Between May 30, 2001, and May 13, 2004, a total of 84 eligible patients were enrolled at PBTC institutions: 35 on stratum 1, 33 on stratum 2A, and 16 on stratum 2B (). Median age at study entry was 7.2 years for stratum 1 and 8.9 and 15.4 years on strata 2A and 2B, respectively. The ratios of male to female patients on the three strata were 18:17, 13:20, and 7:9, respectively. The diagnosis was based on imaging criteria alone in 30 patients in stratum 1; in the remaining five patients, the diagnosis was based on clinical, imaging, and histological determination of malignant brainstem glioma. In stratum 2A, 14 patients had recurrent brainstem glioma, based on imaging characteristics, and 19 had nonbrain-stem recurrent astrocytomas, including seven classified as anaplastic astrocytoma, seven as glioblastoma multiforme or gliosarcoma, and five as other malignant gliomas. In stratum 2B, all patients had recurrent nonbrain-stem malignant gliomas, including 11 with anaplastic astrocytoma, two with glioblastoma multiforme, and three with other malignant gliomas.
Characteristics of eligible patients
summarizes the CRM dose escalation and de-escalation decisions, patient evaluability, and DLT observations. Among the 29 eligible patients who were enrolled on stratum 1 following the amendment to begin imatinib therapy after irradiation, nine were inevaluable because they did not receive the study drug: Three were observed to have had asymptomatic ITH after radiotherapy that was not present before irradiation, two had progressive disease during irradiation, one had an infection that precluded beginning imatinib within the scheduled time interval, and three withdrew from the protocol. Of the 20 patients who received imatinib, 3 were not evaluable due to incomplete courses of treatment. All six patients enrolled on stratum 1 prior to the amendment received imatinib and were evaluable. Six of the 33 eligible patients enrolled in stratum 2A were not evaluable for dose finding because of incomplete course of treatment (five) and withdrawal prior to receiving imatinib (one); in addition, seven patients were enrolled at the MTD after dose finding (not included in ) to better define toxicities, and one of these patients was not evaluable because of noncompliance. Four of the eligible patients enrolled in stratum 2B were not evaluable for dose finding because of incomplete course of treatment (three) and withdrawal prior to receiving imatinib (one).
Safety and Toxicity
Prior to amending the protocol to exclude patients with previous evidence of spontaneous ITH, six evaluable patients were enrolled on stratum 1, nine on stratum 2A, and six on stratum 2B. None of three patients on stratum 1 treated with a dose of 200 mg/m2 had a symptomatic hemorrhage, but one experienced a DLT associated with renal insufficiency; one of three patients treated at a dose of 150 mg/m2 had an asymptomatic hemorrhage detected on the scheduled MRI eight weeks after beginning therapy, and a second patient experienced a DLT with an absolute neutrophil count of less than 500/μl. On stratum 2A, nine patients, three each at doses of 350, 465, and 620 mg/m2, were treated, with no patient experiencing a DLT. However after the dose-finding observation period, one child treated at the 465-mg/m2 dose level had a symptomatic hemorrhage, as did two children treated with 620 mg/m2. Two of these children had evidence of previous spontaneous hemorrhages. Similarly on stratum 2B, no DLTs were observed among six evaluable patients; three children each were treated at 350- and 465-mg/m2 dose levels. One child at the 350-mg/m2 dose level had a documented hemorrhage after the dose-finding period and was taken off of therapy after having had multiple previous hemorrhages.
These observations provided an impetus to amend the protocol in October 2001 to exclude patients with evidence of previous hemorrhage, to deliver irradiation and imatinib sequentially in stratum 1, and to increase the DLT monitoring interval from four to eight weeks for patients in strata 2A and 2B. Subsequently, 17, 11, and 6 evaluable patients were enrolled in strata 1, 2A, and 2B, respectively. A summary of the dose-limiting toxicities observed is provided in . Of note, two of the five hemorrhages classified as DLTs were asymptomatic. At the time that dose-finding was stopped for stratum 1, the CRM estimated the MTD (i.e., the dose at which 20% of patients would be expected to experience a DLT during the first eight weeks of treatment) to be 334 mg/m2, implying a dose-finding MTD estimate of 350 mg/m2. However, two of six patients experienced hemorrhages at 350 mg/m2 compared with only one DLT among 11 patients treated with 265 mg/m2. (The latter patient was noted to have had an asymptomatic bleed just outside of the DLT monitoring period. Based on the protocol definitions at that time, this would have met the criteria for a DLT, but this was recognized retrospectively and therefore did not influence dose-escalation determinations, as noted in .) Because of concerns that DLTs are usually reversible but neurological deficits from ITHs often are not, PBTC investigators concluded that the maximum safe dose to recommend for study in a phase II trial for patients with newly diagnosed brainstem gliomas was 265 mg/m2. The CRM-estimated MTD for recurrent high-grade glioma patients not receiving EIACDs (stratum 2A) was 541 mg/m2, implying a dose-finding MTD of 465 mg/m2. However, an MTD was not established in the group of recurrent high-grade glioma patients receiving EIACDs (stratum 2B), with no DLTs in four patients enrolled at the 620- and 800-mg/m2 dose levels. Given the increasing trend during the time period of the study toward using non-enzyme-inducing agents in children with brain tumors who require anticonvulsant therapy and the resultant slow accrual, further escalation was not pursued in this stratum.
Non-dose-limiting adverse events during the DLT monitoring period included nausea, vomiting, headache, and fatigue, generally grade 2 or lower, in approximately half of the patients, which were symptoms that would not be unexpected as a result of the underlying disease process. Grade 3 neutropenia and lymphopenia were observed in five patients each. One additional patient who was entered on stratum 2A after the MTD had been assigned had grade 4 neutropenia during the aforementioned interval. No instance of grade 3 or greater liver function abnormalities was observed. Similarly, none of the patients had grade 3 or greater dermatological toxicity, and only one patient, who was entered on stratum 2A after the MTD had been assigned, had a grade 2 rash.
After the DLT monitoring period, the predominant adverse event that led to stopping the study drug was hemorrhage, which was observed in 10 children. Two of these hemorrhages were asymptomatic and detected only on imaging (grade 3 on CTC 2.0), whereas eight were clinically apparent as a result of new neurological symptoms (grade 4) and confirmed on imaging. A summary of these events is provided in . The six-month estimates of cumulative incidences of hemorrhage for patients treated prior to the protocol amendment, all of whom received study drug, were 33.3% ± 21.3% for the six patients in stratum 1 and 16.7% ± 9.1% for the 18 in stratum 2. Among patients enrolled after the amendment, the six- and nine-month estimates of cumulative incidences of hemorrhage were 18.2% ± 7.5% and 21.9% ± 8.2%, respectively, for the 29 patients in stratum 1 and 13.8% ± 6.6% at both time points for the 31 in stratum 2. Among the patients treated after the amendment who received study drug, six- and nine-month estimates were 10% ± 6.9% and 15% ± 8.4%, respectively, for the 20 patients in stratum 1, and 14.3% ± 6.8% at both time points for the 29 in stratum 2. Subset analyses from strata 2A and 2B showed that both groups had comparable estimates of hemorrhage frequency at both six and nine months.
Imatinib PK data for day 1 of course 1 were available for 37 patients. The median value of the maximum plasma concentration of imatinib (Cmax) ranged from 1.0 μg/ml (2.0 μM) at a dose of 150 mg/m2 on stratum 1 to 6.2 μg/ml (12.6 μM) at a dose of 800 mg/m2 on stratum 2A. The PK parameters for imatinib and its principal metabolite, including the minimum, maximum, and median values, are summarized in and . As indicated, there was substantial variation in the PK parameters among patients. Plasma concentrations as a function of time for imatinib are shown in .
Values of imatinib pharmacokinetic parameters: median (range)
Values of CGP74588 pharmacokinetic parameters: median (range)
Plasma concentrations of imatinib (ng/ml) as a function of time on day 1 of course 1.
Pharmacokinetic data were also available for day 8 of course 1 in 39 patients. As anticipated, the Cmax
and AUC for both imatinib and its metabolite were correspondingly higher on these steady-state measurements ( and ). The mean (±SD) accumulation ratio across different doses (day 8 AUC over day 1 AUC) was 1.57 (±0.43) for strata 1 and 2A combined, and slightly lower 1.25 (±0.44) for stratum 2B. Concentrations of imatinib as a function of time are illustrated in . Steady-state levels obtained before drug administration on days 14, 21, and 28 were available in 32, 33, and 31 patients, respectively, and were comparable to those obtained prior to drug administration on day 8. A mixed model (Diggle et al., 1994
) adjusting for strata and dose found no significant (P
= 0.70) change over time, indicating that steady-state levels were reached by day 8 of drug administration.
Plasma concentrations of imatinib (ng/ml) as a function of time on day 8 of course 1.
Influence of EIACDs on Pharmacokinetic Parameters in Stratum 2A (No EIACDs) Compared with Stratum 2B
To determine whether there was any influence of EIACDs on the metabolism of imatinib, a generalized linear model was used to compare PK parameters between strata 2A and 2B for imatinib and CGP74588 separately for both days 1 and 8, adjusting for dose level as well as potential interactions between stratum and dose. Each of the PK parameters listed in and were analyzed in these models. The interaction term was highly nonsignificant (P > 0.50) in all models except the analysis with respect to the half-life of imatinib on day 8. Since the interaction between dose and stratum was significant (P < 0.001), it was necessary to compare the two strata within each dose level separately. These analyses were performed with exact Wilcoxon tests, and no comparisons were significant at any of the dose levels (all P > 0.10).
Significant differences between the two strata were found among parameters related to plasma concentrations of imatinib itself, and all data pointed to greater systemic exposure in the stratum not receiving EIACDs. Maximum concentrations of imatinib differed significantly between stratum 2A and 2B patients on both days 1 and 8 (P = 0.039 and P = 0.001, respectively). Also, the AUCs differed between the two strata on days 1 and 8 (P = 0.059 and P < 0.001, respectively) and were approximately 60% lower in stratum 2B compared with 2A. In contrast, maximum concentrations and AUCs for the metabolite CGP74588 did not differ significantly between stratum 2A and 2B patients on either day 1 or day 8 (P > 0.34). Accordingly, the dose-normalized CGP74588 to imatinib exposure ratio was approximately doubled in stratum 2B compared with 2A, suggesting an induced imatinib metabolism by EIACDs ().
Dose-normalized exposures as a function of stratum and treatment day for imatinib, CGP74588, and the CGP74588- imatinib ratios.
Association between Pharmacokinetic Parameters and DLTs
Among the eight patients who experienced DLTs, five had at least one PK parameter estimated. Because the number of patients was small, only anecdotal inferences could be made regarding the association between DLTs and PK parameters. For example, the patient treated on stratum 1 at a dose level of 350 mg/m2 who experienced a CNS hemorrhage and had PK data had the highest AUC for both STI571 and its metabolite on day 1 of PK sampling, although this patient represented one of only three with PK data for that stratum and dose. One of the two patients treated on stratum 2A at a dose level of 620 mg/m2 who had a hemorrhage had the highest AUC for STI571 on day 8 among the eight patients with PK data for that stratum, dose, and day, although this patient’s parameters for the metabolite were close to the median values for days 1 and 8. When examined independently of dose level, no obvious association was apparent between either Cmax or AUC and the presence or absence of either a DLT in general or hemorrhage in particular, although the small numbers of patients precluded any statistically based conclusions.
Because this was a phase I study, assessing response and outcome was not a major objective of the analysis, even though the data about them were collected. For stratum 1, among patients treated at or above the recommended phase II dose (n = 20), six-month and one-year EFS rates were 80.0% ± 8.7% and 20.0% ± 8.0%, and survival rates were 100% and 45.0% ± 11.1%, respectively. From an intent-to-treat perspective, taking into consideration all 35 eligible patients who were entered on stratum 1, six-month and one-year EFS rates were 69.9% ± 7.8% and 24.3% ± 7.1%, and survival rates were 94.0% ± 4.1% and 45.5% ± 8.7%, respectively (). Among the subset of 29 who were enrolled after the amendment to receive imatinib after irradiation, including those who did not receive the study drug because of hemorrhage during irradiation, disease progression, or other factors, six-month and one-year EFS rates were 74.4% ± 8.2% and 22.3% ± 7.4%, and survival rates were 92.7% ± 4.9% and 40.8% ± 9.5%, respectively (). For stratum 2A patients treated at or above the MTD (n = 29), the six-month EFS rate was 17.9% ± 6.6%, and the disease of all patients had progressed by one year. For stratum 2B, an MTD was not determined, although the corresponding EFS rates for patients who were treated at dose levels at or above the MTD of stratum 2A (n = 11) were 18.2% ± 9.5% at six months, and again, the disease of all patients had progressed by one year.
Event-free survival and survival among all eligible patients entered on stratum 1 (n = 35).
Event-free survival and survival among the subset of patients entered on stratum 1 to receive imatinib upon completion of irradiation (n = 29).
Two patients from stratum 1 had objective responses, corresponding to a greater than 50% decrease in tumor cross-sectional area compared with the results of the pretreatment scan, although it is impossible to discern whether this simply related to the effect of radiotherapy, the study drug, or a combination thereof. One patient on stratum 2A, who was treated with a dose of 350 mg/m2, also had a greater than 50% reduction in tumor area noted on the scan obtained two months after beginning therapy, although this child subsequently had disease progression at 2.5 months. This response was therefore not sustained for the six-week duration specified by the protocol for declaring a partial response.