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

Primary Purpose

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

Status
Unknown status
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
NM-IL-12 and TSEBT
Sponsored by
Neumedicines Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cutaneous T Cell Lymphoma (CTCL) focused on measuring CTCL, Total Skin Electron Beam Therapy (TSEBT), Mycosis fungoides, Sézary syndrome, recombinant human Interleukin-12 (rHuIL-12), T Cell

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Stanford Cancer Center
  • Columbia University Medical Center
  • University of Pennsylvania

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

NM-IL-12 and TSEBT

Arm Description

TSEBT and subcutaneous doses of NM-IL-12

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Clinical Response measured by a modified severity-weighted assessment tool (mSWAT)
Exploratory skin clinical responses measured by a modified severity-weighted assessment tool (mSWAT)
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

Full Information

First Posted
September 1, 2015
Last Updated
November 14, 2018
Sponsor
Neumedicines Inc.
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02542124
Brief Title
NM-IL-12 in Cutaneous T-Cell Lymphoma (CTCL) Undergoing Total Skin Electron Beam Therapy (TSEBT)
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)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2018
Overall Recruitment Status
Unknown status
Study Start Date
December 2015 (Actual)
Primary Completion Date
February 2019 (Anticipated)
Study Completion Date
May 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Neumedicines Inc.
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cutaneous T Cell Lymphoma (CTCL), Mycosis Fungoides, Sézary Syndrome
Keywords
CTCL, Total Skin Electron Beam Therapy (TSEBT), Mycosis fungoides, Sézary syndrome, recombinant human Interleukin-12 (rHuIL-12), T Cell

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
NM-IL-12 and TSEBT
Arm Type
Experimental
Arm Description
TSEBT and subcutaneous doses of NM-IL-12
Intervention Type
Biological
Intervention Name(s)
NM-IL-12 and TSEBT
Other Intervention Name(s)
HemaMax, rHu-IL12, LD-TSEBT
Intervention Description
The LD-TSEBT treatment will start on Day 1 of the study. NM-IL-12 will be administered subcutaneously.
Primary Outcome Measure Information:
Title
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) :
Description
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)
Time Frame
107 weeks
Secondary Outcome Measure Information:
Title
Clinical Response measured by a modified severity-weighted assessment tool (mSWAT)
Description
Exploratory skin clinical responses measured by a modified severity-weighted assessment tool (mSWAT)
Time Frame
107 weeks
Title
Progression free survival
Description
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
Time Frame
107 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Youn H Kim, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford Cancer Center
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
24725395
Citation
Gokhale MS, Vainstein V, Tom J, Thomas S, Lawrence CE, Gluzman-Poltorak Z, Siebers N, Basile LA. Single low-dose rHuIL-12 safely triggers multilineage hematopoietic and immune-mediated effects. Exp Hematol Oncol. 2014 Apr 11;3(1):11. doi: 10.1186/2162-3619-3-11.
Results Reference
background
PubMed Identifier
24852354
Citation
Gluzman-Poltorak Z, Vainstein V, Basile LA. Recombinant interleukin-12, but not granulocyte-colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: evidence for the development of a frontline radiation medical countermeasure. Am J Hematol. 2014 Sep;89(9):868-73. doi: 10.1002/ajh.23770. Epub 2014 Jun 19.
Results Reference
background
PubMed Identifier
24708888
Citation
Gluzman-Poltorak Z, Mendonca SR, Vainstein V, Kha H, Basile LA. Randomized comparison of single dose of recombinant human IL-12 versus placebo for restoration of hematopoiesis and improved survival in rhesus monkeys exposed to lethal radiation. J Hematol Oncol. 2014 Apr 6;7:31. doi: 10.1186/1756-8722-7-31.
Results Reference
background
PubMed Identifier
22383962
Citation
Basile LA, Ellefson D, Gluzman-Poltorak Z, Junes-Gill K, Mar V, Mendonca S, Miller JD, Tom J, Trinh A, Gallaher TK. HemaMax, a recombinant human interleukin-12, is a potent mitigator of acute radiation injury in mice and non-human primates. PLoS One. 2012;7(2):e30434. doi: 10.1371/journal.pone.0030434. Epub 2012 Feb 24.
Results Reference
background
PubMed Identifier
10419880
Citation
Rook AH, Wood GS, Yoo EK, Elenitsas R, Kao DM, Sherman ML, Witmer WK, Rockwell KA, Shane RB, Lessin SR, Vonderheid EC. Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood. 1999 Aug 1;94(3):902-8.
Results Reference
background
Links:
URL
http://www.ehoonline.org/content/3/1/11
Description
Single Low-dose rHuIL-12 Safely Triggers Multilineage Hematopoietic and Immune-mediated Effects.

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

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