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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01158300
• Other study ID #: CDR0000680634
• Secondary ID: U01CA081457PBTC-
• Status: Completed
• Phase: Phase 1
• First received: July 7, 2010
• Last updated: May 1, 2015
• Start date: November 2010
• Est. completion date: January 2015

Study information

• Verified date: May 2015
• Source: Pediatric Brain Tumor Consortium
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years to 21 Years

Eligibility

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

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

Drug:
• VEGF inhibitor PTC299
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)

Locations

Country	Name	City	State
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	UCSF Cancer Center and Cancer Research Institute	San Francisco	California
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Pediatric Brain Tumor Consortium	National Cancer Institute (NCI), PTC Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum-tolerated dose		First four weeks of treatment	Yes
Primary	Adverse events		From the first day of treatment until 30 days after the last dose	Yes
Secondary	Percentage of study participants with complete response or partial response to the study treatment	Brain images to assess partial or complete response are performed every 8 weeks after the first dose of the study drug.	Every 8 weeks	No
Secondary	Pharmacokinetics	Blood samples from study participants will be collected on day 1 and day 28 of course 1 for standard full pharmacokinetic studies.	Day 1 and day 28 of course 1	No
Secondary	Change from baseline in blood angiogenic markers and cytokines at 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.	Before the first dose of drug on day 1 of course 1 and at the discontinuation or completion of treatment	No