Glioblastoma (GBM)Phase 2NCT02758366
Prolonged Exposure to Doxorubicin in Patients With Glioblastoma Multiforme and Diffuse Intrinsic Pontine Glioma
A Phase 2 study testing Doxorubicin in people with Glioblastoma (GBM) and DIPG, run by Meyer Children's Hospital IRCCS at 1 site in Italy.
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. Read more about this study
- Who is it for?
- Ages 3 to 30 years
- Conditions the study is for
- Glioblastoma (GBM), DIPG, Brainstem Glioma, Pediatric
- What is being tested?
- Doxorubicin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteItaly
- Study dates
- Feb 2016to 16 Jan 2020
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 30 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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 %;
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- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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)
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
- Being tested
- Doxorubicin
- 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
- Medical subject headings
- Glioblastoma, Neoplasms, Neuroepithelial, Astrocytoma, Glioma, Diffuse Intrinsic Pontine Glioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DoxorubicinDrug
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Doxorubicin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to early discontinuation of the study drug (doxorubicin)
Measured: 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
Measured: 32 months
Number of patients who died for SAE as assessed by CTCAE v4.0
Mortality due to adverse events
Measured: 32 months
Number of patients who undergone to withdrawal of doxorubicin
Rate of early suspension of the study drug (doxorubicin)
Measured: 6 months
Secondary outcomes (4)
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.
Measured: 2 months
Overall survival
Overall survival (OS) defined as time between the date of the enrolment and the death to any cause
Measured: 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
Measured: 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
Measured: 2 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2016 (estimated)
- Study startFeb 2016
- Primary completion16 Jan 2020
- Study completion16 Jan 2020
Why it stopped: Study was terminated due to high heterogeneity of enrolled patients
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Glioblastoma (GBM)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Meyer Children's Hospital IRCCS
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Iacopo Sardi, Meyer Children's Hospital IRCCS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02758366
- Sponsor's protocol ID
- GBMTMZ/DOX2015
- Other IDs
- 2015-002307-28, 2015
- Status last verified
- Feb 2021
- First submitted
- 27 Apr 2016
- Last updated
- 9 Feb 2021
- Results posted
- No
- Data monitoring committee
- No
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. doi: 10.1038/sj.cdd.4401872. Epub 2006 Feb 3. No abstract available.
PubMed 16456578Stupp 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.
PubMed 15758009Ananda 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.
PubMed 21813279Beier 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.
PubMed 19725960Cohen 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.
PubMed 21345842Krauze 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.
PubMed 26194676Lesniak 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.
PubMed 16312042Masoudi 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.
PubMed 18751431Stan 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.
PubMed 10368637van 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.
PubMed 19821337Veringa 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.
PubMed 23637844Weller 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.
PubMed 21880994