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

Study Overview
=================
Brief 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.

Detailed Description
-----------------
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. -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.

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

Conditions
-----------------
Diffuse Intrinsic Pontine Glioma

Intervention / Treatment
-----------------
* Drug: Nimotuzumab
* Drug: Vinorelbine
* Other: Radiotherapy


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, non-blinded, randomised two cohorts study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard treatment<br>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: Nimotuzumab<br>* humanized therapeutic monoclonal antibody against epidermal growth factor receptor (EGFR)<br>* Other names: humanized therapeutic monoclonal antibody;Drug: Vinorelbine<br>* Chemotherapy<br>* Other names: Chemotherapy;Other: Radiotherapy<br>* RADIOTHERAPY SCHEDULE IS DESCRIBED FOR BOTH GROUPS IN THE PERAGRAPH TITLET ARMS<br>|
| Experimental: Experimental treatment<br>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: Nimotuzumab<br>* humanized therapeutic monoclonal antibody against epidermal growth factor receptor (EGFR)<br>* Other names: humanized therapeutic monoclonal antibody;Drug: Vinorelbine<br>* Chemotherapy<br>* Other names: Chemotherapy;Other: Radiotherapy<br>* RADIOTHERAPY SCHEDULE IS DESCRIBED FOR BOTH GROUPS IN THE PERAGRAPH TITLET ARMS<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 years | 
| 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. | 3 years | 
| 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. | 3 years | 
| 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. | 3 years | 
| PedsQL (Paediatric Quality of Life Questionnaire) | quality of life evaluation; | 3 years | 
| EORTC QLQ-C30 (Quality of Life Questionnaire) | quality of life evaluation | 3 years | 
| Brain module (BN20) | quality of life evaluation | 3 years | 
| SDQ (Strength and Difficulties Questionnaire) | quality of life evaluation | 3 years |