A total of 40 patients were included in the phase II analyses; 6 were accrued during the phase I portion of the study and were reported as part of the phase I manuscript11
and 34 were accrued in the phase II component. Of the 40 eligible patients, 25 (62.5%) were female and 15 (37.5%) were male; the median age was 5.5 years (range, 3.3–16.5 years), and the median Karnofsky Lansky Score was 70 (range, 50–100). The median PFS for the 40 eligible patients was 5.9 months (range, 0.2–23.9 months), and the median OS was 8.9 months (range, 0.2–23.9 months). One-year PFS and OS estimates (±standard error) were 7.5% ±3.6% and 35% ±7.3%, respectively (Figure ). PFS and OS rates (±standard error) at 18 months were 2.5% ±1.8%) and 10% ±4.2%, respectively. The stopping criterion for inefficacy was not met during the accrual period.
Overall survival (solid line) and progression-free survival (dashed line) distributions.
The duration of presenting signs and symptoms varied among patients; onset occurred at a median of 6 days (range, 0-55 days) before the date of diagnosis. In decreasing order of frequency, these presenting signs and symptoms included cranial and motor neuropathies, ataxia, speech impairment, double vision, nystagmus, and mood alterations.
Tables and list toxicities that were at least grade 3 in severity and were considered possibly, probably, or definitely related to tipifarnib use. Those toxicities that occurred during course 1 and course 2 (the dose-limiting toxicity observation period for the phase I trial of PBTC-014) are shown in Table , whereas those toxicities that occurred later during therapy are shown in Table . The most frequent toxicity was lymphopenia: all cases but 1 were reported to be grade 3, and all patients but 1 received steroids prior to experiencing lymphopenia, a factor contributing to this toxicity.
Grade 3–5 toxicities during dose-limiting toxicity observation period (courses 1 and 2) at least possibly attributable to tipifarnib
Grade 3–5 toxicities after dose-limiting toxicity observation period (courses 3 +) at least possibly attributable to tipifarnib
Nonhematologic grade 4 toxicities included low serum bicarbonate, seizure, and encephalopathy (1 case each). The single grade 5 toxicity consisted of a central nervous system hemorrhage. This grade 5 hemorrhage occurred in a 4-year-old girl with BSG who had unusually rapid clinical deterioration and radiographic progression before enrollment on study. CNS hemorrhage resulted in death after 2 days of tipifarnib therapy, prior to commencement of RT. The patient had no thrombocytopenia, but tipifarnib could not be excluded as a contributing factor.
Seven patients experienced intratumoral hemorrhage, 1 case of which occurred before initiation of protocol treatment. Of the remaining 6 intratumoral hemorrhages, 4 occurred during the first 2 courses of treatment, and 2 occurred after completion of RT. Except for the case of grade 5 intratumoral hemorrhage described above, all cases were asymptomatic lesions noted on imaging.
Although the starting dose of tipifarnib was 125 mg/m2 per dose for all patients, 1 patient required a toxicity-related dose reduction due to rash. One patient continued to receive tipifarnib without evidence of progression or unacceptable toxicities at the completion of the study, 24.2 months (727 days) after initiation of treatment. At the first disease assessment, ~8 weeks after initiation of treatment, 1 patient experienced disease progression. At this 8-week disease evaluation, 5 patients had documented partial responses, and 34 patients had stable disease by institutional call. At the second disease evaluation, ~16 weeks after start of treatment, 2 additional patients had partial responses. Seven patients were without disease progression clinically or radiographically for at least 6 months, 3 of whom had disease controlled for >1 year.
Central neuroimaging review revealed that 1 patient had a >25% increase in tumor size at the completion of irradiation at week 8, followed by 25% decrease on the next scheduled scan at week 16, thus meeting the criteria for “pseudo-progression” (Figure ). On the basis of central review, 3 patients at week 8 showed progressive disease by MRI; for 2 of them, the treating site reported progressions as well, one concurrently and another 20 weeks later; the third patient withdrew from therapy without institutional documentation of progression at week 17. At the scheduled week 16 scan, central reviews of MRIs showed progression for 14 additional patients, of which 5 cases were synchronous with progression reports by the treating sites. One patient withdrew from therapy without institutional documentation of progression at week 20. For the remaining 8 patients, progression was reported by the treating site at a median of 16 weeks (range, 3.7–34 weeks) later than documented by central review.
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 (more ...)
Overall, of 36 patients with at least 1 on-treatment MRI, 29 patients met the 25% threshold for progressive disease by central review, of which 11 cases (38%) were synchronous with progression reported by the treating sites. For 4 patients, the treating sites never reported progression; 3 of these 4 patients discontinued tipifarnib therapy without institutional documentation of progression and died 3, 6, and 6 months after discontinuation of therapy. The fourth patient for whom the treating site never reported progression completed tipifarnib therapy per protocol and is still alive 24.2 months after initiating therapy. This patient's MRI is shown in Figure . For the remaining patients, treating sites reported progression at a median of 14 weeks later (range, 3.7–40.4 weeks) documented by central review.
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 (more ...)
Figure shows an example of bi-dimensional and volumetric measurements for a patient whose condition progressed by both criteria on the same scan and who discontinued treatment at that time (Figure ). Also shown is an example from a patient whose condition progressed at week 30 by volumetric but not by bi-dimensional measurements or clinical criteria. This patient continued to receive treatment, with clinical stability, for 104 weeks despite earlier progression by volumetric criteria; he completed all therapy per protocol, and remains alive as above (Figure ).
Four patients had progression noted by volumetric measurements but never had progression noted by bi-dimensional measurements, whereas 1 patient demonstrated progression by bi-dimensional measurements without reaching the threshold for progression by volumetric analysis. In 4 cases, disease progression was seen by bi-dimensional measurements earlier than by volumetric measurements, whereas in 6 cases, tumor volume indicated progressive disease earlier than tumor area; in each of the 10 cases, the opposite metric subsequently confirmed progression. In sum, Figure demonstrates no differences in PFS regardless of whether progressive disease was defined by central documentation of either increased tumor volume or area or by the treating investigator's summary evaluation of clinical and imaging parameters.
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).