AGuIX Gadolinium-based Nanoparticles in Combination With Chemoradiation and Brachytherapy

Study Overview
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Brief Summary
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This is a phase 1 clinical trial evaluating the safety, tolerability of escalating doses of AGuIX-NP in combination with radiation and cisplatin in patients with locally advanced cervical cancer. Dose escalation will be conducted using the modified toxicity probability interval (mTPI) method. Three dose levels of intravenous AGuIX nanoparticles will be explored: 20mg/kg (level -1), 30 mg/kg (level 1) and 50 mg/kg (level 2).

Official Title
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Phase I Study of AGuIX Gadolinium-based Nanoparticles in Combination With Chemoradiation and Brachytherapy in Locally Advanced Cervical Cancer

Conditions
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Gynecologic Cancer

Intervention / Treatment
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* Drug: Polysiloxane Gd-Chelates based nanoparticles (AGuIX)
* Radiation: External beam radiotherapy (EBRT)
* Radiation: Uterovaginal brachytherapy
* Drug: Chemotherapy (cisplatin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed cancer of the uterine cervix: squamous cell carcinoma or adenocarcinoma stage IB2-IVA according to the International Federation of Gynecology and Obstetrics classification, regardless of the pelvic lymph node stage. No evidence of metastatic disease. Primary staging should include: clinical examination, Pelvic MRI and 18-FDG PET. A coelioscopic para-aortic lymph node staging should be done in patients without para-aortic lymph node uptake to guide radiotherapy fields in the situation of pelvic lymph node metastases. If there is no pelvic lymph node metastases, para-aortic lymph node dissection is optional. ECOG performance status 0-1. Age between 18 - 70 years. Neutrophils > 2000/mm^3. Hemoglobin > 9 g/L after transfusion if necessary. Platelets > 100,000/mm^3. Creatinine < 1.5 upper limit of normal or calculated creatinine clearance (Cockcroft-Gault Formula) ≥ 60 mL/min. Liver function (GOT, GPT, alkaline phosphatase and bilirubin) < 1.5 upper limit of normal. Cardiovascular: no clinically relevant cardiovascular disease, no congestive heart failure, no symptomatic coronary artery disease, no poorly controlled cardiac arrhythmia, no myocardial infarction within the past year. Gastrointestinal: no active inflammatory bowel disease, no lack of physical integrity of the upper gastrointestinal tract, no malabsorption syndrome. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment. Proteinuria < 2 g/L (200mg/dL) and creatinine clearance ≥ 60 mL/min. Signed informed consent after informing the patient. Patient affiliated to a social security regimen or beneficiary of the same. Exclusion Criteria: Other histological types of cervical cancer than those listed in the inclusion criteria or stage IVB. History of cancer other than basal cell carcinoma within five past years. Prior treatment with radiotherapy, chemotherapy, targeted therapy or immune therapy for cervical cancer or for any cancer within five past years. Prior pelvic radiotherapy or prior surgical treatment for cervical cancer (excluding diagnostic conisation). Pregnancy or breastfeeding. Obesity (Body Mass Index > 30). History of prior or current psychiatric illness. Nephropathy, regardless of the grade. Peripheral neuropathy ≥ grade 2. Patients with pre-existing hearing impairments. Active infection or other serious underlying pathology that could prevent the patient from receiving the treatment (especially liver or heart conditions). Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Inclusion in another clinical trial protocol with an experimental molecule (during this study or within 5 years prior to enrollment). Unable to undergo the follow-up required by study for geographical, social or psychological reasons. Contra-indication for Magnetic Resonance Imaging enhanced with gadolinium and/or any contra-indication to the use of cisplatin. History of allergic reaction to cisplatin or other platinum containing compounds. Concurrent administration of yellow fever vaccine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Interventional Model Description: This is a phase 1 clinical trial evaluating the safety, tolerability of escalating doses of AGuIX-NP in combination with radiation and cisplatin in patients with locally advanced cervical cancer. Dose escalation will be conducted using the modified toxicity probability interval (mTPI) method. Three dose levels of intravenous AGuIX nanoparticles will be explored: 20mg/kg (level -1), 30 mg/kg (level 1) and 50 mg/kg (level 2).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with locally advanced cervical cancer<br> | Drug: Polysiloxane Gd-Chelates based nanoparticles (AGuIX)<br>* Three intravenous injections of AGuIX will be delivered. The first injection of AGuIX will be delivered intravenously the 1st day and the 11th day of EBRT. The first injection will be preceded with an MRI (unenhanced T1 and T2 sequences) then followed with another MRI performed 4 hours later, to monitor tumor uptake. Irradiation will be performed after the second MRI. The second injection will be followed by an MRI 4 hours later. The third injection will be delivered intravenously the day of the brachytherapy procedure. Intravenous hydration will be performed during all brachytherapy courses to ensure AGuIX clearance. Up to three dose levels may be explored: 20mg/kg (level -1), 30 mg/kg (level 1) and 50 mg/kg (level 2). The starting dose level will be 30mg/kg.<br>Radiation: External beam radiotherapy (EBRT)<br>* to the pelvis, with intensity modulated technique: 45 Gy in 5 weeks, with integrated boost to 55 - 57.5 Gy in case of macroscopic lymph node metastases<br>Radiation: Uterovaginal brachytherapy<br>* 15 Gy (maximal interval between EBRT and brachytherapy: 14 days).<br>Drug: Chemotherapy (cisplatin)<br>* Concomitant weekly intravenous cisplatin 40 mg/m2 will be delivered (total 5 cycles).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) |  | Day 84 after inclusion | 
| Recommended Phase 2 Dose (RP2D) |  | Day 84 after inclusion |