Combination Chemotherapy and Radiation Therapy With or Without Lapatinib in Treating Patients With Locally Advanced Cancer of the Larynx or Hypopharynx
Condition: Head and Neck Cancer
MeSH terms: Head and Neck Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Drugs used in chemotherapy, such as docetaxel, cisplatin, fluorouracil, and
      carboplatin, work in different ways to stop the growth of tumor cells, either by killing the
      cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill
      tumor cells. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth. Giving combination chemotherapy together with radiation therapy, with
      or without lapatinib, before surgery may make the tumor smaller and reduce the amount of
      normal tissue that needs to be removed or eliminate the need for surgery.

      PURPOSE: This phase I/II trial is studying the side effects and best dose of combination
      chemotherapy given together with radiation therapy with or without lapatinib and to see how
      well it works in treating patients with locally advanced cancer of the larynx or hypopharynx.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the maximum tolerated dose and recommended dose for phase II of lapatinib
           ditosylate in patients with locally advanced squamous cell carcinoma of the larynyx or
           hypopharynx who are concomitantly treated with neoadjuvant induction chemotherapy
           comprising docetaxel, cisplatin, and fluorouracil, followed by chemoradiotherapy
           comprising carboplatin and radiotherapy. (Phase I)

        -  To document the feasibility, in the framework of an organ preservation program, of this
           regimen in these patients. (Phase II)

      Secondary

        -  To look at the role of PET in patients with N1-3 disease, in terms of PET being used as
           a reliable method to spare patients from planned neck dissection. (Phase II)

      OUTLINE: This is a multicenter, dose-escalation phase I study followed by a randomized phase
      II study. Patients are stratified by institution and EGFR status (negative vs positive).

        -  Phase I:

             -  Neoadjuvant chemotherapy: Patients receive neoadjuvant chemotherapy comprising
                docetaxel IV and cisplatin IV on day 1 and fluorouracil IV continuously on days
                1-5. Treatment repeats every 21 days for up to 4 courses in the absence of disease
                progression or unacceptable toxicity. Patients with a complete or partial response
                after 4 courses of neoadjuvant chemotherapy proceed to chemoradiotherapy. Patients
                with less than a partial response after course 2 or course 4 proceed to surgery,
                including total laryngectomy.

             -  Chemoradiotherapy: Within 3 weeks after completion of neoadjuvant chemotherapy,
                patients undergo radiotherapy on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and
                43-47 and receive carboplatin IV on days 1, 8, 15, 22, 29, 36, and 43.

             -  Concurrent lapatinib ditosylate: Patients receive oral lapatinib ditosylate once
                daily during neoadjuvant chemotherapy, during the break between neoadjuvant
                chemotherapy and chemoradiotherapy, and during chemoradiotherapy.

        -  Phase II: Patients are randomized to 1 of 2 treatment arms.

             -  Arm I: Patients receive neoadjuvant chemotherapy and undergo chemoradiotherapy as
                in phase I.

             -  Arm II: Patients receive neoadjuvant chemotherapy and undergo chemoradiotherapy as
                in phase I. Patients also receive concurrent lapatinib ditosylate as in phase I at
                the recommended dose determined in phase I.

      In both phases, treatment continues in the absence of disease progression or unacceptable
      toxicity.

      Patients with node-positive disease (initially) undergo tumor and blood sample collection for
      biological studies. Samples are analyzed for ErbB-related activation via
      immunohistochemistry, in situ hybridization, and PCR/sequencing of genes/proteins, to detect
      DNA amplification and polysomy (for AKT, ErbB2, EGFR) and genomic losses (for PTEN) via FISH,
      and the ratio between EGFR and EGFRvIII via QRT-PCR. Patients with node-positive disease
      undergo at least elective neck dissection to evaluate the negative predictive value of PET
      scanning.

      Patients are followed every 3 months for one year and then every 6 months thereafter.
    

Intervention name(s): carboplatin; cisplatin; docetaxel; fluorouracil; lapatinib ditosylate; cytogenetic analysis; fluorescence in situ hybridization; in situ hybridization; polymerase chain reaction; reverse transcriptase-polymerase chain reaction; immunohistochemistry staining method; laboratory biomarker analysis; conventional surgery; neoadjuvant therapy; fludeoxyglucose F 18; radiation therapy
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Genetic; Genetic; Genetic; Genetic; Genetic; Other; Other; Procedure; Procedure; Radiation; Radiation
Intervention MeSH terms: Carboplatin; Docetaxel; Fluorouracil; Lapatinib; Fluorodeoxyglucose F18
Allocation: Randomized
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: stage II squamous cell carcinoma of the hypopharynx; stage III squamous cell carcinoma of the hypopharynx; stage IV squamous cell carcinoma of the hypopharynx; stage III squamous cell carcinoma of the larynx; stage IV squamous cell carcinoma of the larynx