Vorinostat and Azacitidine in Treating Patients With Locally Recurrent or Metastatic Nasopharyngeal Cancer or Nasal Natural Killer T-Cell Lymphoma

• Pharmacokinetics of SAHA in patients with locally recurrent and metastatic nasopharyngeal carcinoma and NK-T cell Nasal Lymphoma [ Time Frame: Days 1 and 14 of course 1 ] [ Designated as safety issue: No ]
  Performed using a validated high performance liquid chromatography (HPLC) method. Maximum concentration (Cmax) and time to Cmax will be read off the curve, terminal T1/2 will be derived using the slope of the terminal portion of the semilogarithmic concentration-time plot, incorporating at least 3 time points in the extrapolation of the curve. Area-under-the curve (infinity) of the semilog plot will be estimated using the trapezoidal method, and oral clearance (CL/F) will be derived using Dose/AUC, volume of distribution will be calculated.
• Proportions of patients with high and low histone acetylation [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  Will be estimated with its 95% confidence interval.

This phase I trial is studying the side effects and best dose of vorinostat when given together with azacitidine in treating patients with locally recurrent or metastatic nasopharyngeal cancer or nasal natural killer T-cell lymphoma. Drugs used in chemotherapy, such as vorinostat and azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Vorinostat and azacitidine also may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving vorinostat together with azacitidine may kill more cancer cells

PRIMARY OBJECTIVES:

I. Determine the dose-limiting toxicity of vorinostat (SAHA) in combination with azacitidine in patients with locally recurrent or metastatic nasopharyngeal carcinoma or nasal type natural killer (NK)/T-cell lymphoma.

II. Determine the maximum tolerated dose of SAHA given in combination with a fixed dose azacitidine in these patients, based on evidence of Epstein-Barr virus (EBV) lytic induction in tumor biopsies and plasma.

SECONDARY OBJECTIVES:

I. Assess the effect of SAHA on histone acetylation as measured in tumor and peripheral blood mononuclear cells of these patients.

II. Assess the effect of azacitidine on EBV promoter demethylation in these patients.

III. Study the effect of azacitidine on the pharmacokinetics of SAHA in these patients.

OUTLINE: This is a multicenter, dose-escalation study of vorinostat (SAHA).

Patients receive azacitidine subcutaneously (SC) on days 1-10 and oral SAHA twice daily on days 1-14. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients with responding disease may continue treatment at the discretion of the principal investigator. Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Six patients are treated at the MTD. Patients undergo blood collection periodically during study for pharmacologic and biomarker correlative studies. Some patients also undergo tumor biopsies for biomarker correlative studies.

• Adult Nasal Type Extranodal NK/T-cell Lymphoma
• Recurrent Lymphoepithelioma of the Nasopharynx
• Recurrent Squamous Cell Carcinoma of the Nasopharynx
• Stage IV Lymphoepithelioma of the Nasopharynx
• Stage IV Squamous Cell Carcinoma of the Nasopharynx

• Drug: azacitidine
  Given SC
  Other Names:

  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
• Drug: vorinostat
  Given orally
  Other Names:

  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
• Other: diagnostic laboratory biomarker analysis
  Correlative studies
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies
• Procedure: axillary lymph node biopsy
  Correlative studies
  Other Name: axillary node biopsy

Inclusion Criteria:

• Biopsy proven nasopharyngeal carcinoma (WHO type 3) or extranodal nasal type natural killer (NK)/T-cell non-Hodgkin's lymphoma

  • Recurrence or metastases does not require tissue documentation

• Meets 1 of the following staging criteria:

  • Locally recurrent disease

    • Treated with ≥ 1 chemotherapy regimen after relapse
    • Not amenable to surgical resection
    • Not amenable to further curative radiotherapy
  • Metastatic disease

• No clinical evidence of CNS involvement, including brain metastases or carcinomatous meningitis

  • Skull base involvement allowed
• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy > 6 months
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST/ALT ≤ 2.5 times ULN (< 5 times ULN if liver metastases present)
• PTT ≤ 1.5 times ULN
• Albumin ≥ 2.7 g/dL
• Creatinine ≤ 1.5 times ULN OR creatinine clearance > 50 mL/min

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit study compliance
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Negative pregnancy test
• No history of allergic reaction to compounds of similar chemical or biologic composition to azacitidine or vorinostat (SAHA)
• No chronic active hepatitis B
• See Disease Characteristics
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy and recovered
• At least 2 weeks since prior valproic acid
• No more than 1 concurrent multivitamin daily
• No concurrent prophylactic hematopoietic growth factors
• No other concurrent investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer agents or therapies
• No other concurrent chemotherapy (including photopheresis), psoralen-ultraviolet treatment (PUVA), radiotherapy, or biologic therapy