E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN) |
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E.1.1.1 | Medical condition in easily understood language |
Advanced cancer of the head and neck |
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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 | 10060121 |
E.1.2 | Term | Squamous cell carcinoma of head and neck |
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 |
Cohort 1: cisplatin-ineligible participants
• To compare the event free survival (EFS) of nivolumab in combination with radiotherapy (RT) to that of cetuximab in combination with RT in participants with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who are ineligible for cisplatin based chemoradiotherapy (CRT)
Cohort 2: cisplatin-eligible participants
• To compare the EFS of nivolumab plus cisplatin in combination with RT to that of cisplatin alone in combination with RT, in participants with locally advanced SCCHN who are eligible for cisplatin based CRT |
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E.2.2 | Secondary objectives of the trial |
Cohort 1: cisplatin-ineligible participants
• To compare the duration of loco-regional control (DLRC) of nivolumab in combination with RT to that of cetuximab in combination with RT
• To compare the overall survival (OS) of nivolumab in combination with RT to that of cetuximab in combination with RT
• To compare the proportion without meaningful symptom deterioration of nivolumab in combination with RT to that of cetuximab in combination with RT
Cohort 2: cisplatin-eligible participants
• To compare the DLRC of nivolumab plus cisplatin in combination with RT to that of cisplatin alone in combination with RT
• To compare the OS of nivolumab plus cisplatin in combination with RT to that of cisplatin alone in combination with RT
• To compare the proportion without meaningful symptom deterioration of nivolumab plus cisplatin in combination with RT to that of cisplatin alone in combination with RT |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically proven SCCHN from one of the following primary sites: oral cavity, oropharynx, hypopharynx, and larynx
• Locally advanced disease which is un-resectable, or resectable but suitable for an organ sparing approach
• No previous radiotherapy or systemic treatment for SCCHN
• Eastern cooperative oncology group (ECOG) score of 0-1
• Age ≥ 18 years or age of majority
• Measurable disease by RECIST 1.1 criteria, and tumor assessment performed prior to randomization
• Sufficient sample of fresh or archival (< 3 months from informed consent date) formalin-fixed, paraffin-embedded (FFPE) tissue block, or unstained tumor tissue sections, with an associated pathology report, must be submitted for biomarker evaluation for PD-L1 status. Central lab must provide Interactive Response Technology (IRT) with confirmation of receipt of evaluable tumor tissue prior to randomization. Biopsy should be excisional, incisional or core needle. Fine needle or aspiration is unacceptable for submission. PD-L1 status must be available prior to randomization.
• HPV p16 test result available (performed locally or centrally) for participants with oropharyngeal disease
•Patients must be of intermediate or high risk categories*:
• High risk:
• Oral cavity, hypopharynx, larynx, oropharynx (p16 negative): Stage III/ IV
• Oropharynx (p16 positive): Stage III (T4 any N or T1-3 N3) - irrespective of smoking status.
• Intermediate risk:
• Oropharynx (p16 positive): T3 N0-2 or T1-3 N2 disease if smoking > 20 pack year history
*TNM clinical staging according to AJCC version 8
Cohort 1 (cisplatin-ineligible participants) Specific Inclusion Criteria (Arm A and Arm B)
• Physician assesses participant to be non-eligible for treatment with platinum based combined CRT. This must be for one or more of the following reasons:
• Age ≥ 70 years at enrolment
• Creatinine clearance < 60mL/min and > 30mL/min (using the Cockcroft and Gault formula– see below**)
• Severe hearing loss (minimal hearing threshold of 80 dB or more in either ear)
Cohort 2 (cisplatin-eligible participants) Specific Inclusion Criteria (Arm C and Arm D)
• Adequate renal function within 28 days prior to randomization as follows:
• Creatinine clearance ≥ 60 mL/min. as determined by 24 hour collection or estimated by Cockcroft-Gault formula:
Creatinine Clearance = [(140 - age) x (wt in kg)/Serum Cr mg/dL x 72**
**Participants aged ≥ 70 years may enter either Cohort 1 or 2 dependent on whether the physician’s assessment is that
the participant is eligible for cisplatin (Cohort 2) or ineligible for cisplatin (Cohort 1) based on their age. It is anticipated that in the majority of cases, patients aged ≥ 70 years will be considered ineligible for cisplatin and enter cohort 1. |
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E.4 | Principal exclusion criteria |
• Carcinoma originating in the nasopharynx or paranasal sinus, squamous cell carcinoma that originated from the skin and salivary gland or non-squamous histology (eg, mucosal melanoma), squamous cell carcinoma of unknown primary
• Clinical or radiological evidence of metastatic disease
• Prior radiotherapy that overlaps with radiation fields
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results
• Active unstable angina and/or congestive heart failure
• Myocardial infarction within 6 months prior to randomization
• Participants who have a weight loss of > 10% of body weight between screening and randomization will be removed from the study
• Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Participants with active interstitial lung disease (ILD) / pneumonitis or with a history of ILD /pneumonitis requiring steroids. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in both cohorts is EFS. EFS is defined as the time from randomization to radiographic progression, as determined by a Blinded Independent Central Review (BICR) using RECIST 1.1 or, for participants who do not have radiographic progression, the time from randomization to death. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
EFS will be compared formally between arms in each cohort, please refer to section 10.3 of the protocol |
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E.5.2 | Secondary end point(s) |
• DLRC is defined as the time from randomization to loco-regional relapse.
• OS is defined as time from randomization until death from any cause.
• Proportion without meaningful symptom deterioration is defined as the proportion with no meaningful worsening in a disease-related symptom score derived from items included in the EORTC QLQC30 and QLQ-H&N35, at 24 weeks following treatment completion. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluated throughout the study, please refer to section 10.3 of the protocol |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | Yes |
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 | Yes |
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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
China |
Colombia |
France |
Germany |
Italy |
Japan |
Korea, Republic of |
Mexico |
Poland |
Romania |
Russian Federation |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
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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
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 27 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 10 |