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

Anaplastic Astrocytoma Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02758366
• Other study ID #: GBMTMZ/DOX2015
• Secondary ID: 2015-002307-28
• Status: Terminated
• Phase: Phase 2
• Start date: February 2016
• Est. completion date: January 16, 2020

Study information

• Verified date: February 2021
• Source: Meyer Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 21
• Est. completion date: January 16, 2020
• Est. primary completion date: January 16, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 30 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Doxorubicin

Locations

Country	Name	City	State
Italy	Meyer Children's Hospital	Florence

Sponsors (1)

Lead Sponsor	Collaborator
Meyer Children's Hospital

Country where clinical trial is conducted

Italy, 

References & Publications (12)

Ananda S, Nowak AK, Cher L, Dowling A, Brown C, Simes J, Rosenthal MA; Cooperative Trials Group for Neuro-Oncology (COGNO). Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. J Clin Neurosci. 2011 Nov;18(11):1444-8. doi: 10.1016/j.jocn.2011.02.026. Epub 2011 Aug 2. — View Citation

Beier CP, Schmid C, Gorlia T, Kleinletzenberger C, Beier D, Grauer O, Steinbrecher A, Hirschmann B, Brawanski A, Dietmaier C, Jauch-Worley T, Kölbl O, Pietsch T, Proescholdt M, Rümmele P, Muigg A, Stockhammer G, Hegi M, Bogdahn U, Hau P. RNOP-09: pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma--a phase II study. BMC Cancer. 2009 Sep 2;9:308. doi: 10.1186/1471-2407-9-308. — View Citation

Cohen KJ, Heideman RL, Zhou T, Holmes EJ, Lavey RS, Bouffet E, Pollack IF. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group. Neuro Oncol. 2011 Apr;13(4):410-6. doi: 10.1093/neuonc/noq205. Epub 2011 Feb 22. — View Citation

Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C, De Maria R. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006 Jul;13(7):1238-41. Epub 2006 Feb 3. — View Citation

Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, Tofilon PJ, Fine HA, Camphausen K. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma. Int J Radiat Oncol Biol Phys. 2015 Aug 1;92(5):986-992. doi: 10.1016/j.ijrobp.2015.04.038. Epub 2015 Apr 30. — View Citation

Lesniak MS, Upadhyay U, Goodwin R, Tyler B, Brem H. Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. Anticancer Res. 2005 Nov-Dec;25(6B):3825-31. Erratum in: Anticancer Res. 2006 Jan-Feb;26(1a):445. — View Citation

Masoudi A, Elopre M, Amini E, Nagel ME, Ater JL, Gopalakrishnan V, Wolff JE. Influence of valproic acid on outcome of high-grade gliomas in children. Anticancer Res. 2008 Jul-Aug;28(4C):2437-42. — View Citation

Stan AC, Casares S, Radu D, Walter GF, Brumeanu TD. Doxorubicin-induced cell death in highly invasive human gliomas. Anticancer Res. 1999 Mar-Apr;19(2A):941-50. — View Citation

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. — View Citation

van Dalen EC, van der Pal HJ, Caron HN, Kremer LC. Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD005008. doi: 10.1002/14651858.CD005008.pub3. Review. Update in: Cochrane Database Syst Rev. 2016;3:CD005008. — View Citation

Veringa SJ, Biesmans D, van Vuurden DG, Jansen MH, Wedekind LE, Horsman I, Wesseling P, Vandertop WP, Noske DP, Kaspers GJ, Hulleman E. In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma. PLoS One. 2013 Apr 29;8(4):e61512. doi: 10.1371/journal.pone.0061512. Print 2013. — View Citation

Weller M, Gorlia T, Cairncross JG, van den Bent MJ, Mason W, Belanger K, Brandes AA, Bogdahn U, Macdonald DR, Forsyth P, Rossetti AO, Lacombe D, Mirimanoff RO, Vecht CJ, Stupp R. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology. 2011 Sep 20;77(12):1156-64. doi: 10.1212/WNL.0b013e31822f02e1. Epub 2011 Aug 31. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to early discontinuation of the study drug (doxorubicin)		6 months
Primary	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
Primary	Number of patients who died for SAE as assessed by CTCAE v4.0	Mortality due to adverse events	32 months
Primary	Number of patients who undergone to withdrawal of doxorubicin	Rate of early suspension of the study drug (doxorubicin)	6 months
Secondary	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
Secondary	Overall survival	Overall survival (OS) defined as time between the date of the enrolment and the death to any cause	2 months
Secondary	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
Secondary	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