Bortezomib and Gemcitabine in Treating Patients With Recurrent or Metastatic Nasopharyngeal Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving bortezomib together with gemcitabine works in treating patients with recurrent or metastatic nasopharyngeal cancer. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with gemcitabine may kill more tumor cells

Detailed Description
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OBJECTIVES: Primary I. Assess the response probability (confirmed and unconfirmed, complete and partial responses) and 3-month progression-free survival rate in patients with metastatic or recurrent nasopharyngeal carcinoma (NPC) who are treated with bortezomib. Secondary I. Estimate 1-year progression-free survival and assess quantitative toxicities in this group of patients treated with bortezomib. II. Evaluate the response probability (confirmed and unconfirmed, complete and partial) in the subset of patients who progress on bortezomib, with measurable disease at the time of progression, and go on to receive bortezomib and gemcitabine hydrochloride combination therapy. III. Estimate 1-year overall survival of all patients treated with this regimen. IV. Estimate 6-month progression-free survival from the start of combination therapy and assess quantitative toxicities in the subset of patients who progress on bortezomib and receive combination therapy. V. Explore, in a preliminary manner, the relationship between changes in Epstein-Barr virus DNA level, NF-kB DNA-binding activity, and methylation status of E-cadherin promoter with clinical outcomes. OUTLINE: This is a multicenter study of bortezomib. Patients receive bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients achieving a complete response (CR) receive 2 additional courses of treatment with bortezomib. Patients who experience disease progression on single-agent bortezomib and did not receive prior gemcitabine hydrochloride may begin combination therapy within 10-28 days of the last dose of bortezomib. Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and bortezomib IV on days 1, 4, 8, 11. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients achieving a CR receive 2 additional courses beyond the confirmed CR. After the completion of study treatment, patients are followed periodically for up to 3 years. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Official Title
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Phase II Trial of PS-341 (Bortezomib, NSC-681239) Followed by the Addition of Gemcitabine at Progression in Recurrent or Metastatic Nasopharyngeal Carcinoma

Conditions
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Recurrent Nasopharyngeal Cancer, Stage IV Nasopharyngeal Cancer

Intervention / Treatment
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* Drug: bortezomib
* Drug: gemcitabine hydrochloride
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed nasopharyngeal carcinoma (NPC) of one of the following subtypes: Non-keratinizing (WHO type II) Undifferentiated (WHO type III) Disease meets one of the following stage criteria: Stage IVC at diagnosis Persisted, metastasized, or recurred after definitive surgery, radiotherapy, and/or chemotherapy Measurable disease If only measurable disease is within a prior radiation therapy port, disease progression must be clearly demonstrated No known CNS metastases Serum creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin normal SGOT or SGPT ≤ 2.5 times ULN Zubrod performance status 0-2 No peripheral neuropathy > grade 1 No prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient has been disease-free for 5 years Not pregnant or nursing Fertile patients must use effective contraception More than 6 months since prior myocardial infarction No New York Heart Association class III or IV cardiac problems No uncontrolled angina No severe uncontrolled ventricular arrhythmias No acute ischemia by ECG No active conduction system abnormalities No known hypersensitivity to bortezomib, boron, or mannitol See Disease Characteristics No prior therapy with gemcitabine hydrochloride, bortezomib, or other proteasome inhibitors No more than 28 days since discontinuation of single-agent bortezomib Patients with prior gemcitabine hydrochloride treatment are eligible for single-agent bortezomib treatment but NOT for combination treatment No more than one prior chemotherapy regimen for the treatment of metastatic or recurrent NPC At least 28 days since prior treatment and recovered At least 24 weeks since prior adjuvant chemotherapy At least 24 weeks since prior chemotherapy as a radiosensitizer for initial locally advanced disease At least 28 days since prior radiotherapy and recovered At least 28 days since prior surgery and recovered No other concurrent therapy for NPC, including any of the following: Radiotherapy Chemotherapy Immunotherapy Biologic therapy Other investigational drugs Gene therapy No colony-stimulating factor therapy during the first course of study therapy No concurrent highly active antiretroviral therapy (HAART) in HIV-positive patients

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bortezomib, gemcitabine hydrochloride)<br>Patients receive bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients achieving a CR receive 2 additional courses of treatment with bortezomib. Patients who experience disease progression on single-agent bortezomib and did not receive prior gemcitabine hydrochloride may begin combination therapy within 10-28 days of the last dose of bortezomib. Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and bortezomib IV on days 1, 4, 8, 11. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients achieving a CR receive 2 additional courses beyond the confirmed CR. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (confirmed and unconfirmed, complete and partial response) based on the Response Evaluation Criteria in Solid Tumors (RECIST) in patients treated with bortezomib |  | Up to 3 years | 
| Progression-free survival rate |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response probability (confirmed and unconfirmed, complete and partial response) based on the RECIST in patients treated with bortezomib and gemcitabine hydrochloride |  | Up to 3 years | 
| Progression-free survival rate |  | 6 months | 
| Progression-free survival rate |  | 1 year | 
| Adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 | 95% confidence intervals will be estimated. | Up to 3 years | 
| Overall survival |  | 1 year | 
| Relationship between Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) level, NF-kB DNA- binding activity, and methylation status of E-cadherin promoter with clinical outcome |  | Day 4 |