TerminatedNCT00686842Updated Jun 6, 2018Results posted

PTC299 in Treating Patients With HIV-Related Kaposi Sarcoma

A Phase 1/2 interventional study of VEGF inhibitor PTC299 and gene expression analysis in Kaposi's Sarcoma, sponsored by AIDS Malignancy Consortium. Terminated at 8 sites in United States. Open to participants aged 18 Years to 120 Years. Per ClinicalTrials.gov, last updated 2018-06-06.

Sponsored by AIDS Malignancy Consortium · Phase 1/2, Interventional, and Treatment

Why this study was terminated

Drug supply unavailable.

Phase: Phase 1/2
Study type: Interventional
Enrollment: 17
Allocation: Not applicable
Ages: 18 Years to 120 Years
Sex: All

Study summary

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.

Read the detailed 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.

Conditions studied

Kaposi's Sarcoma

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Keywords

HIV infection
AIDS-related Kaposi sarcoma
recurrent Kaposi sarcoma
Treatment Experienced

In context

Sarcoma, Kaposi

162 studies on the registry are indexed under Sarcoma, Kaposi; 29 are open to participants now.

This study's enrollment of 17 is below the median of 32 across 114 interventional studies indexed under Sarcoma, Kaposi.

Browse Sarcoma, Kaposi studies →

Lead sponsor

AIDS Malignancy Consortium is the lead sponsor of 61 studies on the registry; 10 are open to participants now.

Of its 10 completed or terminated interventional studies of FDA-regulated products, 8 (80%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 120 Years
Sexes eligible: All
Accepts healthy volunteers: No

Eligibility 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

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 17 participants (actual)

Study arms

Experimental
VEGF Inhibitor PTC299
Single arm study - all subjects received PTC299
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

Interventions

DrugVEGF inhibitor PTC299
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.
Geneticgene expression analysis
To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.
Geneticpolymerase chain reaction
To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.
Geneticprotein expression analysis
To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.
Otherimmunohistochemistry staining method
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.
Otherlaboratory biomarker analysis
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.
Otherpharmacological study
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.
Procedurebiopsy
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.

What researchers measure

Primary outcomes

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

Secondary outcomes

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

Results

Posted Mar 5, 2012

Participant flow

Participant flow — Overall Study
Milestone	VEGF Inhibitor PTC299
Started	17
Completed	17
Not completed	0

Outcome measures

PrimarySafety and Toxicity of Anti-VEGF Small Molecule PTC299

Patients who experienced an adverse event of grade 3 or greater

Time frame:: All study visits
Reported as:: Number · participants

Safety and Toxicity of Anti-VEGF Small Molecule PTC299
participants	VEGF Inhibitor PTC299
Safety and Toxicity of Anti-VEGF Small Molecule PTC299	7

PrimaryMaximum Tolerated Dose

Time frame:: After each group of 3 subjects completes cycle 1 of treatment