined, up to 18 additional adult subjects may be enrolled in an expansion cohort at the TCD. Rimiducid will be given to subjects in the expansion cohort who develop grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) that does not improve to grade ≤1 within 72 hours with standard of care interventions, and subjects with grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus. Subjects in the expansion cohort who experience ≥grade 2 CRS or ICANS that remains ≥grade 2 twenty-four hours after initial standard of care treatment (tocilizumab for CRS or steroids for ICANS) may be part of the rimiducid sub-study. These subjects will receive one of two assigned dose levels of rimiducid with their second standard of care treatment. The percent reduction in CAR T cells will be measured in these subjects. If the subjects' CRS or ICANS is unresponsive to standard treatment and the assigned dose level of rimiducid, subjects with ≥grade3 CRS or ICANS will then be given a full dose (0.4 mg/kg) of rimiducid. If the subject's CRS or ICANS is at grade 2 48 hours after the first dose of rimiducid, they will receive another dose of rimiducid at the assigned dose level.
Cell Procurement Peripheral blood, up to 300 mL (in up to 3 collections) will be obtained from subjects for cell procurement. In subjects with inadequate lymphocyte count in the peripheral blood, a leukapheresis may be performed to isolate sufficient T cells. The parameters for apheresis will be up to 2 blood volumes.
Lymphodepleting Regimen 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 guidelines. At the discretion of the clinical investigator, subjects with a known history of intolerance to bendamustine may be considered for lymphodepletion with cyclophosphamide 500 mg/m2/day administered by 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.
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. Post lymphodepletion iC9-CAR19 will be administered at dose levels specified in the protocol. A recently published trial in refractory DLBCL established that a dose of 2 x 10 6 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 30
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Expansion Cohort iC9-CAR19 cells iC9-CAR19 T cells After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects). Expansion Cohort iC9-CAR19 cells AP1903 After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects). Single Arm iC9.CAR19 T cells 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 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. 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 immune effector cell-associated neurotoxicity syndrome (ICANS). Single Arm iC9.CAR19 T cells AP1903 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 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. 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 immune effector cell-associated neurotoxicity syndrome (ICANS). Single Arm iC9.CAR19 T cells Fludarabine 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 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. 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 immune effector cell-associated neurotoxicity syndrome (ICANS). Single Arm iC9.CAR19 T cells Bendamustine 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 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. 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 immune effector cell-associated neurotoxicity syndrome (ICANS). Single Arm iC9.CAR19 T cells Cyclophosphamide 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 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. 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 immune effector cell-associated neurotoxicity syndrome (ICANS). Expansion Cohort iC9-CAR19 cells Bendamustine After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects). Expansion Cohort iC9-CAR19 cells Fludarabine After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects). Expansion Cohort iC9-CAR19 cells Cyclophosphamide After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects).
- Primary Outcome Measures
Name Time Method Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells 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. ICANS symptoms will be graded per ASBMT ICANS Consensus Grading for Adults (scale from 1-mild to 4-critical) and cytokine release syndrome (CRS) symptoms will be graded according to ASBMT CRS Consensus Grading (a scale from 1-mild to 5-death).
- Secondary Outcome Measures
Name Time Method Duration of response (DOR) in subjects with relapsed or refractory B-cell lymphoma or CLL/SLL who experience an objective response following infusion of iC9-CAR19 T cells 15 years DOR is defined for subjects who experience an objective response as the date of first objective response to the date of disease progression (per the Lugano criteria, Response Criteria for Primary CNS Lymphoma Response Criteria for WM or IWCLL Revised Criteria for Response Assessment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma) 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.
Identify a recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in subjects with relapsed or refractory B-cell lymphoma or CLL/SLL 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, CRS grading criteria, and ICANS grading criteria.
Survival of iC9-CAR19 T cells in vivo 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) (rate of Complete Response (CR)) mediated by autologous iC9-CAR19 T cells administered to subjects with relapsed or refractory B-cell lymphoma or CLL/SLL 15 years ORR:
* Revised Lugano criteria CR= no new lesions; normal bone marrow (BM); Target nodes/masses ≤ 1.5 cm; no extra lymphatic sites; and/or PET-CT score of 1-3.
* For Primary CNS Lymphoma CR= No contrast enhancement on brain imaging; no corticosteroid dose; normal eye exam; negative cerebrospinal fluid (CSF) cytology.
* For Waldenström Macroglobulinemia (WM) CR= normal Immunoglobulin M (IgM)); no monoclonal protein by immunofixation; no histological evidence of BM involvement; resolution of any adenopathy/organomegaly; no signs or symptoms of WM.
* International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Revised Criteria Assessment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) CR=Target nodes/nodal masses ≤ 1.5 cm; normal lymphocyte count; platelets \> 100E9/L; Hemoglobin \> 11.0 g/dL; ANC \> 1.5E9/L; no evidence for typical CLL lymphocytes and without nodular lymphoid aggregates on BM biopsy; no constitutional symptoms from CLL/SLL; no hepatosplenomegalyOverall survival (OS) in subjects with relapsed or refractory B-cell lymphoma or CLL/SLL following infusion of iC9-CAR19 T cells 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.
Change in health related quality of life 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.
Progression free survival (PFS) in subjects with relapsed or refractory B-cell lymphoma or CLL/SLL following infusion of iC9-CAR19 T cells 15 years PFS is day of infusion to date of disease progression (PD) or death due to any cause.
* Lugano criteria PD= PET-CT score 4 or 5 with increase in intensity of uptake from baseline and/or New FDG-avid foci consistent with lymphoma
* Response Criteria for Primary CNS Lymphoma PD=25% increase in lesion or new site of disease on brain imaging; recurrent/new ocular disease; recurrent/positive CSF cytology
* Response Criteria for WM PD= ≥ 25% increase in serum IgM or progression of clinically significant findings due to disease; or symptoms attributable to WM
* IWCLL Revised Criteria for Response Assessment of CLL/SLL PD= New enlarged lymph node \> 1.5 cm; new hepato- and/or splenomegaly or organ infiltration; 50% increase from baseline of previous site; 50% increase from baseline of circulating lymphocyte count or CLL cells on marrow biopsy; 50% decrease in platelet count from baseline prior to therapy; Or \> 2 gm g/dL decrease in hemoglobin from baselineChange in patient-reported symptoms 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 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.
Trial Locations
- Locations (1)
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States