NBTXR3 and Radiation Therapy in Treating Patients With Locally Advanced SCC of the Oral Cavity or Oropharynx

Study Overview
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Brief Summary
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RATIONALE: Cancers of the oral cavity represent 30% of head and neck carcinomas in the western world. The oropharynx is the posterior continuation of the oral cavity and connects with the nasopharynx (above) and laryngopharynx (below). It is also a frequent site of primary head and neck cancers. These structures play a crucial role in swallowing, breath and speech. Locally advanced oropharyngeal cancers can obstruct the air flow or infiltrate muscles or nerves, which significantly disturb local functions. The incidence of Head and Neck Squamous Cell Cancer in patients older 65 years is high, 47% occurred in this population as recorded by the Surveillance, Epidemiology, and End Results registries in the United States. Regarding the therapeutic strategies, the association of radiotherapy with chemotherapy or biologics has demonstrated significant improvement of outcomes with the drawback of higher toxicity, or as demonstrated by 2 meta-analyses, without survival improvement in older patients. NBTXR3 and radiation therapy may increase the cancer cell killing and complete tumor shrinkage allowing a definitive treatment and preservation of local structures and functions in patients older 65 years, who cannot receive cisplatin.

Detailed Description
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Patients will receive a single administration of NBTXR3 on day 1,as an intratumor injection, followed by Intensity Modulated Radiation Therapy starting 24 hours later (Day 2), and up to completion of 7 weeks, i.e. 70 Grays, 2Grays/fraction. Patients whose tumor has completely shrunk will be followed for the post-radiotherapy evaluation up to the End of Treatment visit. Those patients whose tumor has not shrunk more than 50% of the baseline size, will stop the radiotherapy and may have a salvage tumor surgery. Then, all patients will be followed every 8 weeks, for the safety evaluation and cancer disease status until the end of the study.

Official Title
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A Phase I Dose-Escalation/Dose Expansion Study Of NBTXR3 Activated By Intensity Modulated Radiation Therapy In Patients With Locally Advanced Squamous Cell Carcinoma Of The Oral Cavity Or Oropharynx

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Device: NBTXR3 activated by IMRT


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients aged ≥ 70 years old, or Patients aged ≥ 65 years old and < 70 years old who are unable to receive cisplatin, or Patients who have contraindication to cisplatin or that are intolerant to cisplatin or cetuximab or that cannot receive the combination of chemoradiation, regardless the age Histologically or cytologically confirmed squamous cell carcinoma (SCC) of the oral cavity or oropharynx T3 or T4 primary tumor or Stage III or IVA according to AJCC guidelines (8th Edition, 2018) No evidence of distant metastatic disease, as determined by a negative PET scan or CT scan Clinically eligible for intratumor implantation by injection Karnofsky Performance Status ≥ 70 Adequate function of Bone marrow: White Blood Cell (WBC) > 3.0 x 10^9/L Absolute neutrophil count (ANC) > or = 1.0 x 10^9/L Platelet count > or = 100 x 10^9/L Hemoglobin > or = 9.0 g/dL Adequate function of Kidney: o Creatinine < or = 3.0 x ULN or creatinine clearance > or = 30 mL/min/1.73m² Adequate function of the liver: AST < or = 5 x ULN ALT < or = 5 x ULN Bilirubin < or = 1.5 x ULN Negative pregnancy test ≤ 7 days of NBTXR3 injection in all females of child-bearing potential Exclusion Criteria: Written Informed Consent not obtained, signed and dated Prior radiotherapy to any area within the planned radiotherapy field Tumor-related dyspnea Tumor ulceration which implies vascular risk Non measurable disease as defined by RECIST criteria History of stroke, CABG, or significant blockage of carotid arteries or coronary arteries or current blockage of coronary or carotid arteries equal to or in excess of 50% blockage Uncontrolled intercurrent illness including, but not limited to, ongoing or active severe infection, symptomatic congestive heart failure, acute coronary syndrome, etc. Medical history of life-threatening ventricular arrhythmia Prior or concurrent non-head and neck malignancies, excluding adequately treated basal or squamous cell cancer of the skin, and in situ cervical cancer, and any other cancer from which the subject has been cancer free for 5 years Concurrent treatment with any other anticancer therapy, including chemotherapy, immunotherapy, targeted therapy, gene therapy, or patients planning to receive these treatments during the study Patients unable to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures or those with severe psychiatric illness/social situations that would limit compliance with study requirements Patients participating in another clinical investigation at the time of signature of the informed consent.

Ages Eligible for Study
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Minimum Age: 65 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
Intervention Model: Single Group Assignment
Interventional Model Description: This study consists of two parts: Dose Escalation and Dose Expansion. This phase I is an open-label non-randomized, dose-escalation/dose expansion study of safety and tolerability evaluation of NBTXR3, administered as an intratumoral implantation by injection, activated by intensity modulated radiation therapy (IMRT), in patients with locally advanced squamous cell carcinoma of the oral cavity or oropharynx.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NBTXR3 IntraTumoral injection (IT)<br>Single intratumor injection | Device: NBTXR3 activated by IMRT<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Incidence of DLTs and determination of the Recommended Phase 2 Dose | The incidence of early DLTs (early adverse effects related to NBTXR3, as an intratumor injection, activated by IMRT) | 12 months | 
| Dose Escalation: Determination of the Recommended Phase 2 Dose | The recommended Phase II dose (RD) of NBTXR3 administered as intratumor injection, activated by Intensity Modulated Radiation Therapy (IMRT) | 12 months | 
| Dose Expansion: Overall Response Rate | The Objective Response Rate (ORR) of the primary tumor, by imaging according to RECIST 1.1 | 12-24 months | 
| Dose Expansion: Complete Response Rate | The Complete Response Rate (CRR) of the primary tumor, by imaging according to RECIST 1.1 | 12-24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Objective Response Rate (ORR) of the primary tumor | The Objective Response Rate (ORR) of the primary tumor, by imaging according to RECIST 1.1 | 12-24 months | 
| Dose Escalation: Complete Response Rate | The Complete Response Rate (CRR) of the primary tumor, by imaging according to RECIST 1.1 | 12 months | 
| Dose Expansion: Local Progression Free Survival | Local Progression Free Survival (LPFS) defined as any recurrence at the site of the primary tumor | 12-24 months | 
| Dose Expansion: Progression Free Survival | Progression Free Survival (PFS) defined as the time to any progression at the site of the primary tumor, in regional lymph nodes and/or distant metastasis | 12-24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oral cavity Cancer, Oropharynx Cancer