RAPTOR

Trial Info

Status: Open

Specialty: Head & Neck

Date Opened: 27/06/2024

Planned Close Date: 30/04/2025

Sponsor: University of Liverpool

Principal Investigator: Miss Lucy Koh

Trial Description

Research question

RAPTOR aims to establish the value of the repurposed drug combination Pentoxifylline,Tocopherol & Clodronate (termed PENTOCLO) in treating osteoradionecrosis (ORN) of the mandible.

Background

Osteoradionecrosis is a well-recognized and feared complication following curative treatment of head and neck cancer with radiotherapy. There are no medical treatments with high level evidence to support their use and many patients deteriorate to the point where they need multiple hospital admissions,destructive removal of all necrotic bone and complex jaw and facial reconstruction. A combination of three repurposed drugs: pentoxifylline,tocopherol and clodronate has been suggested as being able to heal ORN in the majority of cases but requires at least 12 months treatment. In successful cases it has stopped disease progression,improved symptoms and facilitated the exfoliation of necrotic bone. There have,to date,been no randomized trials,or trials making a comparison of PENTOCLO against control treatments,but single arm studies have been encouraging.

Aims and objectives

The aim of RAPTOR is to compare standard supportive care (SSC) against SSC plus PENTOCLO,measuring time-to-healing as primary endpoint. The secondary endpoints are to measure patient symptoms,quality of life,SOMA,extent of necrotic bone,mandibular preservation rate.

Methods

RAPTOR is an unblinded randomised controlled trial where patients in the control arm receive standard supportive care dependent on symptoms including antibiotics,analgesia and antiseptic mouthwash. In the treatment arm,patients additionally receive PENTOCLO and both arms are assessed at clinic visits every 3 months. Blinded remote assessment of primary and secondary endpoints are supported by clinical photographs. Rich data on patients’ symptom burden are collected remotely using a dedicated App every 15 days throughout the trial.

Timelines for delivery

Following 6-months set up time,the trial will be opened with the aid of the national maxillofacial trainee collaborative (MTREC) which we believe may greatly facilitate recruitment. 15 sites will be selected,and recruitment is expected to take 24 months for a total study length of 48 months.

Anticipated impact and dissemination

For the first time,the activity of PENTOCLO will be robustly compared with a control group and these results will form the basis of future treatment decisions and / or to inform the necessity for a larger phase III trial

Inclusion Criteria

1. Patients with ORN of the mandible

2. Patients considered suitable for medical management

3. Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study

Exclusion Criteria

1. Cannot swallow tablets

2. Prior treatment with PENTOCLO or any element thereof within 12 months of the date of randomisation

3. Very early ORN (<20 mm2 exposed bone) occurring within 12 months of a dental extraction or other dentoalveolar operation (‘Minor Bone Spicules’ see flowchart below)

4. Mandibular pathological fracture secondary to ORN

5. Extra-oral communicating fistula secondary to ORN

6. Prior surgery/jaw resection

7. Pregnancy

8. Lactation

9. Age <18 years

10. Acute infection at site of the necrotic bone.

11. Contraindications to PENTOCLO medications:

a. Known hypersensitivity,allergy or anaphylaxis to pentoxifylline,tocopherol or sodium clodronate

b. Treated hypotension

c. Severe coronary artery disease,defined as grade IV of the Canadian Cardiology Society Angina Grading

d. Severe atrial fibrillation,defined as grade 4 on modified CCC-SAF

e. Myocardial infarction within 6 months

f. Prior history of extensive retinal haemorrhage

g. Prior history of intracranial bleeding

h. Impaired renal function (Creatinine clearance <30 ml/minute,will be formally assessed only if U&E out of reference)

i. Severe liver failure (class B or C Pugh-Child Score,will be formally assessed only if LFT values,out of reference)

j. Concomitant prescription of anti-platelet agents: clopidogrel,eptifibatide,tirofiban,epoprostenol,iloprost,abciximab,anagrelide,NSAIDs,acetylsalicylates (ASA/LAS) including aspirin >75 mg*,ticlopidine,dipyridamole. (*low dose =<75 mg aspirin is permitted)

k. Concomitant prescription of ketorolac,cimetidine,ciprofloxacin,theophylline,estramustine phosphate

l. Hereditary fructose intolerance,glucose-galactose malabsorption or sucrase-isomaltase insufficiency

m. Concomitant prescription other bisphosphonates e.g. risedronate,alendronate,aIbandronate,zoledronic acid,pamidronate,etidronate or prescription of denosusamab

n. Concomitant prescription of aminoglycoside antibiotics e.g. gentamicin,tobramycin,amikacin,plazomicin,streptomycin,neomycin,paromomycin

Contacts

Research Contact: Miss Lucy Koh - Lucy.Koh@LTHTR.nhs.uk

Link to EDGE

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