This is a single center, single arm, open-label pilot study to determine the feasibility and
safety of a single dose administered as spilt 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" cells) in pediatric patients with relapsed or refractory
B-cell acute lymphoblastic leukemia.
The study will consist of three sequential phases: 1) a screening phase, 2) a manufacturing
and pre- treatment phase, consisting of apheresis (if applicable) and chemotherapy (if
applicable), and 3) a treatment phase, consisting of a CART22 transfused cell infusion and
follow up evaluations.
After signing informed consent, patients will undergo screening tests and procedures to
determine eligibility. Once patient eligibility is confirmed, patients will have cells
collected by leukapheresis to obtain peripheral blood mononuclear cells (PBMC) for CART22
manufacturing, unless adequate numbers of cells are available from a prior apheresis. Cells
will be transduced with the anti-CD22 TCRζ/4-1BB lentiviral vector, expanded in vitro and
then frozen for future administration. Cryopreserved historical apheresis products collected
from the patient prior to study entry are usable for CART22 manufacturing if collected at an
appropriately certified apheresis center and the product meets adequate mononuclear cell
yields. If a historical apheresis product is not available, an apheresis procedure will be
scheduled for cell procurement after study entry.
Unless contraindicated and medically not advisable based on previous chemotherapy, patients
will be given conditioning chemotherapy prior to CART22 cell infusion with the intent of
lymphodepletion. Additionally, if the patient's white blood cell (WBC) count is ≤ 1,000 /uL,
conditioning/lymphodepleting chemotherapy is NOT required. The chemotherapy will be planned
so that the last dose is completed 1-4 days BEFORE the planned infusion of CART22 cells. The
chemotherapy start date will vary based on the duration of the selected chemotherapy regimen.
If the period from chemotherapy to CART22 infusion is delayed 4 or more weeks, the patient
will need to be re-treated with lymphodepleting chemotherapy prior to CART22 infusion.
We will enroll 15 evaluable patients for the primary safety endpoint analysis. Primary safety
evaluable patients are those who have received any CART22 cells. The first three subjects
infused with CART22 will be staggered by 14 days to allow for monitoring of adverse events,
including CRS.
Subjects with a manufactured cell dose that is less than the protocol-specified dose will be
scored as a manufacturing failure. These subjects will receive their cell infusion, provided
that all other manufacturing release criteria are met.
All patients will have blood tests to assess CART22 safety, engraftment and persistence at
regular intervals throughout the study (Visit Evaluation Schedule in Appendix 1). Circulating
CART22 T cells subsets will be assessed at various times after infusion. CART22 trafficking
will be assessed in bone marrow aspirates, and other tissues, if available. Follow up is
planned at a minimum of weekly for 4 weeks, monthly for 6 months, then patients will be
followed quarterly for the remainder of the year to obtain a medical history, undergo a
physical examination, and blood tests. Additional samples collections and assessments between
schedule visits after CART22 cell infusion will be performed as clinically indicated.
Following these evaluations, patients will enter a roll-over study for long term follow-up
for up to an additional fourteen years to assess for safety assessments per the FDA
guidelines.
Inclusion 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 BM relapse OR
2. Any marrow 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 or peripheral blood by flow
cytometry at relapse.
4. Adequate organ function defined as:
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. A clinical marrow
showing disease may be performed at enrollment or within 12 weeks of enrollment.
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. For additional details regarding the use of steroids and
immunosuppressant medication, please see Section 5.6.
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.
