Treatment of Classical Non-HIV-Related Kaposi's Sarcoma With the Antiviral Drug Indinavir

This study has been completed.
Sponsor:
Information provided by:
Istituto Superiore di Sanità
ClinicalTrials.gov Identifier:
NCT00362310
First received: August 9, 2006
Last updated: April 11, 2008
Last verified: April 2008
  Purpose

Recent studies have described a reduced incidence or the regression of Kaposi's sarcoma (KS) in HIV-infected patients treated with the highly active anti-retroviral therapy (HAART) that contains at least one inhibitor of the HIV protease (HIV-PI) such as Indinavir. Experimental studies have shown that part of the anti-KS actions of HIV-PI are not related to their antiretroviral actions, but, at least in part, to their capability of blocking angiogenesis and tumor growth.

This study will be conducted on HIV-negative (classical) KS patients to prove that Indinavir has anti-angiogenic and anti-KS effects in humans independently of its antiretroviral activity.


Condition Intervention Phase
Classical Kaposi's Sarcoma
Drug: indinavir
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial With the HIV Protease Inhibitor Indinavir for the Treatment of Classical Kaposi's Sarcoma

Resource links provided by NLM:


Further study details as provided by Istituto Superiore di Sanità:

Primary Outcome Measures:
  • Assessment of clinical response every 3 months during treatment and every 6 months during follow-up based on the recommendations of ACTG.

Secondary Outcome Measures:
  • Monthly evaluation of toxicity and of biological endpoints every 3 months and their correlation with drug plasma levels

Estimated Enrollment: 28
Study Start Date: June 2003
Estimated Study Completion Date: July 2007
Detailed Description:

Kaposi's sarcoma (KS) is a rare vascular tumor affecting elderly individuals from Mediterranean countries (CKS), post transplant patients and, with increased incidence and aggressiveness, HIV-infected individuals (AIDS-KS). No definitive cure has been established for KS and all conventional therapies result in low response rate, high toxicity and tumor relapse.

Antiretroviral therapies including a HIV protease inhibitor (HIV-PI) have reduced AIDS-KS incidence and induce KS regression in treated patients. This cannot be explained solely with drug-mediated HIV suppression and immune reconstitution. We have shown that HIV-PI such as Indinavir or Saquinavir block KS-like lesions in mice by inhibiting angiogenesis and tumor cell invasion through a blockade of matrix metalloprotease 2 (MMP2) proteolytic activation.

Based on these data, a proof-of-concept clinical study on HIV-negative (classic) KS (C-KS) patients was planned to prove that Indinavir has anti-angiogenic and anti-KS effects in humans independently of its antiretroviral activity.

Recent concepts in the evaluation of non cytotoxic anti-cancer drugs such as anti-angiogenic agents suggest novel criteria for the design of clinical studies due to the specific mechanism of action of these drugs. In particular, the use of the conventional evaluation criteria based on cytotoxic actions may mislead the interpretation of the therapeutic efficacy of non cytotoxic agents. The study was therefore designed to compare the clinical response to Indinavir in early-stage vs. late-stage KS and by relating it to key biological endpoints and plasmatic drug concentrations. This was also motivated by the rareness of C-KS and by ethical reasons which prevented the inclusion of a control group.

Patients will be treated per os with 800 mg x 2/daily of Indinavir for 12 months. Follow-up will be one year.

Primary objectives:

Evaluation of the tumor response rate (complete response, partial response, improved disease and stable disease) to indinavir in the treatment of mild or severe classical KS patients; Evaluation of the duration of response in indinavir-treated patients.

Secondary objectives:

Evaluation of Indinavir safety in classical KS population; Determination of the pharmacokinetic profile of Indinavir; Evaluation of key Kaposi's sarcoma biological endpoints including markers of angiogenesis and tumor invasion, Th1 and Th2 polarization of the immune response, immunoactivation, and immune responses to HHV8, herpesviruses and common pathogens.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have a documented diagnosis of classical KS
  • Be HIV-negative
  • Be 18 years old and over
  • Have one or more of the following: a minimum of 3 measurable progressive lesions; all stages of complicated KS, i.e. showing functional impotency of the affected limbs, lymphedema, lymphorrea or pain; visceral disease; lack of response to conventional therapy (radiotherapy, chemotherapy); contraindication to conventional therapies-

Exclusion Criteria:

  • Presence of life-threatening lesions or other concomitant illness, neoplasia or any other clinical condition threatening the health of the patient or his compliance to the treatment
  • Inability to provide informed consent
  • Concomitant treatment (within 30 days of initiating study treatment) with systemic immunomodulatory agents (e.g., glucocorticoids as immunosuppressive agents, interferons) or chemotherapy
  • Pregnancy
  • Impaired clinical conditions (Karnofsky's index <60
  • Diabetes, history of nephrolithiasis or monolateral nephropathy
  • Difficulty swallowing capsules/tablets
  • Any clinically significant laboratory findings obtained during screening, including:

    • Alkaline phosphatase (AP) >2 fold upper limit of normal (ULN)
    • Aspartate aminotransferase (AST)
    • Alkaline aminotransferase (ALT)
    • Gamma-glutamyl transferase (gamma-GT) or total bilirubin >3 fold the ULN
    • Serum creatinine >1.2 mg/d for women and >1.4 mg/dL for men or creatinine clearance > 100 +/- 25
    • Pancreatic amylase >1.5 folds ULN
    • Hemoglobin <10.0 g/dL for males, <9.0 g/dL for females
    • Platelet count <75.000/cubic millimeter (mm3)
    • Neutrophil count <850/mm3
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00362310

Locations
Italy
Centro di Riferimento Oncologico (CRO),
Aviano, Italy
Department of Internal Medicine, University of Cagliari
Cagliari, Italy
Dermatologic Clinic, Ospedale S. Anna
Ferrara, Italy
Ospedale Maggiore, Mangiagalli e Regina Elena, IRCCS,
Milan, Italy
Ospedale Civico Benfratelli
Palermo, Italy
Istituto Dermatologico S. Gallicano-IRCCS
Rome, Italy
Istituto Dermopatico dell'Immacolata-IRCCS (IDI)
Rome, Italy
Department of Dermatological/Venereal Diseases and Plastic Surgery, University "La Sapienza"
Rome, Italy
Dermatology Clinic, University of Sassari
Sassari, Italy
Sponsors and Collaborators
Istituto Superiore di Sanità
Investigators
Study Chair: Barbara Ensoli, MD, PhD National AIDS Center, Istituto Superiore di Sanità, Rome, Italy
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00362310     History of Changes
Other Study ID Numbers: CKS/IND/02
Study First Received: August 9, 2006
Last Updated: April 11, 2008
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by Istituto Superiore di Sanità:
classical kaposi's sarcoma
treatment
HIV protease inhibitor indinavir

Additional relevant MeSH terms:
Sarcoma, Kaposi
Sarcoma
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Vascular Tissue
Antiviral Agents
Indinavir
Protease Inhibitors
HIV Protease Inhibitors
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents

ClinicalTrials.gov processed this record on August 20, 2014