title: Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas.
abstract: We performed a phase II study to assess the efficacy and toxicity of tipifarnib, a farnesyltransferase inhibitor, administered with radiation therapy (RT) in children with newly diagnosed diffuse intrinsic pontine gliomas. Children 3-21 years old with pontine gliomas (BSGs) were treated with concurrent tipifarnib and RT, followed by adjuvant tipifarnib. Tipifarnib was taken orally twice daily (125 mg/m(2)/dose) during RT; after RT, it was taken at 200 mg/m(2) twice daily for 21 days, in 28-day cycles. Initial and follow-up neuroimaging was centrally reviewed. Forty eligible patients (median age, 5.5 years; range, 3.3-16.5 years) had a median progression-free survival of 6.8 months (range, 0.2-18.6 months) and median overall survival of 8.3 months (range, 0.2-18.6 months). Kaplan-Meier estimates (± standard error) of 1-year progression-free and overall survival were 12.9% ±4.9% and 34.3% ±7.4%, respectively. A single patient remained on tipifarnib without progression at the completion of the study, two years after initiation of treatment. Seven patients were without disease progression for at least six months, three of whom remained controlled for more than a year. The most frequent toxicity was grade 3 lymphopenia. We documented a single instance of "pseudoprogression" by neuroimaging review. We found no discordance among 3 approaches to defining disease progression: as interpreted by treating institutions (based on clinical status and/or imaging) and by central review (using bi-dimensional tumor "area" versus volumetric measurements). For children with diffuse BSGs, tipifarnib administered with irradiation offered no clinical advantage over historical controls. Biopsies and molecular analyses of pediatric BSGs are vital for identification of new agents and for rational use of targeted agents.
authors.affiliation: University of California—San Francisco, San Francisco, CA, USA. dhaaskogan@radonc.ucsf.edu
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
authors.forename: Anuradha
authors.initials: A
authors.lastname: Banerjee
authors.forename: Tina Young
authors.initials: TY
authors.lastname: Poussaint
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kocak
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: J Russell
authors.initials: JR
authors.lastname: Geyer
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.forename: Jane E
authors.initials: JE
authors.lastname: Minturn
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.forename: Larry E
authors.initials: LE
authors.lastname: Kun
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D002648:Child; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D011149:Pons; D015363:Quinolones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015363:Quinolones; C402769:tipifarnib