Oblimersen, Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Treating Patients With Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

OBJECTIVES:

Primary

• Determine the feasibility and safety of oblimersen administered in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, in terms of short-term and long-term toxicity, in patients with previously untreated stage III or IV or extensive or bulky stage II diffuse large B-cell lymphoma.
• Determine the maximum tolerated dose of oblimersen administered with this regimen in these patients.

Secondary

• Determine the remission rate and failure-free, progression-free, and overall survival of patients treated with this regimen.

OUTLINE: This is a nonrandomized, non-blinded, multicenter, dose-escalation study of oblimersen.

Patients receive CHOP-R* therapy comprising cyclophosphamide IV over 15-45 minutes, doxorubicin IV over 5-10 minutes, vincristine IV, and rituximab IV over 30-90 minutes on day 1 and oral prednisone on days 1-5. Patients also receive oblimersen IV continuously on days -4 to 3. Treatment repeats every 21 days for 6-8 courses in the absence of disease progression or unacceptable toxicity. Patients who discontinue treatment due to unacceptable toxicity to oblimersen may continue to receive standard therapy comprising CHOP-R.

NOTE: *Patients treated at the British Columbia Cancer Agency receive cyclophosphamide, doxorubicin, vincristine, and rituximab on days 1 and 2 and prednisone as above.

Cohorts of 3-6 patients receive escalating doses of oblimersen 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. Once the MTD is determined, at least 10 patients are treated at that dose level.

Patients are followed every 3 months for 2 years, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 19-28 patients will be accrued for this study within 5-10 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed* CD20+ diffuse large B-cell lymphoma, including any of the following stages:

• Extensive stage II (not radio-encompassable within a single involved field or not a candidate for brief chemotherapy and radiotherapy)
• Bulky stage II (any single mass greater than 10 cm)
• Stage III
• Stage IV NOTE: *Confirmed by tissue biopsy
• Previously untreated disease
• Measurable disease

• At least 2 cm by imaging studies
• Circulating lymphoma cells no greater than 5,000/mm^3
• No history of other lymphoproliferative disorder
• No history of indolent lymphoma
• No T-cell lymphoma
• No CNS involvement
• No post-transplantation lymphoproliferative disorder

PATIENT CHARACTERISTICS:

Age

• 19 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3 (unless due to bone marrow involvement with lymphoma)
• Platelet count at least 100,000/mm^3 (unless due to splenomegaly or bone marrow involvement with lymphoma)

Hepatic

• Bilirubin no greater than 3 mg/dL (unless due to lymphoma)
• No known hepatitis B virus

Renal

• Creatinine no greater than 2 mg/dL (unless due to lymphoma)

Cardiovascular

• No cardiac contraindication to doxorubicin therapy (e.g., abnormal contractility on echocardiography)
• History of cardiac disease allowed provided ejection fraction is normal

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Adequate venous access
• HIV negative
• No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer, localized basal cell or squamous cell skin cancer, or curatively treated carcinoma in situ of the cervix
• No neurological contraindication to vincristine (e.g., peripheral neuropathy)
• No active systemic infection
• No medical condition that would compromise study treatment, add toxicity, or impair assessment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior systemic chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

• Prior radiotherapy for localized basal cell or squamous cell skin cancer used with curative intent allowed

Surgery

• Not specified