Oblimersen Sodium & Combination Chemotherapy in Treating Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma

Investigator Initiated Pilot Study of Microarray Directed Therapy for Diffuse Large B-cell Lymphoma Using Genasense With CHOP-R

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Oblimersen sodium may help chemotherapy work better by making cancer cells more sensitive to the drugs. Giving oblimersen sodium together with combination chemotherapy may kill more cancer cells. PURPOSE: This clinical trial is studying the side effects of giving oblimersen sodium together with combination chemotherapy and to see how well it works in treating patients with newly diagnosed stage I, stage II, stage III, or stage IV diffuse large B-cell lymphoma

Study Overview

• Status: Terminated
• Conditions: Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma
• Intervention / Treatment: Drug: cyclophosphamide; Biological: oblimersen sodium; Biological: rituximab; Drug: doxorubicin hydrochloride; Drug: vincristine sulfate; Drug: prednisone; Other: immunohistochemistry staining method; Procedure: biopsy; Genetic: microarray analysis; Genetic: cytogenetic analysis; Genetic: gene expression analysis

Detailed Description

PRIMARY OBJECTIVES: I. To assess the feasibility and determine the rate of rapid turn around, that is within 7 working days of receipt of adequate tissue at UNMC for a AFFYmetrix microarray study of newly diagnosed patients with Diffuse Large B-cell Lymphoma (DLBCL) who will then receive treatment on this protocol. II. To evaluate efficacy (complete response rate) of Genasense (antisense bcl-2) given in addition to standard cyclophosphamide, vincristine, doxorubicin, and prednisone -rituximab (CHOP-R) to newly diagnosed patients with DLBCL who are found to have the ABC type after gene expression profiling or IHC as compared to newly diagnosed patients with DLBCL who do not express the ABC type that go on to receive standard CHOP-R (control). III. To evaluate the toxicity of Genasense (antisense bcl-2) given in addition to standard cyclophosphamide, vincristine, doxorubicin, and prednisone -rituximab (CHOP-R) for newly diagnosed patients with DLBCL who are found to have the ABC type after gene expression profiling. OUTLINE: Patients with diffuse large B-cell lymphoma (DLBCL) that expresses ABC type proceed to treatment in group I. Patients with DLBCL that does not express ABC type proceed to treatment in group II. GROUP I (oblimersen sodium and standard CHOP-R): Patients receive oblimersen sodium IV continuously on days 1-7. Patients also receive CHOP-R comprising rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 5 and prednisone orally on days 5-10. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity. GROUP II (standard CHOP-R alone): Patients receive CHOP-R comprising rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1 and prednisone orally on days 1-5. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed periodically.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • Saint Francis Medical Center
    • Omaha, Nebraska, United States, 68198-6805
      • University of Nebraska Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Newly diagnosed patients with Diffuse Large B-cell Lymphoma (DLBCL) (any stage) OR composite lymphoma with >= 50% DLBCL
• Adequate diagnostic tissue for microarray gene expression analysis or IHC analysis
• Karnofsky Performance Status >= 70 (ECOG 0, 1)
• No prior chemotherapy (with the exception of 1 cycle CHOP-R based on current diagnosis, clinical condition, and availability/feasibility of initiating Genasense), immunotherapy, radiotherapy, or investigational therapies for NHL; steroid therapy is allowed only if required for maintenance of another chronic disease (e.g., rheumatoid arthritis)
• Patients aged >= 60 years, or patients with a history of coronary artery disease, congestive heart failure, hypertension, diabetes, or hyperlipidemia must have an estimated ejection fraction >= 0.45 (45%) by MUGA or echocardiography, performed within two months of study entry
• Patients must be willing to give written informed consent, and sign an institutionally approved consent form prior to initiating genasense or any study related activities (i.e., Genasense & microarray)
• Females of childbearing potential must have a negative serum pregnancy test prior to enrollment in the study
• Adequate venous access for 7-day continuous infusion
• Patients without evidence of severe organ dysfunction as determined within two weeks of 1st cycle of CHOP-R: 1) Hemoglobin > 8 g/dl; 2) Absolute neutrophil count > 1000/; 3) Platelets > 100,000 (lower blood counts may be acceptable if due to lymphoma after review with principal investigator); 4) Creatinine =< 2.0 mg/dL (unless due to NHL); 5) Bilirubin =< 2.0 mg/dL; 6) AST =< 3 x upper normal; 7) ALP =< 3 x upper normal (unless due to NHL)
• Men and women of reproductive potential must agree to use TWO of the following forms of birth control every time they have sex throughout the study and for up to 3 months following discontinuation of study drug: hormonal birth control methods, condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicidal, IUD, or surgical sterilization while participating in this study

Exclusion Criteria:

• Significant medical disease other than cancer including: 1) Any bleeding or coagulation disorder including a history of autoimmune hemolytic anemia or autoimmune thrombocytopenia; 2) Severe pulmonary disease; 3) Uncontrolled congestive heart failure; 4) New York Heart Association class III or IV disease; 5) Uncontrolled seizure disorder; and 6) Active infections
• Less than 3 weeks from prior major surgery
• Prior organ allograft
• Known HIV infection (due to expected frequent occurrence of myelo-suppression and immunosuppression)
• Women who are pregnant (confirmed by a serum pregnancy test in females of reproductive potential) or breast-feeding (women of child-bearing potential and sexually active males must be advised to take precautions to prevent pregnancy during treatment or remain abstinent)
• Women of child-bearing potential and sexually active males must be advised to take precautions to prevent pregnancy during treatment (unless the subject or subject's partner(s) is sterile, i.e., women who have had a hysterectomy or have been post-menopausal for at least twelve consecutive months) or remain abstinent
• Known hypersensitivity to phosphorothiate-containing oligonucleotides
• Concurrent investigational, corticosteroid therapy or any other anti-cancer treatments (such as chemotherapy, radiation, biologic or investigational therapies) while receiving protocol therapy; other than one cycle CHOP-R allowed based on current diagnosis, clinical condition, and availability/feasibility of initiating Genasense; other than chronic steroid use for another indication (For stage I/II or as clinically indicated- involved field irradiation as per standard practice is accepted)
• Other investigational drug therapy within 30 days of study entry
• Secondary leukemia or history of antecedent hematologic disorder
• History of second cancer (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for three or more years)
• No active CNS disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma
• Concomitant anticoagulant therapy is not permitted (with the exception of 1 mg/day of warfarin for central line prophylaxis)
• Known hypersensitivity to G3139 (Genasense) or R-CHOP
• Neurologic disorders, overt psychosis, mental disability or evidence of limited capacity to provide fully informed consent or cooperation with the complexities of the treatment program

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: Arm I; See Detailed Description

Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: oblimersen sodium; Given IV; Other Names: augmerosen; G3139; G3139 bcl-2 antisense oligodeoxynucleotide; Genasense; Biological: rituximab; Given IV; Other Names: Rituxan; Mabthera; IDEC-C2B8; IDEC-C2B8 monoclonal antibody; MOAB IDEC-C2B8; Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM; Adriamycin PFS; Adriamycin RDF; ADR; Adria; Drug: vincristine sulfate; Given IV; Other Names: VCR; leurocristine sulfate; Vincasar PFS; Drug: prednisone; Given orally; Other Names: DeCortin; Deltra; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry; Procedure: biopsy; Correlative studies; Other Names: biopsies; Genetic: microarray analysis; Correlative studies; Other Names: gene expression profiling; Genetic: cytogenetic analysis; Correlative studies; Genetic: gene expression analysis; Correlative studies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Perform Microarray Study After Receipt of Tissue	The time from tissue harvest to release of microarray test and IHC assay results will be noted in days.	Upto 14 days
Number of Participants With Microarray Testing Results Are Completed Within 7 Days.		Upto 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of Treatment, in Terms of Complete Response Rate (Anyone Achieving a CR or Cru)	Response criteria are the recommendations of the International Harmonization Project's update to the International Working Group guidelines. Complete response (CR) is defined as disappearance of all evidence of disease; Partial response (PR) is defined as regression of measurable disease and no new sites	End of treatment, an average of 4 months

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: National Cancer Institute (NCI); Genta Incorporated
• Investigators: Principal Investigator: Julie M Vose, MD MBA, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2008
• Primary Completion (Actual): October 9, 2012
• Study Completion (Actual): October 9, 2012

Study Registration Dates

• First Submitted: August 14, 2008
• First Submitted That Met QC Criteria: August 14, 2008
• First Posted (Estimated): August 15, 2008

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 20, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, B-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Rituximab; Prednisone; Doxorubicin; Liposomal doxorubicin; Vincristine; Oblimersen
• Other Study ID Numbers: 0462-07-FB; P30CA036727 (U.S. NIH Grant/Contract); NCI-2009-01692 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No