Adult Patients Who Have Relapsed or Refractory CLL (3rd Line) or SLL
Conditions
Brief summary
This is a randomized, open-label, parallel group study to determine the optimal dose of CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR Zeta and 4-1 BB co-stimulatory domains) of the two dose levels being assessed (1-5x10e8 vs. 1-5x10e7 CART-19 cells). This trial will be conducted in two stages.
Detailed description
This study is being conducted to determine the optimal dose of autologous CART-19 T cells engineered to express anti-CD19 chimeric antigen receptors in patients with relapsed or refractory CD19 positive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The two dose levels being assessed are 1-5x10e8 versus 1-5x10e7. The trial will be conducted in two stages. In stage I subjects will be randomized into one of the two dose cohort with a1:1 ratio for a total of 12 subjects per dose cohort. Stage II will be to enroll an additional 8 subjects to the selected dose cohort once safety, tolerability and clinical responses have been evaluated to determine the optimal dose cohort.
Interventions
BIOLOGICALCART-19
CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented CD19+ CLL or SLL * Successful test expansion of T-cells * At least 2 prior chemotherapy regimens, not including single agent monoclonal antibody (rituxan) therapy. Single agent ofatumumab will be counted as a regimen. -Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior regimen. * Patients who progress within 2 years after the second or higher line of therapy will be eligible. For instance, patients who had progression \< 2 years after second or greater line therapy, but who have responded to their most recent treatment (3rd line or higher) will be eligible. * Subject is not appropriate candidate for a potentially curative allogeneic SCT due to the state of disease, co-morbid illness, lack of an available donor, or patient declines Performance status (ECOG) 0 or 1 * Age \>/= 18 years * Adequate organ system function including: 1. Creatinine \< 1.6 mg/dl 2. ALT/AST \< 3x upper limit of normal 3. Total Bilirubin \<2.0 mg/dl * Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy * Patients with relapsed disease after prior allogeneic SCT (myeloablative or nonmyeloablative) will be eligible if they meet all other inclusion criteria and: 1. Have no active GVHD and require no immunosuppression 2. Are more than 6 months from transplant * No contraindications for leukapheresis * Left Ventricular Ejection fraction \>40% * Gives voluntary informed consent Retreatment Inclusion Criteria * Performance Status 0-1 * Adequate organ system function including: * Creatinine \< 1.6 mg/dl * ALT/AST \< 3x upper limit of normal * Total Bilirubin \< 2.0 mg/dl * Subject is not an appropriate candidate for a potentially curative allogeneic SCT due to the state of disease, co-morbid illness, lack of an available donor, or patient declines. * Left Ventricular Ejection Fraction \> 40% * No contraindications for leukapheresis (if required for retreatment) * Gives voluntary informed consent for retreatment
Exclusion criteria
* Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion. * Uncontrolled active infection * Active hepatitis B or hepatitis C infection * Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled steroids is not exclusionary. For additional details regarding use of steroid and immunosuppressant medications. * Any uncontrolled active medical disorder that would preclude participation as outlined * HIV infection * Patients with active CNS involvement with malignancy. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was \>4 weeks before enrollment. * Class III/IV cardiovascular disability according to the New York Heart Association Classification Retreatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Achieving Complete Response Within 3 Months | 3 months | Complete response (including complete response with incomplete marrow recovery) within 3 months (in evaluable patients). The eveluable set comprise of patients who have received CART19 at intended dose level and completed at least 3-month follow-up after the infusion or discontinued due to disease progression, new cancer therapy or death. |
Countries
United States
Participant flow
Recruitment details
First Patient Enrolled - 02-Jan-2013 Last Patient Completed - 13-Dec-2017
Pre-assignment details
Study was conducted in 2 stages. Stage 1: subjects were randomized into one of the two arms (Arm 1: Higher dose & Arm 2 : Lower dose) Stage 2: the selected dose cohort was expanded to enroll additional subjects. Based on the Stage 1 analysis performed in Nov 2014, Arm 1 was chosen for expansion in Stage 2 and enrolled additional 12 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Target Dose of 1-5x10e8 Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells)
CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)
Note: For baseline measures, subjects from stage 1 (15) and stage 2 (12) are combined to have total 27 subjects. In stage 2, higher dose arm (arm 1) was chosen based on the stage 1 analysis performed to expand and enrolled 12 additional subjects. | 27 |
| Target Dose of 1-5x10e7 Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells)
CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)
Note: In stage 1, 15 subject were enrolled in this arm. Since this arm was not chosen for stage 2, no additional subjects were enrolled. total subjects in this arm were 15. | 15 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Stage 1 | Death | 1 | 1 |
| Stage 1 | Disease progression | 4 | 9 |
| Stage 1 | Physician Decision | 3 | 0 |
| Stage 1 | Withdrawal by Subject | 4 | 3 |
| Stage 2 | Disease Progression | 3 | 0 |
| Stage 2 | New Cancer Therapy | 3 | 0 |
| Stage 2 | Physician Decision | 2 | 0 |
| Stage 2 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Target Dose of 1-5x10e8 | Target Dose of 1-5x10e7 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 3 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 12 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 15 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 15 Participants | 41 Participants |
| Region of Enrollment United States | 27 participants | 15 participants | 42 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 21 Participants | 11 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 27 | 6 / 15 |
| other Total, other adverse events | 24 / 27 | 11 / 15 |
| serious Total, serious adverse events | 23 / 27 | 9 / 15 |
Outcome results
Primary
Number of Patients Achieving Complete Response Within 3 Months
Complete response (including complete response with incomplete marrow recovery) within 3 months (in evaluable patients). The eveluable set comprise of patients who have received CART19 at intended dose level and completed at least 3-month follow-up after the infusion or discontinued due to disease progression, new cancer therapy or death.
Time frame: 3 months
Population: The Evaluable Set comprised all patients who received high dose (1-5×10\^8) or low dose (1-5×10\^7) CTL019 transduced cells as randomized, and completed at least 3-month follow-up after the infusion or discontinued due to disease progression, new cancer therapy or death.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Target Dose of 1-5x10e8 | Number of Patients Achieving Complete Response Within 3 Months | CR with incomplete marrow recovery (CRi) | 5 Participants |
| Target Dose of 1-5x10e8 | Number of Patients Achieving Complete Response Within 3 Months | PR with incomplete marrow recovery (PRi) | 0 Participants |
| Target Dose of 1-5x10e8 | Number of Patients Achieving Complete Response Within 3 Months | Partial Response (PR) | 4 Participants |
| Target Dose of 1-5x10e8 | Number of Patients Achieving Complete Response Within 3 Months | No Response (NR)/ Progressive Disease (PD) | 8 Participants |
| Target Dose of 1-5x10e8 | Number of Patients Achieving Complete Response Within 3 Months | Complete Response (CR) | 1 Participants |
| Target Dose of 1-5x10e7 | Number of Patients Achieving Complete Response Within 3 Months | No Response (NR)/ Progressive Disease (PD) | 9 Participants |
| Target Dose of 1-5x10e7 | Number of Patients Achieving Complete Response Within 3 Months | Complete Response (CR) | 1 Participants |
| Target Dose of 1-5x10e7 | Number of Patients Achieving Complete Response Within 3 Months | CR with incomplete marrow recovery (CRi) | 0 Participants |
| Target Dose of 1-5x10e7 | Number of Patients Achieving Complete Response Within 3 Months | Partial Response (PR) | 2 Participants |
| Target Dose of 1-5x10e7 | Number of Patients Achieving Complete Response Within 3 Months | PR with incomplete marrow recovery (PRi) | 1 Participants |