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.

Fig. 1.

Overall survival (solid line) and progression-free survival (dashed line) distributions.

Fig. 2.

Examples of volumetric (above) and bi-dimensional or area (below) central imaging measures (provided in percentage compared with the smallest measurement in serial MRI scans during a patient's on-study time) and the duration of a patient's “on study” interval. The solid lines represent a patient who progressed early by both volumetric and area criteria (on the same scan) and was called “progressive disease” by the treating institution at the same time. The dashed lines represent a patient who progressed by volumetric measurements on day 210 but never met criteria for progressive disease by bi-dimensional measurements or clinical criteria; he remained in the study and receiving treatment for >103 weeks (725 days) and completed all therapy per protocol. The dotted lines represent the patient who had “pseudo-progression”.

Fig. 3.

MRI for long-term survivor. (A) Sagittal T1 image demonstrates expansile T1 hypointense mass in pons with mass effect on fourth ventricle. (B) Axial T2 and (C) FLAIR images demonstrate expansile mass in the pons with mass effect on the fourth ventricle surrounding the basilar artery. (D) Axial T1 image with gadolinium demonstrates nonenhancing pontine mass.

Fig. 4.

Progression-free survival estimates based on central review tumor volume (solid line), central review tumor area (dashed line), and evaluations by treating sites (dotted line).