CompARE: Phase III randomised controlled trial Comparing Alternative Regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The University Of Birmingham

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Dec 2024 → ongoing

Decision date (initial)

2024-10-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Cancer Research UK, Clinical Trials Awards & Advisory Committee · AstraZeneca UK Limited

External identifiers

EU CT number

2024-516108-41-00

EudraCT number

2014-003389-26

ClinicalTrials.gov

NCT04116047

ISRCTN

ISRCTN41478539

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

1. To examine the outcomes of alternative treatments aiming to improve overall survival time in intermediate and high-risk oropharyngeal cancer.
2. To compare Quality of Life, toxicity outcomes and swallowing function of these alternative treatments

Secondary objectives 7

1. Health Economics Objectives: 1. To compare cost-effectiveness in all treatment arms through cost-utility analysis
2. Health Economics Objectives: 2. To estimate the cost per Quality-Adjusted Life Years (QALY) over the two year period of the trial
3. Qualitative Recruitment Investigation (QRI) Objectives: 1. To monitor recruitment rates and identify sources of recruitment difficulties in the first year of the trial
4. QRI Objectives: 2. To develop a plan to optimise randomisation and informed consent
5. Translational Research Objectives: 1. To prospectively collect and 'bank' high quality tissue, saliva and blood samples from patients with intermediate and high-risk OPC
6. Translational Research Objectives: 2. To develop and validate biomarker classifiers to aid better stratification of treatment selection
7. Translational Research Objectives: 3. To develop several inter-related and complementary head and neck translational research projects

Conditions and MedDRA coding

Oropharyngeal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Oropharyngeal squamous cell carcinoma (OPSCC) in base of tongue and tonsil (includes bilateral tumours) and uvula, with a Multidisciplinary Team (MDT) recommendation for treatment with definitive concurrent chemoradiotherapy.
2. 2. All OPC T4 or N3 (HPV-pos and HPV-neg) OR all HPV-neg OPC T1-T4, N1-N3 or T3-4, N0 OR HPV-pos OPC T1-T4 with N2b-N3 nodes AND who are smokers ≥ 10 pack years current or previous smoking history
3. 3. Minimum life expectancy of 3 months
4. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
5. 5. Body weight of >30kg
6. 6. Adequate renal function, estimated glomerular filtration rate (eGFR) >50ml/min calculated using Cockcroft-Gault formula
7. 7. Adequate bone marrow function (absolute neutrophil count (ANC) ≥1.5 x 10^9/L, haemoglobin ≥9.0g/dL and platelets ≥100 x 10^9/L)
8. 8. Adequate liver function i.e. serum bilirubin ≤1.5 times the upper limit of normal (ULN), AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
9. 9. Prothrombin time (PT) ≤1.5 x ULN or International Normalised Ratio (INR) ≤1. 5
10. 10. No cancers in previous 5 years, except basal cell carcinoma of skin and cervical intra-epithelial neoplasia (CIN)
11. 11. Aged 18-70
12. 12. Written informed consent given for the trial
13. 13. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following agespecific requirements apply: - Women <50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and folliclestimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). - Women ≥50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >12 months ago, had chemotherapy-induced menopause with last menses >12 months ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
14. 14. 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 18

1. 1. All T1-T2,N0 OPC (HPV-pos or HPV-neg)
2. 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. 3. Unfit for chemoradiotherapy regimens
4. 4. Creatinine Clearance <50ml/min
5. 5. Treatment with any of the following, prior to randomisation: a. Any Investigational Medicinal Products (IMP) within 30 days b. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks c. Major surgical procedure (as defined by the Investigator) within 4 weeks, unless for diagnostic purposes. d. Concurrent use of hormonal therapy for non-cancerrelated conditions (e.g., hormone replacement therapy is acceptable)
6. 6. History of allergic reactions or hypersensitivity to any of the IMPs and excipients used in this trial
7. 7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea or any subject known to have psychiatric illness/social situations that would limit compliance with study requirement, substantially increase the risk of incurring AEs or compromise the ability of the subject to give written informed consent
8. 8. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
9. 9. Women who are pregnant or breast-feeding. Women of childbearing potential must have a negative pregnancy test performed within 7 days prior to randomisation
10. 10. 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
11. 11. Any condition that, in the opinion of the Investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
12. 12. Republic of Ireland only – Treatment with live vaccines, including yellow fever vaccine.
13. 13. Any previous treatment with PD-L or PD-L1 inhibitor, including durvalumab
14. 14. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, The following are exceptions to this criterion: • Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection) • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent • Steroids as premedication for hypersensitivity reactions (e.g., CT scan, premedication)
15. 15. 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), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis etc.). 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 • Patients with celiac disease controlled by diet alone
16. 16. History of active primary immunodeficiency
17. 17. History of allogeneic organ transplant
18. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 1. Definitive (efficacy) endpoint: Overall Survival (OS) time
2. 2. Interim outcome measure (activity stages): Event Free Survival (EFS) time

Secondary endpoints 8

1. 1. Total number of acute (<3 months post-treatment) and late (up to 2 years) severe (grade 3-5) toxicity events at 2 years post randomisation, measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and version 3.0 for scoring mucositis. Radiation Therapy Oncology Group (RTOG) Radiation Morbidity Scoring Criteria will be used to grade late side effects due to radiotherapy
2. 2. Overall and head and neck specific QoL at 2 years post randomisation, using the European Organisation for Research and Treatment of Cancer (EORTC) C30 and H&N35 Questionnaires
3. 3. Swallowing outcomes using M.D. Anderson Dysphagia Inventory (MDADI) Questionnaire at 24 months and percutaneous endoscopic gastrostomy (PEG) utilisation rates at 1 year
4. 4. Cost effectiveness using EuroQol Group (EQ-5D) and primary and secondary resource utilisation data
5. 5. Surgical complication rates in each arm
6. Translation Research Outcome Measures: 1. To determine tumour phenotype correlation with treatment response by molecular analyses
7. Translational Research Outcome Measures: 2. To develop validation of a patient stratification classifier using markers of proliferation, p53 and related pathways, apoptotic markers, hypoxia and DNA damage response and other genomic and mRNA and circulating DNA markers
8. Translational Research Outcome Measures: 3. To correlate OS and EFS with Programmed cell death ligand 1 (PD-L1) expression and treatment with durvalumab

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The University Of Birmingham

Sponsor organisation

The University Of Birmingham

Address

Vincent Drive

City

Birmingham

Postcode

B15 2TT

Country

United Kingdom

Scientific contact point

Organisation

The University Of Birmingham

Contact name

Clinical Trial Coordinator

Public contact point

Organisation

The University Of Birmingham

Contact name

Clinical Trial Coordinator

Third parties 5

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications