Clinical Trial: Bortezomib in Treating Patients With Relapsed or Refractory AIDS-Related Kaposi Sarcoma

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Single-Arm, Dose-Finding Pilot Trial of Single-Agent Bortezomib in Patients With Relapsed/Refractory AIDS-Associated Kaposi Sarcoma With Correlative Assessments of KSHV and HIV

Brief Summary: This pilot, phase I trial studies the side effects and best dose of bortezomib in treating patients with acquired immune deficiency syndrome (AIDS)-related Kaposi sarcoma that has come back or has not responded to treatment. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Summary:

PRIMARY OBJECTIVES:

I. Estimate the maximum tolerated dose (MTD) of single agent bortezomib in subjects with AIDS-related Kaposi sarcoma (KS).

SECONDARY OBJECTIVES:

I. Evaluate the clinical response of KS tumors to bortezomib. II. Evaluate the impact of bortezomib on human immunodeficiency virus (HIV) plasma viral loads and peripheral blood mononuclear cells (PBMC) apolipoprotein B messenger ribonucleic acid (mRNA) editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) levels.

III. Determine the impact of bortezomib on Kaposi's sarcoma-associated herpesvirus (KSHV).

IV. Assess bortezomib effects on KSHV copy number in PBMC and plasma and whether changes in viral copy number measured in PBMC and plasma are associated with clinical response of KS tumors.

V. Monitor KSHV gene expression in KS biopsy specimens and PBMC pre- and post-bortezomib and assess whether changes in viral gene expression (i.e., to a lytic pattern) in tumor biopsy are associated with clinical response.

VI. Assess whether changes in viral copy number in PBMC and plasma occur in concert with or independently of changes in viral antigen expression in tumor biopsy specimens.

VII. Assess effects of bortezomib on proteins relevant to KS tumor survival and proliferation (i.e., P53, von Hippel-Lindau [VHL], p27, hypoxia-inducible factor 1 [HIF1]-alpha) as well as levels of nuclear factor-kappaB (NFkappaB) gene target mRNAs in tumor biopsies.

OUTLINE: This is a dose-escalation study.

MTD is defined as the highest assigned dose at which < 2 patients (out of 6) experience dose-limiting toxicity. Adverse events will be summarized by type, timing, and severity grade.



Original Primary Outcome: Maximum tolerated dose of single-agent bortezomib

Current Secondary Outcome:

  • Change in lytic gene expression [ Time Frame: Baseline to 1 year ]
    The association between change in lytic gene expression with clinical response of KS tumors will be investigated with exact logistic regression. Hierarchical clustering will be used to explore if gene expression patterns differ according to clinical response.
  • Changes in bortezomib in KSHV copy number in PBMC and plasma [ Time Frame: Baseline to 1 year ]
    Analyzed using the Wilcoxon signed rank test. The association between change in KSHV copy number with clinical response of KS tumors will be investigated with exact logistic regression.
  • Changes in levels of tumor survival, proliferation proteins, and NFKappaB gene target mRNA levels [ Time Frame: Baseline to 1 year ]
    Analyzed using the Wilcoxon signed rank test.
  • Changes in viral antigen expression in biopsy specimens [ Time Frame: Baseline to 1 year ]
    Spearman's rank correlations will be calculated to examine whether the changes in KSHV viral copy number in PBMC and plasma occur in concert or independently with changes in viral antigen expression in biopsy specimens collected at baseline, day 2 and treatment discontinuation.
  • Clinical KS response rates based on the Response Evaluation Criteria in Solid Tumors [ Time Frame: Up to 1 year ]
    Exact binomial 95% confidence intervals will be computed. Descriptive statistics will also be presented for complete and partial response rates.


Original Secondary Outcome:

  • Clinical response (CR)
  • Impact of bortezomib on HIV serum viral loads and peripheral blood mononuclear cell (PBMC) APOBEC3G levels
  • Effects of bortezomib on KSHV copy number in PBMC, plasma, and saliva and whether changes in viral copy number are associated with CR
  • Pre- and post-treatment KSHV gene expression in tumor biopsy specimens and PBMC and whether changes in viral gene expression are associated with CR
  • Association of changes in viral copy number in PBMC, plasma, and saliva with changes in viral antigen expression in tumor biopsy specimens
  • Effects of bortezomib on proteins relevant to KS tumor survival and proliferation (i.e., p53, VHL, p27, HIF1-α) as well as levels of NFkappaB gene target mRNAs in tumor biopsy specimens


Information By: National Cancer Institute (NCI)

Dates:
Date Received: November 18, 2009
Date Started: January 2010
Date Completion:
Last Updated: April 17, 2017
Last Verified: April 2017