PTC299 in Treating Patients With HIV-Related Kaposi Sarcoma

AIDS Malignancy Consortium

Status and phase

Terminated

Phase 2

Phase 1

Conditions

Kaposi's Sarcoma

Treatments

Genetic: polymerase chain reaction

Procedure: biopsy

Other: laboratory biomarker analysis

Genetic: gene expression analysis

Other: pharmacological study

Genetic: protein expression analysis

Other: immunohistochemistry staining method

Drug: VEGF inhibitor PTC299

Study type

Interventional

Funder types

NETWORK

Industry

NIH

Identifiers

NCT00686842

U01CA121947 (U.S. NIH Grant/Contract)

PTC299-ONC-005-KS (Other Identifier)

CDR0000596565 (Other Identifier)

AMC-059

Details and patient eligibility

About

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.

Full description

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.

Enrollment

17 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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