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

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01125293
• Collaborator: Novartis (Industry), Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 46
• Location: 1
• Arms: 6
• Actual Duration (Months): 52
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Waldenstrom's Macroglobulinemia	Drug: Everolimus; Drug: Rituximab; Drug: Bortezomib	Phase 1/Phase 2

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I Stage A Level 1 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; Other Names: RAD001 ; Drug: Rituximab; Other Names: Rituxan
Experimental: Phase I Stage A Level 2 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; Other Names: RAD001 ; Drug: Rituximab; Other Names: Rituxan
Experimental: Phase I Stage B Level 1 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; Other Names: RAD001 ; Drug: Rituximab; Other Names: Rituxan ; Drug: Bortezomib; Other Names: Velcade PS-341
Experimental: Phase I Stage B Level 2 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; Other Names: RAD001 ; Drug: Rituximab; Other Names: Rituxan ; Drug: Bortezomib; Other Names: Velcade PS-341
Experimental: Phase I Dose Expansion 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; Other Names: RAD001 ; Drug: Rituximab; Other Names: Rituxan ; Drug: Bortezomib; Other Names: Velcade PS-341
Experimental: Phase II 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; Other Names: RAD001 ; Drug: Rituximab; Other Names: Rituxan ; Drug: Bortezomib; Other Names: Velcade PS-341

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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

4. 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.

Secondary Outcome Measures

1. Treatment-Emergent Sensory Neuropathy Rate [Phase I] [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.]

   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.

2. Phase II Overall Response Rate [Up to 6 cycles (Day 168)]

   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

3. 2-year Time-to-progression Probability (TTP) [Phase II] [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.

4. 2 Year Progression-free-survival [Phase II] [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 (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.

5. Phase II Duration of Response (DoR) [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.

6. PTEN Mutation Rate [Phase II] [Samples were collected pre-therapy before the beginning therapy (baseline) and post-therapy after finishing the 6th treatment cycle (168 days).]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Novartis
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Irene Ghobrial, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Irene Ghobrial, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01125293
• Other Study ID Numbers: 09-280; R01FD003743; X05310; R01FD003743
• First Posted: May 18, 2010
• Last Update Posted: Apr 23, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Irene Ghobrial, MD, Principal Investigator, Dana-Farber Cancer Institute: everolimus; rituximab; bortezomib; RAD001; Rituxan; Velcade
• Additional relevant MeSH terms: Waldenstrom Macroglobulinemia; Rituximab; Everolimus; Bortezomib

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from April 2010 to July 2013.

Arm/Group Title	Phase I Stage A Level 1	Phase I Stage A Level 2	Phase I Stage B Level 1	Phase I Stage B Level 2	Phase I Dose Expansion	Phase II
Arm/Group Description	Combination of everolimus & rituximab for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)	Combination of everolimus & rituximab for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Period Title: Overall Study
STARTED	3	3	4	3	10	23
Evaluable for Phase I Dose-Limiting Toxicity	3	3	3	3	0	0
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	3	3	4	3	10	23

Baseline Characteristics

Arm/Group Title	Phase I Stage A Level 1	Phase I Stage A Level 2	Phase I Stage B Level 1	Phase I Stage B Level 2	Phase I Dose Expansion	Phase II	Total
Arm/Group Description	Combination of everolimus & rituximab for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)	Combination of everolimus & rituximab for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Total of all reporting groups
Overall Participants	3	3	4	3	10	23	46
Age, Customized (Count of Participants)
<=50 years	0 0%	0 0%	0 0%	1 33.3%	0 0%	3 13%	4 8.7%
>50 and <=60 years	1 33.3%	1 33.3%	2 50%	1 33.3%	4 40%	2 8.7%	11 23.9%
>60 and <=70 years	2 66.7%	1 33.3%	2 50%	1 33.3%	5 50%	12 52.2%	23 50%
70+ years	0 0%	1 33.3%	0 0%	0 0%	1 10%	6 26.1%	8 17.4%
Sex: Female, Male (Count of Participants)
Female	0 0%	2 66.7%	2 50%	2 66.7%	3 30%	11 47.8%	20 43.5%
Male	3 100%	1 33.3%	2 50%	1 33.3%	7 70%	12 52.2%	26 56.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%	1 4.3%	1 2.2%
Not Hispanic or Latino	3 100%	3 100%	4 100%	3 100%	10 100%	22 95.7%	45 97.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	1 2.2%
White	2 66.7%	3 100%	4 100%	3 100%	10 100%	22 95.7%	44 95.7%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	1 4.3%	1 2.2%
Study Site (Count of Participants)
Colorado Blood Cancer Institute	0 0%	0 0%	0 0%	0 0%	0 0%	1 4.3%	1 2.2%
Dana Farber Cancer Institute	3 100%	3 100%	4 100%	3 100%	10 100%	21 91.3%	44 95.7%
Morale, Welfare, and Recreation	0 0%	0 0%	0 0%	0 0%	0 0%	1 4.3%	1 2.2%
Disease Status (Count of Participants)
Refractory	0 0%	0 0%	0 0%	0 0%	0 0%	2 8.7%	2 4.3%
Relapsed	0 0%	0 0%	1 25%	2 66.7%	6 60%	6 26.1%	15 32.6%
Relapsed and Refractory	0 0%	0 0%	0 0%	0 0%	0 0%	3 13%	3 6.5%
ECOG Performance Status (Count of Participants)
00 - Fully Active	3 100%	3 100%	4 100%	3 100%	8 80%	13 56.5%	34 73.9%
01 - Restricted	0 0%	0 0%	0 0%	0 0%	2 20%	7 30.4%	9 19.6%
02 - Ambulatory and Capable of Self Care	0 0%	0 0%	0 0%	0 0%	0 0%	3 13%	3 6.5%
International Prognostic Scoring System for Waldenstrom Macroglobulinemia (Count of Participants)
Low	2 66.7%	1 33.3%	1 25%	2 66.7%	6 60%	6 26.1%	18 39.1%
Intermediate	0 0%	1 33.3%	2 50%	1 33.3%	4 40%	13 56.5%	21 45.7%
High	1 33.3%	1 33.3%	1 25%	0 0%	0 0%	4 17.4%	7 15.2%
Number of Prior Therapies (Continuous) (number of therapies) [Median (Full Range) ]
Median (Full Range) [number of therapies]	5	3	2	1	2	2	2
Prior Rituximab Treatment (Count of Participants)
No	0 0%	0 0%	0 0%	0 0%	0 0%	1 4.3%	1 2.2%
Yes	3 100%	3 100%	4 100%	3 100%	10 100%	22 95.7%	45 97.8%
Prior Bortezomib Treatment (Count of Participants)
No	0 0%	2 66.7%	2 50%	1 33.3%	5 50%	10 43.5%	20 43.5%
Yes	3 100%	1 33.3%	2 50%	2 66.7%	5 50%	13 56.5%	26 56.5%
Prior Rituximab/Bortezomib Combination Treatment (Count of Participants)
No	0 0%	2 66.7%	2 50%	1 33.3%	5 50%	11 47.8%	21 45.7%
Yes	3 100%	1 33.3%	2 50%	2 66.7%	5 50%	12 52.2%	25 54.3%
Time from Initial Diagnosis to Study Entry (Months) (month) [Median (Full Range) ]
Median (Full Range) [month]	142.2	83.9	61.8	38.2	48.2	64.5	63.1

Outcome Measures

1. Primary Outcome

Title	Everolimus Maximum Tolerated Dose (MTD) Stage A [Phase I]
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis dataset includes all participants enrolled to Stage A.

Arm/Group Title	Phase I Stage A Level 1 and 2
Arm/Group Description	Combination of everolimus & rituximab for 6 cycles: Level 1:Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Level 2:Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Levels 1 and 2: Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)
Measure Participants	6
Number [mg]	10

2. Primary Outcome

Title	Everolimus Maximum Tolerated Dose (MTD) Stage B [Phase I]
Description	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase I Stage B Level 1 & 2 and Dose Expansion
Arm/Group Description	Combination of everolimus & rituximab with bortezomib for 6 cycles Level 1: Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Level 2 and Dose Expansion: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Level 1 & 2 and Dose Expansion: Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Level 1 & 2 and Dose Expansion: Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	6
Number [mg]	10

3. Primary Outcome

Title	Everolimus Dose Limiting Toxicity (DLT) [Phase I]
Description	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase I Stage A Level 1	Phase I Stage A Level 2	Phase I Stage B Level 1	Phase I Stage B Level 2
Arm/Group Description	Combination of everolimus & rituximab for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)	Combination of everolimus & rituximab for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	3	3	3	3
Number [participants]	0 0%	0 0%	0 0%	0 0%

4. Primary Outcome

Title	Very-good-partial-response-or-better Rate [Phase II]
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase II
Arm/Group Description	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	23
Number (95% Confidence Interval) [percentage of participants]	4.3 143.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I Stage A Level 1 and 2
	Comments	In a two-stage Simon design, a VGPR or better rate of at least 18% is considered promising versus a 5% or less rate. In stage 1, if 1 or fewer of 23 evaluable participants achieve VGPR, the regimen is considered non-promising else continue with 24 more patients enrolled. If </=4 of 47 evaluable patients have VGPR or better, the regimen is considered non-promising. If >/=5, then the regimen is considered promising for further study. With this design, there is 90% power and 1-sided 10% alpha.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Two stage design, exact method
	Comments
Other Statistical Analysis		The study did not continue to stage 2 given 1 VGPR or better response was observed in 23 evaluable participants in stage 1.

5. Secondary Outcome

Title	Treatment-Emergent Sensory Neuropathy Rate [Phase I]
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I Stage A Level 1	Phase I Stage A Level 2	Phase I Stage B Level 1	Phase I Stage B Level 2	Phase I Dose Expansion	Phase II
Arm/Group Description	Combination of everolimus & rituximab for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)	Combination of everolimus & rituximab for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	3	3	4	3	10	23
Number (95% Confidence Interval) [percentage of participants]	33 1100%	33 1100%	100 2500%	67 2233.3%	50 500%	48 208.7%

6. Secondary Outcome

Title	Phase II Overall Response Rate
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase II
Arm/Group Description	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	23
Number (95% Confidence Interval) [percentage of participants]	87 2900%

7. Secondary Outcome

Title	2-year Time-to-progression Probability (TTP) [Phase II]
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase II
Arm/Group Description	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	23
Number (95% Confidence Interval) [percent probability of progression]	28

8. Secondary Outcome

Title	2 Year Progression-free-survival [Phase II]
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase II
Arm/Group Description	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	23
Number (95% Confidence Interval) [percent probability of PFS]	28

9. Secondary Outcome

Title	Phase II Duration of Response (DoR)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase II
Arm/Group Description	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	23
Median (Full Range) [months]	14

10. Secondary Outcome

Title	PTEN Mutation Rate [Phase II]
Description	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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase II
Arm/Group Description	Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
Measure Participants	20
MYD88/L265P mutation	80 2666.7%
CXCR4/C1013G mutation	5 166.7%

Adverse Events

Time Frame	Adverse events (AEs) were assessed each cycle (ever 28 days) for 6 cycles then every 3 months on maintenance therapy. In this study cohort, AE assessment was a median (range) of 10 (1-42 months).
Adverse Event Reporting Description	Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	Phase I Stage A Level 1		Phase I Stage A Level 2		Phase I Stage B Level 1		Phase I Stage B Level 2		Phase I Dose Expansion		Phase II
Arm/Group Description	Combination of everolimus & rituximab for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)		Combination of everolimus & rituximab for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days)		Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 5 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)		Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)		Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)		Combination of everolimus & rituximab with bortezomib for 6 cycles Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle) Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Bortezomib 1.6 mg/m^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days)
All Cause Mortality
	Phase I Stage A Level 1		Phase I Stage A Level 2		Phase I Stage B Level 1		Phase I Stage B Level 2		Phase I Dose Expansion		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Serious Adverse Events
	Phase I Stage A Level 1		Phase I Stage A Level 2		Phase I Stage B Level 1		Phase I Stage B Level 2		Phase I Dose Expansion		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		3/3 (100%)		3/4 (75%)		3/3 (100%)		8/10 (80%)		11/23 (47.8%)
Blood and lymphatic system disorders
Hemoglobin	1/3 (33.3%)		1/3 (33.3%)		1/4 (25%)		1/3 (33.3%)		2/10 (20%)		5/23 (21.7%)
Infections and infestations
Infection Gr0-2 neut, lung	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Infection Gr0-2 neut, upper airway	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Infection w/ gr3-4 neut, upper airway	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Infection w/ unk ANC lung	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Investigations
ALT, SGPT	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Leukocytes	1/3 (33.3%)		2/3 (66.7%)		1/4 (25%)		2/3 (66.7%)		4/10 (40%)		2/23 (8.7%)
Lymphopenia	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		1/3 (33.3%)		1/10 (10%)		0/23 (0%)
Neutrophils	1/3 (33.3%)		2/3 (66.7%)		2/4 (50%)		2/3 (66.7%)		3/10 (30%)		2/23 (8.7%)
Platelets	1/3 (33.3%)		0/3 (0%)		1/4 (25%)		1/3 (33.3%)		1/10 (10%)		3/23 (13%)
Metabolism and nutrition disorders
Hyperglycemia	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Hypertriglyceridemia	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Hyponatremia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Hypophosphatemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Nervous system disorders
Neuropathy-sensory	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Pneumonitis/pulmonary infiltrates	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		1/10 (10%)		0/23 (0%)
Skin and subcutaneous tissue disorders
Hand-foot reaction	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Skin-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	Phase I Stage A Level 1		Phase I Stage A Level 2		Phase I Stage B Level 1		Phase I Stage B Level 2		Phase I Dose Expansion		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		4/4 (100%)		3/3 (100%)		10/10 (100%)		23/23 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Hematologic-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Hemoglobin	2/3 (66.7%)		3/3 (100%)		2/4 (50%)		2/3 (66.7%)		5/10 (50%)		9/23 (39.1%)
Lymph node, pain	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Cardiac disorders
Atrial flutter	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Cardiac-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Left ventricular diastolic dysfunction	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		2/10 (20%)		1/23 (4.3%)
Palpitations	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Sinus tachycardia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		3/23 (13%)
Ear and labyrinth disorders
Hearing w/w-o audiogr in monitor prg	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Eye disorders
Eyelid dysfunction	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Vision-blurred	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Gastrointestinal disorders
Abdomen, pain	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Colitis	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Constipation	1/3 (33.3%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		3/23 (13%)
Diarrhea w/o prior colostomy	0/3 (0%)		2/3 (66.7%)		2/4 (50%)		2/3 (66.7%)		4/10 (40%)		10/23 (43.5%)
Distention/bloating, abdominal	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Dry mouth	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Dyspepsia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		1/23 (4.3%)
Dysphagia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Enteritis	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Esophagitis	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Flatulence	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
GI-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Incontinence, anal	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Muco/stomatitis (symptom) oral cavity	1/3 (33.3%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Muco/stomatitis by exam, oral cavity	0/3 (0%)		1/3 (33.3%)		3/4 (75%)		3/3 (100%)		3/10 (30%)		0/23 (0%)
Nausea	0/3 (0%)		0/3 (0%)		2/4 (50%)		1/3 (33.3%)		2/10 (20%)		3/23 (13%)
Obstruction, small bowel NOS	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Oral cavity, hemorrhage	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Oral cavity, pain	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Oral gums, pain	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Perforation, cecum	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Perforation, rectum	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Rectum, pain	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Stomach, pain	1/3 (33.3%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Vomiting	0/3 (0%)		0/3 (0%)		1/4 (25%)		1/3 (33.3%)		0/10 (0%)		2/23 (8.7%)
General disorders
Chest/thoracic pain NOS	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		2/10 (20%)		2/23 (8.7%)
Constitutional, other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Edema head and neck	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Edema limb	0/3 (0%)		0/3 (0%)		2/4 (50%)		1/3 (33.3%)		2/10 (20%)		8/23 (34.8%)
Edema visceral	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Extremity-lower (gait/walking)	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Fatigue	3/3 (100%)		3/3 (100%)		3/4 (75%)		3/3 (100%)		9/10 (90%)		8/23 (34.8%)
Fever w/o neutropenia	1/3 (33.3%)		2/3 (66.7%)		0/4 (0%)		1/3 (33.3%)		3/10 (30%)		3/23 (13%)
Injection site reaction	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Pain-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		1/10 (10%)		2/23 (8.7%)
Rigors/chills	1/3 (33.3%)		0/3 (0%)		1/4 (25%)		1/3 (33.3%)		0/10 (0%)		2/23 (8.7%)
Immune system disorders
Allergic reaction	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		3/10 (30%)		6/23 (26.1%)
Infections and infestations
Infection Gr0-2 neut, colon	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Infection Gr0-2 neut, eye NOS	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Infection Gr0-2 neut, heart	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Infection Gr0-2 neut, lung	0/3 (0%)		1/3 (33.3%)		1/4 (25%)		0/3 (0%)		2/10 (20%)		1/23 (4.3%)
Infection Gr0-2 neut, middle ear	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Infection Gr0-2 neut, nerve-cranial	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		2/10 (20%)		0/23 (0%)
Infection Gr0-2 neut, nerve-periph	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Infection Gr0-2 neut, nose	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Infection Gr0-2 neut, salivary	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Infection Gr0-2 neut, sinus	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		1/23 (4.3%)
Infection Gr0-2 neut, stomach	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Infection Gr0-2 neut, ungual	0/3 (0%)		2/3 (66.7%)		2/4 (50%)		2/3 (66.7%)		1/10 (10%)		2/23 (8.7%)
Infection Gr0-2 neut, urinary tract	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		2/10 (20%)		2/23 (8.7%)
Infection w/ unk ANC bronchus	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Infection w/ unk ANC lung	1/3 (33.3%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Infection w/ unk ANC sinus	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		3/23 (13%)
Infection w/ unk ANC skin (cellulitis)	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		2/23 (8.7%)
Infection w/ unk ANC upper airway NOS	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		4/23 (17.4%)
Infection w/ unk ANC urinary tract NOS	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Infection-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Injury, poisoning and procedural complications
Fracture	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Intra-op injury Heart	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Wound - non-infectious	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Investigations
Alkaline phosphatase	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
AST, SGOT	0/3 (0%)		0/3 (0%)		1/4 (25%)		2/3 (66.7%)		3/10 (30%)		0/23 (0%)
Creatinine	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		2/10 (20%)		2/23 (8.7%)
Hypercholesterolemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		8/23 (34.8%)
Leukocytes	1/3 (33.3%)		2/3 (66.7%)		1/4 (25%)		3/3 (100%)		4/10 (40%)		9/23 (39.1%)
Lymphopenia	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Neutrophils	1/3 (33.3%)		2/3 (66.7%)		2/4 (50%)		3/3 (100%)		4/10 (40%)		9/23 (39.1%)
Platelets	0/3 (0%)		0/3 (0%)		1/4 (25%)		1/3 (33.3%)		2/10 (20%)		4/23 (17.4%)
Weight loss	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		3/23 (13%)
Metabolism and nutrition disorders
Anorexia	1/3 (33.3%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		2/10 (20%)		1/23 (4.3%)
Hypercalcemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Hyperglycemia	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		1/3 (33.3%)		5/10 (50%)		8/23 (34.8%)
Hyperkalemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Hypernatremia	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Hypertriglyceridemia	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		2/10 (20%)		9/23 (39.1%)
Hypoalbuminemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		1/10 (10%)		1/23 (4.3%)
Hypocalcemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Hypokalemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Hypomagnesemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Hyponatremia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Hypophosphatemia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		9/23 (39.1%)
Musculoskeletal and connective tissue disorders
Arthritis	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Back, pain	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		1/10 (10%)		2/23 (8.7%)
Chest wall, pain	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Extremity-limb, pain	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		1/23 (4.3%)
Joint, pain	0/3 (0%)		1/3 (33.3%)		2/4 (50%)		0/3 (0%)		3/10 (30%)		2/23 (8.7%)
Joint-function	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Muscle, pain	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Musculoskeletal/soft tissue-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Neck, pain	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Nonneuropathic generalized weakness	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		1/23 (4.3%)
Nonneuropathic lower extr muscle weak	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		1/23 (4.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Nervous system disorders
Dizziness	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		1/23 (4.3%)
Head/headache	2/3 (66.7%)		1/3 (33.3%)		2/4 (50%)		3/3 (100%)		1/10 (10%)		1/23 (4.3%)
Memory impairment	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Neurologic-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		1/23 (4.3%)
Neuropathy CN VII face-motor / taste	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Neuropathy CN VIII hearing + balance	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Neuropathy-motor	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		2/10 (20%)		1/23 (4.3%)
Neuropathy-sensory	1/3 (33.3%)		0/3 (0%)		2/4 (50%)		1/3 (33.3%)		6/10 (60%)		7/23 (30.4%)
Sinus, pain	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		1/10 (10%)		0/23 (0%)
Taste disturbance	0/3 (0%)		0/3 (0%)		1/4 (25%)		2/3 (66.7%)		2/10 (20%)		7/23 (30.4%)
Psychiatric disorders
Anxiety	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Depression	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Insomnia	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Renal and urinary disorders
Bladder spasms	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Hemoglobinuria	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		2/10 (20%)		0/23 (0%)
Incontinence urinary	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Obstruction-ureteral	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Renal/GU-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Urinary hemorrhage NOS	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Reproductive system and breast disorders
Irregular menses	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Pelvic, pain	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		2/10 (20%)		1/23 (4.3%)
Cough	3/3 (100%)		3/3 (100%)		1/4 (25%)		2/3 (66.7%)		3/10 (30%)		4/23 (17.4%)
Dyspnea	1/3 (33.3%)		1/3 (33.3%)		0/4 (0%)		1/3 (33.3%)		6/10 (60%)		4/23 (17.4%)
Nose, hemorrhage	1/3 (33.3%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		3/23 (13%)
Pleural effusion (non-malignant)	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Pneumonitis/pulmonary infiltrates	2/3 (66.7%)		2/3 (66.7%)		2/4 (50%)		1/3 (33.3%)		5/10 (50%)		7/23 (30.4%)
Pulmonary/Upper Respiratory-other	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Throat/pharynx/larynx, pain	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		2/23 (8.7%)
Voice changes/dysarthria	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Skin and subcutaneous tissue disorders
Alopecia	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Nail changes	0/3 (0%)		2/3 (66.7%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Petechiae	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)
Pruritus/itching	0/3 (0%)		1/3 (33.3%)		0/4 (0%)		0/3 (0%)		4/10 (40%)		2/23 (8.7%)
Rash/desquamation	0/3 (0%)		2/3 (66.7%)		1/4 (25%)		1/3 (33.3%)		2/10 (20%)		6/23 (26.1%)
Sweating	1/3 (33.3%)		1/3 (33.3%)		1/4 (25%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Ulceration	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Vascular disorders
Flushing	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/10 (10%)		0/23 (0%)
Hot flashes	1/3 (33.3%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Hypertension	0/3 (0%)		0/3 (0%)		1/4 (25%)		0/3 (0%)		0/10 (0%)		0/23 (0%)
Thrombosis/thrombus/embolism	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/3 (33.3%)		0/10 (0%)		0/23 (0%)
Vascular access,Thrombosis/embolism	0/3 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		0/10 (0%)		1/23 (4.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.