Clinical trial NCT02650414: CD22 Redirected Autologous T Cells for ALL
Official title: Pilot Study of Autologous Anti-CD22 Chimeric Antigen Receptor Redirected T Cells in Pediatric Patients With Chemotherapy Resistant Or Refractory Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: B Cell Leukemias
B Cell Lymphomas
Keywords: Biological: CART 22
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Children's Hospital of Philadelphia
First posted: 2016-01-08
Enrollment: 41
Sex: ALL
Minimum age (years): 1
Maximum age (years): 29
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a pilot study to determine the feasibility and safety of a single dose of autologous T cells expressing CD22 chimeric antigen receptors expressing tandem TCR-ζ and 4-1BB signaling domains (CART22/CART22-65s cells) in pediatric and young adult subjects with relapsed or refractory B cell acute lymphoblastic leukemia.

Detailed description: This is a single center, single arm, dual-cohort, open-label pilot study to determine the feasibility and safety of a single dose (administered as split fractions) of autologous T cells expressing CD22 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ/4-

1BB) co-stimulatory domains (referred to as "CART22" and "CART22-65s" cells) in pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Cohort assignment will be dependent on the date of consent and confirmation of eligibility by a physician-investigator as follows:

* Cohort 1: was closed to additional recruitment as of Protocol Version 8. All subjects who received CART22 cells will be retrospectively assigned to Cohort 1.
* Cohort 2: was opened as of Protocol Version 8. All subjects assigned to Cohort 2 will receive CART22-65s cells given over 3 days.
* Cohort 3: will open as of Protocol V12, with subjects enrolled sequentially after all infusion slots in Cohort 2 are filled. All subjects assigned to Cohort 3 will also receive CART22-65s cells, however the product will be administered over 2 days.

Eligibility criteria: 1. Signed informed consent form must be obtained prior to any study procedure.
2. Relapsed or refractory B-cell ALL:

   1. 2nd or greater relapse OR
   2. Any marrow or extramedullary relapse after allogeneic HSCT and ≥ 6 months from SCT at infusion OR
   3. Any marrow relapse after CAR-modified T cell therapy OR
   4. Refractory disease defined as having not achieved a CR after \> 2 chemotherapy regimens OR
   5. Patients with Ph+ ALL are eligible if they are intolerant to or have failed tyrosine kinase inhibitor therapy OR
   6. Ineligible for allogeneic SCT because of:

   i. Comorbid disease ii. Other contraindications to allogeneic SCT conditioning regimen iii. Lack of suitable donor iv. Prior SCT v. Declines allogeneic SCT as a therapeutic option after documented discussion, with expected outcomes, about the role of SCT with a BMT physician not part of the study team g. Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy (at infusion, must meet criteria in Section 5.2)
3. Documentation of CD22 tumor expression in bone marrow, other tumor biopsy, CSF or peripheral blood by flow cytometry (or a recent marrow in the case of refractory disease). If the patient has received CD22-directed therapy (i.e., inotuzumab), then the marrow or other sample should be obtained after this therapy to show CD22 expression.
4. Adequate organ function defined as:

   a. A serum creatinine based on age/gender as follows:
   1. A serum creatinine based on age/gender as follows:

      Maximum Serum Creatinine (mg/dL) Age 1 to \< 2 years Male 0.6 Female 0.6 Age 2 to \< 6 years Male 0.8 Female 0.8 Age 6 to \< 10 years Male 1.0 Female 1.0 Age 10 to \< 13 years Male 1.2 Female 1.2 Age 13 to \< 16 years Male 1.5 Female 1.4 Age ≥ 16 years Male 1.7 Female 1.4
   2. Adequate liver function

   i. ALT \< 500 U/L ii. Bilirubin \<3x upper limit of normal

   iii. ALT and/or bilirubin that exceed these ranges is acceptable if, in the opinion of the investigator (or 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, pulse oxygen \> 92% on room air; DLCO \> 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator

   d. Left Ventricle Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA; in cases where quantitative assessment of LVEF is not possible, a statement by the cardiologist that the ECHO shows qualitatively normal ventricular function will suffice.
5. Evidence of disease by standard morphologic or by MRD criteria. If the results of a historical biopsy (obtained at the time of the patient's most recent relapse) are available, this does not need to be repeated at screening.
6. Age 1-29 years.
7. Adequate performance status (Lansky or Karnofsky score ≥50).
8. 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 immunosuppressant medications. Recent or current use of inhaled steroids or physiologic replacement with hydrocortisone is not exclusionary.
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. Receipt of a prior investigational study agent within 4 weeks prior to screening visit. \*Note - patients who have received anti-CD19 CART cells (e.g., CART19/CTL019) on an investigational study where cell infusion occurred greater than 4 weeks before the screening visit are NOT excluded.

Primary outcomes:
measure: Frequency and severity of adverse events, including, but not limited to, cytokine release syndrome (CRS)
timeFrame: From date of dosing ( day 1 ) up 15 years
Secondary outcomes:
measure: Percentage of manufacturing products that do not meet release criteria.
timeFrame: 3 months
measure: Overall Complete Remission Rate (ORR) at Day 28.
timeFrame: 4 months
measure: Evaluate overall response rate (CR/CRi by or at Month 6) at Month 6.
timeFrame: 9 months
measure: Evaluate disease status at Month 6.
timeFrame: 9 months
measure: Overall survival (OS)
timeFrame: 15 years
measure: Duration of remission (DOR)
timeFrame: 15 Years
measure: Number of subjects with relapse free survival (RFS)
timeFrame: 15 years
measure: Number of subjects with event free survival (EFS).
timeFrame: 15 years
measure: Describe cause of death (COD) when appropriate
timeFrame: 15 years
measure: Describe response in terms of minimal residual disease (MRD).
timeFrame: 1 year
measure: Incidence of any acute GVHD
timeFrame: 15 year
measure: Incidence of any grade II-IV aGVHD
timeFrame: 15 year
measure: Incidence any chronic GVHD.
timeFrame: 15 year
measure: Incidence any extensive, limited cGVHD.
timeFrame: 15 year
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Stephan Grupp, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Singh N, Frey NV, Engels B, Barrett DM, Shestova O, Ravikumar P, Cummins KD, Lee YG, Pajarillo R, Chun I, Shyu A, Highfill SL, Price A, Zhao L, Peng L, Granda B, Ramones M, Lu XM, Christian DA, Perazzelli J, Lacey SF, Roy NH, Burkhardt JK, Colomb F, Damra M, Abdel-Mohsen M, Liu T, Liu D, Standley DM, Young RM, Brogdon JL, Grupp SA, June CH, Maude SL, Gill S, Ruella M. Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells. Nat Med. 2021 May;27(5):842-850. doi: 10.1038/s41591-021-01326-5. Epub 2021 Apr 22.