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

Sponsor

Pediatric Brain Tumor Consortium (Other)

Overall Status

Completed

CT.gov ID

NCT01158300

Collaborator

National Cancer Institute (NCI) (NIH), PTC Therapeutics (Industry)

Enrollment

Locations

Duration (Months)

3.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: VEGF inhibitor PTC299	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Nov 1, 2010

Actual Primary Completion Date :

Jan 1, 2015

Actual Study Completion Date :

Jan 1, 2015

Outcome Measures

Primary Outcome Measures

Maximum-tolerated dose [First four weeks of treatment]
Adverse events [From the first day of treatment until 30 days after the last dose]

Secondary Outcome Measures

Percentage of study participants with complete response or partial response to the study treatment [Every 8 weeks]
Brain images to assess partial or complete response are performed every 8 weeks after the first dose of the study drug.
Pharmacokinetics [Day 1 and day 28 of course 1]
Blood samples from study participants will be collected on day 1 and day 28 of course 1 for standard full pharmacokinetic studies.
Change from baseline in blood angiogenic markers and cytokines at discontinuation or completion of treatment [Before the first dose of drug on day 1 of course 1 and at the discontinuation or completion of treatment]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed diagnosis of primary central nervous system (CNS) malignancy at time of diagnosis or recurrence
Histology verification not required for intrinsic brain stem tumors and optic pathway gliomas
Must have radiographic evidence of progression
Recurrent, progressive, or refractory disease to standard therapy and for which there is no known curative therapy

PATIENT CHARACTERISTICS:

Karnofsky performance status (PS) 50-100% (patients > 16 years of age) OR Lansky PS 50-100% (patients ≤ 16 years of age)
Body weight ≥ 15 kg and ≤ 100 kg
Patients with neurological deficits allowed provided they are stable for ≥ 1 week
Able to swallow capsules
ANC ≥ 1,000/μL (unsupported)
Platelet count ≥ 100,000/μL (unsupported)
Hemoglobin ≥ 8 g/dL (may be supported)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2 OR serum creatinine normal based on age as follows:
0.8 mg/dL (≤ 5 years of age)
1.0 mg/dL (> 5 to ≤ 10 years of age)
1.2 mg/dL (> 10 to ≤ 15 years of age)
1.5 mg/dL (> 15 years of age)
Urine protein/creatinine ratio < 1.0
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
ALT and AST ≤ 2.5 times ULN
Albumin ≥ 2.5 g/dL
PT and activated PTT ≤ 1.2 times ULN
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No clinically significant unrelated systemic illness that would compromise the patient's ability to tolerate protocol therapy, or would likely interfere with the study procedures or results, including any of the following:
Serious infections including ongoing systemic bacterial, fungal, or viral infection
Significant cardiac, pulmonary, hepatic, or other organ dysfunction
Willing and able to comply with schedule visits, drug administration plan, laboratory tests, including pharmacokinetic and pharmacodynamic assessments, or other study procedures
No known coagulopathy or bleeding diathesis
No known history of drug-induced liver injury
No CNS, pulmonary, gastrointestinal, or urinary bleeding within the past month
No uncontrolled systemic hypertension (systolic BP or diastolic BP > 95% percentile for age)
No alcohol or drug addiction
Able to tolerate periodic MRI scans and gadolinium contrast

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Recovered from the acute toxic of all prior therapy (excluding alopecia and neurotoxicity)
At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosourea)
At least 14 days since prior investigational or biological agent
At least 3 half-lives since prior biological agents that have a prolonged half-life
At least 3 half-lives since prior monoclonal antibody
At least 2 weeks since prior local palliative radiotherapy
At least 6 weeks since prior total-body irradiation, craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis
At least 90 days since prior allogeneic bone marrow transplantation
No active graft-versus-host disease
Concurrent dexamethasone or other corticosteroids allowed provided dose is stable for ≥ 7 days
At least 1 week since prior colony-forming growth factors (e.g., filgrastim, sargramostim, erythropoietin)
At least 14 days since long-acting colony-forming growth factor formulations (e.g., pegfilgrastim)
More than 4 weeks since prior major surgical procedures
More than 2 weeks since prior intermediate surgical procedures
More than 7 days since minor surgical procedures
No other concurrent anticancer or investigational drug therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Cancer Center and Cancer Research Institute	San Francisco	California	United States	94143-0128
2	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
3	Children's Memorial Hospital - Chicago	Chicago	Illinois	United States	60614
4	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
5	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-4318
6	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
7	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
8	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas	United States	77030-2399