TPExtreme: Platinum-Cetuximab Combined With Docetaxel or With 5FU in Patients With Recurrent/Metastatic HNSCC

Sponsor

Groupe Oncologie Radiotherapie Tete et Cou (Other)

Overall Status

Completed

CT.gov ID

NCT02268695

Collaborator

Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (Other), AIO-Studien-gGmbH (Other)

541

Enrollment

Locations

Arms

86.7

Actual Duration (Months)

31.8

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study evaluates the efficacy of the new docetaxel-cisplatin-cetuximab regimen (TPEx) versus the standard platinum-5FU-cetuximab EXTREME regimen as a first-line treatment in recurrent and/or metastatic HNSCC. Half of patients will be treated by TPEx regimen, while the other half will be treated by EXTREME regimen.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Squamous Cell Carcinoma	Drug: Cisplatin Drug: 5-Fluorouracile Drug: Docetaxel Drug: Cetuximab Drug: granulocyte colony-stimulating factor (G-CSF)	Phase 2

Detailed Description

The EXTREME regimen, i.e. cetuximab added to platinum (100 mg/m² every 3 weeks ) and 5FU (96h continuous infusion at 1000 mg/m²/day every 3 weeks) during 6 cycles of treatment and continued as maintenance in patients with stable disease, is currently the standard of care in first line recurrent metastatic HNSCC.

From our previous experience (phase II GORTEC "TPEx" study), the TPEx regimen of 4 cycles of docetaxel-cisplatin-cetuximab followed by maintenance with cetuximab every 2 weeks seems more efficient (overall survival) compared to EXTREME regiment. Docetaxel combined with cisplatine (each administered at 75mg/m² every 3 weeks) also appeared more convenient than the standard Cisplatin-5FU-Cetuximab EXTREME regimen (4 cycles of chemotherapy instead of 6 cycles and no i.v. continuous infusion). Toxicity was manageable with G-CSF support. In addition the toxicity / efficacy profile also seems favourable as suggested by the excellent dose intensity achieved and the high rate of patients (78%) who were able to start maintenance therapy.

Taking together all these considerations, the TPEx regimen might be a good substitute for EXTREME as first-line treatment in patients with recurrent metastatic HNSCC, and it is justified and necessary to perform a direct comparison in a randomized trial to further test this hypothesis.

Study Design

Study Type:

Interventional

Actual Enrollment :

541 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

TPExtreme: Randomized, Controlled Trial of Platinum-Cetuximab Combined Either With Docetaxel (TPEx) or With 5FU (Extreme) in Patients With Recurrent/Metastatic Squamous Cell Cancer of the Head and Neck

Actual Study Start Date :

Oct 10, 2014

Actual Primary Completion Date :

Dec 31, 2021

Actual Study Completion Date :

Dec 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: EXTREME: Cisplatin, 5-FU and Cetuximab Chemotherapy: 6 cycles (every 3 weeks) of Cisplatin (100 mg/m² iv on Day1), 5FU (4000 mg/m² total dose starting on day 1 and during 96h in continuous infusion), and Cetuximab (loading dose of 400 mg/m² iv on Day1, then 250 mg/m² iv weekly). If cisplatin is not tolerated and/or when the total cumulative dose of cisplatin (including prior administration) reaches 600 mg/m², cisplatin has to be replaced by carboplatin, AUC 5 (but not exceeding 750 mg), except in the case of bleeding tumor. Cetuximab maintenance : cetuximab continuation (250 mg/m² iv weekly) will begin only if at least disease stabilization is observed at the end of chemotherapy, and will be continued until PD or unacceptable toxicity.	Drug: Cisplatin Drug: 5-Fluorouracile Drug: Cetuximab
Experimental: TPEx: Cisplatin, Docetaxel and Cetuximab Chemotherapy: 4 cycles (every 3 weeks) of Cisplatin (75 mg/m² iv on Day1), Docetaxel (75 mg/m² iv on Day1), and Cetuximab (loading dose of 400 mg/m² iv on Day1, then 250 mg/m² iv weekly). If Cisplatin is not tolerated, cisplatin is replaced by carboplatin, AUC 5 (but not exceeding 750 mg), except in the case of bleeding tumor. Primary prophylactic administration of GCSF must be administered systematically after each cycle of chemotherapy. Cetuximab maintenance : cetuximab continuation (500 mg/m² iv every two weeks) will begin only if at least disease stabilization is observed at the end of chemotherapy, and will be continued until PD or unacceptable toxicity.	Drug: Cisplatin Drug: Docetaxel Drug: Cetuximab Drug: granulocyte colony-stimulating factor (G-CSF)

Arm

Intervention/Treatment

Active Comparator: EXTREME: Cisplatin, 5-FU and Cetuximab

Chemotherapy: 6 cycles (every 3 weeks) of Cisplatin (100 mg/m² iv on Day1), 5FU (4000 mg/m² total dose starting on day 1 and during 96h in continuous infusion), and Cetuximab (loading dose of 400 mg/m² iv on Day1, then 250 mg/m² iv weekly). If cisplatin is not tolerated and/or when the total cumulative dose of cisplatin (including prior administration) reaches 600 mg/m², cisplatin has to be replaced by carboplatin, AUC 5 (but not exceeding 750 mg), except in the case of bleeding tumor. Cetuximab maintenance : cetuximab continuation (250 mg/m² iv weekly) will begin only if at least disease stabilization is observed at the end of chemotherapy, and will be continued until PD or unacceptable toxicity.

Drug: Cisplatin

Drug: 5-Fluorouracile

Drug: Cetuximab

Experimental: TPEx: Cisplatin, Docetaxel and Cetuximab

Chemotherapy: 4 cycles (every 3 weeks) of Cisplatin (75 mg/m² iv on Day1), Docetaxel (75 mg/m² iv on Day1), and Cetuximab (loading dose of 400 mg/m² iv on Day1, then 250 mg/m² iv weekly). If Cisplatin is not tolerated, cisplatin is replaced by carboplatin, AUC 5 (but not exceeding 750 mg), except in the case of bleeding tumor. Primary prophylactic administration of GCSF must be administered systematically after each cycle of chemotherapy. Cetuximab maintenance : cetuximab continuation (500 mg/m² iv every two weeks) will begin only if at least disease stabilization is observed at the end of chemotherapy, and will be continued until PD or unacceptable toxicity.

Drug: Cisplatin

Drug: Docetaxel

Drug: Cetuximab

Drug: granulocyte colony-stimulating factor (G-CSF)

Outcome Measures

Primary Outcome Measures

Overall survival [Until patient death or at least one year after the end of the treatment]
Overall survival is 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.

Secondary Outcome Measures

Objective response rate [At 12 weeks]
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 patients not evaluable (whatever the reason, including death) will be considered as failure (i.e. no CR, no PR).
Best overall tumor response rate [until progression or at least one year after the end of the treatment]
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 [until progression or death or at least one year after the end of the treatment]
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 [until progression or death or at least one year after the end of the treatment]
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 [until the end of the maintenance, an expected average of 4 months of maintenance]
Toxicity (according to CTC-NCI V4): all grades
Compliance [until the end of the maintenance, an expected average of 4 months of maintenance]
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.
EORTC QLQ-C30 [At baseline before treatment, at Week 12, Week 18 and at Week 26]
Health related quality of life (QoL) assessed by EORTC QLQ-C30. The primary endpoint of the QoL study is the global health status/quality of-life scale of the QLQ-C30 questionnaire
EuroQol-5D [At baseline before treatment, at Week 12, at Week 26 and then every 2 months.until death or at least one year after the end of the treatment]
Quality-adjusted life-years (QALYs) based on Euroqol EQ-5D measurements
Net monetary benefit [until death or at least one year after the end of the treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 71 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

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
Malignancies within 5 years prior to randomization, with the exception of adequately treated basal or squamous cell 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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Institut Sainte Catherine	Avignon	France	84082
2	Centre Hospitalier de la Dracénie	Draguignan	France
3	Centre Médical de Forcilles	Férolles-Attilly	France	77150
4	Clinique des Ormeaux	Le Havre	France	76600
5	Centre Hospitalier de Bretagne Sud (CHBS)	Lorient	France	56322
6	Centre Léon Bérard	Lyon	France	69008
7	Hôpital de la Timone	Marseille	France	13385
8	ICM Val d'Aurelle, Montpellier	Montpellier	France	34298
9	Centre Antoine-Lacassagne	Nice	France	06189
10	Val de Grace	Paris	France	75005
11	Centre Eugene Marquis	Rennes	France	35042
12	Centre Henri Becquerel	Rouen	France	76038
13	Institut de Cancérologie de l'Ouest (ICO) René Gauducheau	Saint Herblain	France	44805
14	L'Institut de Cancérologie de Lorraine (ICL) Alexis Vautrin	Vandoeuvre les Nancy	France	54511
15	Gustave Roussy	Villejuif	France	94805
16	Charité Campus Benjamin Franklin	Berlin	Germany	12203
17	Instituto Catalá de Oncologia (ICO)	Barcelona	Spain	08907

Sponsors and Collaborators

Groupe Oncologie Radiotherapie Tete et Cou
Grupo Español de Tratamiento de Tumores de Cabeza y Cuello
AIO-Studien-gGmbH

Investigators

Study Chair: Joel GUIGAY, MD, Centre Antoine Lacassagne, Nice, France
Study Director: Jean BOURHIS, MD, PhD, GORTEC President
Principal Investigator: Ricardo MESIA, MD, Instituto Catalá de Oncologia (ICO), Barcelona, Spain
Principal Investigator: Ulrich KEILHOLZ, MD, Charité Campus Benjamin Franklin, Berlin, Germany