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

December 5, 2023 updated by: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Milan, Italy, 20133
        • Fondazione IRCCS Istituto Nazionale Tumori

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Standard treatment
Nimotuzumab 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.
Drug: Vinorelbine
Chemotherapy
Other Names:
  • Chemotherapy
Drug: Nimotuzumab
humanized therapeutic monoclonal antibody against epidermal growth factor receptor (EGFR)
Other Names:
  • humanized therapeutic monoclonal antibody
Other: Radiotherapy
RADIOTHERAPY SCHEDULE IS DESCRIBED FOR BOTH GROUPS IN THE PERAGRAPH TITLET ARMS
Experimental: Experimental treatment
Nimotuzumab 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.
Drug: Vinorelbine
Chemotherapy
Other Names:
  • Chemotherapy
Drug: Nimotuzumab
humanized therapeutic monoclonal antibody against epidermal growth factor receptor (EGFR)
Other Names:
  • humanized therapeutic monoclonal antibody
Other: Radiotherapy
RADIOTHERAPY SCHEDULE IS DESCRIBED FOR BOTH GROUPS IN THE PERAGRAPH TITLET ARMS

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression free survival (PFS)
Time Frame: 3 years
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.
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
disease stabilization rate
Time Frame: 3 years
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.
3 years
PFS
Time Frame: 3 years
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.
3 years
OS
Time Frame: 3 years
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.
3 years
radiotherapy toxicity (adverse events)
Time Frame: 3 years
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.
3 years
PedsQL (Paediatric Quality of Life Questionnaire)
Time Frame: 3 years
quality of life evaluation;
3 years
EORTC QLQ-C30 (Quality of Life Questionnaire)
Time Frame: 3 years
quality of life evaluation
3 years
Brain module (BN20)
Time Frame: 3 years
quality of life evaluation
3 years
SDQ (Strength and Difficulties Questionnaire)
Time Frame: 3 years
quality of life evaluation
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Collaborators

University of Roma La Sapienza
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Johannes Gutenberg University Mainz
Wuerzburg University Hospital

Investigators

  • Principal Investigator: Maura Massimino, MD, Fondazione IRCCS Istituto Nazionale Tumori

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 2, 2015

Primary Completion (Actual)

November 11, 2022

Study Completion (Estimated)

November 2, 2024

Study Registration Dates

First Submitted

May 14, 2018

First Submitted That Met QC Criteria

August 2, 2018

First Posted (Actual)

August 8, 2018

Study Record Updates

Last Update Posted (Actual)

December 6, 2023

Last Update Submitted That Met QC Criteria

December 5, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2015-002185-23

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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