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

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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoma
• Intervention / Treatment: Drug: sirolimus

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093-0658
      • Rebecca and John Moores UCSD Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Active Comparator: Rapamycin; The target rapamycin trough level will be 5-10 ng/mL. The initial dose will be dependent upon the type of HAART regimen.

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.; Other Names: rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and toxicity	All study visits
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

Secondary Outcome Measures

Outcome Measure	Time Frame
Clinical response	Days 1, 29, 57, 85, every 28 days thereafter, at treatment discontinuation, and at study discontinuation.
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
Serum cytokine profile	baseline, days 1, 15, 29, 57, 113, every 28 days thereafter, study discontinuation
Effect of sirolimus on HIV and KS-associated herpesvirus viral loads	Days 1, 15, 29, 57, 113, every 28 days thereafter, study discontinuation
Effect of sirolimus on T-lymphocyte subsets	Baseline, Days 29, 113, and at treatment discontinuation

Collaborators and Investigators

• Sponsor: AIDS Malignancy Consortium
• Collaborators: National Cancer Institute (NCI); The Emmes Company, LLC
• Investigators: Principal Investigator: Dirk Dittmer, PhD, UNC Lineberger Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: March 20, 2007
• First Submitted That Met QC Criteria: March 20, 2007
• First Posted (Estimate): March 22, 2007

Study Record Updates

• Last Update Posted (Estimate): August 29, 2014
• Last Update Submitted That Met QC Criteria: August 27, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: AIDS-related Kaposi sarcoma; recurrent Kaposi sarcoma
• Additional Relevant MeSH Terms: Virus Diseases; Infections; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; DNA Virus Infections; Herpesviridae Infections; Neoplasms, Vascular Tissue; Sarcoma; Sarcoma, Kaposi; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: AMC-051; U01CA070019 (U.S. NIH Grant/Contract); CDR0000536481 (Other Identifier: NCI); WYETH-0468X-4420 (Other Identifier: Wyeth)