Cellular Immunotherapy Treatment Antigen-Directed for EBV Lymphoma

A Phase 2 Single Arm Study to Investigate the Efficacy of Autologous EBV-specific T-cells for the Treatment of Patients With Aggressive EBV Positive Extranodal NK/T-cell Lymphoma (ENKTCL)

To investigate the efficacy of autologous EBV-specific T-cells for the treatment of patients with aggressive EBV positive extranodal NK/T-cell lymphoma

FOR SCREENING PHASE:

Inclusion Criteria:

1. Diagnosis of extranodal NK/T lymphoma, per WHO classification, 4th ed., which must include EBV tumor positivity, measured either by EBV encoded RNA (EBER) or LMP1 immunostaining.
2. a) Active Disease

(1) Clinically suspected or documented relapse/progression, in first or second relapse following at least one cycle of an asparaginase-based chemotherapy regimen OR (2) Initial disease or first or second relapse and unable to tolerate one full cycle of asparaginase-based chemotherapy regimen OR b) High-risk disease (stage III/IV, KPI groups 3-4 or IPI intermediate-high) prior to second CR regardless of previous chemotherapy.

3. Male or female ≥ 18 years of age. 4. Weigh ≥ 35 kg. 5. ECOG performance score 0-2, inclusively. 6. Negative β-hCG test in women of childbearing potential. 7. Able to understand and comply with the requirements of the study and to provide written informed consent.

Exclusion Criteria:

1. CNS lymphoma.

2. NK cell leukemia.

3. Hemophagocytic lymphohistiocytosis.

4. Positive for HIV, hepatitis B, hepatitis C, syphilis or human T Cell leukemia virus (HTLV).

5. Use of systemic corticosteroids >0.5 mg/kg/day within 10 days prior to obtaining 200 mL whole blood starting material.

6. Patient is pregnant or lactating.

7. Active second malignancy.

8. Any prior allogeneic hematopoietic stem cell or solid organ transplant.

9. Asparaginase refractory disease, defined by any one of the following:

   1. Progression at any time during initial asparaginase based chemotherapy and up to 3 months after end of initial asparaginase based chemotherapy, OR
   2. Failure to achieve at least PR with initial asparaginase based chemotherapy.

10. Absolute lymphocyte count (ALC) <400/µL.

11. Any previous autologous EBV specific T cell treatment.

12. Systemic fungal, bacterial, viral or other infection that is not controlled.

13. Third or greater relapse.

FOR TREATMENT PHASE:

Inclusion Criteria:

1. Documented relapse or progression following at least one prior cycle of an asparaginase-containing chemotherapy regimen.

2. Active disease based on any one of the following present at the baseline study visit or within two weeks prior to the baseline study visit:

   1. Imaging (may use local imaging)
   2. Clinical sign(s) including skin lesions consistent with lymphoma, organ dysfunction or organomegaly not attributable to other causes; or other clinical sign(s)
   3. Detectable blood or plasma ENV DNA (may use local laboratory)

3. Completed most recent course of chemotherapy at least 2 weeks prior to first study drug dose.

4. Recovery from acute hematological, hepatic and renal chemotherapy-related toxicities as defined by ≤ Grade 1 according to NCI CTCAE v4.0.

5. Life expectancy ≥ 8 weeks.

Exclusion Criteria:

1. Use of any investigational agents within prior 4 weeks.
2. Radiotherapy within prior 3 weeks.
3. Major surgery within prior 2 weeks.
4. Systemic corticosteroids within 24 hours prior to study drug administration.
5. Evidence of hepatic dysfunction based on serum total bilirubin >3 times upper limit of normal (ULN), or ALT >5 times ULN or AST >5 times ULN.