| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10031096 |
| E.1.2 | Term | Oropharyngeal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Trial Objectives:
1. To examine the outcomes of alternative treatments aiming to improve overall survival in intermediate and high-risk oropharyngeal cancer
2. To compare Quality of Life, toxicity outcomes and swallowing function of these alternative treatments to a lay person. |
|
| E.2.2 | Secondary objectives of the trial |
Health Economics Objectives:
1. To compare cost-effectiveness in all treatment arms through cost-utility analysis
2. To estimate the cost per Quality-Adjusted Life Years over the two year period of the trial
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|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Quality of Life and Health Economics.
PD-L1 analysis translational research.
The protocol includes additional sub-studies which will not open in Ireland. |
|
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
Note: from 12th September 2019 all patients who enter the trial must be eligible for Arm 5
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)
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
8. Prothrombin time (PT) ≤1.5 x ULN or International Normalised Ratio (INR) ≤1. 5
9. No cancers in previous 5 years, except basal cell carcinoma of skin and cervical intra-epithelial neoplasia (CIN)
10. Age 18-70
11. Written informed consent given for the trial
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 age-specific requirements apply:
-Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating 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 post-menopausal 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. Willingness to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations including follow up
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|
| E.4 | Principal exclusion criteria |
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 <50ml/min
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-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 pector-is, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, including any patient known to have psychiatric illness/social sit-uations 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, phys-ical examination and radiographic findings, and TB testing in line with local practice), hepati-tis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immuno-deficiency 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 effi-cacy 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. Republic of Ireland only Treatment with live vaccines, including yellow fever vaccine
Additional Exclusion Criteria for Arm 5 Only:
Note: from 12th September 2019 all patients who enter the trial must be eligible for Arm 5
13. Any previous treatment with a PD-L or PD-L1 inhibitor, including durvalumab
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 in-jection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of predni-sone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g, CT scan, premedica-tion).
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 diverticu-losis), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uvei-tis, etc). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hor-mone 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. History of active primary immunodeficiency
17. History of allogeneic organ transplant
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Outcome Measures:
1. Definitive (efficacy) endpoint: overall survival time
2. Interim outcome measure (activity stages): Event Free Survival (EFS) time
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
INTERIM ANALYSIS:
Arm 5:
45 (1st stage) and 75 (2nd stage) contemporaneous control (arm 1) EFS events have been observed.
MAIN ANALYSIS:
Overall analysis comparing experimental arm 3 (if reopened) in the study to the control arm will be triggered when 128 control patients (for the ‘eligible comparison’ between the experimental arm & the control arm) have died in the study (of approx. 279 contemporaneous control patients recruited).
Overall analysis for comparing arm 5 to the control arm will be triggered when 84 control patients (for the ‘eligible comparison’ between the experimental arm and the control arm) have died in the study (of approx. 302 contemporaneous control patients recruited). |
|
| E.5.2 | Secondary end point(s) |
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 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. Overall and head and neck specific Quality of Life at 2 years post randomisation, using the European Organisation for Research and Treatment of Cancer (EORTC) C30 and HN35 Questionnaires
3. Swallowing outcomes using M.D. Anderson Dysphagia Inventory (MDADI) Questionnaire at 24 months and percutaneous endoscopic gastrostomy utilisation rates at 1 year
4. Cost effectiveness using EuroQol Group (EQ-5D) and primary and secondary resource utilisation data
5. Surgical complication rates in each arm
6. To correlate OS and EFS with Programmed cell death ligand 1 (PD-L1) expression and treatment with durvalumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Measured weekly during treatment and then monthly during year 1 of follow-up and 2 monthly during year 2 of follow-up
2. Measured at baseline (trial entry) and at months 3, 6, 12, 18 and 24 of follow-up.
3. Measured at baseline (trial entry) and at months 3, 6, 12, 18 and 24 of follow-up.
4. Measured at baseline (trial entry) and at months 3, 6, 12, 18 and 24 of follow-up.
5. Following surgical resection
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The trial end date is deemed to be 6 months after the last patient’s last follow-up visit. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 13 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 13 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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