Randomized Trial of Avelumab-cetuximab-radiotherapy Versus SOCs in LA SCCHN (REACH)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to demonstrate that treatment with avelumab in combination with RT-cetuximab is superior to standard of care (SOC) cisplatin-RT and/or to SOC RT-cetuximab alone in terms of progression-free survival (PFS) in front-line patients with locally advanced SCCHN.

Detailed Description
-----------------
This open-label, randomized, controlled, multicenter phase III study will include 688 patients with LA SCCHN (420 fit for HD cisplatin and 268 unfit for HD cisplatin), histologically confirmed who had not received previous treatment for this setting. The study is designed with the primary objective of demonstrating that treatment with avelumab in combination with cetuximab-RT is superior to SOC Cisplatin-RT or cetuximab-RT alone in terms of PFS. Randomization will assign the 2 treatment arms of each cohort with a 1:1 ratio. In each cohort (fit for cisplatin and unfit for cisplatin), the randomization will be stratified for the 2 most established prognostic factors N stage (N0-N1 vs N2-3) and p16 expression (OPC p16+ versus OPC p16- or non OPC). All patients will be followed until death or at least 60 months.

Official Title
-----------------
A Phase III Randomized Trial of Avelumab-cetuximab-Radiotherapy Versus Standards of Care in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Conditions
-----------------
HNSCC

Intervention / Treatment
-----------------
* Drug: Cetuximab
* Drug: avelumab
* Drug: Cisplatin
* Radiation: IMRT


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≤ 80 years Performance Status ECOG 0-1 Squamous cell carcinoma, previously untreated Stage III, stage IVa (i.e. operable, but not operated) or IVb (non resectable) Oral cavity, oropharynx, hypopharynx or larynx Availability of pre-treatment tumour tissue sample (for p16 & PD -L1 expression, TILs and immune landscape) Recording of alcohol consumption and smoking history Determination of the patient's ability to receive cisplatin 100 mg /m2 for 3 cycles (fit / unfit)* Written informed consent Criteria for determining if a patient is fit for receiving high dose cisplatin: Calculated creatinin clearance ≥ 60 mL/min as determined by the modified. method of Cockcroft and Gault or by the EDTA method Absolute neutrophil count ≥1 500/μL, platelets ≥100 000/μL, hemoglobin ≥ 10 g/dL, aspartate (AST) and alanine transaminase (ALT) less than 2 times the upper limit of the normal range (ULN), total bilirubin ≤ 1.5 mg/dL, serum albumin > 35 g/L Peripheral neuropathy < grade 2 No clinical hearing loss (confirmed by audiogram) Cardiac function compatible with hyperhydration; Left ventricular ejection fraction within the institutional normal ranges as measured by echocardiogram Exclusion Criteria: Nasopharyngeal, paranasal sinuses, nasal cavity tumors or thyroid cancers Squamous cell carcinoma involving cervical neck nodes with unknown primary site Metastatic disease (stage IVc) Viral infection (HIV, Hepatitis B/C) Autoimmune disease Immunodeficiency or immunosuppressive therapy Active CNS disease Interstitial lung disease Active infection Any prior or current treatment for invasive head and neck cancer. This will include but is not limited to: prior tyrosine kinase inhibitors, any monoclonal antibody, induction chemotherapy, prior surgical resection or RT, or use of any investigational agent Weight loss of > 10% during the last 4 weeks (except if renutrition with a feeding tube is planned before the onset of treatment or is ongoing) Concurrent treatment with any other systemic anti-cancer therapy that is not specified in the protocol Concomitant treatment with any drug on the prohibited medication list such as live vaccines History of other malignancy within the last 3 years (exception of in situ carcinoma and skin carcinomas) Significant disease which, in the judgment of the investigator, as a result of the medical interview, physical examinations, or screening investigations would make the patient inappropriate for entry into the trial Known hypersensitivity reaction to study drugs Any social, personal, medical and/or psychological factor(s) that could interfere with the observance of the patient to the protocol and/or the follow-up and/or the signature of the informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A Patient FIT<br>Lead-in phase (Day-8) : no treatment Concomitant radiotherapy phase : Radiotherapy by IMRT + cisplatin 100mg/m2 Maintenance phase : no treatment until follow-up phase | Drug: Cisplatin<br>* 100 mg/m² IV after hyperhydration and at a maximal rate of 1 mg/min, on days 1, 22, 43.<br>Radiation: IMRT<br>* RT will be performed using IMRT (intensity modulated radiotherapy), with a simultaneous integrated boost (SIB) technique. RT dose to the GTV will be 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions). Prophylactic dose will be 52.8 Gy in 1.6 Gy daily fractions over 6.5 weeks (33 fractions).<br>|
| Experimental: Arm B Patient FIT<br>Lead-in phase (Day-8) : Cetuximab 400mg/m2 and avelumab 10mg/kg Concomitant radiotherapy phase : Radiotherapy by IMRT + cetuximab 250mg/m2 and avelumab 10mg/kg Maintenance phase : avelumab 10mg/kg every 2 weeks during 12 months | Drug: Cetuximab<br>* Loading dose of 400 mg/m² IV on Day-8, followed by weekly dose of 250 mg/m² IV during the whole course of RT.<br>Drug: avelumab<br>* IV infusion of avelumab (10 mg/kg over 1 hour) once every 2 weeks. Avelumab will start on Day-8 together with cetuximab and subsequently every 2 weeks during the course of RT. Avelumab with be continued every 2 weeks for an additional 12 months following RT.<br>Radiation: IMRT<br>* RT will be performed using IMRT (intensity modulated radiotherapy), with a simultaneous integrated boost (SIB) technique. RT dose to the GTV will be 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions). Prophylactic dose will be 52.8 Gy in 1.6 Gy daily fractions over 6.5 weeks (33 fractions).<br>|
| Experimental: Arm C Patient UNFIT<br>Lead-in phase (Day-8) : Cetuximab 400mg/m2 and avelumab 10mg/kg Concomitant radiotherapy phase: Radiotherapy by IMRT + cetuximab 250mg/m2 and avelumab 10mg/kg Maintenance phase : avelumab 10mg/kg every 2 weeks during 12 months | Drug: Cetuximab<br>* Loading dose of 400 mg/m² IV on Day-8, followed by weekly dose of 250 mg/m² IV during the whole course of RT.<br>Drug: avelumab<br>* IV infusion of avelumab (10 mg/kg over 1 hour) once every 2 weeks. Avelumab will start on Day-8 together with cetuximab and subsequently every 2 weeks during the course of RT. Avelumab with be continued every 2 weeks for an additional 12 months following RT.<br>Radiation: IMRT<br>* RT will be performed using IMRT (intensity modulated radiotherapy), with a simultaneous integrated boost (SIB) technique. RT dose to the GTV will be 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions). Prophylactic dose will be 52.8 Gy in 1.6 Gy daily fractions over 6.5 weeks (33 fractions).<br>|
| Active Comparator: Arm D Patient UNFIT<br>Lead-in phase (Day-8): Cetuximab 400mg/m2 Concomitant radiotherapy phase: Radiotherapy by IMRT + cetuximab 250mg/m2 Maintenance phase : no treatment until follow-up phase | Drug: Cetuximab<br>* Loading dose of 400 mg/m² IV on Day-8, followed by weekly dose of 250 mg/m² IV during the whole course of RT.<br>Radiation: IMRT<br>* RT will be performed using IMRT (intensity modulated radiotherapy), with a simultaneous integrated boost (SIB) technique. RT dose to the GTV will be 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions). Prophylactic dose will be 52.8 Gy in 1.6 Gy daily fractions over 6.5 weeks (33 fractions).<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Time between randomization and the first event among progression (per modified Response Evaluation Criteria in Solid Tumors (RECIST) version v1.1) and death, whatever the cause of death. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 74 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | From date of randomization until the date of death from any cause, assessed up to 74 months | 
| Safety: acute adverse events graded by NCI CTCAE v4.03 |  | From date of randomization to end of study, assessed up to 74 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Head and Neck cancer, Immunotherapy