Gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma

Veldhuijzen van Zanten SEM, El-Khouly FE, Jansen MHA, Bakker DP, Sanchez Aliaga E, Haasbeek CJA, Wolf NI, Zwaan CM, Vandertop WP, van Vuurden DG, Kaspers GJL. A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol. 2017 Jul 26. doi:10.1007/s11060-017-2575-9.

Abstract

The purpose of this phase I/II, open-label, single-arm trial is to investigate the safety, tolerability, maximum tolerated dose and preliminary efficacy of the potential radiosensitizer gemcitabine, administered concomitantly to radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Six doses of weekly gemcitabine were administered intravenously, concomitantly to 6 weeks of hyperfractionated radiotherapy. Successive cohorts received increasing doses of 140, 175 and 200 mg/m2 gemcitabine, respectively, following a 3 + 3 dose-escalation schedule without expansion cohort. Dose-limiting toxicities (DLT) were monitored during treatment period. Clinical response was assessed using predefined case report forms and radiological response was assessed using the modified RANO criteria. Quality of life (QoL) was assessed using PedsQL questionnaires. Between June 2012 and December 2016, nine patients were enrolled. Treatment was well tolerated, and no DLTs were observed up to the maximum dose of 200 mg/m2. All patients experienced reduction of tumor-related symptoms. QoL tended to improve during treatment. PFS and MOS were 4.8 months (95% CI 4.0-5.7) and 8.7 months (95% CI 7.0-10.4). Classifying patients according to the recently developed DIPG survival prediction model, intermediate risk patients (n = 4), showed a PFS and MOS of 6.4 and 12.4 months, respectively, versus a PFS and MOS of 4.5 and 8.1 months, respectively, in high risk patient (n = 5). Gemcitabine up to 200 mg/m2/once weekly, added to radiotherapy, is safe and well tolerated in children with newly diagnosed DIPG. PFS and MOS were not significantly different from literature.

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A phase I/II, open–label, single–arm trial was carried out with the goal to study the safety, tolerability, maximum tolerated dose and preliminary efficacy of the potential radiosensitizer gemcitabine, administered concomitantly to radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). For this group of patients, gemcitabine up to 200 mg/m2/once weekly, added to radiotherapy, was found to be safe and well tolerated.

Methods

The clinicians administered six doses of weekly gemcitabine intravenously, concomitantly to 6 weeks of hyperfractionated radiotherapy.

Moreover, they gave increasing doses of 140, 175 and 200 mg/m2 gemcitabine to successive cohorts, following a 3+3 dose-escalation schedule without expansion cohort.

Monitoring was done for dose-limiting toxicities (DLT) during treatment period.

They used predefined case report forms to evaluate clinical response.

Radiological response was assessed using the modified RANO criteria.

PedsQL questionnaires were utilized to appraise quality of life (QoL).

Results

This study incorporated nine patients, between June 2012 and December 2016.

Treatment was found to be well tolerated.

This study did not find DLTs up to the maximum dose of 200 mg/m2.

Reduction of tumor-related symptoms were observed in all patients.

Findings reported that QoL tended to improve during treatment.

4.8 months (95% CI 4.0–5.7) and 8.7 months (95% CI 7.0–10.4) were PFS and MOS.

By classifying patients according to the recently developed DIPG survival prediction model, this study noticed a PFS and MOS of 6.4 and 12.4 months in intermediate risk patients (n=4), versus a PFS and MOS of 4.5 and 8.1 months, respectively, in high risk patient (n=5).

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