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

Sponsor

Istituto Superiore di Sanità (Other)

Overall Status

Completed

CT.gov ID

NCT00362310

Collaborator

(none)

Enrollment

Locations

Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Classical Kaposi's Sarcoma	Drug: indinavir	Phase 2

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.

Study Design

Study Type:

Interventional

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Jun 1, 2003

Study Completion Date :

Jul 1, 2007

Outcome Measures

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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	Country
1	Centro di Riferimento Oncologico (CRO),	Aviano	Italy
2	Department of Internal Medicine, University of Cagliari	Cagliari	Italy
3	Dermatologic Clinic, Ospedale S. Anna	Ferrara	Italy
4	Ospedale Maggiore, Mangiagalli e Regina Elena, IRCCS,	Milan	Italy
5	Ospedale Civico Benfratelli	Palermo	Italy
6	Department of Dermatological/Venereal Diseases and Plastic Surgery, University "La Sapienza"	Rome	Italy
7	Istituto Dermatologico S. Gallicano-IRCCS	Rome	Italy
8	Istituto Dermopatico dell'Immacolata-IRCCS (IDI)	Rome	Italy
9	Dermatology Clinic, University of Sassari	Sassari	Italy