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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
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)

Conditions
-----------------
Cutaneous T Cell Lymphoma (CTCL), Mycosis Fungoides, Sézary Syndrome

Intervention / Treatment
-----------------
* Biological: NM-IL-12 and TSEBT


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years of age or older Biopsy-confirmed CD4+ mycosis fungoides or Sézary syndrome, stage IB to IIIB The patient is eligible for TSEBT Eastern Cooperative Oncology Group (ECOG) of ≤ 2. Adequate bone marrow function: WBC > 2000/μL; platelet count > 75,000/μL; Neutrophil count > 1000/μL, without use of colony stimulating factors (CSF). 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 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. 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. 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 Adequate renal function: creatinine ≤1.5 x ULN Ability to comply with the treatment schedule Exclusion Criteria: Biopsy confirmed CD8+ CTCL histology Large cell transformation Prior systemic use of any immunosuppressive chemotherapy (except low dose methotrexate) and/or monoclonal antibody treatment for CTCL Prior courses of TSEBT (Note: localized skin-directed radiotherapy is allowed if administered at least 4 weeks prior to initiation on study). Concomitant use of any anti-cancer therapy or immune modifier. Prior allogeneic hematopoietic cell transplant. 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. Known history of human immunodeficiency virus (HIV), hepatitis B or C 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. 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 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 Any other medical issue, including laboratory abnormalities, deemed by the Investigator to be likely to interfere with patient participation Unresolved toxicity from previous anticancer therapy or incomplete recovery from surgery Major surgery within 12 weeks of enrolment 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 Cerebrovascular event (transient ischemic attack, stroke or CNS bleeding) within the last 12 months. Major bleeding within the last 6 months. Use of any investigational agents within 30 days prior to enrollment and for the duration of the study Pregnant or lactating Unwilling or unable to provide informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NM-IL-12 and TSEBT<br>TSEBT and subcutaneous doses of NM-IL-12 | Biological: NM-IL-12 and TSEBT<br>* The LD-TSEBT treatment will start on Day 1 of the study. NM-IL-12 will be administered subcutaneously.<br>* Other names: HemaMax, rHu-IL12, LD-TSEBT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability will be evaluated on the basis of the following parameters (Vital signs, physical examination,Toxicity according to the NCI CTCAE, Immunogenicity evaluated by the presence of anti-drug antibody) : | General safety: Vital signs (temperature, blood pressure, pulse rate, respiratory rate) and physical examination. Toxicity according to the NCI CTCAE (v4.03) for AEs and clinical laboratory profile; AEs will be collected in all patients who received at least one dose of NM-IL-12 and up to four weeks post last NM-IL-12 dose. Immunogenicity of NM-IL-12 will be evaluated by the presence of anti-drug antibody (ADA) | 107 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response measured by a modified severity-weighted assessment tool (mSWAT) | Exploratory skin clinical responses measured by a modified severity-weighted assessment tool (mSWAT) | 107 weeks | 
| Progression free survival | Progression free survival based on every 4 week follow up after the monthly dose until one of the events below occurs first: Progressive disease is documented Another treatment for CTCL is administered (topical or systemic) 107 weeks are completed after the patient's first dose of NM-IL-12 | 107 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CTCL, Total Skin Electron Beam Therapy (TSEBT), Mycosis fungoides, Sézary syndrome, recombinant human Interleukin-12 (rHuIL-12), T Cell