NM-IL-12 (rHuIL-12) In Relapsed/Refractory Diffuse Large B- Cell Lymphoma (DLBCL) Undergoing Salvage Chemotherapy

Single-Arm, Open-Label Study To Evaluate The Safety, Tolerability And Preliminary Efficacy Of NM-IL-12 (rHuIL-12) In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing Salvage Chemotherapy

NM-IL-12 is being evaluated as an immunotherapeutic with concomitant hematopoietic regenerating properties for treatment of relapsed/refractory DLBCL, an aggressive type of B-cell non-Hodgkin's lymphoma (NHL). Determination of the maximum tolerated dose (MTD) for NM-IL-12 is not planned in this study, rather, a pre-defined dose of 150 ng/kg will be explored; this dose is based on two safety and tolerability studies of NM-IL-12 in healthy volunteers.

This is a single-arm, open-label, non-randomized, multi-center study with NM-IL-12 dosed in combination with salvage chemotherapy regimens (R-ICE = rituximab plus ifosfamide-carboplatin-etoposide, R-DHAP = rituximab plus cytosine arabinoside-cisplatin-dexamethasone) for treatment of patients with relapsed/refractory DLBCL.

NM-IL-12 (150 ng/kg) will be administered subcutaneously. Patients will be monitored as routinely practiced; in addition, approximately 1 day after NM-IL-12 injection, patients will have a home visit by a nurse for blood sampling related to pharmacokinetic and pharmacodynamic (PK/PD) evaluation.

Twelve patients are planned to be enrolled into the study; initially 6 patients will be enrolled. The decision to continue and recruit the remaining six patients will be made by Data Safety Monitoring Board (DSMB) after review of relevant safety data, clinical laboratory evaluations, and vital signs collected up to 21 days post enrollment of the last patient in the first treated group. Common Terminology Grades for Adverse Events (CTCAE) guidelines will be used to determine dose-modifying criteria (DMC).

Inclusion Criteria:

1. Diagnosis of relapsed/refractory diffuse large B- cell lymphoma (DLBCL) within 28 days prior to enrollment

2. PET/CT evaluation performed within 28 days prior to enrollment demonstrates measurable disease

3. Age >18 years

4. Eligible for intensive salvage chemotherapy with R-ICE, R-DHAP

5. Patient received first line of chemotherapy when DLBCL was initially diagnosed and did not receive any further chemotherapy until enrollment in this study

6. All treatment-related toxicities from prior chemotherapy resolved to grade ≤ 1or resolved to grade 2 only if deemed clinically not significant and approved by the Sponsor

7. ECOG performance status ≤ 2

8. Adequate organ function obtained within 28 days prior to enrollment:

   • Absolute neutrophil count ≥ 1,000/μL
   • Platelet count ≥ 50,000/μL
   • Total bilirubin ≤ 1.5x institutional upper limit of normal (IULN)
   • AST and ALT ≤ 2x IULN
   • Creatinine ≤ 2x IULN
   • Creatinine clearance ≥ 45 mL/min/1.73m2 for participants with creatinine levels above IULN
   • Albumin ≥ 2.5 g/dL
   • Prothrombin time (PT) and PTT 80% to 120% of institutional normal range

9. Women of childbearing potential must have a negative serum pregnancy test and must agree to use effective contraception, defined as intrauterine devices, double barrier method (condom plus spermicide or diaphragm) or abstain from sexual intercourse during the study

10. Male subjects must be willing to use an appropriate method of contraception (e.g., condoms) or abstain from sexual intercourse and inform any sexual partners that they must also use a reliable method of contraception (e.g., birth control pills) during the study

11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures

12. Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

1. Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose of the first cycle of the chemotherapy regimen. Infections controlled on concurrent antimicrobial agents are acceptable, and antimicrobial prophylaxis per institutional guidelines are acceptable. Patient needs to be clinically stable as defined as being afebrile and hemodynamically stable for 24-48 hours prior to study enrollment

2. Known active hepatitis B or C infections, known human immunodeficiency virus (HIV) infection or known to be positive for HCV RNA or HBsAg (HBV surface antigen)

3. History of or active central nervous system (CNS) involvement by lymphoma

4. Prior or concomitant malignancy in the past 5 years that is currently active and likely to interfere with the patient's treatment for DLBCL or that is likely to increase the patient's morbidity or mortality

5. Concomitant illness associated with a likely survival of < 1 year

6. Any life-threatening illness, medical condition or organ system dysfunction that, in the investigator's opinion, could compromise the patient's safety, or put the study outcomes at undue risk

7. Prior chemotherapy or radiation therapy (unless related to NHL / DLBCL treatment) within the last 5 years

8. Cytotoxic drug therapy within 21 days prior to enrollment

9. Unresolved toxicity from previous anticancer therapy (unless resolved to grade ≤ 1or resolved to grade 2 only if deemed clinically not significant and approved by the Sponsor) or incomplete recovery from surgery

10. Major surgery (excluding that for diagnosis) within 28 days of enrollment

11. Unstable cardiovascular function defined as:

    • Symptomatic ischemia
    • Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmic agents are excluded; first degree AV block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), or
    • Congestive heart failure NYHA Class ≥ 3, or myocardial infarction within 3 months prior to enrollment

12. Cerebrovascular event (transient ischemic attack or stroke) within the last 12 months.

13. Major bleeding within the last 6 months.

14. Bleeding involving CNS within the last 12 months.

15. Use of any investigational agents within 30 days prior to enrollment and for the duration of the study

16. Pregnancy or lactation -