Bortezomib, Dexamethasone, and Rituximab in Previously Untreated Patients With Waldenstrom's Macroglobulinemia

• Status: Completed
• Trial end date: 2015-11-01
• Target enrollment: 0
• Participant gender: All

Summary

Rituximab is a monoclonal antibody with proven efficacy in WM but responses are slow. Bortezomib has shown significant and rapid activity in WM. Combinations of bortezomib with rituximab nad dexamethasone with rituximab have shown synergistic activity in laboratory studies and clinical trials. This is a Phase II multicenter study designed to evaluate the safety and efficacy of the combination of Bortezomib , Rituximab and dexamethasone (BDR). BDR will be administered in one 21-day treatment cycle followed by four 35-day treatment cycles to patients with WM. Bortezomib will be administered as an iv push over 3 to 5 seconds at a dose of 1.3mg/m2/day on days 1,4,8 and 11 of cycle 1. On cycles 2-5 bortezomib will be given at a dose of 1.6mg/m2/day on days 1,8,15 and 22 of each cycle. Only on cycles 2 and 5, following the administration of Bortezomib, dexamethasone 40mg iv and Rituximab 375 mg/m2 iv will be administered. A total of 8 infusions of rituximab will be administered. Subsequently patients rated as CR, PR, MR or SD will be followed without any treatment until there is evidence of progressive disease.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Meletios A. Dimopoulos
• Collaborator: European Myeloma Network
• Treatments: BB 1101; Bortezomib; Dexamethasone; Dexamethasone 21-phosphate; Dexamethasone acetate; Rituximab

Criteria

Inclusion Criteria:

• Clinicopathological diagnosis of Waldenstrom's macroglobulinemia as defined by consensus panel one of the Second International Workshop on Waldenstrom's macroglobulinemia.1 All patients with the diagnosis of WM will be evaluable for response according to the response criteria (section 8.1)

• No prior systemic treatment for WM. Prior plasmapheresis to control hyperviscosity, is allowed. In that case baseline monoclonal protein levels for assessment of response will be the levels prior to plasmapheresis, if this is the higher value prior to treatment initiation

• Patients must have at least one of the following indications to initiate treatment as defined by "Consensus Panel Two" recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia41.

1. Recurrent fever, night sweats, weight loss, fatigue

2. Hyperviscosity

3. Lymphadenopathy which is either symptomatic or bulky (≥5cm in maximum diameter)

4. Symptomatic hepatomegaly and/or splenomegaly

5. Symptomatic organomegaly and/or organ or tissue infiltration

6. Peripheral neuropathy due to WM

7. Symptomatic cryoglobulinemia

8. Cold agglutinin anemia

9. Immune hemolytic anemia and/or thrombocytopenia

10. Nephropathy related to WM

11. Amyloidosis related to WM

12. Hemoglobin ≤10g/dL

13. Platelet count <100x109/L

14. Serum monoclonal protein >5g/dL even with no symptoms

• CD20 positive disease based on any previous bone marrow immunohistochemistry or flow cytometric analysis performed up to 3 months prior to enrollment.

• Karnofsky performance status >=60.

• Life-expectancy >3 months.

• Baseline platelet count >=50 10^9/L, and absolute neutrophil count >= 0.75 10^9/L.

• Meet the following pretreatment laboratory criteria at the Screening visit conducted within 28 days of study enrollment:

• AST (SGOT): >3 times the upper limit of institutional laboratory normal.

• ALT (SGPT): >3 times the upper limit of institutional laboratory normal.

• Total Bilirubin: >2 times the upper limit of institutional laboratory normal, unless clearly related to the disease.

• Calculated or measured creatinine clearance: >=30 mL/minute.

• Serum sodium >130 mmol/L.

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

Exclusion Criteria:

• Prior systemic treatment with WM (plasmapheresis is allowed)

• Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

• Patient has hypersensitivity to dexamethasone, bortezomib, boron or mannitol.

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• Cardiac amyloidosis

• Peripheral neuropathy or neuropathic pain grade 2 or higher as defined by NCI CTCAE version 3

• Women who are pregnant. Women who are breast-feeding and do not consent to discontinue breast-feeding. Women of childbearing age who are not willing to use effective anti-conceptive methods for the duration of the study and 6 months thereafter. Men who do not consent not to father a child during the treatment period and six months thereafter.