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

Study Overview
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Brief Summary
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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

Detailed Description
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Study Design This is a phase I/II study. The phase I portion of the study will determine the maximum tolerated dose of everolimus, rituximab, and bortezomib combination, while the phase II portion will evaluate the depth of responses to the everolimus, rituximab, and bortezomib combination. If patients show response, they will continue on therapy for a total of 6 cycles, and then go on maintenance therapy with everolimus alone until progression. Patients on maintenance will be monitored every 3 months for response. Because of the potential of an IgM flare after rituximab, patients who show an increase in IgM after rituximab in the first 3 months will not be deemed as having progressive disease unless they show evidence of clinical progression and not just an increase of IgM levels. If biochemical progression is confirmed by m-spike, but the participant is clinically benefitting from therapy, the participant may continue on treatment for a few additional points of assessment and re-discuss benefit of therapy. Additionally, if the participant progressed because the treatment was held, participant may remain on study at the discretion of the overall Principal Investigator. Relapse from CR is defined by the reappearance of monoclonal IgM protein and/or recurrence of bone marrow involvement, lymphadenopathy/splenomegaly or symptoms attributable to active disease (Owen et al., 2012). Progression from PR is defined by ≥ 25% increase in IgM level from lowest recorded value and confirmed by a repeat assessment. The development of new signs and symptoms of disease, including Bing Neel syndrome and histological transformation, is also considered as evidence of disease progression. An absolute increase of at least 5 g/l is required to define progression when the IgM level is the only applicable criterion (Owen et al., 2012).

Official Title
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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

Conditions
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Waldenstrom's Macroglobulinemia

Intervention / Treatment
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* Drug: Everolimus
* Drug: Rituximab
* Drug: Bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Patients must have received prior therapies for their WM and have relapsed or refractory WM requiring therapy. Any number of prior therapies is acceptable. Patients must not have been refractory to rituximab. The last rituximab must be at least 3 months prior to the start of treatment. Prior treatment with bortezomib and/or everolimus is permitted. Measurable monoclonal IgM protein in the serum OR measurable quantitative immunoglobulin M (serum IgM). Lymphoplasmacytic cells in the bone marrow during any previous bone marrow biopsy. CD20 positive disease based on any previous bone marrow immuno-histochemistry or flow cytometric analysis performed prior to enrollment. ECOG Performance Status 0, 1 or 2 Laboratory values as outlined in the protocol Capable of swallowing intact study medication tablets Life expectancy of 12 weeks or greater Exclusion Criteria: Uncontrolled infection Other active malignancies Cytotoxic chemotherapy 3 weeks or less, or biologic or targeted novel therapy 2 weeks or less, or corticosteroids 2 weeks or less, or radiation therapy 2 weeks or less, or any ancillary treatment considered investigation 2 weeks or less, prior to registration. Patients may be receiving chronic corticosteroids if they are being given for disorders other than WM. Pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception throughout the trial and for 8 weeks after the last dose of study treatment. Known to be HIV positive, or Hepatitis B positive. If the status of HIV is not known and patients are not at risk, then patients will not be specifically tested for HIV. Patients will be tested for Hepatitis B at time of screening. If patients are not considered high risk and have been vaccinated at an earlier date, results of the test are not required at the time of registration. For patients that are high risk, results must be obtained prior to registration. Patient has Grade 2 or higher peripheral neuropathy within 14 days of enrollment Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection fo basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. Severely impaired lung function Uncontrolled diabetes Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis Impairment of gastrointestinal function or gastrointestinal disease Patients with active, bleeding diathesis Myocardial infarction within 6 months prior to enrollment or had NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Hypersensitivity to everolimus or other rapamycins or to is excipients Patients who may need or are receiving live vaccines for immunization Serious medical or psychiatric illness likely to interfere with participation in this clinical study

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Stage A Level 1<br>Combination of everolimus & rituximab for 6 cycles: Everolimus 5 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons. | Drug: Everolimus<br> <br> * Other names: RAD001;Drug: Rituximab<br> <br> * Other names: Rituxan;|
| Experimental: Phase I Stage A Level 2<br>Combination of everolimus & rituximab for 6 cycles: Everolimus 10 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons. | Drug: Everolimus<br> <br> * Other names: RAD001;Drug: Rituximab<br> <br> * Other names: Rituxan;|
| Experimental: Phase I Stage B Level 1<br>Combination of everolimus & rituximab with bortezomib for 6 cycles: Everolimus 5 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons. | Drug: Everolimus<br> <br> * Other names: RAD001;Drug: Rituximab<br> <br> * Other names: Rituxan;Drug: Bortezomib<br> <br> * Other names: PS-341;|
| Experimental: Phase I Stage B Level 2<br>Combination of everolimus & rituximab with bortezomib for 6 cycles: Everolimus 10 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons. | Drug: Everolimus<br> <br> * Other names: RAD001;Drug: Rituximab<br> <br> * Other names: Rituxan;Drug: Bortezomib<br> <br> * Other names: PS-341;|
| Experimental: Phase I Dose Expansion<br>Combination of everolimus & rituximab with bortezomib for 6 cycles: Everolimus 10 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons. | Drug: Everolimus<br> <br> * Other names: RAD001;Drug: Rituximab<br> <br> * Other names: Rituxan;Drug: Bortezomib<br> <br> * Other names: PS-341;|
| Experimental: Phase II<br>Combination of everolimus & rituximab with bortezomib for 6 cycles: Everolimus 10 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons. | Drug: Everolimus<br> <br> * Other names: RAD001;Drug: Rituximab<br> <br> * Other names: Rituxan;Drug: Bortezomib<br> <br> * Other names: PS-341;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Everolimus Maximum Tolerated Dose (MTD) Stage A [Phase I] | 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. | Assessed within the first cycle (28 days) of the study. | 
| Everolimus Maximum Tolerated Dose (MTD) Stage B [Phase I] | 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. | Assessed within the first cycle (28 days) of the study. | 
| Everolimus Dose Limiting Toxicity (DLT) [Phase I] | 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 | Assessed within the first cycle (28 days) of the study. | 
| Very-good-partial-response-or-better Rate [Phase II] | 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. | Up to 6 cycles (Day 168) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-Emergent Sensory Neuropathy Rate [Phase I] | 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. | 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. | 
| Phase II Overall Response Rate | 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 | Up to 6 cycles (Day 168) | 
| 2-year Time-to-progression Probability (TTP) [Phase II] | 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. | 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 Progression-free-survival [Phase II] | 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. | 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. | 
| Phase II Duration of Response (DoR) | 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. | 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. | 
| PTEN Mutation Rate [Phase II] | 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. | Samples were collected pre-therapy before the beginning therapy (baseline) and post-therapy after finishing the 6th treatment cycle (168 days). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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everolimus, rituximab, bortezomib, RAD001, Rituxan, Velcade