E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Loco-regionally advanced head and neck squamous cell carcinoma with no evidence of disease after chemo-radiotherapy |
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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 | 18.0 |
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 |
To investigate the efficacy and safety of afatinib over placebo when given as adjuvant therapy after chemo-radiotherapy (CRT) in primary unresected patients with loco-regionally advanced squamous cell carcinoma stage III or IVa/b of the oral cavity, oropharynx, or hypopharynx, or larynx stage IVa/b. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to determine;
-Disease Free Survival (DFS) rate at 2 years
-Duration of Overall Survival (OS), defined as the time from randomisation until death (irrespective of reason)
-Health related quality of life (HRQOL) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed loco-regionally advanced squamous cell carcinoma
a) stage III, IVa, or IVb, of the oral cavity, oropharynx, or hypopharynx; or
b) larynx stage IVa or IVb
2. Unresected tumour prior to chemo-radiotherapy due to:
a) Technical unresectability (e.g. tumour fixation/invasion to either base of the skull, cervical vertebrae, nasopharynx, or fixed lymph nodes); and/or
b) Low surgical curability (T3-T4, N2-N3 excluding T1N2); and/or
c) Organ preservation
3. Concomitant platinum-based chemo-radiotherapy completed no longer than 24 weeks prior to randomisation:
a) Head and neck radiotherapy with curative intent to a dose of minimum 66 Gy in 33 fractions (or its radiobiological equivalent) with adequate nodal coverage. Cumulative break in radiotherapy for no more than 10 days; and
b) Minimum cumulative platinum dose for cisplatin equalling 200 mg/m2 or for carboplatin minimum cumulative area under the concentration-time curve (AUC) 9; and
c) At randomisation, chemo-radiotherapy induced side effects CTCAE grade ≤ 2 (exception: patients with feeding tube are eligible)
4. No evidence of disease (NED), defined as no measurable or palpable tumour on clinical and radiographic (e.g. CT scan or MRI) examination as judged by the investigator in either of the following a) No residual tumour after CRT b) No residual tumour after CRT followed by R0 tumour resection c) No evidence of nodal disease after CRT followed by neck dissection. In case of palpable mass, NED must be confirmed by biopsy
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at the time of randomisation
6. Male and female patients age > 18 years
7. Written informed consent that is in compliance with ICH GCP and local law |
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E.4 | Principal exclusion criteria |
- Patients with smoking history of ≤ 10 pack years and with primary tumour site base of tongue
- Patients with smoking history of ≤ 10 pack years and with primary tumour site tonsil
- Primary cancer of nasopharynx, sinuses, and/or salivary glands
- Resection of the primary tumour (isolated biopsies are not regarded as radical surgical procedure) prior to chemo-radiotherapy
- Any other malignancy (except for simultaneous HNSCC primaries, appropriately treated superficial basal cell skin cancer and surgically cured cervical cancer in situ) unless free of disease for at least five years
- Treatment with any investigational drug or anti-cancer therapy less than four weeks prior to randomisation
- Prior treatment with any EGFR-targeted small molecules, EGFR-targeted antibodies, and/or any investigational agents for treatment of HNSCC
- Requirement for treatment with any of the prohibited concomitant medications listed in Section 4.2.2.1 of the protocol.
- Known pre-existing interstitial lung disease (ILD)
- Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification ≥ III, unstable angina, myocardial infarction within six months prior to randomisation, or poorly controlled arrhythmia
- Cardiac left ventricular dysfunction with resting ejection fraction of less than institutional lower limit of normal (if no lower limit of normal is defined in the institution, the lower limit is 50%)
- Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohn's disease, malabsorption or CTCAE grade >1 diarrhoea of any aetiology at randomisation
- Known HIV, active hepatitis B and/or active hepatitis C, as judged by the investigator
- Other significant disease that in the investigator's opinion would exclude the subject from the trial
- Screening laboratory values based on central laboratory analysis:
a) Absolute neutrophil count (ANC) <1.5x10^9/l
b) Platelet count <75x10^9/l
c) Total bilirubin >1.5 times the upper limit of normal (ULN)
d) Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 3 times the ULN
e) Calculated creatinine clearance < 50 ml/min (using the Cockcroft-Gault formula, see Appendix 1 of the protocol)
- Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or to use adequate contraception during the trial and for at least 2 weeks after end of treatment. Adequate methods of contraception and definition of child-bearing potential are described in Section 5.2.2.2.1 of the protocol
- Pregnancy or breast feeding
- Known or suspected hypersensitivity to the study medication or the excipients
- Patients unable to comply with the protocol in the opinion of the investigator
21. Currently involved in another clinical trial interfering with imaging schedules required by this protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease Free Survival (DFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
DFS rate at 2 years
Overall Survival (OS)
Health Related Quality of Life (HRQOL)
Adverse events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | Yes |
E.8.1.5 | Parallel group | Yes |
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 | 2 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 107 |
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 |
Austria |
Belgium |
Brazil |
Canada |
Chile |
Czech Republic |
Denmark |
Egypt |
Finland |
France |
Germany |
Greece |
Hungary |
India |
Israel |
Italy |
Japan |
Mexico |
Netherlands |
Peru |
Poland |
Portugal |
Russian Federation |
Spain |
Sweden |
Switzerland |
Ukraine |
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
|
The trial will be completed two years after the last patient is randomised or 309 events (tumour recurrences / second primary tumour or deaths) have occurred, whichever comes last. |
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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 | 7 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |