| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Oropharyngeal Squamous Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the Head and Neck |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079785 |
| E.1.2 | Term | Oropharyngeal squamous cell carcinoma stage IV |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To estimate the efficacy (in terms of event-free survival) of 2 treatment Arms: (A) radiotherapy (RT) and cisplatin; (B) RT and durvalumab followed by adjuvant durvalumab in patients with intermediate risk, HPV-positive, locally advanced oropharyngeal squamous cell carcinoma of the head and neck (LA-OSCC). |
|
| E.2.2 | Secondary objectives of the trial |
• To assess differences between arms in change in FACT-HN score from baseline to 36 months post-RT.
• To estimate and describe the following for Arms A and B:
- Locoregional control (LRC);
- Distant metastasis-free survival (DMFS);
- Overall survival (OS);
- Cost effectiveness of the immunotherapy-based experimental treatment arm vs. the standard of RT and cisplatin in patients with intermediate risk LA-OSC using the EQ-5D-5L;
- Cost utility and lost productivity
• To estimate and describe the following for Arms A, B and C:
- Toxicity;
- Incidence of second cancer;
- Dysphagia: PSS-HN swallowing subscale and MDADI Global at 36 months from the end of RT;
- PRO-CTCAE baseline, last week of treatment, 3 months, 6 months and 12, 24 and 36 months from the end of RT;
- Radiation related late toxicity at 3 months, 6 months and 1 year from the end of RT. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Histologically and/or cytologically confirmed (primary lesion or regional lymph nodes) squamous cell carcinoma of the oropharynx (OSCC) which is locoregionally advanced, intermediate risk and non-metastatic (M0) as defined by the following (UICC/AJCC 8th Edition staging):
• T1-2 N1 (smoking ≥ 10 pack years);
• T3 N0-N1 (smoking ≥ 10 pack years);
• T1-3 N2 (any smoking hx).
- Human papillomavirus (HPV)-related as determined by positive p16 immunohistochemical staining on any tumour specimens. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumour cells. Local testing is acceptable; testing will not be done centrally in real-time.
- Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Appendix I) and a body weight of > 30 kg.
- Must be ≥ 18 years of age.
- The following radiological investigations must be done within 8 weeks of randomization:
• CT or MRI of the neck (with PET-CT and head imaging as indicated);
• CT chest or x-ray, other radiology tests as clinically indicated.
- Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.
- Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation.
- Patient must consent to provision of, and investigator(s) must confirm adequacy, of non-cytology tissue samples and confirm access to and agree to submit within 4 weeks of randomization to the CCTG Central Tumour Bank, a representative formalin fixed paraffin block of non-cytology tumour tissue.
- Patient must consent to provision of samples of blood, saliva and oropharyngeal swab.
- Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and health economics questionnaires in the languages provided.
- Patients must be accessible for treatment and follow-up.
- In accordance with CCTG policy, protocol treatment (cisplatin/RT or durvalumab) is to begin within 1 week of randomization.
- The patient is not receiving anti-cancer therapy in a concurrent clinical study and the patient agrees not to participate in other clinical studies during their participation in this trial while on study treatment.
- Adequate normal organ and marrow function as defined in the protocol (must be done within 14 days prior to randomization).
- Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.
- Patients must be assessed by a radiation oncologist and medical oncologist and deemed suitable for study participation. |
|
| E.4 | Principal exclusion criteria |
- Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.
- Current history of other non-OSCC malignancies of the head and neck.
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, or an anti-CTLA4, including tremelimumab.
- Any previous cisplatin or carboplatin chemotherapy.
- Any previous induction chemotherapy for current SCCHN.
- Any previous surgical treatment of the current cancer (except for a diagnostic biopsy) and no major surgery within 28 days prior to randomization.
- Any previous radiation to the head and neck region that would result in overlap of fields for the current study.
- Peripheral neuropathy ≥ grade 2 (CTCAE v5.0).
- Hearing loss/tinnitus ≥ grade 3 (CTCAE v5.0).
- History of allergic or hypersensitivity reactions to any study drug or their excipients.
- Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥ 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome.
- History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade ≥ 3 infusion reaction.
- Current or prior use of immunosuppressive medication within 28 days of study entry, with the exceptions of intranasal and inhaled corticosteroids or systemic chronic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Corticosteroids used on study for anti-emetic purpose are allowed. Corticosteroids as premedication for hypersensitivity reactions (e.g. computed tomography [CT] scan premedication) are allowed.
- 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 (controlled by diet alone) or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. There are exceptions in the protocol.
- Patients with active or uncontrolled intercurrent illness including, but not limited to:
• cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia);
• active peptic ulcer disease or gastritis;
• active bleeding diatheses;
• psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent;
• known history of previous clinical diagnosis of tuberculosis;
• known human immunodeficiency virus infection (positive HIV 1/2 antibodies);
• known active hepatitis B infection (positive HBV surface antigen (HBsAg).
• known active hepatitis C infection.
- History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline CT scan.
- Receipt of live attenuated vaccination (examples include, but are not limited to, vaccines for measles, mumps, and rubella, live attenuated influenza vaccine (nasal), chicken pox vaccine, oral polio vaccine, rotavirus vaccine, yellow fever vaccine, BCG vaccine, typhoid vaccine and typhus vaccine) within 30 days prior to randomization.
- Pregnant or lactating women.
- Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
- Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Event-free survival (EFS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Event-free survival (EFS), is defined as the time from randomization to the time when a failure is observed. Three-year EFS rate will be calculated by all patients without EFS event before 3 years / total randomized patients. |
|
| E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Loco Regional Control (LRC)
- Distant Metastasis Free Survival (DMFS)
- Toxicity
- Quality of life |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Overall survival (OS) is defined as the time from the date of randomization to the date of death for any cause. The follow-up of subjects still alive will be censored at the date of last visit/contact.
- Local and regional event-free survival, defined as time from randomization to the time of first documented local (primary site) or regional (lymph node) recurrence.
- Distant metastasis free survival, defined as time from randomization to the time of first documented distant metastasis or death from any cause.
- Toxicity (CTC AE v4.0). All patients who have received at least one dose of study treatment will be included in the safety analysis
- QOL as measured on the FACT-H&N is a secondary outcome of the study. |
|
| 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 | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life, biobanking. |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty (30) days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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