Infants With Very High Risk KMT2A B-ALL, Patients With Central Nervous System Relapse Who Did Not Receive Cranial Radiation or Bone Marrow Transplantation, Pediatric and Young Adult Patientswith Hypodiploid or t(17;19) B-ALL
Conditions
Brief summary
This is an open-label, four-cohort, phase 2 study to determine the efficacy of CART19 in pediatric and young adult patientswith hypodiploid (Cohort A) or t(17;19) B-ALL (Cohort B), infants with very high risk KMT2A B-ALL (Cohort C), and in patients with central nervous system (CNS) relapse who did not receive cranial radiation (XRT) or bone marrow transplantation (BMT) (Cohort D).
Interventions
BIOLOGICALMurine CART19
CART19 cells transduced with a lentiviral vector to express anti-CD19 scFv:41-BB:TCRζ, administered by IV injection with a planned dose of 5x106 CART19 cells/kg on day 0 with possible reinfusion/retreatment
Sponsors
Stephan Grupp MD PhD
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to 29 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent form must be obtained prior to any study procedure. 2. Male and female patients with documented CD19+ B-ALL a.Cohort A \& B: Patients, regardless their response to initial or relapsed B ALL therapy, with the following characteristics: i.Cohort A: Subjects with confirmation of a hypodiploid karyotype (chromosome number fewer than 45) ii.Cohort B: Subjects with cytogenetic confirmation of the chromosomal translocation t(17;19) (Cohort B) b.Cohort C: Infants w/ newly diagnosed KMT2A rearranged B-ALL classified as very high risk by the following criteria: i.Age \< 3 months at diagnosis ii.Age \< 6 months and WBC \> 300,000x109/L at diagnosis or a poor prednisone response in induction iii.MRD positive \> 0.01 (or PCR \> 104) after 2 courses of standard infant ALL therapy. c.Cohort D: Subjects in a first or greater CNS relapse, prior to therapy with cranial XRT or HSCT for the current relapse 3. Documentation of CD19 tumor expression in bone marrow, peripheral blood, CSF, or tumor tissue. 4. Age 0 to 29 years 5. Adequate organ function defined as: 1. A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL) Age Male Female 0 to \< 2 years 0.6 0.6 2 to \< 6 years 0.8 0.8 6 to \< 10 years 1.0 1.0 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4 ≥ 16 years 1.7 1.4 2. Adequate liver function: i.ALT≤ 5 x ULN; ALT ii.Total bilirubin ≤ 3 x ULN iii.ALT and/or bilirubin results that exceed this range are acceptable if, in the opinion of the physician-investigator (or as confirmed by liver biopsy), the abnormalities are directly related to ALL infiltration of the liver. c.Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and \< Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the physician-investigator. d.Left Ventricular Shortening Fraction (LVSF) ≥ 28%, or Left Ventricular Ejection Fraction (LVEF) ≥ 45% by echocardiogram. In cases where quanitative assessment of LVSF/LVEF is not possible, a statement by the cardiologist that the ECHO shows qualititatively normal ventricular function wll suffice. 6. Adequate performance status defined as Lansky or Karnofsky score ≥ 50 7. Subjects of reproductive potential must agree to use acceptable birth control methods
Exclusion criteria
1. For subjects with a CNS relapse, prior cranial XRT or BMT for the current relapse is an exclusion. 2. Active hepatitis B or active hepatitis C. 3. HIV Infection. 4. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy. 5. Concurrent use of systemic steroids 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 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. 6. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity. 7. Pregnant or nursing (lactating) women. 8. Uncontrolled active infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival (EFS) | One year | 1 year event-free survival (EFS), where events include no response, relapse, death due to any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EFS Rate 1 | One year | Modified EFS rate in CNS relapse patients, using a definition of events that includes no response, relapse, death, need for XRT or need for BMT |
| To further evaluate the safety of CART19 in the target patient populations | One year | Frequency and severity of adverse events |
| EFS rate 2 | One year | Modified EFS rate in patients with early CNS relapsed B-ALL (CR1 \<18 months) and those with late CNS relapsed B-ALL (CR1 \>18 months) using a definition of events that includes no response, relapse, death, need for XRT or need for BMT |
| MRD conversion | One year | Rate of MRD conversion to less than 0.01% (in patients with MRD) 28 days after CART19 therapy in patients with t(17;19) B-ALL, hypodiploid B-ALL, and very high risk infant B-ALL |
| Relapse Free survival 1 | One year | Relapse-free survival (RFS) at one year in patients with hypodiploid B-ALL, patients with t(17;19) B-ALL, and very high risk infant B-ALL regardless of their initial response to B-ALL therapy and in patients with CNS relapse who did not receive cranial XRT or BMT after CART19 and who achieved a complete remission following CART19 therapy. |
| Relapse Free survival 2 | One year | RFS at one year in patients with hypodiploid B-ALL who were MRD negative at end of induction and those who were MRD positive at end of induction during upfront therapy |
| Relapse Free survival 3 | One year | RFS at one year in patients with t(17;19) B-ALL who were MRD negative at end of induction and those who were MRD positive at end of induction during upfront therapy |
| Relapse Free survival 4 | One year | RFS at one year in very high risk infants with KMT2A rearrangement who were MRD negative at end of induction and those who were MRD positive at end of induction. |
Countries
United States
Contacts
CONTACTCART Nurse Navigator
CONTACTMelissa S Varghese, M.S.
STUDY_DIRECTORStephan Grupp, MD, PhD
Children's Hospital of Philadelphia
PRINCIPAL_INVESTIGATORAmanda DiNofia, MD
Children's Hospital of Philadelphia
Outcome results
None listed