Oblimersen in Treating Patients With Relapsed or Refractory Waldenstrom's Macroglobulinemia

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of oblimersen and to see how well it works in treating patients with relapsed or refractory Waldenstrom's macroglobulinemia. Biological therapies such as oblimersen may interfere with the growth of the cancer cells and slow or stop the growth of Waldenstrom's macroglobulinemia.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximally tolerated dose (MTD) and recommended dosing for Genasense in patients with relapsed or refractory WM following prior chemotherapy. (Phase I) II. To determine the response rate to Genasense in patients with relapsed or refractory WM following prior chemotherapy. III. To determine the safety of Genasense in patients with relapsed or refractory WM following prior chemotherapy. IV. To describe possible clinical benefit from Genasense treatment of relapsed or refractory WM including duration of response, survival, erythropoietin use, improvement in hemoglobin > 11 g/dl, and Improvement in platelet count > 100,000/mm^3. OUTLINE: This is a multicenter, dose-escalation study. Phase I: Patients receive oblimersen IV continuously on days 1-7. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 1-6 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 6 patients experience dose-limiting toxicity. Phase II: Patients receive treatment as in phase I at the MTD of oblimersen. Patients are followed every 3 months for 2 years.

Official Title
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Phase I/II Study of G3139 (Genasense) in Patients With Waldenstrom's Macroglobulinemia

Conditions
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Waldenström Macroglobulinemia

Intervention / Treatment
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* Biological: oblimersen sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Waldenstrom's macroglobulinemia (WM) confirmed by both of the following: Bone marrow lymphoplasmacytosis with greater than 10% lymphoplasmacytic cells or aggregates, sheets, lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy Measurable disease, defined by quantitative IgM monoclonal protein greater than 1,000 mg/dL Symptomatic relapsed or refractory disease requiring therapy, defined by at least 1 of the following: Impaired bone marrow function due to disease infiltration as demonstrated by any of the following: Hemoglobin less than 11 g/dL Requires epoetin alfa therapy to maintain hemoglobin of at least 11 g/dL Platelet count less than 100,000/mm^3 Symptomatic bulky lymphadenopathy Symptoms attributable to hyperviscosity (e.g., nose bleeding, gingival bleeding, or retinal hemorrhage) or serum viscosity level relative to water greater than 4 Received at least 1 prior chemotherapy regimen which included chlorambucil, cyclophosphamide, fludarabine, cladribine, or pentostatin No secondary leukemia or history of antecedent hematologic disorder (e.g., myelodysplasia) prior to initial onset of WM Performance status - ECOG 0-2 Not specified See Disease Characteristics Absolute neutrophil count at least 1,000/mm^3* Platelet count at least 50,000/mm^3* No bleeding disorder Bilirubin no greater than 2 times upper limit of normal (ULN) AST less than 1.5 times ULN Albumin at least 2.5 g/dL PT no greater than 1.5 times ULN INR no greater than 1.3 PTT no greater than 1.5 times ULN No history of chronic hepatitis or cirrhosis Creatinine no greater than 2 times ULN No uncontrolled congestive heart failure No active symptoms of coronary artery disease, including the following: Uncontrolled arrhythmias Recurrent chest pain despite prophylactic medication No New York Heart Association class III or IV heart disease No grade 2 or greater cardiovascular signs and symptoms within the past 4 weeks HIV negative Direct Coombs' test negative No autoimmune thrombocytopenia No uncontrolled serious infection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Adequate venous access for 7-day continuous infusion of study drug Intellectual, emotional, and physical ability to maintain an ambulatory infusion pump No other cancer except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other cancer from which the patient has been disease-free for at least 5 years No known hypersensitivity to phosphorothioate-containing oligonucleotides No uncontrolled seizure disorder More than 21 days since prior immunotherapy for WM More than 21 days since prior cytokine, biologic, or vaccine therapy for WM More than 8 weeks since prior plasmapheresis or plasma exchange No prior allogeneic stem cell transplantation No concurrent plasmapheresis or plasma exchange See Disease Characteristics No concurrent corticosteroid therapy More than 21 days since prior radiotherapy for WM More than 21 days since prior major surgery for WM No prior organ allograft Recovered from all prior therapy More than 21 days since other prior therapy for WM No other concurrent investigational therapy No concurrent immunosuppressive drugs No concurrent therapeutic anticoagulation therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Phase I: Patients receive oblimersen IV continuously on days 1-7. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 1-6 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 6 patients experience dose-limiting toxicity. Phase II: Patients receive treatment as in phase I at the MTD of oblimersen. Patients are followed every 3 months for 2 years. | Biological: oblimersen sodium<br>* Given IV<br>* Other names: Genasense;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose determined by the number of dose-limiting toxicity incidents graded according to CTC standard toxicity (Phase I) | Hematologic dose-limiting toxicity measures will be assessed using the continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization. | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events that are classified as either possibly, probably, or definitely related to study treatment (Phase II) | The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. | Up to 2 years | 
| Proportion of overall confirmed responses (CR + PR) associated with G3139 (Phase II) | The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. | 6 months | 
| Time to progression | The distribution of time to progression will be estimated using the method of Kaplan-Meier. | Time from registration to the time of progression, assessed up to 2 years | 
| Overall survival | The distribution of overall survival will be estimated using the method of Kaplan-Meier. | Time from registration to death due to any cause, assessed up to 2 years | 
| Duration of response |  | From the documentation of response until the date of progression, assessed up to 2 years |