Clinical Trial: Gamma Secretase Inhibitor PF-03084014 in Treating Patients With AIDS-Associated Kaposi Sarcoma

Study Status: Withdrawn
Recruit Status: Withdrawn
Study Type: Interventional

Official Title: A Phase II Study of Gamma Secretase Inhibitor PF-03084014 in Patients With AIDS-Associated Kaposi Sarcoma

Brief Summary: This phase II trial studies the effects, good and bad, of gamma secretase inhibitor PF-03084014 and to see how well it works in treating patients with acquired immune deficiency virus (AIDS)-associated Kaposi sarcoma. Gamma secretase inhibitor PF-03084014 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and may shrink the tumor.

Detailed Summary:

PRIMARY OBJECTIVES:

I. Evaluate the tolerance and clinical response of Kaposi sarcoma (KS) tumors to PF-03084014 (gamma secretase inhibitor PF-03084014) with assessments of partial response (PR) and complete response (CR).

SECONDARY OBJECTIVES:

I. Assess the effect of PF-03084014 on human immunodeficiency virus (HIV) viral load in plasma and the effect of PF-03084014 on cluster of differentiation (CD)4+ cell number.

II. Assess the effect of PF-030840414 in peripheral blood mononuclear cells (PBMCs) and tumors on Kaposi's sarcoma-associated herpesvirus (KSHV) latent and lytic gene expression.

III. Assess effects of PF-03084014 on activation of Notch target genes including tumor-associated endothelial-mesenchymal transition and cell proliferation markers.

IV. Assess effects of trough PF-03084014 drug levels on clinical response and toxicity.

OUTLINE:

Patients receive gamma secretase inhibitor PF-03084014 orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients with PR, CR, or stable disease (SD) at the end of 4 courses may receive an additional 4 courses of gamma secretase inhibitor PF-03084014 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days.

Current Primary Outcome:

• Overall clinical response (PR and CR) [ Time Frame: Up to 28 days after completion of study treatment ]
  The results of tumor evaluations will be tabulated. Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates (i.e., overall response rate, partial response rate, complete response rate).
• Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0) [ Time Frame: Up to 28 days after completion of study treatment ]
  The results of the safety evaluation will be tabulated. The frequency of adverse events (AEs) and their severity will be tabulated to evaluated tolerance.

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Levels of HIV virus load in plasma [ Time Frame: Up to 168 days ]
  The log10 of the level measured at the end of therapy and the log10 of the level obtained at baseline will be calculated for each patient. Descriptive statistics (e.g., mean, standard deviation, minimum and maximum) will be calculated. If sufficient data are available, a paired t-test will be used to test the log10 virus load difference between the end of therapy and baseline.
• CD4+ cell number [ Time Frame: Up to day 168 days ]
  The log10 of the level measured at day 22, at the end of therapy, and baseline will be calculated for each patient. Descriptive statistics (e.g., mean, standard deviation, minimum and maximum) will be calculated. If sufficient data are available, a paired t-test will be used to test the log10 CD4+ cell number difference between the end of therapy and baseline.
• Change in gene expression in tumor samples measured via reverse transcriptase polymerase chain reaction (RT-PCR) [ Time Frame: Baseline to up to day 8 ]
  Latent and lytic gene expression values will be computed compared to housekeeping genes (e.g. glyceraldehyde-3-phosphate dehydrogenase [GAPDH]), and the ratio of values for each gene at day 8 compared to that at baseline computed for each patient. The median and range will be determined for these ratios. Wilcoxon signed rank test will be used to determine if the ratio is significantly different from 1.0.
• Activation of Notch target genes in tumor samples, measured via RT-PCR [ Time Frame: Baseline to up to day 8 ]
  Levels of expression of each gene at baseline and day 8 will be computed compared to housekeeping genes (e.g. GAPDH), and the ratio of values for each gene at day 8 compared to that at baseline computed for each patient. The median and range will be determined for these ratios. Wilcoxon signed rank test will be used to determine if the ratio is significantly different from 1.0.
• Trough gamma secretase inhibitor PF-03084014 drug levels [ Time Frame: Up to day 22 ]
  Analysis of variance will be used to assess the relationship between trough drug levels and the likelihood of response, the response duration, and time to progression. Analysis of variance will be used to assess the relationship between trough drug levels and the likelihood of grade 3 or higher toxicity.

Original Secondary Outcome: Same as current

Information By: AIDS Malignancy Consortium

Dates:
Date Received: May 9, 2014
Date Started: July 2015
Date Completion:
Last Updated: July 21, 2015
Last Verified: July 2015