Acute Lymphoblastic Leukemia
Conditions
Brief summary
This is a phase 2 study to evaluate humanized CD19 redirected autologous T cells (or huCART19 cells) with CD19 expressing relapsed and refractory B-cell acute lymphoblastic leukemia. This study is targeting pediatric and young adult patients aged 3 months - 29 years with CD19+ B cell malignancies in newly diagnosed B-ALL patients predicted to have an exceedingly poor outcome with conventional chemotherapy, in high-risk first relapse, or and in second or greater relapse in this phase 2 trial. In addition, a second cohort will test the efficacy of huCART19 in patients with poor response to prior B cell directed engineered cell therapy.
Interventions
BIOLOGICALhuCART19
IV injection
Sponsors
Children's Hospital of Philadelphia
University of Pennsylvania
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 29 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent form must be obtained. 2. Relapsed or refractory B-cell ALL: a. Cohort A: Patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL who meet one of the following criteria: i. Newly diagnosed NCI HR B-ALL with induction failure: M3 marrow (\>25% blasts) at end of induction OR ii. First marrow relapse of B-ALL at \< 36 months from diagnosis OR iii. 2nd or greater relapse OR iv. Any relapse after allogeneic HSCT and ≥ 4 months from SCT at enrollment OR v. Refractory disease defined as having not achieved an MRD-negative and/or CSF-negative CR after ≥ 2 chemotherapy regimens/cycles of frontline therapy or 1 cycle of reinduction therapy for patients in first relapse OR vi. Ineligible for allogeneic SCT because of: 1. Comorbid disease 2. Other contraindications to allogeneic SCT conditioning regimen 3. Lack of suitable donor 4. Prior SCT 5. Declines allogeneic SCT as the therapeutic option after documented discussion, with expected outcomes, about the role of SCT with a BMT physician not part of the study team b. Cohort B: Patients previously treated with B cell directed engineered cell therapy who meet one of the following criteria: i. partial response or no response to prior cell therapy ii. CD19+ relapse after prior cell therapy iii. demonstrated early (≤6 months from infusion) B cell recovery suggesting loss of engineered cells c. Patients with prior or current history of CNS3 disease will be eligible if CNS disease is responsive to therapy (at infusion, must meet criteria in Section 5.3 of the protocol) 3\. Documentation of CD19 tumor expression in bone marrow, peripheral blood, CSF, or tumor tissue by flow cytometry at relapse (or a recent sample in the case of refractory disease). If the patient has received CD19-directed therapy, then the flow cytometry should be obtained after this therapy to show CD19 expression. 4\. Adequate organ function defined as: 1. A serum creatinine based on age/gender 2. ALT≤ 500 U/L 3. Bilirubin ≤2.0 mg/dl 4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea, \< Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator 5. Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO, or adequate ventricular function documented by a scan or a cardiologist. 5\. Age 3 months to 29 years. 6. Adequate performance status (Lansky or Karnofsky score ≥50). 7. Subjects of reproductive potential must agree to use acceptable birth control methods.
Exclusion criteria
1. Active hepatitis B or active hepatitis C. 2. HIV Infection. 3. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy. 4. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well. 5. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity. 6. Pregnant or nursing (lactating) women. 7. Uncontrolled active infection. 8. Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable CRS or neurotoxicity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Event-Free Survival in Patients With Newly Diagnosed VHR B-ALL or High-risk Relapse of B-ALL 1 Year After Treatment. | 1 year | Time from infusion to the first of event or censoring Events = Relapse, No Response, or Death; Censoring =Initiation of New Anticancer Therapy, Last Day of Follow-up/EOS; whichever occurs first. |
| Number of Subjects With Event-Free Survival in Patients With Poor Response to Prior B Cell Directed Engineered Cell Therapy 1 Year After Treatment. | 1 year | Time from infusion to the first of event or censoring Events = Relapse, No Response (including CR/CRi without B Cell Aplasia), or Death; Censoring =Initiation of New Anticancer Therapy, Last Day of Follow-up/EOS; whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Remission Rate | 28 Days | Overall remission rate as determined by the response at day 28, computed as the number of subjects with CR or Cri, in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL. |
| Overall Remission Rate (Cohort B) | 28 Days | Number of subjects with CR/CRi with B Cell Aplasia at Day 28 |
| Percentage of Subjects With Relapse-free Survival | 1 year | Time from first response of CR/CRi to the first of event or censoring, in responders. Cohort A: Events = Relapse or Death; Censoring = Initiation of New Anticancer Therapy, Last Day of Follow-up/EOS; whichever occurs first. Cohort B: When defining responders, CR/CRi without B Cell Aplasia is considered no response. Events = Relapse or Death; Censoring = Initiation of New Anticancer Therapy, Last Day of Follow-up/EOS; whichever occurs first. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Newly Diagnosed VHR B-ALL or High-Risk Relapse of B | 55 |
| Cohort B Poor Response to Prior B Cell Directed Engineered cell therapy | 51 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Alternative Treatment | 17 | 19 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Disease progression | 8 | 9 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Screen fail | 1 | 0 |
| Overall Study | Second malignancy | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort A | Cohort B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 43 Participants | 44 Participants | 87 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 7 Participants | 19 Participants |
| Age, Continuous | 12.0 years | 11.6 years | 11.8 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 5 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 | 21 Participants | 7 Participants | 28 Participants |
| Race (NIH/OMB) White | 28 Participants | 40 Participants | 68 Participants |
| Sex: Female, Male Female | 20 Participants | 25 Participants | 45 Participants |
| Sex: Female, Male Male | 35 Participants | 26 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 55 | 0 / 51 |
| other Total, other adverse events | 52 / 52 | 46 / 48 |
| serious Total, serious adverse events | 45 / 52 | 32 / 48 |
Outcome results
Primary
Number of Subjects With Event-Free Survival in Patients With Newly Diagnosed VHR B-ALL or High-risk Relapse of B-ALL 1 Year After Treatment.
Time from infusion to the first of event or censoring Events = Relapse, No Response, or Death; Censoring =Initiation of New Anticancer Therapy, Last Day of Follow-up/EOS; whichever occurs first.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Number of Subjects With Event-Free Survival in Patients With Newly Diagnosed VHR B-ALL or High-risk Relapse of B-ALL 1 Year After Treatment. | 68.9 percentage of subjects |
Primary
Number of Subjects With Event-Free Survival in Patients With Poor Response to Prior B Cell Directed Engineered Cell Therapy 1 Year After Treatment.
Time from infusion to the first of event or censoring Events = Relapse, No Response (including CR/CRi without B Cell Aplasia), or Death; Censoring =Initiation of New Anticancer Therapy, Last Day of Follow-up/EOS; whichever occurs first.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Number of Subjects With Event-Free Survival in Patients With Poor Response to Prior B Cell Directed Engineered Cell Therapy 1 Year After Treatment. | 62 percentage of subject |
Secondary
Overall Remission Rate
Overall remission rate as determined by the response at day 28, computed as the number of subjects with CR or Cri, in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL.
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Overall Remission Rate | 46 Participants |
| Cohort B | Overall Remission Rate | 43 Participants |
Secondary
Overall Remission Rate (Cohort B)
Number of subjects with CR/CRi with B Cell Aplasia at Day 28
Time frame: 28 Days
Population: Only subjects in cohort B analyzed in this measurement
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Overall Remission Rate (Cohort B) | 37 Participants |
Secondary
Percentage of Subjects With Relapse-free Survival
Time from first response of CR/CRi to the first of event or censoring, in responders. Cohort A: Events = Relapse or Death; Censoring = Initiation of New Anticancer Therapy, Last Day of Follow-up/EOS; whichever occurs first. Cohort B: When defining responders, CR/CRi without B Cell Aplasia is considered no response. Events = Relapse or Death; Censoring = Initiation of New Anticancer Therapy, Last Day of Follow-up/EOS; whichever occurs first.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Percentage of Subjects With Relapse-free Survival | 76.3 percentage of subjects |
| Cohort B | Percentage of Subjects With Relapse-free Survival | 80.4 percentage of subjects |