Prolonged Exposure to Doxorubicin in Patients With Glioblastoma Multiforme and Diffuse Intrinsic Pontine Glioma

Study Overview
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Brief Summary
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The standard therapy of glioblastoma (GBM) consists of gross total resection followed by focal irradiation to the tumor bed with concomitant and adjuvant temozolomide (TMZ). The association of valproic acid and TMZ during radiotherapy improves survival of GBM. Preclinical studies suggested that doxorubicin had a strong antineoplastic activity against human gliomas. Moreover, some studies showed that the continuous infusion of anthracyclines in patients with solid tumor ensured a better safety profile compared with bolus administration. Based on these findings, the purpose of this study is to evaluate safety and efficacy of prolonged administration of doxorubicin in combination with radiotherapy, temozolomide and valproic acid in pediatric and adult patients with newly diagnosed GBM and diffuse intrinsic pontine glioma (DIPG).

Official Title
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An Open-label, Single-arm, Phase II Study to Evaluate Safety and Efficacy of Doxorubicin in Combination With Radiotherapy, Temozolomide and Valproic Acid in Patients With Glioblastoma Multiforme (GBM) and Diffuse Intrinsic Pontine Glioma (DIPG)

Conditions
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Glioblastoma (GBM), DIPG, Brainstem Glioma, Pediatric, Diffuse Spinal Glioma, Bilateral Thalamic Glioma, Gliomatosis Cerebri, Anaplastic Astrocytoma, Midline Diffuse Glioma

Intervention / Treatment
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* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females patients, aged >3 years and < 30 years; Newly diagnosed of GBM, DIPG, diffuse brainstem glioma, diffuse spinal glioma, bilateral thalamic glioma, gliomatosis cerebri, anaplastic astrocytoma; Patients undergone either surgery or biopsy only; No prior chemotherapy and/or radiotherapy; Life expectancy ≥ 4 weeks; Karnofsky/Lansky ≥ 40 %; Written informed consent obtained from the patient/parents or legal representative; Adequate hematological function (leucocyte ≥ 2.0 x 10^9/l -Hemoglobin ≥ 10 g/dl - platelet ≥ 50 x 10^9 /l); Adequate liver function (total bilirubin ≤ 2.5 x ULN - ALT/AST ≤ 5.0 x ULN); Adequate renal function (serum creatinine ≤ 1.5 x ULN); Adherence to trial treatment and compliance with the protocol Exclusion Criteria: Any disease or condition that contraindicates the use of the study drug (es. serious mental retardation, brain palsy, congenital syndrome, cardiomyopathy) Prior anti-cancer therapy Pregnancy or breastfeeding Non adequate contraception

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxorubicin<br>Patients are treated with Weller-Stupp protocol: initial radiotherapy (1.8 Gy/die, days 1-5; total dose 54-60 Gy) with concomitant oral temozolomide (75mg/m2/die, days 1-7) per 6 weeks. At week 10 (4 weeks after the chemo-radiotherapy treatment completion): 1 cycle of oral temozolomide (150-180 mg/m2, days 1-5) At week 14 (8 weeks after the chemo-radiotherapy treatment completion) 1 cycle of prolonged infusion of Doxorubicin (25mg/m2/die in 24 hours, days 1-4; total cumulative dose 100 mg/m2). At week 18 (4 weeks after the end of doxorubicin administration): 16 cycles of oral temozolomide (initial dose of 150 mg/m2 increasing to 180 mg/m2 days 1-5, 28-day cycle). Oral valproic acid (20-30 mg/Kg/die bid) is administered from week 1 until the last treatment day. | Drug: Doxorubicin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to early discontinuation of the study drug (doxorubicin) |  | 6 months | 
| Number of participants with treatment-related serious adverse events (SAE) as assessed by CTCAE v4.0 | Number of patients with SAE and SAE leading to withdrawal from the study | 32 months | 
| Number of patients who died for SAE as assessed by CTCAE v4.0 | Mortality due to adverse events | 32 months | 
| Number of patients who undergone to withdrawal of doxorubicin | Rate of early suspension of the study drug (doxorubicin) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival | Event free survival (EFS) defined as time (days) between the date of enrolment and the earliest occurence of anyone of the following: progression based on RECIST 1.1 criteria; tumor recurrence; death to any cause. | 2 months | 
| Overall survival | Overall survival (OS) defined as time between the date of the enrolment and the death to any cause | 2 months | 
| Progression free survival | Progression free survival (PFS) defined as time between the date of the enrolment and the date tumor progression based on RECIST 1.1criteria | 2 months | 
| Rate of treatment response | Rate of treatment response (CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease) based on RECIST 1.1 criteria | 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glioblastoma multiforme, high grade glioma, diffuse intrinsic pontine glioma, DIPG, doxorubicin, temozolomide, malignant glioma, Brainstem Glioma, diffuse spinal glioma, bilateral thalamic glioma, Anaplastic Astrocytoma, Gliomatosis Cerebri, Midline Diffuse Glioma