RATIONALE: PTC299 may stop the growth of Kaposi sarcoma by blocking blood flow to the tumor. PURPOSE: This phase I/II trial is studying the side effects and best dose of PTC299 and to see how well it works in treating patients with HIV-related Kaposi sarcoma.
OBJECTIVES: Primary * To define the safety and toxicity of anti-VEGF small molecule PTC299 in patients with HIV-related Kaposi sarcoma. * To establish the maximum tolerated dose of this drug in these patients. * To estimate the response rate in patients treated with this drug. Secondary * To describe the pharmacokinetics of this drug in these patients. * To describe the effects of this drug on serum and plasma VEGF, VEGFR, and cytokine profiles in these patients. * To describe the effects of this drug on HIV and KSHV viral loads in these patients. * To describe the effects of this drug on T-lymphocyte subsets (i.e., CD4 and CD8) in these patients. * To describe the effects of this drug on VEGF, VEGFR-2 and -3, phospho-Akt, p53, and HIF-1α expression and tumor cell proliferation, as measured by Ki-67 staining, in tumor biopsy samples obtained from these patients. * To describe the effects of this drug on viral gene expression and cellular gene transcription, as measured by real-time quantitative PCR-based profiling, in tumor biopsy samples obtained from these patients. OUTLINE: This is a multicenter, phase I dose-escalation study of anti-VEGF small molecule PTC299 followed by a phase II study. Patients receive oral anti-VEGF small molecule PTC299 twice daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients who do not demonstrate an objective response of their Kaposi sarcoma (KS) lesions after 6 courses of treatment are removed from the study. Patients undergo blood sample collection and punch biopsies periodically during study for correlative laboratory studies. Biopsy samples are assessed for VEGF, VEGFR-2, VEGFR-3, phospho-Akt, KSHV LANA, orf59, p53, and HIF-1α expression by IHC; tumor cell proliferation by Ki-67 staining; and viral gene expression at the messenger RNA level and KSHV transcription by real-time quantitative PCR-based profiling. Blood samples are assessed for pharmacokinetics and levels of secreted cytokines or other potential serum markers characteristic for KS. After completion of study treatment, patients are followed at 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
17
20 mg capsules to be taken by mouth BID. Three dose levels will be evaluated: 40 mg, 80mg, and 100mg BID. Subjects will receive PTC299 in consecutive 28-day cycles for a maximum of 12 cycles.
To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.
To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.
Rebecca and John Moores UCSD Cancer Center
La Jolla, California, United States
USC/Norris Comprehensive Cancer Center and Hospital
Los Angeles, California, United States
UCLA Clinical AIDS Research and Education (CARE) Center
Los Angeles, California, United States
Safety and Toxicity of Anti-VEGF Small Molecule PTC299
Patients who experienced an adverse event of grade 3 or greater
Time frame: All study visits
Maximum Tolerated Dose
Time frame: After each group of 3 subjects completes cycle 1 of treatment
Response to Treatment
Time frame: After each 28-day cycle of treatment and at discontinuation of therapy
Pharmacokinetics
Time frame: Days 1, 15, 28, 57
Effects of Study Drug on Serum and Plasma VEGF, VEGFR, and Cytokine Profiles
Time frame: On the first day of every 28-day cycle of treatment, Day 15, and treatment discontinuation
Effects of Study Drug on HIV and KSHV Viral Loads
Time frame: Screening, end of cycle 1, end of every third cycle thereafter, and treatment discontinuation
Effects of Study Drug on T-lymphocyte Subsets (i.e., CD4 and CD8)
Time frame: Screening, day 29, every 3 cycles thereafter, and at treatment discontinuation
Effects of Study Drug on VEGF, VEGFR-2 and -3, Phospho-Akt, p53, and HIF-1α Expression and Tumor Cell Proliferation, as Measured by Ki-67 Staining, in Tumor Biopsy Samples
Time frame: Screening and day 28
Effects of Study Drug on Viral Gene Expression and Cellular Gene Transcription, as Measured by Real-time Quantitative PCR-based Profiling, in Tumor Biopsy Samples
Time frame: Screening and day 28
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To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.
To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.
To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.
To describe the pharmacokinetics of PTC299 in patients with HIV-associated KS. To describe the effects of PTC299 on circulating VEGF, VEGFR and cytokine levels in patients with HIV-associated KS.
To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.
Cancer Research Center of Hawaii
Honolulu, Hawaii, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Floyd and Delores Jones Cancer Institute at Virginia Mason Medical Center
Seattle, Washington, United States