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

This study is currently recruiting participants.

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Contacts and Locations

Verified April 2016 by Iacopo Sardi, Meyer Children's Hospital

Sponsor:

ClinicalTrials.gov Identifier:

NCT02758366

First Posted: May 2, 2016

Last Update Posted: May 2, 2016

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

Information provided by (Responsible Party):

Iacopo Sardi, Meyer Children's Hospital

Purpose

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).

Condition	Intervention	Phase
Glioblastoma (GBM) DIPG	Drug: Doxorubicin	Phase 2


Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment
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)

Resource links provided by NLM:

Drug Information available for: Doxorubicin Doxorubicin hydrochloride

Genetic and Rare Diseases Information Center resources: Glioblastoma Glioma Diffuse Intrinsic Pontine Glioma Neuroepithelioma

U.S. FDA Resources

Further study details as provided by Iacopo Sardi, Meyer Children's Hospital:

Primary Outcome Measures:

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

Secondary Outcome Measures:

Event free survival [ Time Frame: 2 months ]
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.
Overall survival [ Time Frame: 2 months ]
Overall survival (OS) defined as time between the date of the enrolment and the death to any cause
Progression free survival [ Time Frame: 2 months ]
Progression free survival (PFS) defined as time between the date of the enrolment and the date tumor progression based on RECIST 1.1criteria
Rate of treatment response [ Time Frame: 2 months ]
Rate of treatment response (CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease) based on RECIST 1.1 criteria


Estimated Enrollment:	20
Study Start Date:	February 2016
Estimated Study Completion Date:	July 2020
Estimated Primary Completion Date:	July 2020 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Doxorubicin Patients with new diagnose of GBM and DIPG are treated with Weller-Stupp protocol: initial radiotherapy (1.8 Gy/die, days 1-5; total dose 54 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): 3 cycles of prolonged infusion of Doxorubicin (25mg/m2/die in 24 hours, days 1-4, 28-day cycle; total cumulative dose 300 mg/m2). At week 12: 18 cycles of oral temozolomide (initial dose of 150 mg/m2 increasing to 180 mg/m2 days 1-5, 28-day cycle; total cumulative dose 16200 mg/m2). Oral valproic acid (20-30 mg/Kg/die bid) is administered from week 1 until the last treatment day.	Drug: Doxorubicin

Arms

Assigned Interventions

Experimental: Doxorubicin

Patients with new diagnose of GBM and DIPG are treated with Weller-Stupp protocol: initial radiotherapy (1.8 Gy/die, days 1-5; total dose 54 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): 3 cycles of prolonged infusion of Doxorubicin (25mg/m2/die in 24 hours, days 1-4, 28-day cycle; total cumulative dose 300 mg/m2).

At week 12: 18 cycles of oral temozolomide (initial dose of 150 mg/m2 increasing to 180 mg/m2 days 1-5, 28-day cycle; total cumulative dose 16200 mg/m2).

Oral valproic acid (20-30 mg/Kg/die bid) is administered from week 1 until the last treatment day.

Drug: Doxorubicin

Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:	3 Years to 30 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Males and females patients, aged >3 years and < 30 years;
Histologically confirmed newly diagnosed GBM and MRI T2-scans confirmed DIPG;
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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02758366

Contacts


Contact: Iacopo Sardi, MD, PhD	+390555662631	iacopo.sardi@meyer.it

Locations


Italy
Meyer Children's Hospital	Recruiting
Florence, Italy, 50145
Contact: Iacopo Sardi, MD, PhD +390555662631 iacopo.sardi@meyer.it

Sponsors and Collaborators

Meyer Children's Hospital

More Information

Publications:

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.


Responsible Party:	Iacopo Sardi, MD, PhD, Meyer Children's Hospital
ClinicalTrials.gov Identifier:	NCT02758366 History of Changes
Other Study ID Numbers:	GBMTMZ/DOX2015 2015-002307-28 ( EudraCT Number )
First Submitted:	April 27, 2016
First Posted:	May 2, 2016
Last Update Posted:	May 2, 2016
Last Verified:	April 2016

Keywords provided by Iacopo Sardi, Meyer Children's Hospital:


glioblastoma multiforme high grade glioma diffuse intrinsic pontine glioma DIPG	doxorubicin temozolomide malignant glioma

Additional relevant MeSH terms:


Glioblastoma Glioma Astrocytoma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Doxorubicin Liposomal doxorubicin Temozolomide Valproic Acid Antibiotics, Antineoplastic	Antineoplastic Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Alkylating Alkylating Agents Anticonvulsants GABA Agents Neurotransmitter Agents Physiological Effects of Drugs Antimanic Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs

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