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

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

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.

Study Overview

• Status: Completed
• Conditions: Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Docetaxel; Drug: Cetuximab; Drug: Cisplatin; Drug: 5-Fluorouracile; Drug: granulocyte colony-stimulating factor (G-CSF)

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 Type: Interventional
• Enrollment (Actual): 541
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Avignon, France, 84082
    • Institut Sainte Catherine
  • Draguignan, France
    • Centre Hospitalier de la Dracénie
  • Férolles-Attilly, France, 77150
    • Centre médical de Forcilles
  • Le Havre, France, 76600
    • Clinique des Ormeaux
  • Lorient, France, 56322
    • Centre Hospitalier de Bretagne Sud (CHBS)
  • Lyon, France, 69008
    • Centre Léon Bérard
  • Marseille, France, 13385
    • Hôpital de la Timone
  • Montpellier, France, 34298
    • ICM Val d'Aurelle, Montpellier
  • Nice, France, 06189
    • Centre Antoine-Lacassagne
  • Paris, France, 75005
    • Val de Grace
  • Rennes, France, 35042
    • Centre Eugene Marquis
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Saint Herblain, France, 44805
    • Institut de Cancérologie de l'Ouest (ICO) René Gauducheau
  • Vandoeuvre les Nancy, France, 54511
    • L'Institut de Cancérologie de Lorraine (ICL) Alexis Vautrin
  • Villejuif, France, 94805
    • Gustave Roussy
• Germany
  • Berlin, Germany, 12203
    • Charite Campus Benjamin Franklin
• Spain
  • Barcelona, Spain, 08907
    • Instituto Catalá de Oncologia (ICO)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: Cetuximab; Drug: Cisplatin; Drug: 5-Fluorouracile
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: Docetaxel; Drug: Cetuximab; Drug: Cisplatin; Drug: granulocyte colony-stimulating factor (G-CSF)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	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.	Until patient death or at least one year after the end of the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	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).	At 12 weeks
Best overall tumor response rate	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	until progression or at least one year after the end of the treatment
Progression free survival	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.	until progression or death or at least one year after the end of the treatment
Time to Progression	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.	until progression or death or at least one year after the end of the treatment
Toxicity	Toxicity (according to CTC-NCI V4): all grades	until the end of the maintenance, an expected average of 4 months of maintenance
Compliance	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.	until the end of the maintenance, an expected average of 4 months of maintenance
EORTC QLQ-C30	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	At baseline before treatment, at Week 12, Week 18 and at Week 26
EuroQol-5D	Quality-adjusted life-years (QALYs) based on Euroqol EQ-5D measurements	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
Net monetary benefit		until death or at least one year after the end of the treatment

Collaborators and Investigators

• Sponsor: Groupe Oncologie Radiotherapie Tete et Cou
• Collaborators: AIO-Studien-gGmbH; Grupo Español de Tratamiento de Tumores de Cabeza y Cuello
• 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

Publications and helpful links

General Publications

• Guigay J, Auperin A, Fayette J, Saada-Bouzid E, Lafond C, Taberna M, Geoffrois L, Martin L, Capitain O, Cupissol D, Castanie H, Vansteene D, Schafhausen P, Johnson A, Even C, Sire C, Duplomb S, Evrard C, Delord JP, Laguerre B, Zanetta S, Chevassus-Clement C, Fraslin A, Louat F, Sinigaglia L, Keilholz U, Bourhis J, Mesia R; GORTEC; AIO; TTCC, and UniCancer Head and Neck groups. Cetuximab, docetaxel, and cisplatin versus platinum, fluorouracil, and cetuximab as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (GORTEC 2014-01 TPExtreme): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2021 Apr;22(4):463-475. doi: 10.1016/S1470-2045(20)30755-5. Epub 2021 Mar 5.

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2014
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: October 13, 2014
• First Submitted That Met QC Criteria: October 16, 2014
• First Posted (Estimate): October 20, 2014

Study Record Updates

• Last Update Posted (Actual): August 23, 2022
• Last Update Submitted That Met QC Criteria: August 22, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Taxanes; Recurrent/Metastatic HNSCC
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Adjuvants, Immunologic; Docetaxel; Lenograstim; Cetuximab
• Other Study ID Numbers: GORTEC 2014-01