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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	2 Years - 21 Years
Gender	All

More Inclusion & Exclusion Criteria

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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03620032
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Maura Massimino, MD
Principal Investigator Affiliation	Fondazione IRCCS ISTITUTO NAZIONALE TUMORI
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Italy
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Diffuse Intrinsic Pontine Glioma

Additional Details

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.

Arms & Interventions

Arms

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.

Experimental: Experimental treatment

Interventions

Drug: - Nimotuzumab

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

Drug: - Vinorelbine

Chemotherapy

Other: - Radiotherapy

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

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