SCH 66336 in Treating Children With Recurrent or Progressive Brain Tumors

Phase I Trial Of Escalating Oral Doses Of SCH 66336 In Pediatric Patients With Refractory Or Recurrent Brain Tumors

RATIONALE: SCH 66336 may stop the growth of tumor cells by blocking the enzymes necessary for cancer cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of SCH 66336 in treating children with recurrent or progressive brain tumors.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: lonafarnib

Detailed Description

OBJECTIVES:

• Determine the qualitative and quantitative toxicity of SCH 66336 in children with recurrent or progressive brain tumors.
• Estimate the maximum tolerated dose of this drug in these patients.
• Describe the pharmacokinetics of this drug with and without dexamethasone in these patients.
• Investigate the efficacy of this drug in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive oral SCH 66336 twice daily. Treatment repeats every 4 weeks for a total of 26 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 1-6 patients receive escalating doses of SCH 66336 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which it is predicted that 20% of patients may experience dose-limiting toxicity. An additional 6 patients are treated at the determined MTD.

Patients are followed within 30 days of the last administration of the study drug and then for up to 3 months.

PROJECTED ACCRUAL: Approximately 25 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143-0372
      • UCSF Comprehensive Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4318
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Memphis, Tennessee, United States, 38105-2794
      • St. Jude Children's Research Hospital
  • Texas
    • Houston, Texas, United States, 77030-2399
      • Texas Children's Cancer Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed recurrent or progressive (refractory) brain tumors

  • Histologic confirmation waived for brainstem gliomas
• Bone marrow involvement allowed if transfusion independent

PATIENT CHARACTERISTICS:

Age:

• 21 and under

Performance status:

• Lansky 60-100% OR
• Karnofsky 60-100%

Life expectancy:

• More than 8 weeks

Hematopoietic:

• See Disease Characteristics
• Absolute neutrophil count greater than 1,000/mm^3
• Platelet count greater than 75,000/mm^3
• Hemoglobin greater than 9 g/dL

Hepatic:

• Bilirubin no greater than upper limit of normal
• SGPT and SGOT less than 2.5 times normal
• Albumin greater than 3 g/dL
• PT/PTT no greater than 120% upper limit of normal
• No overt hepatic disease

Renal:

• Creatinine no greater than 1.5 times normal OR
• Glomerular filtration rate greater than 70 mL/min
• No overt renal disease

Cardiovascular:

• No overt cardiac disease

Pulmonary:

• No overt pulmonary disease

Other:

• Neurologic deficits allowed if stable for at least 1 week prior to study
• More than 3rd percentile weight for height
• Able to swallow pills
• No uncontrolled infection
• No known or suspected allergy to poloxamer 188, croscarmellose sodium, silicon dioxide, or magnesium stearate I
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for up to 10 weeks after study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• More than 6 months since prior bone marrow transplantation
• More than 1 week since prior growth factors

Chemotherapy:

• At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered

Endocrine therapy:

• Concurrent dexamethasone allowed if on stable dose for at least 1 week prior to study
• Concurrent oral contraceptives or other hormonal contraceptive methods allowed

Radiotherapy:

• More than 6 weeks since prior substantial bone marrow radiotherapy
• More than 3 months since prior craniospinal radiotherapy (more than 24 Gy) or total body irradiation
• More than 2 weeks since prior focal radiotherapy for symptomatic metastatic sites

Surgery:

• Not specified

Other:

• No concurrent enzyme-inducing anticonvulsant drugs
• No other concurrent anticancer or experimental drug therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Toxicities of SCH 66336 in children and adolescents with refractory CNS cancers
Maximum tolerated dose of SCH 66336	Four weeks
Pharmacokinetics of SCH 66336

Secondary Outcome Measures

Outcome Measure
Tumor response to SCH 66336

Collaborators and Investigators

• Sponsor: Pediatric Brain Tumor Consortium
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Kieran MW, Packer RJ, Onar A, Blaney SM, Phillips P, Pollack IF, Geyer JR, Gururangan S, Banerjee A, Goldman S, Turner CD, Belasco JB, Broniscer A, Zhu Y, Frank E, Kirschmeier P, Statkevich P, Yver A, Boyett JM, Kun LE. Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a Pediatric Brain Tumor Consortium Study. J Clin Oncol. 2007 Jul 20;25(21):3137-43. doi: 10.1200/JCO.2006.09.4243.

Study record dates

Study Major Dates

• Study Start: January 1, 2002
• Primary Completion (Actual): September 1, 2005
• Study Completion (Actual): March 1, 2007

Study Registration Dates

• First Submitted: May 6, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): October 14, 2009
• Last Update Submitted That Met QC Criteria: October 13, 2009
• Last Verified: October 1, 2009

More Information

Terms related to this study

• Keywords: childhood atypical teratoid/rhabdoid tumor; childhood oligodendroglioma; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; recurrent childhood ependymoma; recurrent childhood medulloblastoma; recurrent childhood visual pathway and hypothalamic glioma; childhood craniopharyngioma; childhood central nervous system germ cell tumor; childhood choroid plexus tumor; childhood grade I meningioma; childhood grade II meningioma; childhood grade III meningioma; childhood spinal cord neoplasm
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neoplasms by Site; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Lonafarnib
• Other Study ID Numbers: CDR0000068571; PBTC-003; SPRI-P02201