Evaluation of the Tolerance of Afatinib in Combination With Docetaxel and Cisplatin in LAHNSCC Induction Chemotherapy
Condition: HNSCC
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of the study is to determine the maximum tolerated dose (MTD) of afatinib
      administrated in combination with docetaxel (Taxotere®) and cisplatin in induction
      chemotherapy of locally advanced head and neck carcinoma in order to move to a phase II,
      allowing the comparison with standard induction chemotherapy TPF.

      It is a multicentric, national, opened, not-randomized phase Ib. Three doses of afatinib (20,
      30 and 40 Mg per day) will be studied in combination with the fixed standard doses of
      docetaxel and cisplatin. For each dose level, beginning with smallest (20 Mg per day of
      afatinib), 3 to 6 patients will be treated at maximum, i.e. 3 cycles of three weeks treatment
      each one (9 weeks on the whole). The next dose level will be studied only if the previous
      dose is well tolerated for the period of the first 4 weeks observation of the treatment (1st
      cycle more first week of the 2nd cycle). Once the MTD is determined, four additional patients
      will be treated with this dose. A maximum of 22 patients should be included in this study.
      The total duration of the study is estimated at 18 months. In case of major safety problems,
      the study may be stopped earlier. In short, the preclinical data, pharmacological and
      clinical on afatinib indicate that the benefit-risk ratio can be regarded as positive and
      that the association of afatinib with cisplatin and docetaxel could be effective in patients
      with head and neck squamous cell carcinoma potentially resulting in an extension of time to
      progression.
    

Detailed description: 
      Cancers of the upper aerodigestive tract correspond in the Western countries about 5% of
      cancers. They are treated by surgery, radiotherapy, and chemotherapy. Although progress in
      radio chemotherapy have reduced mortality and increase the rates of organ preservation in
      patients with locally advanced head and neck cancers, they have metastatic risk or
      particularly high local recurrence. The induction chemotherapy is a first-line treatment of
      cancer in which the patient receives doses of chemotherapy allowing to obtain a significant
      reduction in tumor size, and thus to avoid the surgery and to treat the tumor then by
      radiotherapy alone or combine by certain drugs. The standard treatment of induction
      chemotherapy currently used for the carcinoma of aerodigestive tract is TPF compose of 3
      drugs: the docetaxel (or Taxotere®, T), the cisplatin (P) and the 5-fluorouracil (or 5FU, F).
      Despite of the relative efficacy of this treatment, which provides a survival benefit, it is
      necessary to find a combination of induction to be more effective and less toxic. That is why
      this study intended to check if a new combination called TPA in which the fluorouracil (F) is
      replaced by the afatinib (A), will be more beneficial. The afatinib is a powerful and
      irreversible inhibitor of the EGFR (human Epidermal Growth Factor Receptor type 1), HER2 and
      HER 4. The EGFR is associated with a pejorative prognosis and resistance to the treatments
      through its role in the proliferation (multiplication of tumoral cells), the cell survival
      and replication and angiogenesis (process of growth of new blood-vessels, vital in the growth
      of the malignant tumors). Afatinib has proved effective in patients in with local recurrence
      or metastatic squamous cell carcinoma of the head and neck after first line cisplatin based
      and tolerance is correct.

      The rational of this study is based on the following elements:

        -  Cisplatin and docetaxel on the one hand and the afatinib on the other hand have proved
           effectiveness in head and neck cancers. The tolerance of their association is not known.

        -  In addition, several broad randomized trials have shown that it is possible to improve
           the effectiveness of induction chemotherapy in locally advanced head and neck carcinoma
           by the addition of Taxotere® to the cisplatin-5FU.

        -  Independently, it has been shown in carcinoma of the upper aerodigestive tract with
           recurrence or metastatic, that an anti-EGFR targeted therapy by cetuximab could improve
           the effectiveness of chemotherapy with cisplatin-5FU More recently, Taxotere® and
           Cisplatin + Cetuximab (or Erbitux®) combination for the treatment of head and neck
           squamous cell carcinoma has been tested in a broad study of phase II showing the good
           feasibility of this combination and a particularly high rate of tumoral response.

        -  Finally a comparative study of cetuximab versus afatinib showed an advantage in terms of
           tumoral response in support of afatinib.

      From all these observations, the investigators can hypothesize that the addition of afatinib
      to the docetaxel and the cisplatin could be an induction treatment for locally advanced
      carcinoma both innovating and promising. Indeed, this regimen appears optimized in terms of
      efficiency, incorporating both the combination of the most active cytotoxic agents, Taxotere®
      and the cisplatin, but also potentially more effective than Erbitux®.

      The purpose of the study is to determine the Maximum Tolerated Dose (MTD) of afatinib
      administrated in combination with docetaxel (Taxotere®) and cisplatin in induction
      chemotherapy of locally advanced head and neck carcinoma in order to move to a phase II,
      allowing the comparison with standard induction chemotherapy TPF.

      It is a multicentric, national, opened, not-randomized phase Ib. Three doses of the afatinib
      (20, 30 and 40 Mg per day) will be studied in combination with the fixed standard doses of
      the docetaxel and the cisplatin. For each dose level, beginning with smallest (20 Mg per day
      of afatinib), 3 to 6 patients will be treated at maximum, i.e. 3 cycles of three weeks
      treatment each one (9 weeks on the whole). The next dose level will be studied only if the
      previous dose is well tolerated for the period of the first 4 weeks observation of the
      treatment (1st cycle and first week of the 2nd cycle). Once the MTD is determine, four
      additional patients will be treated with this dose. A maximum of 22 patients should be
      included in this study. The total duration of the study is estimated at 18 months. In case of
      major safety problems, the study may be stopped earlier. In short, the preclinical data,
      pharmacological and clinical on afatinib indicate that the benefit-risk ratio can be regarded
      as positive and that the association of afatinib with cisplatin and docetaxel could be
      effective in patients with head and neck squamous cell carcinoma potentially resulting in an
      extension of time to progression.
    

Intervention name(s): Taxotere, Cisplatin, Afatinib
Intervention type(s): Drug
Intervention MeSH terms: Docetaxel; Afatinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment