Subcutaneously Administered Interleukin-12 Therapy in HIV-Infected Patients With Disseminated Mycobacterium Avium Complex Infection
Subcutaneously Administered Interleukin-12 Therapy in HIV-Infected Patients With Disseminated Mycobacterium Avium Complex Infection
Disseminated infection with Mycobacteria avium complex (MAC) is one of the most common
 systemic bacterial infections in advanced stages of the acquired immunodeficiency syndrome
 (AIDS). Current therapy for disseminated MAC infection in HIV patients consists of multidrug
 chemotherapy regimens are often accompanied by toxicities, and many patients become
 intolerant of one or more agents. Macrolides are the essential component of successful
 therapy, yet macrolide resistant strains are being recognized with increasing frequency.
 Thus, there is an interest in identifying additional therapeutic interventions for
 disseminated MAC in HIV-infected patients. Interleukin-12 (IL-12) is a central, regulatory
 cytokine in cell-mediated immunity. IL-12 enhances the cytolytic activity of cytotoxic T and
 NK cells, and induces interferon-gamma (IFN gamma) production from T and NK cells. This
 open-label Phase I study is designed to evaluate the safety and immunologic/microbiologic
 effects of interleukin-12 administration in HIV-infected patients with concomitant
 disseminated Mycobacterium avium (MAC) infection. Fifteen patients with documented
 disseminated MAC will be randomized to receive double-blinded placebo or escalating doses of
 IL-12 in addition to anti-MAC chemotherapy and standard anti-retroviral therapy for six
 weeks. IL-12 will be administered subcutaneously, with escalating doses every month over the
 dose range of 30 ng/kg, 100 ng/kg, and 300 ng/kg, or until an individual maximum tolerated
 dose (IMTD) is reached. Should a patient receive 2 consecutive blood cultures negative for
 MAC during the course of the study at a lower dose, then he/she will not be further dose
 escalated. Those patients receiving placebo after 6 weeks will be crossed over to receive the
 full treatment course of IL-12. Each new dose or dose escalation will take place on an
 inpatient basis. Once a patient is clinically stable at a dose, the patient will be
 maintained at that dose as an outpatient for the remainder of the month. Total IL-12
 administration will not exceed 12 weeks, or 24 total doses.
Disseminated infection with Mycobacteria avium complex (MAC) is one of the most common
 systemic bacterial infections in advanced stages of the acquired immunodeficiency syndrome
 (AIDS). Current therapy for disseminated MAC infection in HIV patients consists of multidrug
 chemotherapy regimens are often accompanied by toxicities, and many patients become
 intolerant of one or more agents. Macrolides are the essential component of successful
 therapy, yet macrolide resistant strains are being recognized with increasing frequency.
 Thus, there is an interest in identifying additional therapeutic interventions for
 disseminated MAC in HIV-infected patients. Interleukin-12 (IL-12) is a central, regulatory
 cytokine in cell-mediated immunity. IL-12 enhances the cytolytic activity of cytotoxic T and
 NK cells, and induces interferon-gamma (IFN gamma) production from T and NK cells. This
 open-label Phase I study is designed to evaluate the safety and immunologic/microbiologic
 effects of interleukin-12 administration in HIV-infected patients with concomitant
 disseminated Mycobacterium avium (MAC) infection or localized MAC infection. Fifteen patients
 with documented disseminated MAC will be randomized to receive double-blinded placebo or
 escalating doses of IL-12 in addition to anti-MAC chemotherapy and standard anti-retroviral
 therapy for six weeks. IL-12 will be administered subcutaneously, with escalating doses every
 month over the dose range of 30 ng/kg, 100 ng/kg, and 300 ng/kg, or until an individual
 maximum tolerated dose (IMTD) is reached. Should a patient receive 2 consecutive blood
 cultures negative for MAC during the course of the study at a lower dose, then he/she will
 not be further dose escalated. Likewise, patients with localized disease will not be further
 dose escalated if symptoms/evidence of localized infection resolve as assessed by the
 principal investigator. Those patients receiving placebo after 6 weeks will be crossed over
 to receive the full treatment course of IL-12. Each new dose or dose escalation will take
 place on an inpatient basis. Once a patient is clinically stable at a dose, the patient will
 be maintained at that dose as an outpatient for the remainder of the month. Total IL-12
 administration will not exceed 12 weeks, or 24 total doses.
Documented HIV infection (ELISA and Western blot positive).

 18 years or older.

 Clinically stable enough to travel to NIH and meet protocol schedule requirements.

 Negative urine or serum pregnancy test within 14 days prior to study entry (for women of
 childbearing potential).

 Patients should be receiving a combination of FDA approved antiretroviral drugs or expanded
 access antiretroviral therapy for at least two weeks prior to study entry. The exception
 would be that, in the opinion of the primary treating physician, this therapy would not
 likely provide benefit.

 Greater than or equal to 1 positive blood culture or 1 positive culture from a normally
 sterile site (e.g. lymph node, bone marrow, etc.) for MAC within 6 weeks of study. The
 initial screening blood culture at the NIH must be positive.

 The following lab values must be present at study entry:

 Transaminases, alkaline phosphatase, total bilirubin less than or equal to 5x upper limit
 of normal range.

 Serum creatinine less than or equal to 2.0 mg/ml.

 Proteinuria less than or equal to positive 1.

 Normal PT/PTT.

 Granulocyte count greater than or equal to 750/cubic millimeter.

 Hemoglobin greater than or equal to 8 gm/dL and platelet count greater than or equal to
 75,000.

 Fasting Blood glucose 1.25x upper normal limit (126 g/dl). (In persons with no history of
 diabetes.)

 No malignancy other than Kaposi sarcoma. Patients with Kaposi sarcoma are eligible, but
 must not have received systemic therapy for KS.

 No current life threatening AIDS related opportunistic infection other than disseminated
 MAC.

 No evidence of active substance abuse according to the standard 8th floor clinic substance
 abuse assessment, which allows enrollment at the discretion of the principal investigator.

 No patients exhibiting psychiatric disturbance or illness, which in the assessment of the
 protocol team may affect patient safety or compliance.

 No significant cardiac, gastrointestinal, pulmonary, autoimmune, renal, or CNS disease
 which could interfere with patient safety.

 No hypertension requiring anti-hypertensive therapy.

 No pregnant or lactating patients, or any patient with an inability or unwillingness to use
 effective contraception.

 Willingness to comply with current NIH Clinical Center guidelines concerning appropriate
 notification by an individual of current or ongoing sexual partners and/or needle-sharing
 partners regarding his or her HIV seropositivity and the risk of transmission of HIV
 infection.