Phase I Trial of Everolimus and Rituximab or Everolimus, Bortezomib and Rituximab in Relapsed or Relapsed/Refractory Waldenstrom's Macroglobulinemia

This study aimed to determine the safety and maximum tolerated dose of the combination of everolimus and rituximab, or everolimus, bortezomib, and rituximab in relapsed and/or relapsed/refractory Waldenstrom Macroglobulinemia. This trial was based on our preclinical studies that demonstrated synergistic activity of everolimus and bortezomib with rituximab in WM cell lines, and based on our favorable clinical experience with everolimus as single agent in the treatment of WM. METHODS: Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any number of prior lines of therapy, including everolimus and bortezomib 2) not completely refractory to rituximab 3) measurable disease by monoclonal IgM protein in the serum and lymphoplasmacytic cells in the bone marrow, 4) Not receiving chemotherapy > 3 weeks, or biological/novel therapy for WM > 2 weeks. A cycle is 28 days and a total of 6 cycles are given, followed by everolimus maintenance for 2 years. Two stages with a total of four dose levels were planned. In stage A, patients received everolimus at the recommended dose orally daily for 28 days and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. In stage B, patients received everolimus at the recommended dose orally daily for 28 days, bortezomib at the recommended dose IV on days 1, 8, 15 every 28 days, and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. Patients were assessed for response after every cycle. Subjects who had a response continued on therapy for a total of 6 cycles, and then continued on to maintenance therapy with everolimus alone until progression (or for a maximum of 24 months). Because of the potential of an IgM flare after rituximab, patients who showed an increase in IgM after rituximab in the first 3 months were not deemed as having progressive disease unless they showed evidence of clinical progression. To examine the in vivo effect of everolimus, bortezomib, and rituximab, peripheral blood samples were obtained from patients on days 1, 8, 15, and 22 at cycle 1; and on day 1 only at all subsequent cycles. RESULTS: Twenty-three patients were enrolled in this phase I clinical trial from April 2009 to July 2011. The median age is 61 (range, 52–73) yrs and the median lines of prior therapy is 2 (range, 1–8) with all patients receiving prior rituximab and 12 (52%) receiving prior bortezomib. The median number of cycles on therapy was 3.5 (range, 0–15). Overall, this combination therapy is very well tolerated. Grade 4 toxicities included: neutropenia (8.7%), leukopenia (4.3%), thrombocytopenia (17.4%), lymphopenia (4.3%) and hypertriglyceridemia (4.3%). Grade 3 toxicities included: neutropenia (21.7%), leukopenia (26.1%), anemia (13%), lymphopenia (17.4%), pneumonitis (4.3%), SGPT (4.3%), neuropathy (4.3%), Herpes zoster reactivation (4.3%), hyperglycemia (4.3%) and hypernatremia (4.3%). 1 patient discontinued therapy due to grade 3 anemia. Nineteen patients are currently evaluable for response, including 1 (5%) very good partial response (VGPR) and 9 (47%) minimal response (MR), for an overall response rate including MR of 10/19 (53%) in this relapsed/refractory population. Furthermore, overall response including MR in stage A (everolimus/rituximab) was 2/6 (33%) and 8/13 (62%) in stage B (everolimus/bortezomib/rituximab). Additionally, 9 (39%) patients achieved stable disease, and 4 (17%) are early on therapy and not been yet assessed. CONCLUSIONS: The combination of everolimus, bortezomib, and rituximab is generally well tolerated, and importantly no grade 3/4 neuropathy was seen. Moreover, no dose limiting toxicities were observed even at the maximum dose evaluated. The responses observed to date in this relapsed/refractory population are encouraging. Based on the safety of this phase I study, the phase II study of two arms, everolimus/rituximab for low risk patients and everolimus/bortezomib/rituximab for intermediate and high risk patients is underway.

Ghobrial:Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib and everolimus in WM. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Treon:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.