A Phase I/II Trial of VELCADE & Gemcitabine for Patients With Relapsed or Refractory Aggressive B- and T-cell Non-Hodgkin's Lymphoma

Northwestern University

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Lymphoma

Treatments: Drug: bortezomib; Drug: gemcitabine hydrochloride

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00290706

VEL-03-082

NU 04H4 (Other Identifier)

STU00007425 (Other Identifier)

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving gemcitabine together with bortezomib may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of bortezomib when given together with gemcitabine and to see how well they work in treating patients with relapsed or refractory B-cell or T-cell non-Hodgkin's lymphoma.

Full description

OBJECTIVES:

Primary

• Determine the response rate (complete and partial remission) in patients with relapsed or refractory aggressive B- or T-cell non-Hodgkin's lymphoma treated with gemcitabine hydrochloride and bortezomib.
• Determine the maximum tolerated dose of bortezomib when administered with gemcitabine hydrochloride in these patients.

Secondary

• Determine the time to treatment failure, duration of response, and overall survival of patients treated with this regimen.
• Determine the safety and tolerability of this regimen in these patients.

OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II, open-label study.

• Phase I: Patients receive gemcitabine hydrochloride IV over 30 minutes and bortezomib IV over 3-5 seconds on days 1 and 8. Treatment repeats every 21 days for up to 9 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 3 of 6 patients experience dose-limiting toxicity (DLT) OR the dose that at which 2 of 6 patients experience DLT.

• Phase II: Patients receive gemcitabine hydrochloride and bortezomib as in phase I at the MTD.

After completion of study therapy, patients are followed periodically for 3 years.

PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.

Enrollment: 32 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Diagnosis of B- or T-cell non-Hodgkin's lymphoma (NHL)

  • Intermediate histology B-cell NHL, including any of the following:

    • Diffuse large B-cell lymphoma
    • Transformed large cell lymphoma

  • Any T-cell NHL histology

  • Cutaneous T-cell lymphoma (CTCL) or mycosis fungoides (MF) allowed

• Relapsed or refractory disease, defined as disease progressed after prior complete remission (CR), partial remission (PR), or stable disease (SD) to last therapy OR failure to achieve CR, PR, or SD after completion of last therapy

• Must have received 1-3 prior therapeutic regimens

  • Cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (CHOP) AND cyclophosphamide, vincristine, and prednisone (CVP) OR CHOP with rituximab (CHOP-R) AND CVP with rituximab (CVP-R) is considered 1 regimen
  • Monoclonal antibody (e.g., rituximab) given as maintenance therapy is considered 1 regimen
  • Salvage chemotherapy followed by an autologous stem cell transplant is considered 1 regimen
  • No more than 7 prior therapeutic regimens for patients with CTCL or MF

• No mantle cell lymphoma

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Life expectancy > 3 months

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

  • At least 50,000/mm^3 if documented bone marrow involvement

• Hemoglobin ≥ 8.0 g/dL

• AST and ALT ≤ 3 times upper limit of normal (ULN)

• Alkaline phosphatase ≤ 3 times ULN

• Bilirubin ≤ 2 times ULN

• Creatinine ≤ 2.0 mg/dL

• No known history of HIV infection

• No other active infection

• No uncontrolled hypertension

• No peripheral neuropathy ≥ grade 2 within the past 2 weeks

• No myocardial infarction within the past 6 months

• No New York Heart Association class III or IV heart failure

• No uncontrolled angina

• No severe uncontrolled ventricular arrhythmias

• No acute ischemia or active conduction system abnormalities by ECG

• No hypersensitivity to bortezomib, boron, or mannitol

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier-method contraception

• No serious medical or psychiatric illness that would preclude study participation

PRIOR CONCURRENT THERAPY:

• Prior autologous and/or allogeneic stem cell transplantation allowed
• More than 3 weeks since prior chemotherapy, radiotherapy, or immunotherapy
• More than 3 weeks since prior systemic biologic anticancer therapy
• More than 3 weeks since prior systemic corticosteroids (e.g., oral prednisone > 10 mg per day)
• More than 2 weeks since prior investigational drug
• No prior bortezomib or gemcitabine hydrochloride
• No other concurrent systemic cytotoxic chemotherapy or investigational agents

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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32 participants in 1 patient group

Gemcitabine 800 mg/m2 + Bortezomib IVP over 3-5 seconds

Experimental group

Description:

Gemcitabine dose of 800 mg/m2 over 30 minutes followed by Bortezomib IVP given over 3-5 seconds on day 1 and day 15 of each cycle every 28 days for up to 8 cycles.

Treatment:

Drug: gemcitabine hydrochloride

Drug: bortezomib