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

Sponsor

University College, London (Other)

Overall Status

Terminated

CT.gov ID

NCT01313390

Collaborator

(none)

Enrollment

Location

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Cancer	Drug: docetaxel Drug: everolimus Other: laboratory biomarker analysis Other: pharmacological study	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

4 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jun 1, 2009

Actual Primary Completion Date :

Apr 1, 2011

Actual Study Completion Date :

Apr 1, 2011

Outcome Measures

Primary Outcome Measures

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

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) []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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