| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| recurrent or metastatic head and neck squamous cell carcinoma |
| rezidivierenden/metastasierenden Plattenepithelkarzinomen im Kopf/Hals-Bereich |
|
| E.1.1.1 | Medical condition in easily understood language |
| recurrent or metastatic head and neck squamous cell carcinoma |
| rezidivierenden/metastasierenden Plattenepithelkarzinomen im Kopf/Hals-Bereich |
|
| 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 | 19.1 |
| 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) |
|
| 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 compare in terms of overall survival the TPEx and EXTREME regimens
as first line treatment of patients with recurrent / metastatic HN SCC |
| Vergleich des Gesamtüberlebens von Patienten mit rezidivierenden/metastasierenden HNSCC bei Erstlinientherapie mit TPEx vs. EXTREME |
|
| E.2.2 | Secondary objectives of the trial |
To compare TPEX regimen and EXTREME regimen in terms of :
- Objective response rate (complete response (CR) or partial response
(PR) according to RECIST 1.1 criteria) at 12 weeks (centralized review)
- Best overall objective response rate (PR or CR or SD with confirmation
of CR or PR by a second assessment 6 weeks later)
- Progression free survival (PFS)
- Time to progression (TTP)
- Toxicity (all grades, according to CTC-NCI V4)
- Compliance with chemotherapy and Erbitux
- Health related quality of life (QL) assessed by EORTC QLQ-C30
questionnaires
Ancillary objectives :
- A multinational cost-effectiveness study will be performed alongside the trial to determine the most efficient regimen.
- Study of the impact of p16 / HPV tumor status on the efficacy
difference of the 2 regimens in patients with oropharyngeal initial tumor |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Histologically confirmed diagnosis squamous cell carcinoma of head and neck: oral cavity, oropharynx, hypopharynx, larynx (histological confirmation is mandatory at least for initial diagnosis)
• Recurrence and/or metastatic disease not suitable for local therapy
• At least one measurable lesion (RECIST) by CT or MRI
• PS < 2
• Age ≥ 18 years and < 71 years
• Clearance of creatinine > 60ml/mn (MDRD)
• Haematological function as follows: absolute neutrophil count > 1.5 x 109/l, platelet > 100 x 109/l, hemoglobin ≥ 9.5 g/dl
• Hepatic function as followed: bilirubin ≤ Upper limit of normal (ULN); SGOT/SGPT < 1.5 ULN; AP < 2.5 ULN
• Estimated life expectancy > 12 weeks
• Informed Consent Form signed
• Affiliation to an health insurance
• Negative pregnancy test in women of childbearing potential within 14 days prior to treatment initiation (premenopausal or less than 12 months of amenorrhea post-menopause, and who have not undergone surgical sterilization). Both men and women (of childbearing potential) who are sexually active must use adequate contraception, during and for at least 6 months post-treatment. |
• Histologisch bestätigtes Plattenepithelkarzinom der Kopf/Hals-Region: Mundhöhle, Oropharynx, Hypopharynx, Larynx (die histologische Bestätigung ist zumindest für die Initialdiagnose obligatorisch)
• Rezidiv und/oder Metastasierung ohne Möglichkeit der lokalen Therapie
• Mindestens eine messbare Läsion (nach RECIST) in der CT oder MRT
• PS < 2
• Alter > 18 und < 71 Jahre
• Kreatinin-Clearance > 60 ml/min (nach MDRD berechnet)
• Hämatologische Parameter: absolute Neutrophilenzahl (ANC) > 1,5 x 109/l, Thrombozytenzahl > 100 x 109/l, Hämoglobin ≥ 9,5 g/dl
• Leberwerte: Bilirubin ≤ ULN, SGOT/SGPT < 1,5 x ULN; AP < 2,5 x ULN (ULN = Obergrenze des Normbereichs)
• Lebenserwartung > 12 Wochen
• Unterschriebene Einverständniserklärung liegt vor
• Krankenversicherung besteht
• Bei gebärfähigen Frauen (prämenopausal oder mit postmenopausaler Amenorrhö < 12 Monate): negativer Schwangerschaftstest innerhalb von 14 Tagen vor Behandlungsbeginn. Sexuell aktive Männer und (gebärfähige) Frauen müssen während und bis mindestens 6 Monate nach der Behandlung eine wirksame Kontrazeption durchführen.
|
|
| E.4 | Principal exclusion criteria |
Patients with nasopharyngeal cancer, paranasal sinus cancer or unknown primary
• Prior systemic chemotherapy for the head and neck carcinoma, except if given as part of a multimodal treatment for locally advanced disease which was completed more than 6 months prior to study entry
• Surgery (excluding diagnostic biopsy) or radiotherapy within 6 weeks before study entry
• Contra-indication to receive cisplatin
• Known dihydropyrimidine dehydrogenase (DPD) deficiency
• Administration of prophylactic phenytoin
• Recent or planed yellow fever vaccination
• Prior dose of cisplatin > 300 mg/m² (a patient who received prior RT + 3 cycles of cisplatin or 3 cycles induction TPF, i.e. total dose of cisplatin ≤ 300 mg/m², for locally advanced primary HN cancer can be included)
• Prior anti-EGFR treatment received less than 12 months before enrolment in the trial
• Known hypersensitivity reaction to 5FU, cisplatin, carboplatin, docetaxel or cetuximab
• Documented or symptomatic brain or leptomeningeal metastasis
• Clinically significant cardiovascular disease, e.g. cardiac failure of New York Heart Association classes III-IV, uncontrolled coronary artery disease, cardiomyopathy, uncontrolled arrhythmia, uncontrolled hypertension, or history of myocardial infarction in the last 12 months
• Other malignancies within 5 years prior to randomization, with the exception of adequately treated basal skin cancer and carcinoma in situ of the cervix.
• Active infection (infection requiring IV antibiotics), including active tuberculosis and known and declared human immunodeficiency virus (HIV).
• Significant disease which, in the judgment of the investigator, would make the patient inappropriate for entry into the trial.
• Any social, personal, medical and/or psychologic factor(s) that could interfere with the observance of the patient to the protocol and/or the follow-up and/or the signature of the informed consent.
• Pregnant or breast feeding women |
• Patienten mit Karzinomen des Nasopharynx, der Nasennebenhöhlen oder unbekanntem Primärtumor
• Vorausgegangene systemische Chemotherapie des Kopf/Hals-Karzinoms (außer im Rahmen einer multimodalen Therapie bei lokal fortgeschrittenem Tumor, die mehr als 6 Monate vor Beginn der Studienteilnahme beendet wurde)
• Operativer Eingriff (außer diagnostische Biopsie) oder Radiotherapie innerhalb von 6 Wochen vor Beginn der Studienteilnahme
• Vorliegende Kontraindikationen gegen die Anwendung von Cisplatin
• Bekannte Dihydropyrimidin Dehydrogenase Defizienz (DPD)
• Prophylaktische Verabreichung von Phenytoin
• Kürzliche oder geplante Gelbfiebervakzinierung
• Vorausgegangene Cisplatin-Gaben > 300 mg/m2
(nach RT + 3 Zyklen Cisplatin bzw. nach 3 Zyklen TPF-Induktion, d.h. einer Cisplatin-Gesamtdosis ≤ 300 mg/m², bei lokal fortgeschrittenen Kopf/Hals-Tumoren ist die Studienteilnahme möglich)
• Behandlung mit EGFR-Antikörpern weniger als 12 Monate vor der Aufnahme in die Studie
• Bekannte Überempfindlichkeit gegen irgendein Studienmedikament
• Nachgewiesene oder symptomatische zerebrale oder leptomeningeale Metastasierung
• Klinisch relevante kardiovaskuläre Erkrankung, z.B. Herzinsuffizienz Klasse III–IV (nach NYHA), unkontrollierte koronare Herzkrankheit, Kardiomyopathie, unkontrollierte Arrhythmie, unkontrollierte Hypertonie oder Z.n. Myokardinfarkt in den letzten 12 Monaten
• Andere Malignitäten innerhalb von 5 Jahren vor der Randomisierung, mit Ausnahme der ausreichend behandelt basalen Hautkrebs und Carcinoma in situ der Cervix.
• Aktive Infektion (die eine i.v. antibiotische Therapie erfordert), einschließlich aktiver Tuberkulose und bekannter/angegebener HIV-Infektion
• Vorliegen einer relevanten Erkrankung, die den Patienten nach Einschätzung des Prüfarztes ungeeignet für eine Studienteilnahme macht
• Jegliche sozialen, persönlichen, medizinischen und/oder psychischen Umstände, die den Patienten daran hindern könnten, das Studienprotokoll einzuhalten oder die Einverständniserklärung zu unterzeichnen
• Schwangere und stillende Frauen |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall survival (OS): defined as the time to death from any cause
measured from randomization. Patients with disease progression may be
treated with off protocol therapy but will be followed for overall survival
evaluation |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall Survival will be evaluated one year after the end of the treatment |
|
| E.5.2 | Secondary end point(s) |
Objective response rate (complete response (CR) or partial response
(PR) according to RECIST 1.1 criteria and assessed by central imaging
review) at 12 weeks. For the statistical analysis of this endpoint,
patients not evaluable (whatever the reason, including death) will be
considered as failure (i.e. no CR, no PR) for this endpoint.
• Best overall tumor response rate (RECIST 1.1 criteria) during
chemotherapy and maintenance: CR or PR or SD confirmed for CR or PR
by a second assessment 6 weeks later
• Progression free survival (PFS): minimum time from randomization to
progression as defined by RECIST 1.1 criteria or to death from any
cause. Patients who don't have any of these events are censored at the date of last follow-up.
• Time to Progression (TTP): minimum time from randomization to
progression as defined by RECIST 1.1 criteria. In case of death from
other cause than cancer and no prior progression, the patient will be
censored at the time of death. In case of death related to cancer without
an accurate date of progression before death, the patient will be
considered in progression at the time of death. In the event of no
progression and no death, the patient will be censored at the date of last
follow-up.
• Toxicity (according to CTC-NCI V4): all grades
• Compliance: Insufficient compliance for cetuximab is defined as a
patient missing more than 2 consecutive infusions of cetuximab, even if
the missed infusions are due to toxicity. Insufficient compliance for
chemotherapy is defined as a patient missing more than 2 consecutive
infusions of chemotherapy, even if the missed infusions are due to
toxicity.
• Health related quality of life (QoL) assessed by EORTC QLQ-C30. The
primary endpoint of the QoL study is the global health status/quality oflife
scale of the QLQ-C30 questionnaire.
• Quality-adjusted life-years (QALYs) based on Euroqol EQ-5D
measurements
• Net monetary benefit |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease evaluation by imaging (RECIST 1.1 criteria): every 6 weeks until
week 18 or progression and, if no progression, every 8 weeks during
maintenance and follow-up until progression.
Toxicity: weekly during chemotherapy and every two weeks during
maintenance.
Quality of life QLQ-C30 questionnaire will be completed at baseline
before treatment, at Week 12 (i.e. end of cycle 4), Week 18 (i.e. end of
cycle 6 or after 6 weeks of maintenance) for all patients whatever the
treatment arm and at Week 26.
EuroQol-5D (EQ-5D) will be completed at baseline before treatment, at
Week 12 (i.e. end of cycle 4), Week 18 (i.e. end of cycle 6 or after 6
weeks of maintenance) for all patients whatever the treatment arm, at
Week 26 and then every 2 months. |
|
| 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 | 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) | 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 | Yes |
| 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 | 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) | Yes |
| 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
| 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 | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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