Clinical Trials /

NHS-IL12 for Solid Tumors

NCT01417546

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: NHS-IL12 for Solid Tumors
  • Official Title: First In-Human Phase I Trial of NHS-IL12 in Patients With Metastatic Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 110225
  • SECONDARY ID: 11-C-0225
  • NCT ID: NCT01417546

Conditions

  • Epithelial Neoplasms, Malignant
  • Epithelial Tumors, Malignant
  • Malignant Mesenchymal Tumor

Interventions

DrugSynonymsArms
NHS-IL-12A

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....

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.
    

Trial Arms

NameTypeDescriptionInterventions
AExperimentalNHS-IL12 will be administered in the dose escalation cohorts every 4 weeks at a starting dose level of 2 mcg/kg as a subcutaneous injection.
  • NHS-IL-12

Eligibility 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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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 ormesenchymal tumors.
Time Frame:2-3 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Exploring the pharmacokinetics, immunogenicity and immune response of subcutaneously administered NHS-IL12.
Time Frame:2-3 years
Safety Issue:
Description:
Measure:Describe tumor response (irRC) and progression free survival and overall survival.
Time Frame:2-3 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Dose-Limiting Toxicity
  • Maximum Tolerated Dose
  • Immune Response
  • Pharmacokinetics
  • Dose Escalation
  • Cancer
  • Metastatic Solid Tumor
  • Solid Tumor

Last Updated

April 20, 2017