Everolimus and Docetaxel in Treating Patients With Recurrent, Locally Advanced, or Metastatic Head and Neck Cancer

Study Overview
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Brief Summary
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RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving everolimus together with docetaxel is more effective than giving docetaxel alone in treating patients with head and neck cancer. PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus given together with docetaxel in treating patients with recurrent, locally advanced, or metastatic head and neck cancer.

Detailed Description
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OBJECTIVES: Primary To determine the safety and tolerability of the combination of everolimus and docetaxel in treating patients with recurrent, locally advanced or metastatic squamous cell carcinoma of the head and neck. (Phase I) To determine the maximum-tolerated dose and recommended phase II dose of everolimus when combined with docetaxel in these patients. (Phase I) To examine the response rates in patients receiving the combination of docetaxel and everolimus and those receiving docetaxel alone. (Phase II) Secondary To investigate possible pharmacokinetic interactions between docetaxel and everolimus in these patients. (Phase I) To investigate the effect of everolimus on downstream targets of mTOR in tumor in these patients. (Phase I) To examine the time to progression after docetaxel and everolimus in these patients. (Phase II) To perform a pilot study to attempt to identify predictors of response, including evaluation of EGFR family member expression, mutations, or amplifications. (Phase II) To attempt to identify downstream targets of the EGFR pathway including phosphorylation of S6 and phosphorylation of AKT. (Phase II) OUTLINE: This is a multicenter, phase I, dose-escalation study of everolimus with docetaxel followed by a randomized phase II study. Phase I: Patients receive docetaxel IV over 1 hour on day 1 and escalating doses of oral everolimus on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses of therapy, patients may continue to receive everolimus weekly as a single agent until evidence of progressive disease. Phase II: Patients are randomized to 1 of 2 treatment arms: Arm A: Patients receive docetaxel IV over 1 hour on day 1.Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with progressive disease are eligible to cross over into the everolimus arm at the investigator's discretion. Arm B: Patients receive docetaxel as in arm A and oral everolimus (at a dose determined in the phase I portion of the study) on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After the completion of combination therapy, patients may continue to receive maintenance everolimus weekly, at the investigator's discretion. Blood samples are collected for pharmacokinetic monitoring in the phase I study. Tissue samples are collected at baseline and periodically during the study for biomarker and other laboratory analysis. After completion of study treatment, patients are followed up every 3 months for at least 1 year. Peer Reviewed and Funded or Endorsed by Cancer Research UK. PROJECTED ACCRUAL: Approximately 18 patients will be accrued for phase I and a total of 100 patients will be accrued for phase II of this study.

Official Title
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DORA: A Phase I and Randomized Phase II Study of Docetaxel and RAD001 (Everolimus) in Advanced/Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: docetaxel
* Drug: everolimus
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed squamous cell carcinoma of the head and neck Locally advanced or metastatic disease No patients with locally advanced disease for whom radiotherapy is indicated Recurrent disease Incurable disease Measurable disease by RECIST criteria Recurrent disease within a prior radiation field can be considered to be measurable Patients may have received 1 line of prior chemotherapy (but not a taxane) for locally advanced or metastatic disease Patients may have received prior radiation therapy for locally advanced or metastatic disease (but must have completed the radiotherapy > 6 months before recruitment) No disease relapsed within 6 months of radiotherapy No evidence of central nervous system metastases PATIENT CHARACTERISTICS: ECOG performance status 0-1 Life expectancy ≥ 12 weeks Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 10 g/dL Urea and creatinine normal Serum bilirubin normal AST or ALT ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase < 2.5 times ULN Negative pregnancy test Not pregnant or nursing Fertile patients must use effective contraception during and for 3 months (female) or 2 months (male) after the last dose of the study treatment No uncontrolled infection No mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study No prior malignancy likely to interfere with the patient's ability to comply with treatment and/or follow up PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy for any cancer, except for head and neck cancer No prior taxane No prior therapy with any erbB inhibitors (except cetuximab given with radiotherapy, as indicated in treatment algorithm) More than 6 months since prior radiotherapy for locally advanced or metastatic disease At least 4 weeks since prior investigational drug No concurrent use of drugs known to inhibit CYP3A4 (except dexamethasone), or block P-glycoprotein, including grapefruit juice No other concurrent chemotherapy, immunotherapy, hormonal cancer therapy, radiotherapy, or experimental medications No concurrent live vaccines during everolimus therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: docetaxel|nan|
|Drug: everolimus|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose and recommended phase II dose of everolimus in combination with docetaxel (phase I) |  |  | 
| Safety and tolerability of the combination of everolimus and docetaxel |  |  | 
| Response using RECIST criteria (phase II) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile of docetaxel with and without concurrent everolimus (phase I) |  |  | 
| Pharmacokinetic profile of everolimus with and without concurrent docetaxel (phase I) |  |  | 
| Time to progression following response (time from treatment start to tumor progression as defined by RECIST criteria) (phase II) |  |  | 
| Mutations in EGFR1, AKT, mTOR, ras, or p53 to be tested on paraffin-embedded tissue from the primary or secondary tumor; results to be correlated with outcome (phase II) |  |  | 
| Amplifications of EGFR1 and bcl2 expression to be tested by FISH and immunostaining on paraffin-embedded tissue from primary tumor; results to be correlated with outcome (phase II) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent 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 III verrucous carcinoma of the larynx, stage IV squamous cell carcinoma of the larynx, stage IV verrucous carcinoma of the larynx, recurrent squamous cell carcinoma of the larynx, recurrent verrucous carcinoma of the larynx, recurrent squamous cell carcinoma of the lip and oral cavity, stage III squamous cell carcinoma of the lip and oral cavity, stage IV squamous cell carcinoma of the lip and oral cavity, recurrent verrucous carcinoma of the oral cavity, stage III verrucous carcinoma of the oral cavity, stage IV verrucous carcinoma of the oral cavity, metastatic squamous neck cancer with occult primary squamous cell carcinoma, recurrent metastatic squamous neck cancer with occult primary, recurrent squamous cell carcinoma of the nasopharynx, stage III squamous cell carcinoma of the nasopharynx, stage IV squamous cell carcinoma of the nasopharynx, recurrent squamous cell carcinoma of the oropharynx, stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, recurrent squamous cell carcinoma of the paranasal sinus and nasal cavity, stage III squamous cell carcinoma of the paranasal sinus and nasal cavity, stage IV squamous cell carcinoma of the paranasal sinus and nasal cavity, recurrent salivary gland cancer, salivary gland squamous cell carcinoma, stage III salivary gland cancer, stage IV salivary gland cancer, tongue cancer