Treatment of Children With Recurrent Refractory Brain/Solid Tumours and Recurrent Ependymoma

Official Title

Phase I/Ib Trial of Combined 5'Azacitidine and Carboplatin for Recurrent/Refractory Pediatric Brain and Solid Tumours

Summary:

Many pediatric brain and solid tumours have altered epigenetic landscapes, and altered DNA methylation. As such this study is a Phase I/Ib study of combined 5'Azacitidine with an escalating dose of carboplatin for all recurrent/refractory pediatric brain and solid tumours. The phase I component will establish with maximum tolerated dose of carboplatin with azacytidine. An expansion cohort will be recruited of up to 30 patients will follow consisting of 20 recurrent posterior fossa ependymoma and 10 recurrent supratentorial ependymoma.

Trial Description

Primary Outcome:

• Establish maximum tolerated dose of carboplatin in combination with 5'azacytidine

Secondary Outcome:

• Characterization of the pharmacodynamics of 5'-azacitidine in combination with carboplatin
• Assessment of intratumoural DNA demethylation as a preliminary indication of biological efficacy of this combination.
• Assessment of disease response as a preliminary indication of efficacy of this combination against recurrent, refractory pediatric brain and solid tumours

Aberrant DNA methylation is frequently observed in many pediatric solid tumours, but in particularly several entities such as ependymoma, medulloblastoma, embryonal tumour with multilayered rosettes, atypical/teratoid rhabdoid tumour, neuroblastoma and wilm's tumour have promoter hypermethylation. Treatment with DNMTi (DNA methyltransferase inhibitors) agents such as 5-azacytidine has been shown to be safe and efficacious in adult myelodysplastic syndromes, causing significant decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. However, monotherapy with DNMTi has been shown to result in resistance in leukamia's and efficacy in solid tumours is limited. Synergy between DNMTi and platinum agents has shown promise in pre-clinical models including pediatric ependymoma, and in addition, the combination of demethylating agents with carboplatin has provided promising results in platinum resistant ovarian cancers. However, this approach has not been applied to pediatric solid malignancies, which are attractive targets due to their frequent epigenetic dysregulation.

Platinums are the backbone of therapy for most pediatric solid tumours, and as such it is an attractive hypothesis that part of the reason for resistance to upfront therapies is platinum resistance. Specifically, ependymoma's are highly chemoresistant tumours and studies in preclinical models of ependymoma support that this chemoresistance can be overcome with DNMTi.

There is a clear medical need for new therapies, particularly for relapsed solid tumours, specifically brain tumours. Although pre-clinical data from our group and others suggests DNA demethylase inhibitors to be promising therapies for high risk ependymoma, medulloblastoma and ETMR (embryonal tumour with multilayered rosettes), 5'azacitidine monotherapy has been disappointing in clinical studies of adult solid tumours. Previous studies have suggested that platinum therapy can be effectively combined with azacitidine therapy and based on adult studies, maximum demethylation occurs approximately 5-10 days after treatment with 5'azacitidine. As such combination of azacitidine and carboplatin is a rationale therapy for several pediatric brain tumours, particularly those with a hypermethylated phenotype.

Two phases of the study will be conducted. The Phase I will establish the maximum tolerated dose of carboplatin and 5'azacytidine in a rolling 6 design. 5'azacytidine will be administered on Days 1-7 followed by Carboplatin on Day 15. The initial dose level will be 5'Azacytidine 75mg/m2/day for 7 days with Carboplatin administered on Day 15 at AUC (Area under curve) 4. Carboplatin will be dose escalated to a maximum of AUC 6, or de-escalated to AUC 3. The Phase Ib will be an ependymoma specific expansion cohort at the established MTD (maximum tolerated dose), to determine the feasibility and initial efficacy of the combination of carboplatin and 5'azacytidine in patients with recurrent/refractory posterior fossa and supratentorial ependymoma.

View this trial on ClinicalTrials.gov