International Cooperative Phase III Trial of the HIT-HGG Study Group (HIT-HGG-2013)

Indication:

First-line treatment of high grade gliomas, diffuse intrinsic pontine glioma, and gliomatosis cerebri in paediatric patients < 18 years of age.

Background:

Based on published preclinical and clinical results regarding the potential therapeutic benefit of adult and pediatric high grade glioma patients receiving the histone deacetylase (HDAC) inhibitor valproic acid (VPA; Barker et al. 2013; Wolff et al. 2008, 2011; Felix et al. 2011; Su et al. 2011; Rokes et al. 2010; Masoudi et al. 2008; Guthrie et al. 2013; Weller et al. 2011) in addition to radiochemotherapy, the present trial is aimed to investigate if the addition of VPA to radiochemo- and maintenance therapy with temozolomide (Stupp et al. 2005; Cohen et al. 2011a, b) provides a survival advantage in comparison to radiochemo- and maintenance therapy with temozolomide alone. Therapeutic efficiency of VPA will be evaluated by comparison with a historical patient control from the previous trial HIT-HGG-2007 with temozolomide radiochemo- and maintenance therapy alone. Besides therapeutic efficiencies as indicated by event-free survival (EFS) and overall survival (OS) treatment-related toxicities will also be analysed.

Therapy:

TMZ and VPA will be studied as investigational medicinal products in the present trial.

• Trial treatment will be performed as follows: Surgery with best possible extent of tumour resection

• Start as soon as diagnosis is confirmed with VPA 10 mg/kg/d in two daily doses preferencially as NONRETARDED FORMULA (e.g. Valproat-neuraxpharm®, Valproat-neuraxpharm® Lösung, Ergenyl®, Ergenyl®-Lösung or Orfiril® Saft; however, any VPA preparation including generic drugs is allowed; the use of a retarded formula might be helpful in some case as indicated below), increase by 10 mg/kg/d once per week up until recommended target Serum level of 75-100 μg/ml (520-694 μmol/L) is reached. If target serum levels cannot be reached with non-retarded formula and/or side effects occur which might be connected to VPA, change to a retarded formula may be helpful to obtain sufficient VPA serum levels and/or reduce side effects. If VPA target serum levels are still not reached and/or side effects occur even with a retarded VPA formula, please contact the HIT-HGG study office.

After start of VPA induction with simultaneous radiochemotherapy:

• Fractionated, locoregional radiotherapy, total dose 54-60 Gy

• Simultaneous chemotherapy with oral temozolomide, 7 days per week at 75 mg/m2/d, starting at day 1 for the entire period of radiotherapy (at maximum 49 days; oral temozolomide treatment may be started in single cases at maximum 7 days before radiotherapy if the 49 days treatment period still fully covers radiotherapy).

• Please, use temozolomide capsules (for oral application) and temozolomide powder (for preparation of an intravenously applicable solution). Any temozolomide preparation including generic drugs is allowed except for patients who are not able to swallow capsules and in whom the use of an intravenous solution is no Option only Temodal® capsules must be used to generate a temozolomide suspension as described in the Appendix A.11. Parents have to be advised how to prepare the Temodal® suspension at the trial site. PLEASE NOTE: Capsules of generic temozolomide drugs other than Temodal® MUST NOT be opened and used for generating temozolomide suspension.

• Maintenance therapy with daily VPA and temozolomide four weeks after simultaneous radiochemotherapy initiation of a 5 day-course of oral temozolomide [150-200 mg/m2/d], repeated every 28 days for in total 12 courses VPA treatment is performed until day 28 of the 12th course of temozolomide.

• Treatment doses may vary according to available medication formulations and sizes. Thus, deviances of +/- 15% of the recommended doses may be acceptable if not stated otherwise.The starting points of treatment may also vary in single cases. Thus, deviances of +/- 7 days of the recommended time periods to start treatment may be acceptable if not stated otherwise.

Primary end point : Event-free survival

Biometry (regarding the primary objectives):

1. Confirmatory statistical design:

   1. Difference between the treatment with additional VPA and the historic sample from the HIT-HGG-2007 study with respect to EFS. Rejection of H0 will be interpreted as a significant difference between VPA treatment and the historic sample. A directional interpretation will detect either a superiority of the VPA-treatment compared to the historic sample, or a superiority of the historic sample compared to the VPA Treatment sample.

   Statistical tests: adaptive Log-rank test / (conventional) Log-rank test

   Multiple Significance level α(overall) = 5% Power = 80% Assumed 6 months EFS-rates = 55% vs. 70%

   Multiple Testing: No Multiplicity Problem in this trial.

2. Estimated sample sizes:

About 167 recruitments at final analysis

Patient recruitment will be performed for 5,4 years. Individual follow-up (including study treatment) is required for this protocol for at least 1 year and 30 days after study entry. Long-term follow-up is strongly recommended and will be organised according to national guidelines and recommendations.

Financial support:

Deutsche Kinderkrebsstiftung, Bonn, Germany