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

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

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

Study Overview

• Status: Completed
• Conditions: Recurrent Nasopharyngeal Cancer; Stage IV Nasopharyngeal Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: gemcitabine hydrochloride; Drug: bortezomib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78245
      • Southwest Oncology Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (bortezomib, gemcitabine hydrochloride); 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.

Other: laboratory biomarker analysis; Correlative studies; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; gemcitabine; dFdC; difluorodeoxycytidine hydrochloride; Drug: bortezomib; Given IV; Other Names: MLN341; LDP 341; VELCADE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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
Overall survival		1 year
Progression-free survival rate		1 year
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
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
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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Stephen Shibata, Southwest Oncology Group

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): July 1, 2007

Study Registration Dates

• First Submitted: March 21, 2006
• First Submitted That Met QC Criteria: March 21, 2006
• First Posted (Estimate): March 22, 2006

Study Record Updates

• Last Update Posted (Estimate): January 25, 2013
• Last Update Submitted That Met QC Criteria: January 24, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Recurrence; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine; Bortezomib
• Other Study ID Numbers: NCI-2012-02690; U10CA032102 (U.S. NIH Grant/Contract); SWOG-S0506; CDR0000462635 (Registry Identifier: PDQ (Physician Data Query))