Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Recurrence

Glioma

Brain Neoplasms

Astrocytoma

Meningioma

Oligodendroglioma

Endodermal Sinus Tumor

Teratoma

Central Nervous System Neoplasms

Medulloblastoma

Germinoma

Nervous System Neoplasms

Spinal Cord Neoplasms

Pinealoma

Ependymoma

Rhabdomyosarcoma

Choriocarcinoma

Germ Cells Tumors

Central Nervous System Germinoma

Pineocytoma

Brain Tumor, Childhood

Optic Pathway Glioma

Childhood Brain Stem Glioma

Malignant Germ Cell Tumor

Pineoblastoma

Medulloblastoma, Childhood

Subependymal Giant Cell Astrocytoma

Cerebellar Astrocytoma, Childhood

Cerebral Astrocytoma, Childhood

This is a dose escalation study. Study participants will receive .6 or 1.2 mg/kg orally twice daily or 1.2, 1.5, or 2.0 mg/kg orally three times daily for four consecutive weeks (a course). In the absence of unacceptable toxicity or disease progression, treatment may continue for up to 12 courses (approximately one year)

VEGF inhibitor PTC299

Roger J. Packer, MD

RATIONALE: PTC299 may stop the growth of tumor cells by blocking blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and the best dose of PTC299 in treating young patients with recurrent or refractory primary central nervous system tumors.

OBJECTIVES:

Primary

* To estimate the maximum-tolerated dose and the recommended phase II dose of VEGF inhibitor PTC299 (PTC299) in pediatric patients with recurrent or progressive primary central nervous system (CNS) tumors.
* To evaluate and characterize the adverse events associated with this regimen in these patients.
* To evaluate and characterize the pharmacokinetics and pharmacodynamics of this regimen in these patients.

Secondary

* To investigate the relationships between PTC299 plasma exposure and other outcomes measures.
* To evaluate the antitumor activity of this regimen in these patients.
* To evaluate changes in angiogenic and inflammatory markers in the blood and the relationship between these changes and other outcome measures.
* To obtain preliminary evidence of biologic activity of PTC299 by using magnetic resonance diffusion to assess tumor cellularity.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive oral VEGF inhibitor PTC299 twice or thrice daily. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for pharmacokinetic and pharmacodynamic studies by ELISA.

After completion of study therapy, patients are followed up for 30 days.

PTC299 in Treating Young Patients With Refractory or Recurrent Primary Central Nervous System Tumors

Phase I and Pharmacokinetic Trial of PTC299 in Pediatric Patients With Refractory or Recurrent CNS Tumors

Brain images to assess partial or complete response are performed every 8 weeks after the first dose of the study drug.

Blood samples from study participants will be collected on day 1 and day 28 of course 1 for standard full pharmacokinetic studies.

Blood samples will be collected and analyzed on Day 1 of pre-AM dosing at baseline and at the discontinuation or completion of treatment. Changes from baseline in blood angiogenic markers and cytokines (VEGF-A, VEGF-C, VEGF-D, PlGF, VEGFR-1, VEGFR-2, IL-6, and IL-8) will be assessed.

National Cancer Institute (NCI)

PTC Therapeutics

Pediatric Brain Tumor Consortium

Infections

Immune System Diseases

Communicable Diseases

Sarcoma

Acquired Immunodeficiency Syndrome

HIV Infections

Sarcoma, Kaposi

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Herpesviridae Infections

Virus Diseases

DNA Virus Infections

Neoplasms, Vascular Tissue

Soft Tissue Sarcoma

Kaposi Sarcoma

Single arm study - all subjects received 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.

To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.

gene expression analysis

polymerase chain reaction

protein expression 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.

immunohistochemistry staining method

laboratory biomarker analysis

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.

pharmacological study

biopsy

Susan E. Krown, MD

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.

PTC299 in Treating Patients With HIV-Related Kaposi Sarcoma

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

Patients who experienced an adverse event of grade 3 or greater

The Emmes Company, LLC

AIDS Malignancy Consortium

VEGF Inhibitor PTC299

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Susan Krown, MD, Protocol Chair

Safety and Toxicity of Anti-VEGF Small Molecule PTC299

Maximum Tolerated Dose

Response to Treatment

Pharmacokinetics

Effects of Study Drug on Serum and Plasma VEGF, VEGFR, and Cytokine Profiles

Effects of Study Drug on HIV and KSHV Viral Loads

Effects of Study Drug on T-lymphocyte Subsets (i.e., CD4 and CD8)

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

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

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PTC299 in Treating Young Patients With Refractory or Recurrent Primary Central Nervous System Tumors	NCT01158300	Brain and Centr...	VEGF inhibitor ...	3 Years - 21 Years	Pediatric Brain Tumor Consortium
PTC299 in Treating Patients With HIV-Related Kaposi Sarcoma	NCT00686842	Kaposi's Sarcom...	VEGF inhibitor ... gene expression... polymerase chai... protein express... immunohistochem... laboratory biom... pharmacological... biopsy	18 Years - 120 Years	AIDS Malignancy Consortium

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