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Phase I/II Study of Combination Everolimus (RAD001), and Rituximab (Rituxan), OR Everolimus, Bortezomib (Velcade, PS-341), and Rituximab in Patients With Relapsed and/or Relapsed/Refractory Waldenstrom's Macroglobulinemia
The purpose of this research study is to test the safety of the combination of everolimus, rituximab and bortezomib. Everolimus is a drug that works by preventing cells in your body from growing and dividing. Information from basic and other clinical research suggests that everolimus may also inhibit tumor growth in people with relapsed or refractory lymphoma. The FDA has approved everolimus for the treatment of multiple myeloma, a cancer that is closely related to Waldenstrom's Macroglobulinemia. Rituximab is approved by the FDA for the treatment of non-Hodgkin's lymphoma, which included Waldenstrom's Macroglobulinemia. Funding Source - FDA OOPD
Details
| Lead sponsor | Dana-Farber Cancer Institute |
|---|---|
| Phase | Phase 1/Phase 2 |
| Status | TERMINATED |
| Enrolment | 46 |
| Start date | 2010-04 |
| Completion | 2014-08 |
Conditions
- Waldenstrom's Macroglobulinemia
Interventions
- Everolimus
- Rituximab
- Bortezomib
Primary outcomes
- Everolimus Maximum Tolerated Dose (MTD) Stage A [Phase I] — Assessed within the first cycle (28 days) of the study.
The MTD of Everolimus/Rituximab combination is determined by the number of patients who have dose limiting toxicity (DLT). See DLT primary outcome measure for definition. MTD is defined as the highest dose where \<1/3 participants experience a DLT. If no DLT's are observed on Level 1, 3 subjects will be enrolled in the Level 2. If \>1/3 subjects in a cohort have DLT, that dose will not be considered safe, with no escalation (MTD exceeded). If 1/3 subjects experience DLT, the cohort will be expanded to 6 subjects. If \<2 subjects with a DLT among the expanded cohort of 6 evaluable subjects a cohort of 3 subjects will be enrolled in the next higher dose level. If 2 or more subjects with a DLT among the expanded cohort of 6 subjects, that dose level will not be considered safe, no escalation (MTD exceeded). If no DLT's are observed, then the MTD is not reached. The MTD was not reached with 0/3 participants experiencing a DLT in the highest dose level. Higher doses were not planned/tested. - Everolimus Maximum Tolerated Dose (MTD) Stage B [Phase I] — Assessed within the first cycle (28 days) of the study.
The MTD of Everolimus/Bortezomib/Rituximab combination is determined by the number of patients who have dose limiting toxicity (DLT). See DLT primary outcome measure for definition. MTD is defined as the highest dose where \<1/3 participants experience a DLT. If no DLT's are observed on Level 1, 3 subjects will be enrolled in the Level 2. If \>1/3 subjects in a cohort have DLT, that dose will not be considered safe, with no escalation (MTD exceeded). If 1/3 subjects experience DLT, the cohort will be expanded to 6 subjects. If \<2 subjects with a DLT among the expanded cohort of 6 evaluable subjects a cohort of 3 subjects will be enrolled in the next higher dose level. If 2 or more subjects with a DLT among the expanded cohort of 6 subjects, that dose level will not be considered safe, no escalation (MTD exceeded).If no DLT's observed, then the MTD is not reached. The MTD was not reached with 0/3 participants experiencing a DLT in the highest level. Higher doses were not planned/tested. - Everolimus Dose Limiting Toxicity (DLT) [Phase I] — Assessed within the first cycle (28 days) of the study.
The following qualify as dose limiting toxicities: * Grade 3 or greater non-hematologic toxicity, considered by the investigator to be related to study drugs. * Grade 4 hematologic toxicity defined as: thrombocytopenia with platelets \<10,000 µ/L on more than one occasion despite transfusion support; grade 4 neutropenia occurring for more than 7 days and/or resulting in neutropenic fever with elevated temperature (defined as \> 101 degrees F). Lymphopenia, a recognized side effect of bortezomib, is not considered a DLT. * Inability to receive Day 1 dose for Cycle 2 due to toxicity - Very-good-partial-response-or-better Rate [Phase II] — Up to 6 cycles (Day 168)
Very-good-partial-response-or-better rate is the percentage of participants with complete response (CR) or very good partial response (VGPR) on to the combination of everolimus/bortezomib/rituximab. The combination regimen was received for up to 6 cycles. CR: * Absence of serum monoclonal IgM protein by immunofixation * Normal serum IgM level * Complete resolution of extramedullary disease, i.e., lymphadenopathy and splenomegaly if present at baseline * Morphologically normal bone marrow aspirate and trephine biopsy VGPR: * Monoclonal IgM protein is detectable ≥90% reduction in serum IgM level from baseline\* * Complete resolution of extramedullary disease, i.e.
Countries
United States