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

British Columbia Cancer Agency

Status and phase

Completed

Phase 1

Conditions

Lymphoma

Treatments

Drug: doxorubicin hydrochloride

Biological: oblimersen sodium

Drug: cyclophosphamide

Biological: rituximab

Drug: vincristine sulfate

Drug: prednisone

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00070083

BCCA-NCI-5818

CDR0000329985

NCI-5818

Details and patient eligibility

About

RATIONALE: Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, use different ways to stop cancer cells from dividing so they stop growing or die. Oblimersen may increase the effectiveness of a chemotherapy drug by making cancer cells more sensitive to the drug. Combining oblimersen with rituximab and combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of oblimersen when given together with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in treating patients with stage II, stage III, or stage IV large B-cell lymphoma

Full description

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.

Sex

All

Ages

19+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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