Clinical trial NCT04116047: CompARE: Escalating Treatment of Intermediate and High-risk Oropharyngeal Cancer (OPC)
Official title: Phase III Randomised Controlled Trial Comparing Alternative Regimens for Escalating Treatment of Intermediate and High-risk Oropharyngeal Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Oropharyngeal Cancer
Keywords: Oropharyngeal cancer
HPV
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: AstraZeneca
name: Cancer Trials Ireland
First posted: 2019-10-04
Enrollment: 785
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Patient Overall survival (OS)
timeFrame: from randomisation until date of death from any cause (follow-up until 8 years post-treatment)
measure: Patient Event Free Survival (EFS)
timeFrame: From randomisation until date of progression/persistence/recurrence/death (follow-up until 8 years post-treatment)
Secondary outcomes:
measure: Number of Acute (<3 months post-treatment) toxicity events experienced
timeFrame: From date of randomisation until 2 year follow-up
measure: Number of late (up to 2 years post-treatment) toxicity events experienced using CTCAE
timeFrame: From date of randomisation until 2 year follow-up
measure: Number of late (up to 2 years post-treatment) toxicity events experienced using RTOG
timeFrame: From date of randomisation until 2 year follow-up
measure: Head and neck specific quality of life at 2 years post-randomisation using EORTC C30
timeFrame: From date of randomisation until 2 year follow-up
measure: Head and neck specific Quality of Life at 2 years post-randomisation
timeFrame: From date of randomisation until 2 year follow-up
measure: Swallowing outcomes assessed using MDADI Questionnaire at 24 months post-chemoradiotherapy
timeFrame: From date of randomisation until 2 year follow-up
measure: Levels of Percutaneous Endoscopic Gastrostomy (PEG) use
timeFrame: From date of randomisation until 2 year follow-up
measure: Cost effectiveness of treatment as assessed using EuroQol Group (EQ-5D) questionnaire
timeFrame: From date of randomisation until 2 year follow-up
measure: Surgical complication rates in each arm for patients who require a neck dissection at 4 months following the 3 month post-chemoradiotherapy assessment scan.
timeFrame: At 4 months following the 3 month post-chemoradiotherapy scan
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: St Luke's Hospital
city: Dublin
country: Ireland
facility: St James's Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: Devon
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: East Midlands
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital
state: East Yorkshire
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
state: Essex
city: Romford
country: United Kingdom
facility: Queen's Hospital
state: Essex
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
state: Lancashire
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
state: North Yorkshire
city: York
country: United Kingdom
facility: York Hospital
state: North Yorkshire
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: Oxfordshire
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
state: South Yorkshire
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
state: Tyne And Wear
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
state: West Midlands
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
state: West Midlands
city: Wolverhampton
country: United Kingdom
facility: Newcross Hospital
state: West Midlands
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
state: West Yorkshire
city: Leeds
country: United Kingdom
facility: St James's University Hospital
state: West Yorkshire
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
city: London
country: United Kingdom
facility: North Middlesex Hospital
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Shrewsbury
country: United Kingdom
facility: Royal Shrewsbury Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
city: Torquay
country: United Kingdom
facility: Torbay Hospital
city: Wirral
country: United Kingdom
facility: Clatterbridge Cancer Centre
Study officials:
affiliation: University of Birmingham
name: Prof Mehanna
role: PRINCIPAL_INVESTIGATOR
References: