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

NCT02758366 | Terminated Phase 2

• 2 other identifiers: GBMTMZ/DOX20152015-002307-28
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (4)

• Event free survival

  2 months

• Overall survival

  2 months

• Progression free survival

  2 months

• Rate of treatment response

  2 months

Study Arms (1)

Doxorubicin

EXPERIMENTAL

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

Interventions

Doxorubicin DRUG

Doxorubicin

Eligibility Criteria

• Age: 3 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Meyer Children's Hospital IRCCS: lead

Study Sites (1)

Meyer Children's Hospital

Florence, 50145, Italy

Location

Related Publications (12)

• 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. doi: 10.1038/sj.cdd.4401872. Epub 2006 Feb 3. No abstract available.

  PMID: 16456578 BACKGROUND

• 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. doi: 10.1056/NEJMoa043330.

  PMID: 15758009 BACKGROUND

• 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.

  PMID: 21813279 BACKGROUND

• Beier CP, Schmid C, Gorlia T, Kleinletzenberger C, Beier D, Grauer O, Steinbrecher A, Hirschmann B, Brawanski A, Dietmaier C, Jauch-Worley T, Kolbl O, Pietsch T, Proescholdt M, Rummele 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.

  PMID: 19725960 BACKGROUND

• 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.

  PMID: 21345842 BACKGROUND

• 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.

  PMID: 26194676 BACKGROUND

• 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.

  PMID: 16312042 BACKGROUND

• 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.

  PMID: 18751431 BACKGROUND

• 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.

  PMID: 10368637 BACKGROUND

• 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.

  PMID: 19821337 BACKGROUND

• 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.

  PMID: 23637844 BACKGROUND

• 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.

  PMID: 21880994 BACKGROUND

MeSH Terms

Conditions

Glioblastoma; Neoplasms, Neuroepithelial; Astrocytoma; Glioma; Diffuse Intrinsic Pontine Glioma

Interventions

Doxorubicin

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: April 27, 2016
• First Posted: May 2, 2016
• Study Start: February 1, 2016
• Primary Completion: January 16, 2020
• Study Completion: January 16, 2020
• Last Updated: February 9, 2021

Record last verified: 2021-02

Locations

IT (1)