NIMRAD (A Randomised Placebo-controlled Trial of Synchronous NIMorazole Versus RADiotherapy Alone in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Not Suitable for Synchronous Chemotherapy or Cetuximab)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to see whether adding Nimorazole to standard radiotherapy benefits patients with locally advanced head and neck squamous cell carcinoma.

Official Title
-----------------
A Randomised Placebo-controlled Trial of Synchronous NIMorazole Versus RADiotherapy Alone in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Not Suitable for Synchronous Chemotherapy or Cetuximab)

Conditions
-----------------
Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: Nimorazole
* Radiation: Radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed (newly diagnosed/ not recurrent) head and neck squamous cell carcinoma; all primary subsites EXCEPT nasal cavity, oral cavity, nasopharynx and paranasal sinus (i.e. oropharynx, hypopharynx, larynx are allowed) Stage T3/T4 N0; any node +ve case including T1 node +ve; T2N0 base of tongue/hypopharynx Patients suitable for definitive radiotherapy. Block dissections may be performed pre-RT for N2/N3 disease WHO status 0-2 Patient fit and able to undergo RT with nimorazole and be expected to complete treatment Absence of another disease or previous malignancy which is likely to interfere with the treatment or assessment of response No evidence of distant metastases (M0) Unable to tolerate/unlikely to benefit from platinum chemotherapy or monoclonal antibody therapy Women must be postmenopausal (no menstrual period for a minimum of 1 year) or have a negative serum pregnancy test on entry in the study (even if surgically sterilised) and be using an adequate contraception method. This must be continued for 1 week after completion of nimorazole, unless child bearing potential has been terminated by surgery/radical radiotherapy Men must be willing to use an adequate method of contraception during treatment and until 1 week after nimorazole Greater than 18 years of age; no upper age limit Available for follow up within the United Kingdom Adequate renal and liver function - absolute neutrophil count >=1.5 x 109/L, creatinine <=2x ULN, platelets > 100x109/L, total bilirubin <=2 x ULN, AST or ALT <3 x ULN The capacity to understand the patient information sheet and the ability to provide written informed consent Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures Exclusion Criteria: Patients with T1N0 tumours or those within the nasopharynx, nasal cavity or sinus, oral cavity; T2No larynx and tonsil; unknown primary cancer. Any prior chemotherapy in the last 6 months or RT within the planned radiation field Presence of any life threatening illness such as unstable angina or severe chronic obstructive pulmonary disease Mental disability or patient otherwise unable to give informed consent and/or complete patient questionnaires Hb <100 g/l (patients with anaemia may be transfused to bring Hb levels to >100 g/l within 1 week of treatment start. Please repeat Hb following transfusion to confirm now eligible) Peripheral neurophathy as assessed clinically (CTCAE >=2) Use of any investigational drug within 30 days prior to screening Severe and/or uncontrolled medical disease Any malabsorption syndrome (i.e. partial gastrectomy, small bowel resection, Crohn's disease or ulcerative colitis) Use of Lithium or Phenobarbitone during the study Patients who are breastfeeding or pregnant Previous malignancy within 5 years (except BCC, in-situ Ca e.g. of the cervix) Previous definitive surgery to primary site

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo given in parallel with radiotherapy for 6 weeks. | Radiation: Radiotherapy<br> <br> |
| Experimental: Nimorazole<br>Nimorazole given in parallel with radiotherapy for 6 weeks | Drug: Nimorazole<br> <br> Radiation: Radiotherapy<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional Control in patients with more hypoxic tumours (the enriched population) | To examine whether patients with locally advanced head and neck squamous cell carcinoma unsuitable for either cisplatin chemotherapy or monoclonal antibody therapy benefit from the addition of nimorazole to standard definitive radiotherapy in terms of increased locoregional control without additional serious toxicity. | 12 weeks post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (enriched sub-group) |  | Date of death for patient, month 60. | 
| Cancer-specific survival (enriched sub-group) |  | follow up month 60 | 
| Disease-free survival (enriched sub-group) |  | follow up month 60 | 
| Cumulative incidence of loco-regional failure |  | follow up month 60 | 
| Acute toxicity (all patients) |  | baseline, week 1, 2, 3, 4, 5, 6, follow up month 1.5 and 3 | 
| Hypoxia signature prediction of nimorazole benefit (all patients) |  | screening | 
| Quality of life (enriched sub-group) |  | baseline, week 6, month 6, 12, 18, 24, 36 of follow up | 
| Late toxicity (all patients) |  | baseline, follow up month 6, 12, 18, 24, 36 |