Comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer
| ISRCTN | ISRCTN41478539 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN41478539 |
| EudraCT/CTIS number | 2014-003389-26 |
| ClinicalTrials.gov number | NCT04116047 |
| Secondary identifying numbers | 18621 |
- Submission date
- 29/04/2015
- Registration date
- 29/04/2015
- Last edited
- 16/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English summary of protocol
Contact information
Ms Reshma Ali
Scientific
Scientific
Cancer Research UK Clinical Trials Unit (CRCTU)
School of Medical Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0)121 4145101 |
|---|---|
| r.ali.1@bham.ac.uk |
Study information
| Study design | Randomized; Interventional; Design type: Treatment |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | Phase III randomised controlled trial Comparing Alternative REgimens for escalating treatment of intermediate and high-risk oropharyngeal cancer |
| Study acronym | CompARE |
| Study objectives | Pragmatic phase III open-label randomised controlled trial using an efficient, adaptive, multi-arm multi-stage (MAMS) design, with an integrated qualitative recruitment investigation aiming to optimise recruitment and consenting, to determine the optimum treatment of intermediate and high-risk OPC with the aim of improving survival outcomes without significantly worsening toxicity, Quality of Life (QoL) or swallowing function, compared to the current standard treatment of chemoradiotherapy. |
| Ethics approval(s) | West Midlands - Solihull, 27/11/2014, ref: 14/WM/1170 |
| Health condition(s) or problem(s) studied | Oropharyngeal cancer |
| Intervention | Current intervention as of 29/10/2021: 1. Arm 1: Control arm, concomitant chemoradiotherapy, 3-weekly cisplatin 100mg/m2 or weekly 40mg/m2 with Intensity Modulated Radiotherapy (IMRT) using 70Gy in 35F +/- neck dissection as indicated by clinical and radiological assessment 3-months post treatment. This is the international gold standard. 2. Arm 2: Induction chemotherapy (3 cycles at 3-weekly intervals: Docetaxel 75mg/m2 + Cisplatin 80mg/m2 + 5-Fluorouracil (5-FU) 800mg/m2/day, daily for 4 days), followed by Arm 1. 3. Arm 3: Dose-escalated chemoradiotherapy using intensity modulated radiotherapy (IMRT) 64Gy in 25F + Cisplatin 100mg/m2 day 1 of week 1 and of week 5 or weekly 40mg/m2 (neck dissection as indicated by clinical and radiological assessment at 3-months post-treatment). 4. Arm 4: Resection of primary + selective neck dissection followed by chemoradiotherapy. For T1 & T2 primary tumour, resection must be transoral. For T3 & T4 primary tumour, resection preferably transoral if possible otherwise by open surgery. Arm 5: Induction durvalumab plus arm 1 and then adjuvant durvalumab: 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. Follow Up Length: 24 month(s); Study Entry : Registration and One or More Randomisations (updated 12/12/2022: Arms 2, 3, 4 are now closed to recruitment). _____ Previous intervention: 1. Arm 1: Control arm, concomitant chemoradiotherapy, 3-weekly cisplatin 100mg/m2 or weekly 40mg/m2 with Intensity Modulated Radiotherapy (IMRT) using 70Gy in 35F +/- neck dissection as indicated by clinical and radiological assessment 3-months post treatment. This is the international gold standard. 2. Arm 2: Induction chemotherapy (3 cycles at 3-weekly intervals: Docetaxel 75mg/m2 + Cisplatin 80mg/m2 + 5-Fluorouracil (5-FU) 800mg/m2/day, daily for 4 days), followed by Arm 1. 3. Arm 3: Dose-escalated chemoradiotherapy using intensity modulated radiotherapy (IMRT) 64Gy in 25F + Cisplatin 100mg/m2 day 1 of week 1 and of week 5 or weekly 40mg/m2 (neck dissection as indicated by clinical and radiological assessment at 3-months post-treatment). 4. Arm 4: Resection of primary + selective neck dissection followed by chemoradiotherapy. For T1 & T2 primary tumour, resection must be transoral. For T3 & T4 primary tumour, resection preferably transoral if possible otherwise by open surgery. Follow Up Length: 24 month(s); Study Entry : Registration and One or More Randomisations |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Not provided at time of registration |
| Primary outcome measure | 1. Definitive (efficacy) endpoint: Overall Survival (OS) - Interval in whole days between the date of randomisation and the date of death from any cause 2. Interim outcome measure (activity stages): Disease Free Survival (DFS) - Interval between the date of randomisation and the date of death or the 1st documented relapse |
| Secondary outcome measures | 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 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. Swallowing outcomes using M.D. Anderson Dysphagia Inventory (MDADI) Questionnaire at 24 months and percutaneous endoscopic gastrostomy (PEG) utilisation rates at 1 year 4. Cost effectiveness using EuroQol Group (EQ-5D), patient diaries and primary and secondary resource utilisation data 5. Surgical complication rates in each arm |
| Overall study start date | 01/05/2015 |
| Completion date | 30/11/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 70 Years |
| Sex | Both |
| Target number of participants | 785 |
| Total final enrolment | 794 |
| Key inclusion criteria | Current inclusion criteria as of 28/02/2022: 1. Oropharyngeal squamous cell carcinoma (OPSCC) in base of tongue and tonsil (includes bilateral tumours) and uvula, with an Multidisciplinary Team (MDT) recommendation for treatment with definitive concurrent chemoradiotherapy. 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, 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 (APPENDIX 3) 5. Body weight >30kg 6. Adequate renal function, estimated glomerular filtration rate (eGFR) >50mL/min calculated using Cockcroft-Gault formula (APPENDIX 4)* 7. Adequate bone marrow function (absolute neutrophil count (ANC) ≥1.5 x 109/L, haemoglobin ≥9.0g/dL and platelets ≥100 x 109/L) 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. Prothrombin time (PT) ≤1.5 x ULN or International Normalised Ratio (INR) ≤1. 5 10. No cancers in previous 5 years, except basal cell carcinoma of skin and cervical intra-epithelial neoplasia (CIN) 11. Age 18-70 12. Written informed consent given for the trial 13. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female premenopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: - Women - Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiationinduced 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. Willingness to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations including follow up Previous inclusion criteria: 1. Oropharyngeal squamous cell carcinoma in base of tongue and tonsil with an Multidisciplinary Team recommendation for treatment with definitive concurrent chemoradiotherapy 2. Intermediate risk [HPV +ve OPC with N2b+ disease and greater than 10 pack year history of smoking] or high risk (HPV–ve OPC) as per Ang classification 3. Minimum life expectancy of 3 months 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 5. Adequate renal function, glomerular filtration rate >50mL/min calculated using CockcroftGault formula 6. Adequate bone marrow function (absolute neutrophil count ≥1.5 x 109/L and platelets ≥100 x 109/L) 7. Adequate liver function i.e. plasma bilirubin ≤1.5 times the upper limit of normal, and alanine aminotransferase and Alkaline phosphatase ≤2.5 x upper limit of normal 8. Prothrombin time ≤1.5 x upper limit of normal or International Normalised Ratio ≤1. 5 9. Magnesium ≥ lower limit of normal 10. No cancers in previous 5 years, except basal cell carcinoma of skin and cervical intraepithelial neoplasia 11. Age 16-70 12. Written informed consent given 13. Surgically resectable disease if being randomised to all 4 arms |
| Key exclusion criteria | Current exclusion criteria as of 28/02/2022: 1. All T1-T2,N0 OPC (HPV-pos or HPV-neg) 2. HPV positive patients who are: • T1-T3, N0-N2c non-smokers • T1-T3, N0-N2c smokers with ≤10 pack years or • T1-T3, N0-N2a smokers with ≥10 pack years 3. Unfit for chemoradiotherapy regimens 4. Creatinine Clearance 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 urposes d. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy is acceptable) 6. History of allergic reactions or hypersensitivity 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, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, including any patient known to have psychiatric illness/social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs or compromise the ability of the patient to give written informed consent 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. 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 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. 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. Any previous treatment with a PD-L or PD-L1 inhibitor, including durvalumab 13. 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). 14. 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 15. History of active primary immunodeficiency 16. History of allogeneic organ transplant 17. 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 Previous exclusion criteria: 1. Low risk OPSCC defined as: 1.1. HPV+ OPC nonsmokers or 1.2. HPV+ OPC smokers <10 pack years or 1.3. HPV+ OPC smokers >10 pack years with N02A nodal disease 2. Unfit for surgery or chemoradiotherapy regimens 3. Creatinine Clearance <50ml/min 4. Treatment with any of the following, prior to first dose of trial treatment: 4.1. Taxanes 4.2. Any Investigational Medicinal Products (IMP) within 30 days 4.3. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks 4.4. Major surgery within 4 weeks 4.5. Radiotherapy: 4.5.1. With a wide field of radiation or involving >30% of total bone marrow volume, within 4 weeks 4.5.2. With a limited field of radiation, for palliation, within 2 weeks 5. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the exception of alopecia) at the time of registration 6. History of allergic reactions to any of the IMPs used in this trial 7. Women who are pregnant or breastfeeding. Women of childbearing potential must have a negative pregnancy test performed within 7 days prior to the start of trial treatment 8. 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 9. Pre-existing tinnitus or hearing impairment ischaemic heart disease, cerebrovascular disease, peripheral vascular disease or previous arterial embolic event |
| Date of first enrolment | 01/05/2015 |
| Date of final enrolment | 31/01/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
School of Cancer Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
Edgbaston
Birmingham
B15 2TT
United Kingdom
Sponsor information
University of Birmingham
University/education
University/education
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Website | http://www.birmingham.ac.uk/ |
|---|---|
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Government
Cancer Research UK
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/01/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Results of this trial will be submitted for publication in a peer-reviewed journal. Updated 08/08/2019: Planned publication in a high-impact peer reviewed journal (approx. January 2025) |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 15/01/2024 | 15/01/2024 | Yes | No |
Editorial Notes
16/04/2025: The following changes were made to the study record:
1. Contact details updated.
2. The recruitment end date was changed from 31/12/2023 to 31/01/2024.
3. Total final enrolment added.
15/01/2024: Publication reference added.
06/10/2023: The recruitment end date was changed from 30/09/2023 to 31/12/2023.
12/12/2022: The interventions were updated.
05/07/2022: The target number of participants was changed from 695 to 785.
04/07/2022: The following changes were made to the trial record:
1. The overall end date was changed from 31/01/2024 to 30/11/2025.
2. The recruitment end date was changed from 31/01/2022 to 30/09/2023.
28/02/2022: The following changes were made to the trial record:
1. The contact email was changed.
2. The inclusion criteria were changed.
3. The exclusion criteria were changed.
29/10/2021: The following changes have been made:
1. The recruitment end date has been changed from 01/11/2020 to 31/01/2022.
2. The overall trial end date has been changed from 01/11/2020 to 31/01/2024.
3. The total target enrolment number has been changed from 650 to 695.
4. The target number of participants has been changed from "Planned Sample Size: 650; UK Sample Size: 650; Description: Patients with intermediate and high risk oropharyngeal cancer (OPC)." to "695".
5. The intervention has been updated.
27/10/2021: Contact details updated.
13/02/2020: ClinicalTrials.gov number added.
08/08/2019: Publication and dissemination plan and IPD sharing statement added.
12/04/2019: Contact details updated.
03/04/2019: The condition has been changed from "Topic: Cancer; Subtopic: Head and Neck Cancer; Disease: Head and Neck" to "Oropharyngeal cancer" following a request from the NIHR.
