NHS-IL12 for Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01417546
First received: August 13, 2011
Last updated: September 16, 2014
Last verified: April 2014
  Purpose

Background:

- The experimental drug NHS-IL12 may help the immune system become more active and kill cancer cells that have not responded to standard treatments. NHS-IL12 has been designed to cause less severe side effects than other anticancer drugs, and may be more effective. More research is needed to test NHS-IL12 in people who have solid tumors that have not responded to treatment.

Objectives:

- To test the safety and effectiveness of NHS-IL12 as a treatment for solid tumors which have not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age with solid tumors that have not responded to standard treatments.

Design:

  • Participants will be screened with a medical history, physical exam, blood and urine tests, and imaging studies.
  • Participants will receive NHS-IL12 injection every 4 weeks, and will stay in the hospital for at least one day to be monitored with frequent blood tests.
  • Participants will have periodic blood samples taken before treatment and during the first week after treatment for the first two cycles. They will then have blood samples taken before treatment for the rest of the cycles....

Condition Intervention Phase
Epithelial Neoplasms, Malignant
Epithelial Tumors, Malignant
Malignant Mesenchymal Tumor
Drug: NHS-IL-12
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: First In-Human Phase I Trial of NHS-IL12 in Subjects With Metastatic Solid Tumors

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To determine the dose-limiting toxicities (DLTs) and Maximum Tolerated Dose (MTD) of NHS-IL12 administered subcutaneously as a onetime dose in patients with metastatic or locally advanced solid epithelial or mesenchymal tumors. [ Time Frame: 2-3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Exploring the pharmacokinetics, immunogenicity and immune response of subcutaneously administered NHS-IL12. [ Time Frame: 2-3 years ] [ Designated as safety issue: No ]
  • Describe tumor response (irRC) and progression free survival and overall survival. [ Time Frame: 2-3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 78
Study Start Date: July 2011
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: NHS-IL-12
    An investigational agent supplied to investigators by the manufacturer EMS Serono, Inc.
Detailed Description:

Background:

  • Interleukin-12 (IL-12) is a proinflammatory cytokine produced by activated phagocytes and dendritic cells (DCs) that plays a critical role in regulating the transition from innate to adaptive immunity.
  • IL-12 has shown some promising clinical activity in phase I trials, including stabilization of disease in renal cancer patients with partial regression of a metastatic lesion, but has not proceeded further in clinical development due to toxicity.
  • The NHS-IL12 concept is a strategy to reduce the toxicity associated with systemic administration of recombinant human IL-12 by selectively targeting delivery to tumors.

The NHS-IL12 immunocytokine is composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single- and double-stranded DNA. Thus, NHS-IL12 targets delivery to regions of tumor necrosis where DNA has become exposed.

Objectives:

  • To determine the dose-limiting toxicities (DLTs) and Maximum Tolerated Dose (MTD) of NHS-IL12 administered subcutaneously every 4 weeks in patients with metastatic or locally advanced solid epithelial or mesenchymal tumors.
  • Secondary objectives include exploring the pharmacokinetics, immunogenicity and immune response of subcutaneously administered NHS-IL12. Based on analysis of immune response, in a preliminary fashion in two expansion cohorts after repeated treatments, the tumor response (irRC) and progression free survival and overall survival will be described.

Eligibility:

  • Adults with histologically or cytologically proven metastatic or locally advanced solid epithelial or mesenchymal tumors, except unstable brain metastases, for which standard curative or palliative measures do not exist or are no longer effective.
  • Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.
  • Patients with acquired immune defects, systemic autoimmune disease, history of organ transplant, history of chronic infections, or history of active inflammatory bowel disease will be excluded.

Design:

  • With Amendment D, this is a phase I, open-label, dose-escalation study designed to assess the safety, tolerability, PK, and biological and clinical activity of NHS-IL12. Goals are to determine the MTD of every 4 week doses at a starting dose level of 2mcg/kg of NHS IL12 and to define the biologically optimal treatment schedule.
  • Patients will be enrolled in cohorts of 3 to 6 patients using a standard 3+3 approach until MTD is reached.
  • The trial will include a planned schedule-optimization amendment with up to 12 patients at each of the 2 dose levels that are of greater biologic interest (MTD and dose below MTD), which will be submitted as soon as a clear biological response (changes in circulating cytokine levels) is measured in at least 3 patients at a given dose level.
  • With a maximum accrual ceiling of 78 participants, this study will be completed within 2-3 years, enrolling up to 2 participants per month.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Inclusion Criteria Patients must meet the following criteria for participation:

  • Patients must have histologically confirmed malignancy confirmed by the Laboratory of Pathology, NCI, that is metastatic or unresectable locally advanced solid epithelial or mesenchymal tumors.
  • Patients must have completed or had disease progression on at least one prior line of disease-appropriate therapy for metastatic disease, or not be a candidate for therapy of proven efficacy for their disease due to an underlying physical condition.
  • Patients may have disease that is measurable or non-measurable but evaluable disease (e.g. present on bone scan, rising tumor markers, non-measurable by RECIST but visible on CT scan). Patients with third space fluid (for example pleural effusions) as only site of disease will not be eligible.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at study entry.
  • Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of NHS-IL12 in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
  • Patients must have normal organ and marrow function as defined below:

    1. Hematological eligibility parameters (within 16 days of starting therapy):

      • Absolute granulocyte count greater than or equal to 1,500/mcL
      • Absolute lymphocyte count greater than or equal to 500/mcL
      • Platelet count greater than or equal to 100,000/mcL
      • hemoglobin greater than or equal to 9 g/dL
    2. Adequate hepatic function defined by a

      • total bilirubin level less than or equal to 1.5 times ULN or in patients with Gilbert s syndrome, a total bilirubin less than or equal to 3.0, and
      • aspartate aminotransferase (AST) and alanine-aminotransferase (ALT) levels less than or equal to 2.5 times ULN or, for patients with documented metastatic disease to the liver, AST and ALT levels less than or equal to 5 times ULN.
    3. Adequate renal function defined by an estimated creatinine clearance greater than 60 mL/min determined by 24-hour urine sampling or by the Cockcroft-Gault formula:

Ccr = (140 age) (weight, kg) (constant)/[72 times Crserum (mg/100 mL). The constant is 1 for men and 0.85 for women OR Ccr = (140 age) (weight, kg) (constant)/Crserum (micro mol/L). The constant is 1.23 for men and 1.04 for women.

CD4 lymphocyte count or other T lymphocyte subset count will not be used to determine eligibility.

  • Patients must agree to practice effective contraception (both male and female subjects, if the risk of conception exists). The effects of NHS-IL12 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 30 days after the last dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • A minimum of 4 weeks will be required from any prior therapy, including chemotherapy, immunotherapy and/or radiation. In addition, recovery to Grade 1 or less from reversible all reversible toxicities related to prior therapy is required at study entry. Prior immune therapy (e.g. related vaccinia and fowlpox vaccines or antigen-specific peptides) is allowed.
  • Subject must sign a written informed consent document.

EXCLUSION CRITERIA:

Patients with any of the following will not be eligible for participation in this study:

  • Patients who are receiving any other investigational concurrent anticancer treatment (chemotherapy, radiotherapy, immunotherapy, cytokine therapy except erythropoietin) at the time of enrollment except for testosterone lowering therapy in men with prostate cancer.
  • Concurrent use of systemic steroids (within 10 days of enrollment) will be excluded, except for physiologic doses of systemic steroid replacement or local (topical, nasal, or inhaled) steroid use. Limited doses of systemic steroids (e.g., in patients with exacerations of reactive airway disease) must have completed at least 10 days prior to enrollment. Steroid use to prevent IV contrast allergic reaction or anaphylaxis in patients who have known contrast allergies is allowed at any time prior to enrollment.
  • Patients who have previously received rIL-12
  • Acquired immune defects such as HIV or innate immunodeficiency because this agent requires an intact immune system. In addition, these patients are at increased risk of lethal infections when treated with marrow-altering therapy.
  • Systemic autoimmune disease (e.g., lupus erythematosus, rheumatoid arthritis, Addison s disease, autoimmune disease associated with lymphoma).
  • History of organ transplant.
  • History of or active inflammatory bowel disease (e.g., Crohn s disease, ulcerative colitis).
  • Chronic infections (e.g., hepatitis B or C, tuberculosis).
  • Known hypersensitivity or allergic reactions attributed to any compounds of similar chemical or biologic composition to the study medication, such as recombinant IL-12 or other monoclonal antibodies
  • Known hypersensitivity to methotrexate
  • History of brain metastases because of the poor prognosis of patients with brain metastases and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke < 6 months prior to enrollment, myocardial infarction < 6 months prior to enrollment, unstable angina, congestive heart failure (greater than or equal to NYHA III) or serious cardiac arrhythmia requiring medication.
  • Pulmonary disease which, in the opinion of the investigator, may impair the patient s respiratory tolerance to moderate pulmonary fluid overload (e.g., interstitial lung disease, severe chronic obstructive pulmonary disease).
  • All conditions associated with significant necrosis of nontumor-bearing tissues: esophageal or gastroduodenal ulcers < 6 months prior to enrollment, organ infarction < 6 months prior to enrollment, or active ischemic bowel disease.
  • Presence of medically significant third space fluid (symptomatic pericardial effusion, ascites or pleural effusion requiring repetitive paracentesis).
  • History of active alcohol or drug abuse.
  • Any significant disease that, in the opinion of the investigator, may impair the patient s tolerance of study treatment.
  • Significant dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
  • Pregnancy (absence to be confirmed by beta-human chorionic gonadotropin test) or lactation.
  • Pleural effusion as the only evidence of metastatic disease.
  • Expansion Cohorts only

    • Patients must have measurable disease, defined as at least one lesion that can be accurately measured as greater than or equal to 5 times 5 mm.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01417546

Contacts
Contact: Elizabeth A Lamping (301) 435-9227 lampingea@mail.nih.gov
Contact: James L Gulley, M.D. (301) 435-2956 gulleyj@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: James L Gulley, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT01417546     History of Changes
Other Study ID Numbers: 110225, 11-C-0225
Study First Received: August 13, 2011
Last Updated: September 16, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Dose-Limiting Toxicity
Maximum Tolerated Dose
Immune Response
Pharmacokinetics
Dose Escalation
Cancer
Metastatic Solid Tumor
Solid Tumor

Additional relevant MeSH terms:
Neoplasms
Sarcoma
Liver Neoplasms
Mesenchymoma
Carcinoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Neoplasms, Complex and Mixed
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on September 29, 2014