NM-IL-12 in Cutaneous T-Cell Lymphoma (CTCL) Undergoing Total Skin Electron Beam Therapy (TSEBT)

A Single Arm, Open-Label Study To Evaluate The Safety, Tolerability And Preliminary Efficacy Of NM-IL-12 (rHuIL-12) In Patients With Cutaneous T Cell Lymphoma (CTCL) Undergoing Low Dose Total Skin Electron Beam Therapy (TSEBT)

In the proposed study, NM-IL-12 will be evaluated as immunotherapy to increase antitumor efficacy against CTCL, while reducing skin-related toxicity, when combined with low-dose TSEBT therapy. Determination of the maximum tolerated dose (MTD) for NM-IL-12 is not planned in this study, rather, a pre-defined starting dose 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 study with NM-IL-12 dosed in combination with low dose TSEBT in CTCL patients. This study is planned to be conducted in 10 patients, 18 years or older in age, undergoing low dose TSEBT of 12 Gy over a 3-week period.

The study will initially enroll 4 patients and then will be expanded to enroll 6 additional patients (total 10 patients) depending on the presence or absence of Dose Modifying Criteria (DMC). Decision whether to de-escalate will be made after first 4 patients are followed up for 28 days from the first dose of NM-IL-12.

Safety monitoring will continue throughout the whole period of drug administration and the treatment will be discontinued if intolerable toxicity or disease progression occurs during this period.

Inclusion Criteria:

1. 18 years of age or older

2. Biopsy-confirmed CD4+ mycosis fungoides or Sézary syndrome, stage IB to IIIB

3. The patient is eligible for TSEBT

4. Eastern Cooperative Oncology Group (ECOG) of ≤ 2.

5. Adequate bone marrow function: WBC > 2000/μL; platelet count > 75,000/μL; Neutrophil count > 1000/μL, without use of colony stimulating factors (CSF).

6. Required washout period for prior therapies Topical therapy: 2 weeks

   • Phototherapy (PUVA): 4 weeks
   • Local Skin Radiation Therapy (< 10% skin surface): 4 weeks
   • Retinoids: 4 weeks
   • Interferons: 4 weeks
   • Low dose methotrexate: 4 weeks
   • HDAC inhibitors: 8 weeks

7. Women of child-bearing potential must have negative serum pregnancy test and use accepted highly effective methods of birth control throughout the study and for 90 days after dosing and must agree to use effective contraception.

8. Male patients 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 during the study and for 90 days after dosing.

9. Adequate hepatic function: bilirubin ≤1.5 x upper limit of normal (ULN), AST ≤2.5 x ULN, ALT ≤2.5 x ULN, alkaline phosphatase (liver fraction) ≤2.5 x ULN

10. Adequate renal function: creatinine ≤1.5 x ULN

11. Ability to comply with the treatment schedule

Exclusion Criteria:

1. Biopsy confirmed CD8+ CTCL histology

2. Large cell transformation

3. Prior systemic use of any immunosuppressive chemotherapy (except low dose methotrexate) and/or monoclonal antibody treatment for CTCL

4. Prior courses of TSEBT (Note: localized skin-directed radiotherapy is allowed if administered at least 4 weeks prior to initiation on study).

5. Concomitant use of any anti-cancer therapy or immune modifier.

6. Prior allogeneic hematopoietic cell transplant.

7. Any ongoing infection whether receiving or not receiving antibiotics or have received intravenous antibiotics, antiviral, or antifungal agents within 2 weeks prior to the start of the study drug.

8. Known history of human immunodeficiency virus (HIV), hepatitis B or C

9. For women on estrogen based contraceptives, family history of venous thromboembolism (VTE) and/or risk factors predisposing for VTE and other medical conditions known to be associated with VTE.

10. History of prior malignancy with the exception of cervical intraepithelial neoplasia, non-melanoma skin cancer, and adequately treated localized prostate carcinoma (PSA <1.0). Patients with a history of other malignancies must have undergone potentially curative therapy and have no evidence of that disease for five years

11. Uncontrolled intercurrent illness, condition, or circumstances that could limit compliance with the study, including, but not limited to the following: acute or chronic graft versus host disease, uncontrolled diabetes mellitus or hypertension, or psychiatric conditions

12. Any other medical issue, including laboratory abnormalities, deemed by the Investigator to be likely to interfere with patient participation

13. Unresolved toxicity from previous anticancer therapy or incomplete recovery from surgery

14. Major surgery within 12 weeks of enrolment

15. Medically significant cardiac event or unstable cardiovascular function defined as:

    • Symptomatic ischemia, unstable angina pectoris
    • Uncontrolled clinically significant cardiac arrhythmia
    • Symptomatic heart failure NYHA Class ≥ 3
    • Myocardial infarction or cardiac surgery within 6 months prior to enrollment

16. Cerebrovascular event (transient ischemic attack, stroke or CNS bleeding) within the last 12 months.

17. Major bleeding within the last 6 months.

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

19. Pregnant or lactating

20. Unwilling or unable to provide informed consent