Everolimus, Bortezomib and/or Rituximab in Patients With Relapsed/Refractory Waldenstrom's Macroglobulinemia

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

Time frame: Assessed within the first cycle (28 days) of the study.

Population: In Phase I Stage B Level 1, one participant was replaced as an exception granted to the principal investigator having experienced a dose delay due to an adverse event not deemed a DLT.

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.

Time frame: Assessed within the first cycle (28 days) of the study.

Population: The analysis dataset includes all participants enrolled to Stage A.

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.

Time frame: Assessed within the first cycle (28 days) of the study.

Population: In Phase I Stage B Level 1, one participant was replaced as an exception granted to the principal investigator having experienced a dose delay due to an adverse event not deemed a DLT.

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.

Time frame: Up to 6 cycles (Day 168)

2-year progression free survival (PFS) is the probability of participants alive and progression free at 2 years from study entry estimated using Kaplan-Meier methods. PFS is defined as the time from enrollment to progressive disease (PD) or death. PD is defined as ≥25% increase in serum IgM level from lowest nadir and/or progression in clinical features attributable the disease. Patients alive without PD and not reporting use of non-protocol therapy prior to PD are censored at date of last objective progression-free disease assessment. Patients reporting use of non-protocol therapy prior to PD are censored at date of last objective progression-free disease assessment date prior to post-discontinuation therapy.

Time frame: Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.

2-year TTP probability is based on Kaplan-Meier methods. TTP is defined as time from enrollment to the date of progressive disease (PD). PD is defined as ≥25% increase in serum IgM level from lowest nadir and/or progression in clinical features attributable the disease. Patients without PD and not reporting use of non-protocol therapy prior to PD are censored at date of last objective progression-free disease assessment. Patients reporting use of non-protocol therapy prior to PD are censored at date of last objective progression-free disease assessment date prior to post-discontinuation therapy.

Time frame: Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.

The DoR is defined as the elapsed time from date when the measurement criteria are first met for a complete or partial response (whichever status is recorded first) until the date of first observation of objective disease progression. Analysis of DoR will be as follows: * For responding patients who die without objective PD (including death from study disease), DoR will be censored at the date of the last objective progression-free disease assessment. * For responding patients not known to have died as of the data cut-off date and who do not have objective PD, DoR will be censored at the date of the last objective progression-free disease assessment. * For responding patients who receive subsequent systemic anticancer therapy (after discontinuation from the study chemotherapy) prior to objectively determined disease progression, DoR will be censored at the date of the last objective progression-free disease assessment prior to post discontinuation therapy.

Time frame: Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.

Overall response rate is percentage of participants with complete (CR), very good partial (VGPR), partial (PR), or minimal response (MR) as best response during treatment. CR: * No serum monoclonal IgM protein by immunofixation * Normal 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 IgM level from baseline * Complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at baseline * No new signs/symptoms of active disease PR: * Monoclonal IgM protein is detectable ≥50% but \<90% reduction in IgM level from baseline * Reduction in extramedullary disease * No new signs/symptoms of active disease MR: * Monoclonal IgM protein is detectable ≥25% but \<50% reduction in IgM level from baseline * No new signs/symptoms of active disease

Time frame: Up to 6 cycles (Day 168)

The PTEN mutation rate is the percentage of patients with PTEN mutation identified in pre-therapy and post-therapy bone marrow samples per established methods.

Time frame: Samples were collected pre-therapy before the beginning therapy (baseline) and post-therapy after finishing the 6th treatment cycle (168 days).

Population: The correlative objective for the study was to identify molecular regulators of response/resistance. Because the study terminated early with limited efficacy shown in the stage 1 cohort correlative objectives could not be met. Bone marrow and peripheral blood samples were collected pre- and post-therapy for phase II patients but only a few experiments conducted considering resources and the limited potential interpretation.

Percentage of participants experiencing Grade 1 - Grade 3 treatment-emergent peripheral (sensory) neuropathy events based on CTCAEv3 as reported on case report forms for phase I participants.

Time frame: Adverse events were assessed each cycle (ever 28 days) for 6 cycles then every 3 months on maintenance. Duration of therapy for the Phase I study up to 41 months.