CompARE: Escalating Treatment of Intermediate and High-risk Oropharyngeal Cancer (OPC) (CompARE)

Phase III Randomised Controlled Trial Comparing Alternative Regimens for Escalating Treatment of Intermediate and High-risk Oropharyngeal Cancer

CompARE is a multicentre, phase III open-label randomised controlled trial using an adaptive, Multi-Arm, Multi-Stage (MAMS) design.

Study Overview

• Status: Recruiting
• Conditions: Oropharyngeal Cancer
• Intervention / Treatment: Drug: Cisplatin; Procedure: Radiotherapy; Drug: Durvalumab

Detailed Description

The CompARE Trial examines alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer in an adult patient population. The aim is to assess whether escalated radiotherapy, adding surgery or immunotherapy will improve overall survival and quality of life in these patients.

• Study Type: Interventional
• Enrollment (Anticipated): 785
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Isla Humphreys; Email: CompARE@trials.bham.ac.uk
• Study Contact Backup: Name: Annabell Allen; Email: CompARE@trials.bham.ac.uk

Study Locations

• Ireland
  • Dublin, Ireland, Dublin 6
    • Recruiting
    • St Luke's Hospital
    • Contact: Sinead Brennan
    • Principal Investigator: Sinead Brennan
  • Dublin, Ireland, Dublin 8
    • Recruiting
    • St James's Hospital
    • Contact: Cliona Grant
    • Principal Investigator: Cliona Grant
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Recruiting
    • Aberdeen Royal Infirmary
    • Contact: Rafael Moleron, MBBS, MD
    • Principal Investigator: Rafael Moleron
  • Bath, United Kingdom, BA1 3NG
    • Recruiting
    • Royal United Hospital
    • Contact: Emma de Winton
    • Principal Investigator: Emma de Winton
  • Belfast, United Kingdom, BT9 7AB
    • Recruiting
    • Belfast City Hospital
    • Contact: Fionnuala Houghton, MRCP, FRCR
    • Principal Investigator: Fionnuala Houghton
  • Bristol, United Kingdom, BS2 8ED
    • Recruiting
    • Bristol Haematology and Oncology Centre
    • Contact: Georgina Casswell
    • Principal Investigator: Georgina Casswell
  • Cambridge, United Kingdom, CB2 0QQ
    • Recruiting
    • Addenbrooke's Hospital
    • Contact: Richard Benson
    • Principal Investigator: Richard Benson
  • Cardiff, United Kingdom, CF14 2TL
    • Recruiting
    • Velindre Cancer Centre
    • Contact: Richard Webster
    • Principal Investigator: Richard Webster
  • Cheltenham, United Kingdom, GL53 7AN
    • Recruiting
    • Cheltenham General Hospital
    • Contact: Warren Grant
    • Principal Investigator: Warren Grant
  • Edinburgh, United Kingdom, EH4 2XU
    • Recruiting
    • Western General Hospital
    • Contact: Devraj Srinivasan, MRCP, FRCR
    • Principal Investigator: Devraj Srinivasan
  • Glasgow, United Kingdom, G12 0YN
    • Recruiting
    • Beatson West of Scotland Cancer Centre
    • Contact: Stefano Schipani
    • Principal Investigator: Stefano Schipani
  • Liverpool, United Kingdom, L9 7AL
    • Active, not recruiting
    • Aintree University Hospital
  • London, United Kingdom, N18 1QX
    • Recruiting
    • North Middlesex Hospital
    • Contact: Anna Thompson, MRCP, FRCR
    • Principal Investigator: Anna Thompson
  • Manchester, United Kingdom, M20 4BX
    • Recruiting
    • Christie Hospital
    • Contact: Lip Wai Lee
    • Principal Investigator: Lip Wai Lee
  • Norwich, United Kingdom, NR4 7UY
    • Recruiting
    • Norfolk and Norwich University Hospital
    • Contact: Dinos Geropantas, MBBS, CCT
    • Principal Investigator: Dinos Geropantas
  • Nottingham, United Kingdom, NG5 1PB
    • Active, not recruiting
    • Nottingham City Hospital
  • Plymouth, United Kingdom
    • Recruiting
    • Derriford Hospital
    • Contact: Rebecca Goranova, MRCP,FRCR
    • Principal Investigator: Rebecca Goranova
  • Shrewsbury, United Kingdom, SY3 8XQ
    • Recruiting
    • Royal Shrewsbury Hospital
    • Principal Investigator: Laura Pettit
    • Contact: Laura Pettit, MRCP,FRCR
  • Swansea, United Kingdom, SA2 8QA
    • Recruiting
    • Singleton Hospital
    • Contact: Russell Banner, MRCP,FRCR
    • Principal Investigator: Russell Banner
  • Taunton, United Kingdom, TA1 5DA
    • Recruiting
    • Musgrove Park Hospital
    • Contact: Petra Jankowska, MRCP, FRCR
  • Torquay, United Kingdom, TQ2 7AA
    • Recruiting
    • Torbay Hospital
    • Contact: Jonathan Chambers, MRCP, FRCR
    • Principal Investigator: Jonathan Chambers
  • Wirral, United Kingdom, CH63 4JY
    • Recruiting
    • Clatterbridge Cancer Centre
    • Contact: Caroline Brammer, MRCP,FRCP
    • Principal Investigator: Caroline Brammer
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Recruiting
      • Royal Devon and Exeter Hospital
      • Contact: David Hwang, MRCP FRCR
      • Principal Investigator: David Hwang
  • East Midlands
    • Leicester, East Midlands, United Kingdom, LE1 5WW
      • Active, not recruiting
      • Leicester Royal Infirmary
  • East Yorkshire
    • Cottingham, East Yorkshire, United Kingdom, HU16 5JQ
      • Active, not recruiting
      • Castle Hill Hospital
  • Essex
    • Colchester, Essex, United Kingdom, CO4 5JL
      • Recruiting
      • Colchester General Hospital
      • Contact: Vivienne Loo, MRCP, FRCR
      • Principal Investigator: Vivienne Loo
    • Romford, Essex, United Kingdom, RM7 0AG
      • Recruiting
      • Queen's Hospital
      • Contact: Amy Ward, MRCP, FRCR
      • Principal Investigator: Amy Ward
  • Lancashire
    • Preston, Lancashire, United Kingdom, PR2 9HT
      • Recruiting
      • Royal Preston Hospital
      • Contact: Arafat Mirza
      • Principal Investigator: Arafat Mirza, M
  • North Yorkshire
    • Middlesbrough, North Yorkshire, United Kingdom, TS4 3BW
      • Recruiting
      • James Cook University Hospital
      • Contact: Eleanor Aynsley, MRCP, FRCR
      • Principal Investigator: Eleanor Aynsley
    • York, North Yorkshire, United Kingdom, YO31 8HE
      • Recruiting
      • York Hospital
      • Contact: Robin Prestwich, FRCR, PhD
      • Principal Investigator: Robin Prestwich
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LE
      • Recruiting
      • Churchill Hospital
      • Contact: Ketan Shah, MRMCP,FRCR
      • Principal Investigator: Ketan Shah
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2SJ
      • Recruiting
      • Weston Park Hospital
      • Contact: Satya Garikipati
      • Principal Investigator: Satya Garikipati
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE7 7DN
      • Active, not recruiting
      • Freeman Hospital
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Recruiting
      • Queen Elizabeth Hospital
      • Contact: Andrew Hartley, MRCP, FRCP
      • Principal Investigator: Andrew Hartley
    • Coventry, West Midlands, United Kingdom, CV2 2DX
      • Active, not recruiting
      • University Hospital Coventry
    • Wolverhampton, West Midlands, United Kingdom, WV10 OQP
      • Active, not recruiting
      • Newcross Hospital
  • West Yorkshire
    • Bradford, West Yorkshire, United Kingdom, BD9 6RJ
      • Recruiting
      • Bradford Royal Infirmary
      • Contact: Karen Dyker
      • Principal Investigator: Karen Dyker
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF
      • Recruiting
      • St James's University Hospital
      • Contact: Mehmet Sen, MRCP, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Oropharyngeal squamous cell carcinoma (OPSCC) in base of tongue and tonsil with a Multidisciplinary Team (MDT) recommendation for treatment with definitive concurrent chemoradiotherapy
2. All OPC T4 or N3 (HPV+ and HPV-) OR all HPV -ve (negative) OPC T1-T4, N1-N3 or T3-4, N0 OR HPV +ve (positive) OPC T1-T4 with N2b-N3 nodes AND who are smokers ≥ 10 pack years current or previous smoking history
3. Minimum life expectancy of 3 months
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
5. Adequate renal function, glomerular filtration rate (GFR) >50ml/min calculated using Cockcroft-Gault formula
6. Adequate bone marrow function (absolute neutrophil count (ANC) ≥1.5 x 109/L, haemoglobin ≥9.0g/dL and platelets ≥100 x 109/L)
7. Adequate liver function i.e. plasma bilirubin ≤1.5 times the upper limit of normal (ULN), and alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤2.5 x ULN
8. Prothrombin time (PT) ≤1.5 x ULN or International Normalised Ratio (INR) ≤1. 5
9. Magnesium ≥ lower limit of normal
10. No cancers in previous 5 years, except basal cell carcinoma of skin and cervical intra-epithelial neoplasia (CIN)
11. Aged 18-70
12. Written informed consent given for the trial
13. Surgically resectable disease if being randomised to all four arms
14. Females must either be of non-reproductive potential (i.e. post-menopausal by history: ≥55 years old and no menses for ≥1 year without an alternative medical cause; or history of hysterectomy, or history of bilateral tubal ligation or history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
15. Willingness to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations including follow up

Exclusion Criteria:

1. All T1-T2,N0 OPC (HPV +ve or HPV-ve)

2. HPV positive patients who are:

   T1-T3, N0-N2c non-smokers T1-T3, N0-N2c smokers with ≤10 pack years or T1-T2, N0-N2a smokers with ≥10 pack years

3. Unfit for chemoradiotherapy regimens
4. Creatinine Clearance <50ml/min

5. Treatment with any of the following, prior to randomisation:

   1. Any Investigational Medicinal Products (IMP) within 30 days
   2. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks
   3. Major surgery within 4 weeks
6. History of allergic reactions to any of the IMPs and excipients used in this trial
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C, Human Immunodeficiency Virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
8. Women who are pregnant or breast-feeding. Women of child- bearing potential must have a negative pregnancy test performed within 7 days prior to randomisation
9. Men or women who are not prepared to practise methods of contraception of proven efficacy during treatment and for 6 months following the end of treatment

10. Any condition that, in the opinion of the Investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

    Additional Exclusion Criteria for Arm 5 only:

11. Any previous treatment with PD-L or PD-L1 inhibitor, including durvalumab
12. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid dose

13. Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease e.g. colitis or Crohn's disease, diverticulitis (with the exception of diverticulosis), celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptions to this criterion:

    • Patients with vitiligo or alopecia
    • Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
    • Any chronic skin condition that does not require systemic therapy
    • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
14. Patients with an active non-infectious pneumonitis
15. History of primary immunodeficiency
16. History of allogeneic organ transplant
17. Known history of previous clinical diagnosis of tuberculosis
18. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab. Inactivated viruses, such as those in the influenza vaccine, are permitted

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 (control): chemoradiotherapy; Concomitant chemoradiotherapy, 3-weekly cisplatin 100mg/m2 or weekly 40mg/m2 with Intensity Modulated Radiotherapy (IMRT) using 70 gray (Gy) in 35F(fractions) +/- neck dissection as indicated by clinical and radiological assessment 3-months post treatment. This is the international gold standard.	Drug: Cisplatin; Other Names: CDDP, Platinol; Procedure: Radiotherapy
Experimental: Arm 5: Durvalumab + Arm 1; One dose of induction durvalumab 1500mg by intravenous (IV) infusion followed by arm 1 within four weeks. Within one-two weeks after the completion of arm 1, durvalumab 1500mg every four weeks will be initiated for a total of 6 months	Drug: Cisplatin; Other Names: CDDP, Platinol; Procedure: Radiotherapy; Drug: Durvalumab; Other Names: MEDI-4736, Imfinzi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Overall survival (OS)	defined as the interval in whole days between date of randomisation and date of death from any cause	from randomisation until date of death from any cause (follow-up until 8 years post-treatment)
Patient Event Free Survival (EFS)	defined as the interval in whole days between date of randomisation until date of progression/persistence/recurrence/death	From randomisation until date of progression/persistence/recurrence/death (follow-up until 8 years post-treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Acute (<3 months post-treatment) toxicity events experienced	Total number of acute (<3 months post-treatment) severe (grade 3-5) toxicity events experienced. Adverse events will be collected post-treatment and graded according to Common Terminology Criteria for Adverse Events (CTCAE).	From date of randomisation until 2 year follow-up
Number of late (up to 2 years post-treatment) toxicity events experienced using CTCAE	Severe (grade 3-5) adverse events will be collected up to 2 years post randomisation, these events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and version 3.0 for scoring mucositis.	From date of randomisation until 2 year follow-up
Number of late (up to 2 years post-treatment) toxicity events experienced using RTOG	Late and severe toxicity events at 2 years post randomisation,will be collected and graded using Radiation Therapy Oncology Group (RTOG) Radiation Morbidity Scoring Criteria	From date of randomisation until 2 year follow-up
Head and neck specific quality of life at 2 years post-randomisation using EORTC C30	Patients will complete the European Organisation for Research and Treatment of Cancer (EORTC) C30 questionnaire at baseline, at the end of treatment, and during the follow-up period until 2 years post-treatment	From date of randomisation until 2 year follow-up
Head and neck specific Quality of Life at 2 years post-randomisation	Patients will complete the European Organisation for Research and Treatment of Cancer (EORTC) H&N35 questionnaire at baseline, at the end of treatment, and during the follow-up period until 2 years post-treatment	From date of randomisation until 2 year follow-up
Swallowing outcomes assessed using MDADI Questionnaire at 24 months post-chemoradiotherapy	Patients will complete the M.D. Anderson Dysphagia Inventory (MDADI) Questionnaire at baseline, at the end of treatment, and during the follow-up period until 2 years post-treatment	From date of randomisation until 2 year follow-up
Levels of Percutaneous Endoscopic Gastrostomy (PEG) use	PEG use will be assessed at baseline, throughout treatment and during 2 year follow-up period	From date of randomisation until 2 year follow-up
Cost effectiveness of treatment as assessed using EuroQol Group (EQ-5D) questionnaire	Patients will complete the EuroQol Group (EQ-5D) questionnaire at baseline, at the end of treatment, and during the follow-up period until 2 years post-treatment	From date of randomisation until 2 year follow-up
Surgical complication rates in each arm for patients who require a neck dissection at 4 months following the 3 month post-chemoradiotherapy assessment scan.	Surgical complication rates will be assessed at trial visits if a neck dissection is required at 4 months post-chemotherapy	At 4 months following the 3 month post-chemoradiotherapy scan

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: AstraZeneca; Cancer Trials Ireland
• Investigators: Principal Investigator: Prof Mehanna, University of Birmingham

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Anticipated): December 1, 2026
• Study Completion (Anticipated): December 1, 2030

Study Registration Dates

• First Submitted: August 13, 2018
• First Submitted That Met QC Criteria: October 3, 2019
• First Posted (Actual): October 4, 2019

Study Record Updates

• Last Update Posted (Actual): December 19, 2022
• Last Update Submitted That Met QC Criteria: December 14, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Oropharyngeal cancer; HPV
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Oropharyngeal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cisplatin; Durvalumab
• Other Study ID Numbers: RG 14-093; 2014-003389-26 (EudraCT Number); ISRCTN41478539 (Registry Identifier: International Standard Randomised Clinical Trial Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No