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

Sponsor:	European Organization for Research and Treatment of Cancer
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00498953

Purpose

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	Intervention	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 I Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label
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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Head and Neck Cancer Surgery

Drug Information available for: Fluorouracil Cisplatin Carboplatin Fluorodeoxyglucose F18 Docetaxel Lapatinib Lapatinib Ditosylate

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

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 ]

Secondary Outcome Measures:

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 ]

Estimated Enrollment:	133
Study Start Date:	May 2007
Estimated Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

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

PATIENT CHARACTERISTICS:

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

PRIOR CONCURRENT THERAPY:

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00498953

Locations

Belgium
Institut Jules Bordet
Brussels, Belgium, 1000

Sponsors and Collaborators

European Organization for Research and Treatment of Cancer

Investigators

Investigator:

Ahmad Awada, MD, PhD

Institut Jules Bordet

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Specenier PM, Lalami Y, Vermorken J, et al.: EORTC 24051: unexpected side effects of a phase I study of TPF induction chemotherapy (IC) followed by chemoradiation (CRT) with lapatinib (LAP), a dual EGFR/ErbB2 inhibitor, in patients with locally advanced larynx and hypopharynx squamous cell carcinoma (LA-LxHxSCC). [Abstract] J Clin Oncol 27 (suppl 15): A-6017, 2009.

Study ID Numbers:	CDR0000553410, EORTC-24051, EUDRACT-2006-002667-33, GSK-EORTC-24051
Study First Received:	July 10, 2007
Last Updated:	July 25, 2009
ClinicalTrials.gov Identifier:	NCT00498953 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Cancer Institute (NCI):

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:

Antimetabolites
Otorhinolaryngologic Neoplasms
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Protein Kinase Inhibitors
Docetaxel
Neoplasms by Site
Respiratory Tract Diseases
Cisplatin
Therapeutic Uses
Laryngeal Diseases
Neoplasms, Squamous Cell

Respiratory Tract Neoplasms
Neoplasms by Histologic Type
Otorhinolaryngologic Diseases
Enzyme Inhibitors
Laryngeal Neoplasms
Lapatinib
Carboplatin
Immunosuppressive Agents
Pharmacologic Actions
Carcinoma
Neoplasms
Radiation-Sensitizing Agents
Head and Neck Neoplasms
Fluorouracil
Carcinoma, Squamous Cell

ClinicalTrials.gov processed this record on November 30, 2009