Bendamustine Hydrochloride, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01049945
• Collaborator: (none)
• Enrollment: 70
• Locations: 5
• Arm: 1
• Actual Duration (Months): 67.4
• Patients Per Site: 14
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as bendamustine hydrochloride and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Giving bendamustine hydrochloride together with lenalidomide and dexamethasone may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of bendamustine hydrochloride and lenalidomide when given together with dexamethasone and to see how well they work in treating patients with relapsed multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Refractory Multiple Myeloma	Drug: bendamustine hydrochloride; Drug: lenalidomide; Drug: dexamethasone	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES: I. To determine the Maximum Tolerated Dose (MTD) of bendamustine and lenalidomide in combination with dexamethasone in subjects with Multiple Myeloma (MM) in first or second relapse. (Phase I) II. To evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in subjects with MM in first or second relapse. (Phase II) SECONDARY OBJECTIVES: I. To evaluate the safety of bendamustine in combination with lenalidomide and dexamethasone. (Phase I and II) II. To evaluate time-to-tumor-progression, progression-free survival, duration of response, and overall survival. (Phase II) OUTLINE: This is a phase I dose escalation study of bendamustine hydrochloride and lenalidomide followed by a phase II study. Patients receive dexamethasone orally or IV on days 1, 8, 15, and 22; bendamustine hydrochloride IV over 30 minutes on days 1 and 2; and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least stable disease after 6 courses may continue to receive lenalidomide and dexamethasone as above in the absence of disease progression or unacceptable toxicity. Dexamethasone may be discontinued after 12 courses of therapy at the treating investigator's discretion. After completion of study treatment, patients are followed at 4 weeks and then periodically for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II, Multicenter, Open-label, Dose-escalation Study of Bendamustine in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed Multiple Myeloma
• Actual Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Sep 16, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive dexamethasone orally or IV on days 1, 8, 15, and 22; bendamustine hydrochloride IV over 30 minutes on days 1 and 2; and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.	Drug: bendamustine hydrochloride; Given IV; Other Names: bendamustin hydrochloride bendamustine cytostasan hydrochloride Ribomustin SDX-105 Treanda ; Drug: lenalidomide; Given orally; Other Names: CC-5013 IMiD-1 Revlimid ; Drug: dexamethasone; Given orally or IV; Other Names: Aeroseb-Dex Decaderm Decadron Decaspray DM DXM

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicity of Bendamustine Hydrochloride and Lenalidomide in Combination With Dexamethasone (Phase I) [One cycle of treatment]

   The Maximum Tolerated Dose (MTD) is the dose level below that at which a dose limiting toxicity (DLT) is observed in ≥ 33% (i.e., ≥ 2 of 6) subjects in a cohort. A dose limiting toxicity is defined as one of the following adverse events in the Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 deemed at least possibly related to treatment: Grade 2 neuropathy with pain Any grade 3 Non-Hematologic toxicity Any grade Non-Hematologic event requiring a dose reduction in cycle 1 or delaying the next cycle by >14 days. Grade 4 neutropenia Febrile neutropenia Grade 4 thrombocytopenia Grade 3 thrombocytopenia associated with bleeding Any Hematologic event requiring a dose reduction in cycle 1 or a delay in the next cycle of treatment by >14 days. We are reporting the results of this endpoint as the number of DLTs per dose level.

2. Confirmed Response Rate (Dose Level 4) Reported as the Percentage of Patients Achieving a Confirmed Response (sCR, CR, VGPR, or PR). [Up to 6 cycles of treatment]

   Complete response (CR) - Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent complete response (sCR) - A CR plus normal FLC ratio and no clonal cells in bone marrow Near complete response (nCR) A CR, with the persistence of original monoclonal protein Very good partial response (VGPR) - Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component <100 mg per 24 h Partial response (PR) ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h. a ≥50% decrease in the difference between involved and uninvolved FLC levels or a ≥50% reduction in plasma cells is required in place of M-protein, if ≥30% at baseline.

Secondary Outcome Measures

1. Duration of Response (DOR) (Phase II) [Up to 2 years from study completion]

   DOR is the time from the date the patient's objective status is first noted to be PR or better to the earliest date of progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) is documented. Treatment response was assessed using the International Myeloma Working Group uniform criteria. Complete response (CR)=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent complete response (sCR)=A CR plus normal FLC ratio and no clonal cells in bone marrow. Near complete response (nCR)=A CR, with the persistence of original monoclonal protein. Very good partial response (VGPR) =Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component <100 mg per 24 h, Partial response (PR)=≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h.

2. Event Free Survival (Phase II) [Up to 2 years from study completion]

   The event-free survival time is defined as the time from registration to disease progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) while receiving bendamustine, lenalidomide, and dexamethasone, death due to any cause, or subsequent treatment for multiple myeloma. The distribution of event-free survival will be estimated using the method of Kaplan-Meier. Treatment response was assessed using the International Myeloma Working Group uniform criteria.

3. Progression Free Survival (Phase II) [Up to 2 years from study completion]

   The progression-free survival time is defined as the time from registration to disease progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) while receiving bendamustine, lenalidomide, and dexamethasone or death due to any cause, whichever comes first. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. Treatment response was assessed using the International Myeloma Working Group uniform criteria.

4. Overall Survival (Phase II) [at 6 months]

   The overall survival time is defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier. The overall survival rate at 6 months is defined as the percentage of participants who are alive at 6 months.

Eligibility Criteria

Criteria

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

Inclusion:

• Diagnosis of MM and documentation of at least 1 prior therapy (induction therapy followed by stem cell transplantation is considered one prior therapy) but not more than two previous therapies

• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide

• Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

• Able to take aspirin (325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA or at high risk of developing thrombosis may use warfarin or low molecular weight heparin)

• AST (SGOT) and ALT (SGPT) =< 3.0 x upper limit of normal (ULN)

• Creatinine clearance >= 60 mL/min (Cockcroft-Gault calculation) for patients enrolled in Phase 1 and Creatinine clearance >= 30 mL/min (Cockcroft-Gault calculation) for patients enrolled in phase 2 portion

• Patients with measurable disease, defined by any of the following: serum monoclonal protein >= 1.0 g by protein electrophoresis; > 200 mg of monoclonal protein in the urine on 24-hour electrophoresis; serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio; or monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)

• All necessary baseline studies for determining eligibility must be obtained within 21 days prior to enrollment

• Subject has an ECOG =< 2 OR Karnofsky >= 60% performance status; patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible

• FCBP must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing

• Absolute neutrophil count (ANC) >= 1,000 cells/dL (1.0 x 10^9/L) (growth factors cannot be used within 14 days of first drug administration)

• Untransfused platelet count >= 75,000 cells/dL (50 x 10^9/L) for patients in whom < 50% of bone marrow nucleated cells are plasma cells; but platelet count >=50,000/dL for patients in whom 50% of bone marrow nucleated cells are plasma cells

• Total Bilirubin =< 1.5 mg/dL

• Hemoglobin >= 8.0 g/dl

Exclusion:

• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

• Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than 10 mg p.o. q.d. or its equivalent) for symptom management and comorbid conditions; doses of corticosteroid should be stable for at least 7 days prior to study treatment

• Prior radiation therapy within 2 weeks of the first dose of study treatment

• Known active infection requiring parenteral or oral anti-infective treatment

• Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation

• Patient has hypersensitivity to any of the components of study therapy - Known HIV or active hepatitis B or C viral infection

• Known hypersensitivity to required prophylactic medications

• Patient has received other investigational drugs within 14 days before enrollment

• Pregnant or breast-feeding females (lactating females must agree not to breast feed while taking lenalidomide)

• Subjects with evidence of mucosal or internal bleeding and/or platelet transfusion refractory (i.e., unable to maintain a platelet count >= 50,000 cells/mm^3)

• Concurrent therapy with a marketed or investigational anticancer therapy

• Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient

• Other investigational agents are not to be used during the study

• Prior peripheral stem cell transplant within 12 weeks of the first dose of study treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Mayo Clinic in Florida	Jacksonville	Florida	United States	55904
3	University of Chicago	Chicago	Illinois	United States	60637-1470
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Washington Universtiy School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Study Chair: Shaji K. Kumar, M.D., Mayo Clinic
• Principal Investigator: Vivek Roy, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01049945
• Other Study ID Numbers: MMRC-020-021; NCI-2009-01535; MMRC-020-021; 09-004211; C18083/6125; NCT04567862
• First Posted: Jan 15, 2010
• Last Update Posted: Feb 11, 2020
• Last Verified: Apr 1, 2016

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Lenalidomide; Bendamustine Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Phase I, Dose Level 1	Phase I, Dose Level 2	Phase I, Dose Level 3	Phase I, Dose Level 4	Phase I, Dose Level 5	Phase II, Dose Level 4
Arm/Group Description	Bendamustine 50 mg/m^2 IV day 1 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 50 mg/m^2 IV day 1 and 2 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 100 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity
Period Title: Overall Study
STARTED	3	6	3	6	3	49
COMPLETED	3	6	3	6	3	49
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase I	Maximum Tolerated Dose, Dose Level 4	Total
Arm/Group Description	Participant demographics were analyzed according to their status for the Phase II Primary Endpoint. All participants registered to Dose Level 4 (the Maximum Tolerated Dose (MTD)) were eligible for the Phase II Primary Endpoint. This group included the 6 patients registered to Phase I, Dose Level 4 and the 49 participants registered to the Phase II portion. The demographic information for all other participants registered to Phase I (Dose Level 1, Dose Level 2, Dose Level 3, and Dose Level 5) were summarized together.	Participant demographics were analyzed according to their status for the Phase II Primary Endpoint. All participants registered to Dose Level 4 (the Maximum Tolerated Dose (MTD)) were eligible for the Phase II Primary Endpoint. This group included the 6 patients registered to Phase I, Dose Level 4 and the 49 participants registered to the Phase II portion. The demographic information for all other participants registered to Phase I (Dose Level 1, Dose Level 2, Dose Level 3, and Dose Level 5) were summarized together.	Total of all reporting groups
Overall Participants	15	55	70
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63.5	61.9	62.3
Sex: Female, Male (Count of Participants)
Female	3 20%	27 49.1%	30 42.9%
Male	12 80%	28 50.9%	40 57.1%
Region of Enrollment (participants) [Number]
United States	15 100%	55 100%	70 100%

Outcome Measures

1. Primary Outcome

Title	Dose Limiting Toxicity of Bendamustine Hydrochloride and Lenalidomide in Combination With Dexamethasone (Phase I)
Description	The Maximum Tolerated Dose (MTD) is the dose level below that at which a dose limiting toxicity (DLT) is observed in ≥ 33% (i.e., ≥ 2 of 6) subjects in a cohort. A dose limiting toxicity is defined as one of the following adverse events in the Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 deemed at least possibly related to treatment: Grade 2 neuropathy with pain Any grade 3 Non-Hematologic toxicity Any grade Non-Hematologic event requiring a dose reduction in cycle 1 or delaying the next cycle by >14 days. Grade 4 neutropenia Febrile neutropenia Grade 4 thrombocytopenia Grade 3 thrombocytopenia associated with bleeding Any Hematologic event requiring a dose reduction in cycle 1 or a delay in the next cycle of treatment by >14 days. We are reporting the results of this endpoint as the number of DLTs per dose level.
Time Frame	One cycle of treatment

Outcome Measure Data

Analysis Population Description

All participants registered to the Phase I portion of this study were evaluable for this endpoint.

Arm/Group Title	Phase I, Dose Level 1	Phase I, Dose Level 2	Phase I, Dose Level 3	Phase I, Dose Level 4	Phase I, Dose Level 5
Arm/Group Description	Bendamustine 50 mg/m^2 IV day 1 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 50 mg/m^2 IV day 1 and 2 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity	Bendamustine 100 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity
Measure Participants	3	6	3	6	3
Number [Dose Limiting Toxic Events]	0	1	0	0	2

2. Primary Outcome

Title	Confirmed Response Rate (Dose Level 4) Reported as the Percentage of Patients Achieving a Confirmed Response (sCR, CR, VGPR, or PR).
Description	Complete response (CR) - Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent complete response (sCR) - A CR plus normal FLC ratio and no clonal cells in bone marrow Near complete response (nCR) A CR, with the persistence of original monoclonal protein Very good partial response (VGPR) - Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component <100 mg per 24 h Partial response (PR) ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h. a ≥50% decrease in the difference between involved and uninvolved FLC levels or a ≥50% reduction in plasma cells is required in place of M-protein, if ≥30% at baseline.
Time Frame	Up to 6 cycles of treatment

Outcome Measure Data

Analysis Population Description

All participants registered to Dose Level 4 (the Maximum Tolerated Dose (MTD)) were eligible for the Phase II Primary Endpoint. This group included the 6 patients registered to Phase I, Dose Level 4 and the 49 participants registered to the Phase II portion.

Arm/Group Title	Maximum Tolerated Dose, Dose Level 4
Arm/Group Description	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	55
Number (95% Confidence Interval) [percentage of participants]	44 293.3%

3. Secondary Outcome

Title	Duration of Response (DOR) (Phase II)
Description	DOR is the time from the date the patient's objective status is first noted to be PR or better to the earliest date of progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) is documented. Treatment response was assessed using the International Myeloma Working Group uniform criteria. Complete response (CR)=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent complete response (sCR)=A CR plus normal FLC ratio and no clonal cells in bone marrow. Near complete response (nCR)=A CR, with the persistence of original monoclonal protein. Very good partial response (VGPR) =Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component <100 mg per 24 h, Partial response (PR)=≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h.
Time Frame	Up to 2 years from study completion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Maximum Tolerated Dose, Dose Level 4
Arm/Group Description	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	55
Median (95% Confidence Interval) [months]	24.4

4. Secondary Outcome

Title	Event Free Survival (Phase II)
Description	The event-free survival time is defined as the time from registration to disease progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) while receiving bendamustine, lenalidomide, and dexamethasone, death due to any cause, or subsequent treatment for multiple myeloma. The distribution of event-free survival will be estimated using the method of Kaplan-Meier. Treatment response was assessed using the International Myeloma Working Group uniform criteria.
Time Frame	Up to 2 years from study completion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Maximum Tolerated Dose, Dose Level 4
Arm/Group Description	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	55
Median (95% Confidence Interval) [months]	5.6

5. Secondary Outcome

Title	Progression Free Survival (Phase II)
Description	The progression-free survival time is defined as the time from registration to disease progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) while receiving bendamustine, lenalidomide, and dexamethasone or death due to any cause, whichever comes first. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. Treatment response was assessed using the International Myeloma Working Group uniform criteria.
Time Frame	Up to 2 years from study completion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Maximum Tolerated Dose, Dose Level 4
Arm/Group Description	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	55
Median (95% Confidence Interval) [months]	11.8

6. Secondary Outcome

Title	Overall Survival (Phase II)
Description	The overall survival time is defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier. The overall survival rate at 6 months is defined as the percentage of participants who are alive at 6 months.
Time Frame	at 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Maximum Tolerated Dose, Dose Level 4
Arm/Group Description	Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	55
Number (95% Confidence Interval) [percentage of participants]	87 580%

Adverse Events

Arm/Group Title	Phase I, Dose Level 1		Phase I, Dose Level 2		Phase I, Dose Level 3		Phase I, Dose Level 4		Phase I, Dose Level 5		Phase II, Dose Level 4
Arm/Group Description	Bendamustine 50 mg/m^2 IV day 1 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity		Bendamustine 50 mg/m^2 IV day 1 and 2 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity		Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 15 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity		Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity		Bendamustine 100 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity		Bendamustine 75 mg/m^2 IV day 1 and 2 Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity
All Cause Mortality
	Phase I, Dose Level 1		Phase I, Dose Level 2		Phase I, Dose Level 3		Phase I, Dose Level 4		Phase I, Dose Level 5		Phase II, Dose Level 4
	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	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I, Dose Level 1		Phase I, Dose Level 2		Phase I, Dose Level 3		Phase I, Dose Level 4		Phase I, Dose Level 5		Phase II, Dose Level 4
	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%)		2/6 (33.3%)		2/3 (66.7%)		2/6 (33.3%)		1/3 (33.3%)		24/49 (49%)
Blood and lymphatic system disorders
Anemia	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Febrile neutropenia	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	1/3 (33.3%)	1	1/49 (2%)	1
Cardiac disorders
Atrial fibrillation	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Constipation	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Diarrhea	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Ileus	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pancreatitis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/49 (0%)	0
General disorders
Chest pain	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Disease progression	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Fatigue	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Fever	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Hepatobiliary disorders
Cholecystitis	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Infections and infestations
Herpes Zoster	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Appendicitis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Bronchitis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Opportunistic infection	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Pneumonia	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	6/49 (12.2%)	6
Upper respiratory infection	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/49 (0%)	0
Investigations
Creatinine increased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/49 (0%)	0
Neutrophil count decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	2/49 (4.1%)	2
Platelet count decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Metabolism and nutrition disorders
Dehydration	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Hypokalemia	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Serum calcium decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Myalgia	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Nervous system disorders
Ataxia	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
CNS hemorrhage/bleeding	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Ischemia cerebrovascular	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Peripheral motor neuropathy	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Seizure	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/49 (0%)	0
Syncope	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Renal and urinary disorders
Renal failure	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pleural effusion	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Vascular disorders
Hypotension	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Thrombosis	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Other (Not Including Serious) Adverse Events
	Phase I, Dose Level 1		Phase I, Dose Level 2		Phase I, Dose Level 3		Phase I, Dose Level 4		Phase I, Dose Level 5		Phase II, Dose Level 4
	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%)		6/6 (100%)		3/3 (100%)		6/6 (100%)		3/3 (100%)		49/49 (100%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1	0/6 (0%)	0	1/3 (33.3%)	1	2/6 (33.3%)	2	1/3 (33.3%)	1	22/49 (44.9%)	25
Cardiac disorders
Atrial fibrillation	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/49 (2%)	2
Cardiac pain	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Conduction disorder	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Edema	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	5/49 (10.2%)	5
Palpitations	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Sinus bradycardia	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	4/49 (8.2%)	4
Sinus tachycardia	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Ventricular arrhythmia	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Endocrine disorders
Hypothyroidism	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Eye disorders
Cataract	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Eye disorder	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Vision	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Watering eyes	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Gastrointestinal disorders
Abdominal pain	1/3 (33.3%)	2	1/6 (16.7%)	1	0/3 (0%)	0	2/6 (33.3%)	2	1/3 (33.3%)	1	4/49 (8.2%)	5
Colitis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/49 (0%)	0
Constipation	1/3 (33.3%)	1	2/6 (33.3%)	2	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	15/49 (30.6%)	15
Diarrhea	3/3 (100%)	3	2/6 (33.3%)	3	1/3 (33.3%)	1	5/6 (83.3%)	7	1/3 (33.3%)	1	24/49 (49%)	26
Dry mouth	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Dyspepsia	1/3 (33.3%)	1	2/6 (33.3%)	2	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	9/49 (18.4%)	10
Dysphagia	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Flatulence	1/3 (33.3%)	1	1/6 (16.7%)	2	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Melena/GI bleeding	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/49 (0%)	0
Mucositis oral	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	2/49 (4.1%)	2
Nausea	2/3 (66.7%)	2	2/6 (33.3%)	2	0/3 (0%)	0	3/6 (50%)	3	1/3 (33.3%)	1	23/49 (46.9%)	23
Oral pain	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Pancreatitis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/49 (0%)	0
Rectal hemorrhage	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Vomiting	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	14/49 (28.6%)	14
General disorders
Chest pain	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4
Chills	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	3/49 (6.1%)	3
Edema limbs	1/3 (33.3%)	2	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	7/49 (14.3%)	9
Fatigue	3/3 (100%)	4	3/6 (50%)	4	0/3 (0%)	0	4/6 (66.7%)	4	2/3 (66.7%)	2	27/49 (55.1%)	30
Fever	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	11/49 (22.4%)	11
Gait abnormal	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Gait disturbance	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Injection site reaction	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Pain	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hepatobiliary disorders
Cholecystitis	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Immune system disorders
Hypersensitivity	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	4/49 (8.2%)	4
Infections and infestations
Herpes Zoster	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	7/49 (14.3%)	8
Bronchitis	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Colitis, infectious (e.g., Clostridium difficile)	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Gingival infection	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Mucosal infection	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Nail infection	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Opportunistic infection	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Otitis externa	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/49 (2%)	1
Pneumonia	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	2/49 (4.1%)	2
Sinusitis	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/49 (2%)	1
Skin infection	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	1/49 (2%)	1
Upper aerodigestive tract infection	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Upper respiratory infection	1/3 (33.3%)	1	3/6 (50%)	4	0/3 (0%)	0	4/6 (66.7%)	5	2/3 (66.7%)	2	10/49 (20.4%)	11
Urinary tract infection	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Injury, poisoning and procedural complications
Bruising	1/3 (33.3%)	1	2/6 (33.3%)	2	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	11/49 (22.4%)	12
Fracture	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Investigations
Alkaline phosphatase increased	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Creatinine increased	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Leukocyte count decreased	2/3 (66.7%)	3	3/6 (50%)	3	3/3 (100%)	3	5/6 (83.3%)	5	3/3 (100%)	4	39/49 (79.6%)	39
Lymphocyte count decreased	2/3 (66.7%)	3	5/6 (83.3%)	6	3/3 (100%)	3	6/6 (100%)	6	2/3 (66.7%)	2	42/49 (85.7%)	43
Neutrophil count decreased	0/3 (0%)	0	1/6 (16.7%)	2	3/3 (100%)	4	5/6 (83.3%)	7	3/3 (100%)	4	40/49 (81.6%)	48
Platelet count decreased	1/3 (33.3%)	2	1/6 (16.7%)	1	0/3 (0%)	0	4/6 (66.7%)	6	1/3 (33.3%)	1	32/49 (65.3%)	34
Weight gain	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Weight loss	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	2/6 (33.3%)	2	1/3 (33.3%)	1	14/49 (28.6%)	14
White blood cell decreased	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Metabolism and nutrition disorders
Acidosis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Anorexia	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	7/49 (14.3%)	7
Blood bicarbonate decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Blood uric acid increased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Dehydration	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Hyperglycemia	1/3 (33.3%)	2	2/6 (33.3%)	2	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	6/49 (12.2%)	6
Hypokalemia	1/3 (33.3%)	1	0/6 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	7/49 (14.3%)	7
Serum calcium decreased	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Serum calcium increased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Serum magnesium decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/49 (2%)	1
Serum phosphate decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Serum potassium decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Serum sodium decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/49 (2%)	1
Tumor lysis syndrome	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Musculoskeletal and connective tissue disorders
Leg Cramp	2/3 (66.7%)	3	0/6 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	8/49 (16.3%)	14
Arthralgia	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Back pain	3/3 (100%)	3	1/6 (16.7%)	1	1/3 (33.3%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	10/49 (20.4%)	11
Musculoskeletal	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Myalgia	2/3 (66.7%)	2	1/6 (16.7%)	1	1/3 (33.3%)	1	2/6 (33.3%)	2	0/3 (0%)	0	19/49 (38.8%)	23
Neck pain	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pain in extremity	2/3 (66.7%)	2	2/6 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	5/49 (10.2%)	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	3
Nervous system disorders
Ataxia	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Dizziness	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	8/49 (16.3%)	8
Dysgeusia	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Encephalopathy	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Facial nerve disorder	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Headache	1/3 (33.3%)	1	0/6 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	8/49 (16.3%)	8
Ischemia cerebrovascular	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Peripheral motor neuropathy	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Peripheral sensory neuropathy	1/3 (33.3%)	1	3/6 (50%)	3	0/3 (0%)	0	2/6 (33.3%)	4	1/3 (33.3%)	1	14/49 (28.6%)	14
Somnolence	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Tremor	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	3
Psychiatric disorders
Agitation	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/49 (2%)	1
Anxiety	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	2/49 (4.1%)	2
Confusion	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Depression	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/49 (2%)	1
Hallucinations	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Insomnia	2/3 (66.7%)	2	1/6 (16.7%)	1	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	11/49 (22.4%)	11
Psychiatric disorders - Other, specify	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Renal and urinary disorders
Cystitis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Glomerular filtration rate decreased	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hematuria (absence of vaginal bleeding)	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Renal failure	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Urinary frequency	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Reproductive system and breast disorders
Pelvic pain	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Apnea	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Cough	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	8/49 (16.3%)	8
Dyspnea	2/3 (66.7%)	2	0/6 (0%)	0	1/3 (33.3%)	1	2/6 (33.3%)	2	2/3 (66.7%)	2	6/49 (12.2%)	6
Epistaxis	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hemoptysis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hiccups	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pharyngolaryngeal pain	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Pleural effusion	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pneumonitis	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Productive cough	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Skin and subcutaneous tissue disorders
Alopecia	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Decubitus ulcer	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Dry skin	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Erythema multiforme	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Hyperhidrosis	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Nail disorder	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Pain of skin	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Pruritus	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	3/49 (6.1%)	4
Rash acneiform	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Rash desquamating	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Rash maculo-papular	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	2/6 (33.3%)	3	1/3 (33.3%)	1	10/49 (20.4%)	11
Skin atrophy	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Sweating	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/49 (2%)	1
Vascular disorders
Flushing	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hematoma	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/49 (0%)	0
Hypertension	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Hypotension	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/49 (4.1%)	2
Phlebitis	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/49 (2%)	1
Thrombosis	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	4/49 (8.2%)	4

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.