Sirolimus in Treating Patients With HIV-Related Kaposi's Sarcoma

Sarcoma Clinical Trial

Official title:

A Pilot Study of Rapamycin in Patients With HIV-Related Kaposi's Sarcoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00450320
• Other study ID #: AMC-051
• Secondary ID: U01CA070019CDR00
• Status: Completed
• Phase: Phase 1
• First received: March 20, 2007
• Last updated: August 27, 2014
• Start date: October 2007
• Est. completion date: September 2009

Study information

• Verified date: August 2014
• Source: AIDS Malignancy Consortium
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy, such as sirolimus, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sirolimus also may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This pilot study is studying sirolimus in treating patients with HIV-related Kaposi's sarcoma.

Description:

OBJECTIVES:

Primary

• Determine the safety and toxicity of sirolimus in patients with HIV-related Kaposi's sarcoma (KS) receiving protease inhibitor (PI)-based or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral treatment (HAART) regimens.

• Estimate the dose(s) of this drug required to achieve target trough sirolimus plasma concentrations of 5-10 ng/mL in patients receiving PI-based or NNRTI-based HAART regimens.

Secondary

• Evaluate the clinical response of KS in patients treated with this sirolimus.

• Determine the effects of this drug on mTOR-dependent signaling in peripheral blood mononuclear cells (PBMC) and KS tumor biopsies.

• Determine the serum cytokine profiles pre- and post-treatment with this drug.

• Determine the effects of this drug on HIV and KS-associated herpesvirus (KSHV) viral loads.

• Determine the effects of this drug on T-lymphocyte subsets.

OUTLINE: This is a multicenter study. Patients are assigned to 1 of 3 treatment groups.

• Group 1 (patients receiving PI-based HAART regimen with ritonavir): Patients receive oral sirolimus 0.0015 mg/kg/day once daily on days 1-28 for 6 courses as long as KS is stable or the disease is continuing to respond to treatment. Patients may receive 6 additional courses provided they meet criteria for response in the absence of disease progression or unacceptable toxicity. Patients with no more than stable disease after 6 courses are discontinued from treatment.

• Group 2 (patients receiving PI-based HAART regimen without ritonavir): Patients receive oral sirolimus 0.003 mg/kg/day as in group 1.

• Group 3 (patients receiving NNRTI-based HAART regimen): Patients receive oral sirolimus 0.05 mg/kg/day as in group 1.

Blood samples are collected periodically and analyzed for sirolimus levels via LCMSMS.

PROJECTED ACCRUAL: A total of 10 patients will be accrued for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: September 2009
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Biopsy-proven Kaposi's sarcoma (KS) involving 1 or more of the following tissues:

• Skin

• Lymph nodes

• Oral cavity

• Gastrointestinal tract and/or lungs, if the disease meets the following criteria:

• Asymptomatic or minimally symptomatic

• Require systemic cytotoxic therapy

• At least five measurable, previously non-irradiated, cutaneous lesions (indicator lesions)

• Three non-indicator cutaneous lesions = 4 x 4 mm accessible for 3-mm punch biopsy

• Serologic documentation of HIV infection (i.e., positive enzyme-linked immunosorbent assay, positive western blot, or other federally approved licensed HIV test, or a detectable blood level of HIV RNA)

• CD4 count > 50 cells/µL

• Serum HIV RNA level < 400 copies/mL

• KS that is either stable or progressing in the 4 weeks prior to study entry after being on stable antiretroviral therapy for = 12 weeks with a PI-based or NNRTI-based regimen of = 3 drugs, with no intention to change the regimen within 8 weeks of starting study drug

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%

• Life expectancy = 3 months

• Hemoglobin = 8.0 g/dL

• Absolute neutrophil count = 1,000/mm³

• Platelet count = 75,000/mm³

• Glomerular filtration rate > 40 mL/min

• Total bilirubin = 1.5 times upper limit of normal (ULN) (= 3.5 mg/dL if due to indinavir therapy and direct bilirubin normal; no limit if due to atazanavir therapy and direct bilirubin is normal)

• AST and ALT = 2.5 times ULN

• Fasting triglyceride = 400 mg/dL (4.5 mmol/L)

• Total cholesterol = 300 mg/dL (7.8 mmol/L)

• Spot urine protein:creatinine ratio = 0.5 and/or proteinuria = 500 mg

• No other prior or concurrent malignancy except for treated basal cell skin cancer or carcinoma in situ of the cervix

• No evidence of infiltrate, cavitation, or consolidation (i.e., due to infection or other serious medical illness) on chest x-ray within the past 3 months

• No known hypersensitivity to sirolimus or its derivatives or macrolide antibiotics

• No New York Heart Association class III-IV cardiac disease (e.g., myocardial infarction within the past 6 months)

• No other concurrent severe and/or life-threatening medical disease

• No acute or known chronic liver disease (e.g., chronic active hepatitis or cirrhosis)

• Hepatitis C with documentation of no or minimal fibrosis on liver biopsy allowed

• No concurrent active opportunistic infection

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier-method contraception during and for 3 months after completion of study therapy

PRIOR CONCURRENT THERAPY:

• No prior sirolimus

• No acute treatment for infection or other serious medical illness within the past 14 days

• No anticancer therapy for KS, including chemotherapy, radiotherapy, or biological therapy within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C)

• No local therapy for any KS indicator lesion within the past 60 days, unless the lesion has progressed since treatment

• No investigational therapies within the past 4 weeks

• No major surgery within the past 2 weeks

• No prior or concurrent treatment with agents or medications, other than antiretroviral drugs used to treat HIV infection, that would interfere with the metabolism or excretion of sirolimus, including, but not limited to, the following:

• Antifungals (e.g., voriconazole, itraconazole, or ketoconazole)

• Antibiotics (e.g., erythromycin, telithromycin, clarithromycin, rifampin, or rifabutin)

• Cidofovir

• Cisapride

• Diltiazem

• Cyclosporine

• Grapefruit juice

• Hypericum perforatum (St. John's wort)

• No other concurrent anticancer therapies, including chemotherapy, biological therapy, or radiotherapy

• No concurrent systemic corticosteroid treatment, other than replacement doses

• No other concurrent investigational therapies

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Sarcoma
• Sarcoma, Kaposi

Intervention

Drug:
• sirolimus
The target rapamycin trough level will be 5-10 ng/mL. The initial dose will be dependent upon the type of HAART regimen. Subjects will continue on study protocol for six cycles as long as their KS is stable or continuing to respond to study medication. Treatment will be extended for up to six additional cycles if the subject has met criteria for a response. Subjects with no more than stable disease will have treatment discontinued after six cycles. Protocol treatment will be discontinued if the subject develops tumor progression, unacceptable toxicity or develops one of the protocol-defined reasons for treatment discontinuation at any time during the study.

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Rebecca and John Moores UCSD Cancer Center	La Jolla	California
United States	Memorial Sloan-Kettering Cancer Center	New York	New York

Sponsors (3)

Lead Sponsor	Collaborator
AIDS Malignancy Consortium	National Cancer Institute (NCI), The EMMES Corporation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and toxicity		All study visits	Yes
Primary	Dose of sirolimus required to achieve target trough sirolimus plasma concentration		Days 8, 15, 21, 29, 43, 57, 85, 113, and every 28 days thereafter	No
Secondary	Clinical response		Days 1, 29, 57, 85, every 28 days thereafter, at treatment discontinuation, and at study discontinuation.	No
Secondary	Effect of sirolimus on mTOR-dependent signaling in peripheral blood mononuclear cells (PBMC) and Kaposi's sarcoma (KS) tumor biopsies		baseline, days 1, 15, 29, 57, 113, every 28 days thereafter, study discontinuation	No
Secondary	Serum cytokine profile		baseline, days 1, 15, 29, 57, 113, every 28 days thereafter, study discontinuation	No
Secondary	Effect of sirolimus on HIV and KS-associated herpesvirus viral loads		Days 1, 15, 29, 57, 113, every 28 days thereafter, study discontinuation	No
Secondary	Effect of sirolimus on T-lymphocyte subsets		Baseline, Days 29, 113, and at treatment discontinuation	No