Combination Chemotherapy and Radiation Therapy With or Without Lapatinib in Treating Patients With Locally Advanced Cancer of the Larynx or Hypopharynx
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.
Head and Neck Cancer
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
|Study Design:||Allocation: Randomized
Masking: 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|
- Maximum tolerated dose of lapatinib ditosylate (Phase I) [ Designated as safety issue: Yes ]
- Dose-limiting toxicities of lapatinib ditosylate (Phase I) [ Designated as safety issue: Yes ]
- Recommended dose of lapatinib ditosylate (Phase I) [ Designated as safety issue: No ]
- Feasibility (Phase II) [ Designated as safety issue: No ]
- Toxicity (Phase II) [ Designated as safety issue: Yes ]
- Survival with functional larynx (i.e., alive without local progression/relapse, tracheotomy, feeding tube, gastrostomy, or laryngectomy) (Phase II) [ Designated as safety issue: No ]
- Response rate (CR and PR) of neoadjuvant treatment (Phase II) [ Designated as safety issue: No ]
- Overall response rate (Phase II) [ Designated as safety issue: No ]
- Rate of local relapse (Phase II) [ Designated as safety issue: No ]
- Distant metastasis (Phase II) [ Designated as safety issue: No ]
- Overall survival (Phase II) [ Designated as safety issue: No ]
- Predictive value of PET to spare neck dissection in N1-3 patients (Phase II) [ Designated as safety issue: No ]
|Study Start Date:||May 2007|
|Study Completion Date:||March 2009|
|Primary Completion Date:||November 2008 (Final data collection date for primary outcome measure)|
- 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).
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00498953
|Institut Jules Bordet|
|Brussels, Belgium, 1000|
|Study Chair:||Ahmad Awada, MD, PhD||Institut Jules Bordet|