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Diffuse Intrinsic Pontine GliomaPhase 2DIPGNCT03620032

Study of Re-irradiation at Relapse Versus RT and Multiple Elective rt Courses

A Phase 2 study testing Nimotuzumab, Vinorelbine and Radiotherapy in people with Diffuse Intrinsic Pontine Glioma, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

Prospective, non-blinded, randomised two cohorts study on the efficacy of two different radiotherapy schedule for DIPG by using the same concomitant and post-radiotherapy systemic treatment. Read more about this study

Who is it for?
Ages 2 to 21 years
Conditions the study is for
Diffuse Intrinsic Pontine Glioma
What is being tested?
Nimotuzumab, Vinorelbine and Radiotherapy
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
54 participants
Where
1 siteItaly
Study dates
2 Nov 2015to 2 Nov 2024
Phase
Phase 2
Are there results?
None posted in the registry

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 2 to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Patients from 2 to 21 years old will be eligible
  • No previous treatment consented apart from steroids
  • Strict eligibility criteria will radiologically-verified DIPG (an intrinsic, pontine-based infiltrative lesion hypointense on T1- and hyperintense on T2-weighted sequences, involving at least 2/3 of the pons)
  • symptoms lasting less than 6 months, life expectancy ≥4 weeks; Karnowski/Lansky performance status ≥ 40 %
  • no organ dysfunction; no pregnancy or breast-feeding
  • Patients undergo baseline cranial MRI with gadolinium, to be repeated if treatment begins more than 2 weeks; spinal MRI due to the occurrence of metastatic cases at diagnosis will also be mandatory
  • Written and signed informed consent from parents or legal guardians will be obtained before starting the treatment.

Who cannot join

  • Patients below 2 years or over 21
  • Pre-treatment with radio or chemotherapy
  • Neurofibromatosis 1
  • Non-typical imaging
  • Symptoms duration over 6 months, Lansky/Karnowski scores below 40%
  • Metastatic disease as shown by MRI
  • Organ dysfunction, pregnancy or breast-feeding
  • Absence of parents, patient or tutor consent

Trial locations and contacts

1 site in 1 country.

Italy1 site

  • Fondazione IRCCS Istituto Nazionale Tumori

    Milan, 20133

Other trials in Italy

About this study

Official title: Phase 2 Randomized Study of RT and Reirradiation at Relapse vs Multiple Elective RT Courses With Same Concomitant CT for Newly Diagnosed

Prospective, non-blinded, randomised two cohorts study on the efficacy of two different radiotherapy schedule for DIPG by using the same concomitant and post-radiotherapy systemic treatment.

Read the detailed description
  1. st cohort: Standard Arm with Radiotherapy, Nimotuzumab and vinorelbine Nimotuzumab 150 mg /m2/d as iv short-term infusion for 30 min weekly in week 1-12 and Vinorelbine 20 mg/m2/d weekly in week 1-12 as iv short-term infusion for 30 min (Induction phase).1st re-evaluation week 13 (day 85-91). In case of non-progressive disease: Nimotuzumab 150 mg/m2/d iv short-term infusion for 30 min and Vinorelbine 25 mg/m2/d as iv short-term infusion for 30 min every two weeks in week 14, 16, 18, 20, 22, 24 (Consolidation phase I) 2nd re-evaluation week 25, thereafter in case of non-progressive disease.Nimotuzumab 150 mg/m2/d iv short-term infusion for 30 min and Vinorelbine 25 mg/m2/d as iv short-term infusion for 30 min every two weeks , with re-evaluation at week 37 and any 12 weeks until progression or maximum at week 108. Irradiation will be scheduled to begin in the 3rd week after starting the nimotuzumab and vinorelbine treatment. A total dose of 54 Gy will be delivered, in 1.8 Gy daily fractions 5 days a week, with a 6 MV linear accelerator. To plan radiotherapy, CT images will be acquired with a 2 mm slice thickness, with patients positioned ready for treatment, their heads immobilized with a custom-made thermoplastic mask. Each patient's CT images will be co-registered with T2-weighted, gadolinium enhanced T1-weighted, and fluid-attenuated inversion recovery MRI sequences to identify the gross target volume (GTV) precisely. A three-dimensional conformal radiotherapy technique with 5 or 6 coplanar or non-coplanar beams or an intensity modulated radiotherapy technique will be adopted. Re-irradiation at progression.In case of local progressive disease, after obtaining a new consent from parents/patient if the case, a full course of re-irradiation will be proposed with 19.8 Gy, fractionated over 11 days.
  2. -cohort: Experimental arm with Nimotuzumab + Vinorelbine and refracted radiotherapy doses. Nimotuzumab 150 mg/m2/d as iv short-term infusion for 30 min weekly in week 1-12 and Vinorelbine weekly 20 mg/m2/d in week 1-12 as iv short-term infusion for 30 min (Induction phase, as for standard arm); 1st re-evaluation week 13. In case of non-progressive disease, any other week, Nimotuzumab 150 mg/m2 as iv short-term infusion for 30 min and Vinorelbine 25 mg/m2/d as iv short-term infusion for 30 min until progression or maximum at week 108;2nd re-evaluation week 25, thereafter in case of non-progressive disease re-irradiation one for a total of 19.8 Gy in 11 fractions at 1.8 Gy/day from week 26 to week 28 together with vinorelbine/nimotuzumab continuation any other week;3rd re-evaluation week 37, thereafter in case of non-progressive disease vinorelbine/nimotuzumab continuation any other week;4th re-evaluation week 45, thereafter in case of non-progressive disease: re-irradiation two for a total of 19.8 Gy in 11 fractions at 1.8 Gy/day from week 46 to week 48 together with vinorelbine/nimotuzumab continuation any other week;Further re-evaluation will be done at week 61 and thereafter any 12 weeks as for standard arm continuing vinorelbine and nimotuzumab until progression or maximum at week 108 .Patients will continue with re-irradiation courses also in case of progressive disease, and will continue to be evaluated for OS.Irradiation will be scheduled to begin in the 3rd week after starting the nimotuzumab and vinorelbine treatment. For the first course, a total dose of 36 Gy will be delivered, in 1.8 Gy daily fractions 5 days a week, with a 6 MV linear accelerator. To plan radiotherapy, CT images will be acquired with a 2 mm slice thickness, with patients positioned ready for treatment, their heads immobilized with a custom-made thermoplastic mask. Each patient's CT images will be co-registered with T2-weighted, gadolinium enhanced T1-weighted, and fluid-attenuated inversion recovery MRI sequences to identify the gross target volume (GTV) precisely. A three-dimensional conformal radiotherapy technique with 5 or 6 coplanar or non-coplanar beams or an intensity modulated radiotherapy technique will be adopted.The second course will be planned after second evaluation. It will be scheduled from week 26 to week 28 and planning will follow same guidelines as first course. The course of re-irradiation will be proposed with 19.8 Gy, fractionated over 11 days.

The third and last course will be planned after forth evaluation. It will be scheduled from week 46 to week 48 and planning will follow same guidelines as first and second course (radiation and first re-irradiation). The course of re-irradiation will be proposed with 19.8 Gy, fractionated over 11 days.

Re-irradiation at progression. n case of local progressive disease after the whole three radiotherapy courses, after obtaining a new consent form parents/patient if the case, a course of re-irradiation will be proposed with 9 Gy total dose, fractionated over 5 days.

Being tested
Nimotuzumab, Vinorelbine, Radiotherapy
Medical subject headings
Diffuse Intrinsic Pontine Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NimotuzumabDrug

    Also called humanized therapeutic monoclonal antibody

    humanized therapeutic monoclonal antibody against epidermal growth factor receptor (EGFR)

  • VinorelbineDrug

    Also called Chemotherapy

    Chemotherapy

  • RadiotherapyOther

    RADIOTHERAPY SCHEDULE IS DESCRIBED FOR BOTH GROUPS IN THE PERAGRAPH TITLET ARMS

Study groups in NCT03620032
Study groupRoleWhat they receive
Standard treatmentOtherNimotuzumab 150 mg /mq/d as iv weekly and Vinorelbine 20 mg/mq/d weekly, in week 1-12 (Induction phase).If not progression Nimotuzumab 150 mg/m2 as iv and Vinorelbine 25 mg/m²/d as iv until progression or maximum at week 108; in case of non-progressive disease re-irradiation 1 for a total of 19.8 Gy from week 26 to week 28; in case of non-progressive disease: re-irradiation 2 for a total of 19.8 Gy from week 46 to week 48. Irradiation will be scheduled to begin in the 3rd week after starting the nimotuzumab and vinorelbine treatment. For the first course, a total dose of 36 Gy will be delivered, in 1.8 Gy daily fractions 5 days a week.
Receives: Drug: Nimotuzumab; Drug: Vinorelbine; Other: Radiotherapy
Experimental treatmentExperimentalNimotuzumab 150 mg /mq/d as iv weekly and Vinorelbine 20 mg/mq/d weekly, in week 1-12 (Induction phase).If not progression Nimotuzumab 150 mg/m2 as iv and Vinorelbine 25 mg/m²/d as iv until progression or maximum at week 108; in case of non-progressive disease re-irradiation 1 for a total of 19.8 Gy from week 26 to week 28; in case of non-progressive disease: re-irradiation 2 for a total of 19.8 Gy from week 46 to week 48. Irradiation will be scheduled to begin in the 3rd week after starting the nimotuzumab and vinorelbine treatment. For the first course, a total dose of 36 Gy will be delivered, in 1.8 Gy daily fractions 5 days a week.
Receives: Drug: Nimotuzumab; Drug: Vinorelbine; Other: Radiotherapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression free survival (PFS)

    Primary aim of this study will be to compare the best response up to 36 weeks (CR+PR) between conventional and experimental irradiation. Such an end point was chosen since tumor reduction has been demonstrated to be correlated with better PFS and OS. The response will be evaluated according to radiological and clinical criteria. Radiological criteria will be RECIST ones.

    Measured: 3 years

Secondary outcomes (8)

  1. disease stabilization rate

    the disease stabilization rates (considering only the number of patients with stable disease) will be calculated in the two treatment arms, together with the corresponding binomial 95% confidence intervals.

    Measured: 3 years

  2. PFS

    Progression-free survival (PFS) will be measured from the date of randomisation to the date of event, defined as progression or death due to any cause. Patients with no event as the time of the analysis will be censored at their last adequate tumour assessment. PFS will be estimated in the two treatment arms by the Kaplan-Meier method.

    Measured: 3 years

  3. OS

    Overall survival (OS) will be measured from the date of randomisation to the date of death due to any cause and will be censored at the date of last follow-up for patients alive at their last follow-up. OS will be estimated in the two treatment arms by the Kaplan-Meier method.

    Measured: 3 years

  4. radiotherapy toxicity (adverse events)

    The toxicity will be measured through the control of adverse events. The evaluation of adverse events will be done through the CTCAE 4.03 table.

    Measured: 3 years

  5. PedsQL (Paediatric Quality of Life Questionnaire)

    quality of life evaluation;

    Measured: 3 years

  6. EORTC QLQ-C30 (Quality of Life Questionnaire)

    quality of life evaluation

    Measured: 3 years

  7. Brain module (BN20)

    quality of life evaluation

    Measured: 3 years

  8. SDQ (Strength and Difficulties Questionnaire)

    quality of life evaluation

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Aug 2018
  2. Study start2 Nov 2015
  3. Primary completion11 Nov 2022
  4. Study completion2 Nov 2024 (estimated)

Resources

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
Randomised
Intervention model
Parallel groups
Model description
Prospective, non-blinded, randomised two cohorts study
Masking
None (open label)
Enrolment
54 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03620032
Sponsor's protocol ID
2015-002185-23
Other IDs
2015
Acronym
DIPG
Status last verified
Nov 2023
First submitted
14 May 2018
Last updated
6 Dec 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Bode U, Buchen S, Warmuth-Metz M, Pietsch T, Bach F, Fleischhack G. Final report of a phase II trial of nimotuzumab in the treatment of refractory and relapsed high-grade gliomas in children and adolescents [abstract]. J Clin Oncol (2007); 25(Suppl. 2006)

  • Bartels U, Wolff J, Gore L, Dunkel I, Gilheeney S, Allen J, Goldman S, Yalon M, Packer RJ, Korones DN, Smith A, Cohen K, Kuttesch J, Strother D, Baruchel S, Gammon J, Kowalski M, Bouffet E. Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma. Neuro Oncol. 2014 Nov;16(11):1554-9. doi: 10.1093/neuonc/nou091. Epub 2014 May 20.

    PubMed 24847085

  • Bernier-Chastagner V, Grill J, Doz F, Bracard S, Gentet JC, Marie-Cardine A, Luporsi E, Margueritte G, Lejars O, Laithier V, Mechinaud F, Millot F, Kalifa C, Chastagner P. Topotecan as a radiosensitizer in the treatment of children with malignant diffuse brainstem gliomas: results of a French Society of Paediatric Oncology Phase II Study. Cancer. 2005 Dec 15;104(12):2792-7. doi: 10.1002/cncr.21534.

    PubMed 16265674

  • Bode U, Massimino M, Bach F, Zimmermann M, Khuhlaeva E, Westphal M, Fleischhack G. Nimotuzumab treatment of malignant gliomas. Expert Opin Biol Ther. 2012 Dec;12(12):1649-59. doi: 10.1517/14712598.2012.733367. Epub 2012 Oct 8.

    PubMed 23043252

  • Clerk-Lamalice O, Reddick WE, Li X, Li Y, Edwards A, Glass JO, Patay Z. MRI Evaluation of Non-Necrotic T2-Hyperintense Foci in Pediatric Diffuse Intrinsic Pontine Glioma. AJNR Am J Neuroradiol. 2016 Oct;37(10):1930-1937. doi: 10.3174/ajnr.A4814. Epub 2016 May 19.

    PubMed 27197987

  • Conway AE, Reddick WE, Li Y, Yuan Y, Glass JO, Baker JN, Kun LE, Broniscer A, Patay Z. "Occult" post-contrast signal enhancement in pediatric diffuse intrinsic pontine glioma is the MRI marker of angiogenesis? Neuroradiology. 2014 May;56(5):405-12. doi: 10.1007/s00234-014-1348-9. Epub 2014 Mar 14.

    PubMed 24626721

  • Lobel U, Sedlacik J, Reddick WE, Kocak M, Ji Q, Broniscer A, Hillenbrand CM, Patay Z. Quantitative diffusion-weighted and dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging analysis of T2 hypointense lesion components in pediatric diffuse intrinsic pontine glioma. AJNR Am J Neuroradiol. 2011 Feb;32(2):315-22. doi: 10.3174/ajnr.A2277. Epub 2010 Nov 18.

    PubMed 21087935

  • Hargrave D, Chuang N, Bouffet E. Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma. J Neurooncol. 2008 Feb;86(3):313-9. doi: 10.1007/s11060-007-9473-5. Epub 2007 Oct 2.

    PubMed 17909941

  • Jansen MH, Veldhuijzen van Zanten SE, Sanchez Aliaga E, Heymans MW, Warmuth-Metz M, Hargrave D, van der Hoeven EJ, Gidding CE, de Bont ES, Eshghi OS, Reddingius R, Peeters CM, Schouten-van Meeteren AY, Gooskens RH, Granzen B, Paardekooper GM, Janssens GO, Noske DP, Barkhof F, Kramm CM, Vandertop WP, Kaspers GJ, van Vuurden DG. Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria. Neuro Oncol. 2015 Jan;17(1):160-6. doi: 10.1093/neuonc/nou104. Epub 2014 Jun 5.

    PubMed 24903904

  • Poussaint TY, Kocak M, Vajapeyam S, Packer RI, Robertson RL, Geyer R, Haas-Kogan D, Pollack IF, Vezina G, Zimmerman R, Cha S, Patay Z, Boyett JM, Kun LE. MRI as a central component of clinical trials analysis in brainstem glioma: a report from the Pediatric Brain Tumor Consortium (PBTC). Neuro Oncol. 2011 Apr;13(4):417-27. doi: 10.1093/neuonc/noq200. Epub 2011 Feb 4.

    PubMed 21297126

  • Zaghloul MS, Eldebawy E, Ahmed S, Mousa AG, Amin A, Refaat A, Zaky I, Elkhateeb N, Sabry M. Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): a randomized controlled trial. Radiother Oncol. 2014 Apr;111(1):35-40. doi: 10.1016/j.radonc.2014.01.013. Epub 2014 Feb 20.

    PubMed 24560760

  • Wolff JE, Westphal S, Molenkamp G, Gnekow A, Warmuth-Metz M, Rating D, Kuehl J. Treatment of paediatric pontine glioma with oral trophosphamide and etoposide. Br J Cancer. 2002 Oct 21;87(9):945-9. doi: 10.1038/sj.bjc.6600552.

    PubMed 12434281

  • Wolff JE, Wagner S, Reinert C, Gnekow A, Kortmann RD, Kuhl J, Van Gool SW. Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma. J Neurooncol. 2006 Sep;79(3):315-21. doi: 10.1007/s11060-006-9147-8. Epub 2006 Apr 28.

    PubMed 16645718

  • Wolff JE, Kortmann RD, Wolff B, Pietsch T, Peters O, Schmid HJ, Rutkowski S, Warmuth-Metz M, Kramm C. High dose methotrexate for pediatric high grade glioma: results of the HIT-GBM-D pilot study. J Neurooncol. 2011 May;102(3):433-42. doi: 10.1007/s11060-010-0334-2. Epub 2010 Aug 8.

    PubMed 20694800

  • Wolff JE, Driever PH, Erdlenbruch B, Kortmann RD, Rutkowski S, Pietsch T, Parker C, Metz MW, Gnekow A, Kramm CM. Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol. Cancer. 2010 Feb 1;116(3):705-12. doi: 10.1002/cncr.24730.

    PubMed 19957326

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nimotuzumab, Vinorelbine and Radiotherapy in people with Diffuse Intrinsic Pontine Glioma, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 6 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression free survival (PFS) (time frame: 3 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03620032, which also lists 53 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2023.

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