PTC299 in Treating Patients With HIV-Related Kaposi Sarcoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Trial of PTC299 in Patients With HIV-Related Kaposi's Sarcoma

Conditions
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Kaposi's Sarcoma

Intervention / Treatment
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* Drug: VEGF inhibitor PTC299
* Genetic: gene expression analysis
* Genetic: polymerase chain reaction
* Genetic: protein expression analysis
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Biopsy-proven Kaposi sarcoma (KS) involving the skin (with or without lymph node), oral cavity, gastrointestinal (GI) tract, and/or lung Patients with GI and/or pulmonary involvement must be asymptomatic or minimally symptomatic and not require systemic cytotoxic chemotherapy Has at least five bidimensionally measurable cutaneous lesions that have not been previously irradiated AND can be used as indicator lesions Must have a sufficient number of non-indicator cutaneous lesions measuring ≥ 4 x 4 mm available to obtain a total of four 3-mm punch biopsies (two at baseline and two during the course of study treatment) Serologic documentation of HIV infection, as evidenced by positive ELISA, western blot, or other federally approved licensed HIV test OR a detectable blood level of HIV RNA Patients receiving antiretroviral therapy for HIV infection are eligible provided they have been on a stable regimen for ≥ 12 weeks prior to study entry AND there is no evidence of improvement in KS during those 12 weeks or there is evidence of progression of KS within the immediate 4 weeks prior to study entry No symptomatic visceral KS requiring cytotoxic therapy PATIENT CHARACTERISTICS: Karnofsky performance status 60-100% Life expectancy ≥ 3 months Absolute neutrophil count ≥ 1,000/mm³ Platelet count ≥ 75,000/mm³ Hemoglobin ≥ 8 g/dL Creatinine ≤ 2.0 mg/dL Total bilirubin normal (grade 0) No specific limit of total serum bilirubin for patient receiveing indinavir or atazanavir therapy AND direct serum bilirubin ≤ 30% of total bilirubin AST and ALT ≤ 2.5 times upper limit of normal (grade 1) INR and aPTT normal Proteinuria < 2+ Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for up to 3 months after completion of study treatment Capable of complying with the study, in the opinion of the investigator No acute, active opportunistic infection (other than oral thrush or genital herpes) within the past 14 days No other concurrent neoplasia requiring cytotoxic therapy No history of any of the following: Myocardial infarction Severe/unstable angina Coronary/peripheral artery bypass graft Symptomatic congestive heart failure Cerebrovascular accident Transient ischemic attack Pulmonary embolism Deep vein thrombosis Other significant thromboembolic event No known coagulopathy or bleeding diathesis No history of CNS, pulmonary, GI, or urinary bleeding No known history of drug-induced liver injury Resting systolic blood pressure ≤ 160 mm Hg or diastolic blood pressure ≤ 100 mm Hg No history of or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG finding, or laboratory abnormality that, in the opinion of the investigator, could affect the safety of the patient, alter the absorption of the study drug, or impair the assessment of study results PRIOR CONCURRENT THERAPY: More than 4 weeks since prior and no other concurrent anti-neoplastic therapy for KS, including chemotherapy, radiotherapy, local therapy, or biological therapy More than 60 days since prior local therapy for any KS-indicator lesion unless the lesion has clearly progressed since treatment Any prior local therapy for indicator lesions (regardless of the elapsed time) should not be allowed unless there is evidence of clear-cut progression of that lesion More than 28 days since prior and no other concurrent investigational drugs or therapy (other than antiretroviral therapy or agents available on a treatment IND) More than 30 days since prior major surgery and recovered More than 14 days since prior treatment for an acute infection (other than oral thrush or genital herpes) or other serious medical illness No concurrent surgical procedures No concurrent systemic corticosteroid therapy, other than replacement doses No concurrent anticoagulant therapy, including warfarin, heparin (including low molecular weight heparin), or antiplatelet drugs (e.g., clopidogrel bisulfate) Concurrent aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) allowed provided the dose does not exceed the maximum recommended dose

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VEGF Inhibitor PTC299<br>Single arm study - all subjects received PTC299 | Drug: VEGF inhibitor PTC299<br>* 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.<br>Genetic: gene expression analysis<br>* To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.<br>Genetic: polymerase chain reaction<br>* To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.<br>Genetic: protein expression analysis<br>* To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.<br>Other: immunohistochemistry staining method<br>* 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.<br>Other: laboratory biomarker analysis<br>* 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.<br>Other: pharmacological study<br>* 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.<br>Procedure: biopsy<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Toxicity of Anti-VEGF Small Molecule PTC299 | Patients who experienced an adverse event of grade 3 or greater | All study visits | 
| Maximum Tolerated Dose |  | After each group of 3 subjects completes cycle 1 of treatment | 
| Response to Treatment |  | After each 28-day cycle of treatment and at discontinuation of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics |  | Days 1, 15, 28, 57 | 
| Effects of Study Drug on Serum and Plasma VEGF, VEGFR, and Cytokine Profiles |  | 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 |  | 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) |  | 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 |  | 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 |  | Screening and day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV infection, AIDS-related Kaposi sarcoma, recurrent Kaposi sarcoma, Treatment Experienced