AGuIX Nanoparticles With Radiotherapy Plus Concomitant Temozolomide in the Treatment of Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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This is a phase I/II clinical trial evaluating the association of AGuIX nanoparticles with radiotherapy plus concomitant Temozolomide in the treatment of newly diagnosed glioblastoma. The primary objectives of this study were to determine the recommended dose of AGuIX in combination with radiotherapy and TMZ during the concomitant radiochemotherapy period (phase I) and to estimate the efficacy of the combination radiochemotherapy + AGuIX (recommended dose), measured by the 6-month progression-free survival rate (PFS) (phase II) Three dose levels of intravenous AGuIX nanoparticles will be explored: 50 mg/kg, 75 mg/kg and 100 mg/kg.

Official Title
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Phase I/II Study of AGuIX Nanoparticles With Radiotherapy Plus Concomitant Temozolomide in the Treatment of Newly Diagnosed Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Polysiloxane Gd-Chelates based nanoparticles (AGuIX)
* Radiation: radiotherapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological diagnosis of grade IV glioblastoma (biopsy or partial surgery) Patient not operated or partial resection KPS ≥ 70% Age ≥ 18 years old and <75 years old Life expectancy ≥ 6 months Platelets ≥ 100,000 / mm3 PNN ≥ 2000 / mm3 Hb ≥ 10 g / dL Creatinine <1.5 times the upper normal limit or clearance according to Cockcroft-Gault ≥ 50 mL / min Liver function (GGT, PAL, ASAT, ALAT, bilirubin) <1.5 times the upper normal limit For patients receiving treatment with corticosteroids, treatment with corticosteroids must be at a stable or decreasing dose for at least 14 days before inclusion Patient able to swallow and retain oral medication Negative serum pregnancy test within 7 days before the first administration of treatment for women Women of childbearing potential and men whose partners are of childbearing potential must agree to use, themselves or their partners, an approved method of contraception throughout the treatment and at least 6 months after the last administration of study treatment. Obtaining signed informed consent from the patient Patient affiliated to a social security regimen Exclusion Criteria: prior brain radiotherapy prior chemotherapy (including implants containing carmustine (Gliadel®) or immunotherapy (vaccination included) Any contraindication to TMZ listed in the SPCs History of major intestinal resection which may modify the absorption of oral drugs according to the judgment of the investigator Diagnosed inflammatory bowel disease (Crohn's disease or ulcerative colitis) Diarrhea ≥ grade 2 CTCAE (whatever the cause) Current or recent treatment with another investigational drug or participation in another therapeutic clinical trial (within 30 days of inclusion). History of other cancer in the 5 years preceding inclusion, except for basal cell carcinomas of the skin and in situ carcinomas of the cervix Pregnant or breastfeeding women Contraindication to MRI or gadolinium injection History of severe anaphylactic reactions due to the injection of gadolinium-based contrast product (dotarem, etc.) Patient under guardianship or curatorship History of nephropathy Psychological disorder or social or geographic reasons that may compromise medical monitoring of the trial or compliance with treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1 : dose escalation Phase 2 : randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGuIX + chemoradiotherapy (radiotherapy + temozolomide)<br>addition of AGuIX nanoparticles to standard radiotherapy and concomitant treatment by temozolomide (TMZ) for patients of phase I and patients randomized in experimental arm of phase II | Drug: Polysiloxane Gd-Chelates based nanoparticles (AGuIX)<br>* Four intravenous injections of AGuIX will be delivered. Phase I : Three dose levels may be explored 50 mg/kg, 75 mg/kg and 100 mg/ kg. Phase II : recommended dose<br>Radiation: radiotherapy<br>* 60 Gy in 6 weeks<br>Drug: Temozolomide<br>* Concomitant chemotherapy consists of temozolomide (TMZ) at a dose of 75 mg per square meter per day, given 7 days per week from the first day of radiotherapy until the last day of radiotherapy. After a 4 week break after concomitant treatment, patient were then received up to 6 cycles of adjuvant TMZ according to the standard 5-day schedule every 28 days .<br>|
| Sham Comparator: chemoradiotherapy (radiotherapy + temozolomide)<br>standard of care : chemoradiotherapy (radiotherapy + temozolomide) for patients randomized in control arm of phase II | Radiation: radiotherapy<br>* 60 Gy in 6 weeks<br>Drug: Temozolomide<br>* Concomitant chemotherapy consists of temozolomide (TMZ) at a dose of 75 mg per square meter per day, given 7 days per week from the first day of radiotherapy until the last day of radiotherapy. After a 4 week break after concomitant treatment, patient were then received up to 6 cycles of adjuvant TMZ according to the standard 5-day schedule every 28 days .<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The recommended dose (phase I) of AGuIX in combination with TMZ and and radiotherapy during the radio-chemotherapy period | Only toxicities occurring during concomitant radiochemotherapy will be considered for the evaluation of Dose Limiting Toxicity radiotherapy during the radio-chemotherapy period is defined as the highest dose tested in which the % of dose-limiting toxicities (DLT) is less than 33%. DLT is defined as any grade 3-4 toxicity according to the NCI CTCAE v5.0 classification, except alopecia, nausea, and vomiting which can be quickly controlled with appropriate measures. | during 6 weeks after the first injection of AGuIX | 
| 6-month Progression Free Survival (PFS) rate (phase II) |  | 6 months from the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Cmax of AGuIX | maximal plasma concentration (Cmax) of AGuIX | Day 0 , Day 7, Day 14 | 
| Pharmacokinetic Tmax of AGuIX | time of maximal plasma concentration (Tmax) of AGuIX | Day 0 , Day 7, Day 14 | 
| Pharmacokinetic AUC of AGuIX | Area Under the Curve (AUC) of AGuIX | Day 0 , Day 7, Day 14 | 
| Pharmacokinetic t1/2 of AGuIX | pharmacokinetic term half-life (t1/2) of AGuIX | Day 0 , Day 7, Day 14 | 
| distribution of AGuIX | measure of RMI contrast enhancement in tumor and healthy tissue | after the first and last injection of AGuIX, Week 0 and Day 14 | 
| Overall Survival |  | from the start of treatment to death, up to 24 months | 
| Progression Free Survival (PFS) |  | from the start of treatment to progression, up to 24 months | 
| Toxicity (CTCAE criteria) | according to NCI Common Toxicity Criteria for Adverse Effect (CTCAE) criteria | from baseline to 30 days after treatment (concomitant and adjuvant treatment) (week 35) |