RATIONALE: Drugs, such as fenretinide and lonafarnib, may stop the growth of head and neck
cancer by blocking blood flow to the tumor. Fenretinide may also help tumor cells become
normal cells. Lonafarnib may also stop the growth of tumor cells by blocking some of the
enzymes needed for cell growth. Giving fenretinide together with lonafarnib may kill more
PURPOSE: This randomized phase I trial is studying the side effects and best dose of
fenretinide and lonafarnib in treating patients with advanced or recurrent head and neck
- Determine the biological activity and tolerability of fenretinide and lonafarnib in
patients with advanced or recurrent squamous cell carcinoma of the head and neck.
- Determine the toxicity profile of this regimen in these patients.
- Determine the maximum tolerated dose of this regimen in these patients.
- Determine the dose-limiting toxicity of this regimen in these patients.
- Determine a recommended phase II dose of this regimen in these patients.
OUTLINE: This is a dose-escalation study followed by a randomized study.
- Dose-escalation portion: Patients receive oral fenretinide twice daily on days 1-7 and
oral lonafarnib twice daily on days 1*-21. Courses repeat every 21 days in the absence
of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of fenretinide and lonafarnib until the
maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at
which 2 of 6 patients experience dose-limiting toxicity.
- Randomized portion: After the dose-escalation portion of this study is completed,
additional patients (including patients who participate in the dose-escalation portion
of this study) are accrued and randomized to 1 of 4 dose levels. All patients receive
fenretinide and lonafarnib as in the dose-escalation portion of this study.
NOTE: *Lonafarnib is not administered on day 1 of course 1.
After completion of study treatment, patients are followed every 3 months for 2 years.
PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
- Histologically confirmed squamous cell carcinoma of the head and neck
- Advanced or recurrent disease
- Considered incurable by standard measures
- Tumor tissue accessible for biopsy
- Any age
- stern Cooperative Oncology Group (ECOG) 0-1
- Not specified
- White Blood Count (WBC) ≥ 3,000/mm^3
- Absolute neutrophil count ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Hemoglobin ≥ 9.0 g/dL
- Bilirubin ≤ 2.0 mg/dL
- Albumin ≥ 2.5 g/dL
- Aspartate aminotransferase (AST or SGOT) and/or alanine aminotransferase (ALT or
SGPT) ≤ 2.5 times upper limit of normal (ULN) AND alkaline phosphatase normal OR
- Alkaline phosphatase ≤ 4 times Upper Limit of Normal (ULN) AND Aspartate
aminotransferase (AST or SGOT) and/or alanine aminotransferase (ALT or SGPT) normal
- Creatinine < 2 mg/dL
- No history of uncontrolled heart disease
- No arrhythmia
- No angina
- No congestive heart failure
- No other heart condition that cannot be controlled with regular ongoing medication
- Able to swallow oral medication
- No requirement for total parenteral nutrition with lipids
- No significant neuropathy
- No neurotoxicity ≥ grade 3 from prior anticancer treatment
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective double-method contraception during and for at
least 1 month after study participation
- No signs or symptoms of acute infection requiring systemic therapy
- No confusion, disorientation, or major psychiatric illness that would preclude giving
- No serious infection requiring immediate therapy
- No other illness requiring immediate therapy
- No pre-existing retinopathy
- No other medical or social factor that would preclude study compliance
PRIOR CONCURRENT THERAPY:
- See Chemotherapy
- No more than 2 prior chemotherapeutic regimens for recurrent or metastatic disease
- Prior biologic therapy not considered a chemotherapeutic regimen
- More than 2 days since prior and no concurrent high-dose chronic steroids
- More than 2 days since prior and no concurrent ethinylestradiol
- No concurrent anticancer hormonal therapy
- More than 6 months since prior radiotherapy
- No concurrent radiotherapy
- No prior surgery that may affect the ability to swallow study drugs
- More than 2 days since prior and no concurrent cytochrome P450 3A4 (CYP3A4) inducers
or inhibitors, including any of the following:
- Grapefruit juice
- More than 30 days since prior high-dose vitamin A
- No concurrent high-dose synthetic or natural vitamin A derivatives (> 10,000 IU/day)
- No concurrent antioxidants (e.g., vitamin E or vitamin C)
- No other concurrent investigational agents
- No other concurrent antineoplastic agents