huCART19-IL18-eDHFR Cells in Relapsed/Refractory Follicular Lymphoma

Phase 1 Study of huCART19-IL18-eDHFR Cells in Patients With Relapsed or Refractory Follicular Lymphoma

This is a phase 1, open-label study to evaluate the feasibility, safety and preliminary efficacy of huCART19-IL18-eDHFR cells administered in patients with relapsed or refractory follicular lymphoma. This study will be initiated as a single arm study (Treatment Arm A), which will evaluate the use of huCART19-IL18-eDHFR cells without prior lymphodepletion. In this Treatment Arm A, all subjects will receive a single flat dose of 7x10[6] huCART19-IL18-eDHFR cells (Dose Level 1; DL1). Additional treatment arms may also be introduced in the future, via subsequent amendment(s).

Co-expression of eDHFR within huCART19-IL18 cells will allow the trafficking of the transduced CAR T cells to be visualized by PET/CT imaging using an investigational radiolabeled imaging agent [18F]Fluoropropyl-Trimethoprim (also known as [18F]FP-TMP). The feasibility of using [18F]FP-TMP PET/CT imaging to detect and measure the eDHFR-expressing CAR T cells will be investigated, as well as its ability to provide insight into CAR T cell pharmacokinetics, biodistribution, and persistence.

Inclusion Criteria:

1. Signed informed consent form

2. Male or females age ≥ 18 years

3. Diagnosis of follicular lymphoma, grades 1-3A

4. Relapsed or refractory disease after at least 2 prior lines of systemic therapy as follows:

   1. Prior therapy must include an anti-CD20 monoclonal or bispecific antibody and an alkylating agent.
   2. Must have progressed within 2 years after second or higher line of therapy.

5. Documentation of CD19 expression on malignant cells by flow cytometry/IHC from a CLIA certified laboratory. Results must be within 6 months of physician-investigator confirmation of eligibility and after any intervening CD19 directed therapy since expression confirmed.

6. Patients with relapsed disease after prior allogeneic SCT must meet the following criteria:

   1. Have no active GVHD and require no immunosuppression
   2. Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility

7. Evidence of progressive disease within 12 weeks of physician-investigator confirmation of eligibility.

8. ECOG Performance Status that is either 0 or 1.

9. Adequate organ function defined as:

   1. Serum creatinine ≤ 1.5x ULN or estimated creatinine clearance ≥ 35 mL/min and not on dialysis.
   2. ALT/AST ≤ 3 x ULN
   3. Direct bilirubin ≤ 2.0 mg/dl; for patients with Gilbert's syndrome direct bilirubin must be ≤ 3.0 mg/dl
   4. Left Ventricular Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
   5. Must have minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air

Exclusion Criteria:

1. Active hepatitis B or hepatitis C infection
2. Any active, uncontrolled infection.
3. Class III/IV cardiovascular disability according to the New York Heart Association Classification (See Appendix 5).
4. Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
5. Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study.
6. Active acute or chronic GVHD requiring systemic therapy.
7. Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications, please see Section 5.3.
8. Receipt of prior huCART19 or huCART19-IL18 therapy.
9. Active treatment with trimethoprim, methotrexate, or other antifolate chemotherapy, or anticipated use of these drugs during the active treatment phase of the study. For additional details regarding these restrictions, please see Section 5.3.
10. Active CNS involvement. Patients with a history of CNS involvement that was successfully treated are eligible. A CNS evaluation is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement.
11. Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
12. Known allergy to trimethoprim or Bactrim (TMP-SMX).
13. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
14. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg daily of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
15. Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods, as described in Protocol Section 4.3.