Protocol Number: 01-C-0067

Title:

A Phase II Study of Interleukin-12 with either Liposomal Doxorubicin or 96 Hour Continuous Infusion Paclitaxel in AIDS-Associated Kaposi's Sarcoma Followed by Chronic Administration of Interleukin-12

Number:

01-C-0067

Summary:

This study will test the safety and effectiveness of combined therapy using liposomal doxorubicin (Doxil) and interleukin-12 (IL-12) for treating Kaposi's sarcoma (KS ) in people infected with HIV. Doxil is approved to treat KS, but its use in combination with IL-12 is experimental. IL-12 is a substance produced by cells that helps the immune system fight certain viruses-perhaps including KSHV, the virus that causes KS-and also inhibits new blood vessel formation, which is associated with KS. IL-12 production is decreased in people infected with HIV. This study will test whether replacing IL-12 will help the body fight KS and produce better treatment results than Doxil alone.

HIV-positive patients 13 years of age or older with Kaposi's sarcoma may be eligible for this study. Candidates will have a medical history, physical examination, blood and urine tests, electrocardiogram, chest X-ray and biopsy of a KS lesion (removal of a small piece of tumor tissue, under local anesthetic, for microscopic examination), and possibly other tests. Patients with a history of heart disease may also have a MUGA test (nuclear medicine test of the heart).

Participants will receive Doxil infusions intravenously (through a vein) for up to 6 doses once every 3 weeks. They will also receive IL-12 twice a week, injected under the skin. IL-12 injections will continue for up to 3 years, as long as the drug shows benefit and is well tolerated. (Patients will be taught to give themselves the injections.) Pictures of the patient's entire body-focusing on the KS lesions- will be taken when they enter the study, then every 3 weeks while taking Doxil and IL-12, and then once every 8 weeks while receiving IL-12 alone.

Participants will be evaluated in the clinic once a week for the first 6 weeks of therapy, then every 3 weeks until the last dose of Doxil, and monthly thereafter. They will be asked about side effects of treatment and may have a physical examination. KS lesions will also be measured. A chest X-ray and blood tests to measure CD4 cells and HIV viral load will be done every 9 weeks while on Doxil with IL-12 and then every 8 weeks while on IL-12 alone. KS lesions will be biopsied before starting drug treatment, at week 9 of treatment, and when the lesions have responded sufficiently for the disease to be considered in partial remission. Patients may be asked to undergo additional skin biopsies for research purposes. Also at the beginning of the study, at week 12 and at week 24, patients will undergo three noninvasive procedures to determine blood vessel density and blood flow in skin areas affected by KS. They are Doppler imaging, which uses a low power laser beam to measure blood flow through the vessels; multi-spectral imaging, which uses a light instrument that can estimate total blood volume and oxygen content; and infrared thermal imaging, which uses a special camera to produce a picture of the temperature of KS lesions in order to assess blood flow. If medically indicated, patients may undergo additional procedures such as computed tomography (CT) or magnetic resonance imaging (MRI) scans.

The first 10 patients enrolled in the study will also be asked to have intensive blood sampling once every 2 to 6 hours for 24 hours in order to determine blood levels of IL-12 of and other substances affected by IL-12. A small catheter will be placed in an arm vein to draw the samples in order to avoid repeated needle sticks.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA

Age greater than or equal to 18 years.

HIV seropositive

Patients need confirmation of Kaposi's sarcoma diagnosis by CCR pathology.

Evaluable KS involving the skin and/or viscera: If KS restricted to the skin there must be greater than or equal to 5 KS lesions that are evaluable by non-invasive methods that have not been treated with local therapeutic modalities; Pulmonary KS evaluable by CT scanning; Gastrointestinal KS evaluable by direct visualization or fiberoptic instrumentation.

At least one of the following indications for cytotoxic chemotherapy: pulmonary involvement, visceral involvement, pain, edema, ulcerating lesions, decreased range of joint motion due to KS, multiple lesions not amenable to local therapy and significant psychological impact leading to social withdrawal.

KS that has worsened in the 3 weeks prior to protocol evaluation on a stable regimen of highly active antiretroviral therapy that the patient has been taking for greater than or equal to 4 weeks.

Patients in need of urgent chemotherapy as indicated by, but not limited to the following: Symptomatic pulmonary or other visceral KS; Lymphedema that impairs mobility or range of motion; Ulcerating KS lesions.

Life expectancy of greater than 2 months (with standard therapy).

Karnofsky performance status of greater than or equal to 30.

Patients must have the ability to give informed consent.

A total bilirubin less than or equal to 3.8 mg/dl with direct fraction less than or equal to 0.3 mg/dl and indirect fraction of less than or equal to 3.5 mg/dl in patients for whom these abnormalities are felt to be due to protease inhibitor therapy.

21 days since any previous chemotherapy cycle prior to enrollment (6 weeks for mitomycin C or nitrosoureas).

Ejection fraction greater than or equal to 40% as assessed by MUGA scan or by echocardiography - required assessment only if clinically indicated.

EXCLUSION CRITERIA

Refusal to use barrier contraception while on study and for 2 months afterward.

Pregnancy

Any one of the following hematologic abnormalities: Hgb less than 9.0m/dl;An absolute neutrophil count (ANC) less than 750 cells/mm(3);A platelet count less than 75,000 cells/mm(3); APTT or PT greater than 120% of control unless due to the presence of lupus-type anticoagulant.

A history of hepatic cirrhosis or present hepatic dysfunction with AST/GOT greater than 2.5 times the upper limit of normal.

Congestive heart failure.

Serum creatinine greater than 1.5 mg/dL and an estimated or measured creatinine clearance less than 60 mL/min.

Clinically significant autoimmune disease.

Active, gross gastrointestinal bleeding or uncontrolled peptic ulcer disease.

A history of inflammatory bowel disease.

Past or present history of malignant tumors other than KS unless: a) in a complete remission for greater than or equal to 1 year from the time a response was first documented; b) completely resected basal cell carcinoma; or c) in situ squamous cell carcinoma of the cervix or anus.

Evidence of a severe or life-threatening infection within 2 weeks of entry onto the study.

Patients with any other abnormality, except lymphopenia or direct manifestations of KS, that would be scored as grade 3 toxicity.

Known hypersensitivity to IL-12 or other compounds that are known to cross-react with IL-12.

Previous concomitant IL-12 and liposomal doxorubicin except in cases previosly related on the protocol who are being enrolled for the paclitaxel salvage arm of the study.

Suramin treatment within the last 6 months.

Treatment within the last 2 weeks with cytokines or bone marrow stimulating factors other than erythropoietin, filgrastim, and/or sargramostim.

Treatment within the last 2 months with systemic glucocorticoid steroids at doses sufficient to affect the immune response. In general, this would mean an equivalent of more than 20 mg of prednisone for more than 1 week. Replacement glucocorticoid therapy would be allowed.

Any medical condition that, in the opinion of the Principal Investigator or Study Chairperson, would preclude the inclusion of a patient onto this research study.

Special Instructions: Currently Not Provided

Keywords:

KSHV

HIV

Chemotherapy

Cancer

Antiretroviral Therapy

Recruitment Keywords:

HIV

Kaposi's Sarcoma

Cytotoxic Chemotherapy

Conditions:

HIV Infection

Kaposi's Sarcoma

Investigational Drug(s):

Recombinant Interleukin-12

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

Phase I study of Doxil and vinorelbine in metastatic breast cancer

Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma

Liposomal doxorubicin in the treatment of advanced AIDS-related Kaposi sarcoma

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