Combination Chemotherapy and Radiation Therapy With or Without Lapatinib in Treating Patients With Locally Advanced Cancer of the Larynx or Hypopharynx

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00498953
Recruitment Status : Completed
First Posted : July 11, 2007
Last Update Posted : January 8, 2013
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Brief 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.

Condition or disease Intervention/treatment Phase
Head and Neck Cancer Drug: carboplatin Drug: cisplatin Drug: docetaxel Drug: fluorouracil Drug: lapatinib ditosylate Genetic: cytogenetic analysis Genetic: fluorescence in situ hybridization Genetic: in situ hybridization Genetic: polymerase chain reaction Genetic: reverse transcriptase-polymerase chain reaction Other: immunohistochemistry staining method Other: laboratory biomarker analysis Procedure: conventional surgery Procedure: neoadjuvant therapy Radiation: fludeoxyglucose F 18 Radiation: radiation therapy Phase 1 Phase 2

Detailed Description:



  • 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)


  • 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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study on Induction Chemotherapy Followed by Chemoradiation With or Without Lapatinib, a Dual EGFR/ErbB2 Kinase Inhibitor, in Patients With Locally Advanced Larynx and Hypopharynx Squamous Cell Carcinoma
Study Start Date : May 2007
Actual Primary Completion Date : November 2008
Actual Study Completion Date : March 2009

Resource links provided by the National Library of Medicine

Drug Information available for: Lapatinib
U.S. FDA Resources

Primary Outcome Measures :
  1. Maximum tolerated dose of lapatinib ditosylate (Phase I)
  2. Dose-limiting toxicities of lapatinib ditosylate (Phase I)
  3. Recommended dose of lapatinib ditosylate (Phase I)
  4. Feasibility (Phase II)

Secondary Outcome Measures :
  1. Toxicity (Phase II)
  2. Survival with functional larynx (i.e., alive without local progression/relapse, tracheotomy, feeding tube, gastrostomy, or laryngectomy) (Phase II)
  3. Response rate (CR and PR) of neoadjuvant treatment (Phase II)
  4. Overall response rate (Phase II)
  5. Rate of local relapse (Phase II)
  6. Distant metastasis (Phase II)
  7. Overall survival (Phase II)
  8. Predictive value of PET to spare neck dissection in N1-3 patients (Phase II)

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Histologically confirmed newly diagnosed squamous cell carcinoma of the larynx or hypopharynx

    • T3 or T4 disease of the larynx or T2, T3 or T4 disease of the hypopharynx
    • Nodal status must be N0, N1, N2a, N2b, N2c or N3
  • Resectable or unresectable disease (Phase I patients only)
  • Patient must have tumors amenable to surgery (Phase II patients only)
  • No distant metastasis


  • WHO performance status 0-2
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin < 1.5 times the upper limit of the normal range
  • Alkaline phosphatase and transaminases < 2.5 times the upper limit of the normal range
  • Serum creatinine < 1.7 mg/dL
  • All patients (male and female) must use effective contraception methods if of reproductive potential (e.g., implants, injectables, combined oral contraceptives, IUDs, sexual abstinence, or vasectomized partner)
  • Females must not be pregnant or lactating
  • Patients must have normal cardiac function (LVEF assessed by MUGA or ECHO) and clinically satisfactory 12-lead ECG
  • No serious cardiac illness or medical condition within the past 6 months including, but not limited to, any of the following:

    • History of documented congestive heart failure
    • High-risk uncontrolled arrhythmias
    • Angina pectoris requiring antianginal medication
    • Clinically significant valvular heart disease
    • Evidence of transmural infarction on ECG
    • Poorly controlled hypertension (e.g., systolic BP > 180 mm Hg or diastolic BP > 100 mm Hg)
  • Patients should be able to swallow oral agents
  • No current malignancies at other sites with the exception of cone biopsied carcinoma of the cervix and adequately treated basal or squamous cell skin carcinoma or other cancer from which the patient has been disease-free for at least five years
  • Absence of any unstable systemic diseases or active uncontrolled infections
  • Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule


  • No other prior therapy for head and neck cancer
  • More than 10 days since prior and no concurrent CYP3A4 inducers, including the following:

    • Antibiotics (e.g., all rifamycin class agents [rifampicin, rifabutin, or rifapentine])
    • Anticonvulsants (e.g., phenytoin, carbamezepine, or barbiturates [phenobarbital])
    • Oral glucocorticoids (e.g., cortisone [> 50 mg], hydrocortisone [> 40 mg], prednisone [> 10 mg], methylprednisolone [> 8 mg], or dexamethasone [> 1.5 mg])
    • Antiretrovirals (e.g., efavirenz or nevirapine)
    • Other (hypericum perforatum [St. John's Wort] or modafinil)
  • More than 10 days since prior and no concurrent CYP3A4 inhibitors, including the following:

    • Antibiotics (e.g., clarithromycin, erythromycin, or troleandomycin)
    • Antifungals (e.g., itraconazole, ketoconazole, fluconazole [> 150 mg daily], or voriconazole)
    • Antiretrovirals and protease inhibitors (e.g., delavirdine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, or lopinavir)
    • Calcium channel blockers (e.g., verapamil or diltiazem)
    • Antidepressants (e.g., nefazodone or fluvoxamine)
    • Gastrointestinal agents (e.g., cimetidine or aprepitant)
    • Other (e.g., grapefruit, grapefruit juice, or camiodarone)
    • Miscellaneous (e.g., antacids [Mylanta, Maalox, Tums, or Rennies], all herbal [bergamottin or glabridin] or dietary supplements)
  • Patients may not receive any other anticancer therapy or investigational agents while on study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00498953

Institut Jules Bordet
Brussels, Belgium, 1000
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Study Chair: Ahmad Awada, MD, PhD Jules Bordet Institute

Publications of Results:
Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC Identifier: NCT00498953     History of Changes
Other Study ID Numbers: EORTC-24051
2006-002667-33 ( EudraCT Number )
First Posted: July 11, 2007    Key Record Dates
Last Update Posted: January 8, 2013
Last Verified: January 2013

Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
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

Additional relevant MeSH terms:
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Neoplasms by Site
Fluorodeoxyglucose F18
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors