Clinical trial NCT01177683
Conditions: Multiple Myeloma
Sponsor: Sherif Farag, MB, BS
Start date: 2010-07-01; Completion date: 2017-12-01
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label phase I/II trial to determine the safety and the biologic activity of the bendamustine, bortezomib and pegylated liposomal doxorubicin combination.

Detailed description:
Phase I component Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11 Doxorubicin 30 mg/m2 IV over 1 hour, Day 4 Bendamustine escalating cohorts IV over 1 hour, Days 1 and 4 1 Cycle = 28 days

Phase II component Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11 Doxorubicin 30 mg/m2 IV over 1 hour, Day 4 Bendamustine at MTD IV over 1 hour, Days 1 and 4 Filgrastim (if defined in MTD) 5 µg/kg/day SC, Starting day 6 until neutrophil recovery to ANC \>1000

1 Cycle = 28 days; Patients will continue treatment for a total of up to 8 cycles.

ECOG Performance Status: 0-2

Hematopoietic:

* Absolute neutrophil count (ANC) ≥ 1.2 x K/mm3
* Platelets ≥ 75 x K/mm3

Hepatic:

* Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
* AST ≤ 2.5 x ULN
* ALT ≤ 2.5 x ULN

Renal:

* Serum creatinine \< 3.0 mg/dL

Cardiovascular:

* LVEF \>45% corrected by MUGA scan or echocardiogram.
* No unstable angina pectoris or recent myocardial infarction (within 6 months)

Arms: arm 1: Bendamustine in combination with bortezomib and pegylated liposomal doxorubicin.
Interventions: intervention 1: Bendamustine intervention 2: Doxorubicin intervention 3: Bortezomib intervention 4: Bendamustine intervention 5: Filgrastim
Intervention descriptions: intervention 1: Phase I component:

Bendamustine escalating cohorts to determine MTD, IV over 1 hour, Days 1 and 4 intervention 2: Phase I and II components:

Pegylated liposomal doxorubicin, 30 mg/m2 IV over 1 hour, Day 4 intervention 3: Phase I and II components:

Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11 intervention 4: Phase II component:

Bendamustine at at MTD IV over 1 hour, Days 1 and 4 intervention 5: Phase II component:

Filgrastim (if defined in MTD) 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Protocol Title 
A Phase I/II trial of Bendamustine in Combination with Bortezomib and Pegylated Liposomal 
Doxorubicin in Patients with Relapsed or Refractory Multiple Myeloma: Hoosier Cancer Research 
Network MM08-141 
 
 
Sponsor Investigator 
Sherif S. Farag, MD, PhD 
Indiana University Melvin and Bren Simon Cancer Center 
 
 
Co-Investigator  
Erica Campagnaro, MD, Case Comprehensive Cancer Center 
University Hospitals Case Medical Center 
 
 
Statistician 
Ziyue Liu, PhD 
Indiana University School of Medicine 
 
Trial Supported by  
Cephalon Oncology (Investigator Initiated Study) 
 
Investigational New Drug (IND) Application #   
IND exempt 
 
Initial Protocol Version Date: 25SEP2009 
Amendment # 1: Amended Protocol Version Date: 06APR2010 
Amendment #2: Amended Protocol Version Date: 16MAR2012 
Amendment #3: Amended Protocol Version Date: 04APR2013 
Amendment #4: Amended Protocol Version Date: 21AUG2014 
 


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PROTOCOL SIGNATURE PAGE 
 
A Phase I/II trial of Bendamustine in Combination with Bortezomib and Pegylated 
Liposomal Doxorubicin in Patients with Relapsed or Refractory Multiple Myeloma: Hoosier 
Cancer Research Network MM08-141 
 
VERSION DATE: 21AUG2014 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual.  
I will accept the monitor’s overseeing of the study.  I will promptly submit the protocol to 
applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
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 Signature of Investigator 
 
 
 
 
 
       Date 
 
 
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PLEASE COMPLETE AND EMAIL COPY TO  HOOSIER CANCER RESEARCH 
NETWORK 
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to Hoosier Cancer Research Network and keep a copy for 
your files. 


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STUDY SYNOPSIS 
 
TITLE 
A Phase I/II trial of Bendamustine in Combination with Bortezomib and 
Pegylated Liposomal Doxorubicin in Patients with Relapsed or Refractory 
Multiple Myeloma: Hoosier Cancer Research Network MM08-141 
STUDY PHASE  
Phase I/II 
OBJECTIVES 
Primary Objective: 
 
Determine the maximum tolerated dose of bendamustine in association with 
bortezomib and pegylated liposomal doxorubicin in patients with relapsed or 
refractory MM. 
 
Assess the overall response rate (CR+PR) of bendamustine in association with 
bortezomib and pegylated liposomal doxorubicin in patients with relapsed or 
refractory MM.   
Secondary Objective: 
 
Describe the toxicity of the combination of bendamustine with bortezomib and 
pegylated liposomal doxorubicin. 
 
Evaluate the time to progression, overall survival, progression free survival, and 
duration of response of MM patients treated with bendamustine, bortezomib and 
pegylated liposomal doxorubicin. 
 
Correlate bendamustine pharmacokinetics parameters (Cmax, t1/2, and AUC) at cycle 
1 (and cycle 2) with patients’ responses and correlate the DNA damage/repair at day 
1 of cycle 1 and day 4 of cycle 2 with patients’ responses. 
STUDY DESIGN 
This will be an open label phase I/II trial to determine the safety and the biologic activity 
of the bendamustine, bortezomib and pegylated liposomal doxorubicin combination.   
NUMBER OF 
PATIENTS 
A total of up to 69 patients will be enrolled.  Up to 18 patients will be enrolled on the Phase I 
portion.  Up to 51 patients will be enrolled on the Phase II portion.  
ELIGIBILITY 
 Written informed consent, HIPAA authorization for release of personal health 
information, ability to understand the requirements of the study, abide by the study 
restrictions, and agree to return for the required assessments. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained 
separately. 
 Age > 18 years at the time of consent. 
 ECOG Performance Status of 0-2 within 21 days prior to registration for protocol 
therapy. 
 A histologically established diagnosis of multiple myeloma with evidence of relapse 
or refractory disease. 
NOTE: Relapsed myeloma is defined in patients as at least a 25% increasing 
monoclonal (M)-protein in serum or urine or in the size of a plasmacytoma 
compared to a best response reached after a previous therapy. 
NOTE: Refractory myeloma is defined as failure to achieve at least a minor 
response (patient achieved stable disease as his/her best response) or progression of 
disease on current therapy or within 60 days of last dose of current therapy.   
 Must have a detectable serum or urine M-Protein by protein electrophoresis that is at 
least 500 mg/dL (serum) or 1 gm/24 hours (urine), respectively, or serum free light 
chain level >100 mg/l for the involved free light chain.  
NOTE: Patients with non-secretory myeloma or plasmacytoma only will be 
excluded. 


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 Must have received at least one (1) prior line of systemic treatment that has included 
either lenalidomide or thalidomide.  
NOTE: Patients may have undergone prior autologous stem cell transplantation 
(stem cell transplant with high dose induction chemotherapy with/without planned 
maintenance therapy will be considered one line of therapy).  Patients who have 
received prior bortezomib, pegylated liposomal doxorubicin, or the combination are 
eligible.  Patients who have received prior bendamustine for the treatment of MM 
are also eligible if this was not combined with bortezomib or pegylated liposomal 
doxorubicin. 
 Must not have received an excessive cumulative dose of anthracycline.  
NOTE: Permissible prior exposure is doxorubicin  240 mg/m2 (or anthracycline 
equivalent calculated as 1 mg doxorubicin = 1 mg Doxil = 1.8 mg epirubicin = 0.25 
idarubicin = 0.3 mg mitoxantrone) 
 Females of childbearing potential and males must be willing to use an effective 
method of contraception (hormonal or barrier method of birth control; abstinence) 
from the time consent is signed until 30 days after treatment discontinuation.  
 Females of childbearing potential must have a negative pregnancy test within 7 days 
prior to prior to registration for protocol therapy.    
NOTE:  Females are considered not of child bearing potential if they are surgically 
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are naturally postmenopausal for at least 12 consecutive 
months. 
 Females must not be breastfeeding.   
 Must be willing to provide correlative blood samples.  
 No ≥ grade 2 peripheral neuropathy. 
 No cytotoxic chemotherapy within 30 days prior to registration for protocol therapy.  
NOTE: This interval may be reduced to 14 days for thalidomide, lenalidomide, 
bortezomib, or corticosteroids, provided other entry criteria are met. 
 No autologous stem cell transplant within 6 months prior to registration for protocol 
therapy 
 No prior radiation therapy to > 25% of bone marrow forming bones (i.e., pelvis) 
within 30 days prior to registration for protocol therapy.  See Study Procedures 
Manual to calculate percent of prior radiation. 
 No current corticosteroid therapy in doses greater than 10 mg daily of prednisone (or 
equivalent) if given for management of co-morbid conditions. 
 No known central nervous system involvement by myeloma. 
 No poorly controlled intercurrent illness including, but not limited to, ongoing or 
active infection, poorly controlled diabetes, symptomatic congestive heart failure, 
cardiac arrhythmia, or psychiatric illness/social climate that in the opinion of the 
investigator would limit compliance with study requirements. 
 No unstable angina pectoris or recent myocardial infarction (within 6 months). 
 No patients known to be positive for HIV, or active Hepatitis A, B, or C. 
 No major surgery within 30 days prior to registration for protocol therapy.  
Placement of a venous access device within 30 days prior to registration for protocol 
therapy is allowed. 
NOTE:  Organ and marrow function must be assessed within 21 days prior to 
registration for protocol therapy.   


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 Absolute neutrophil count (ANC) ≥ 1.2 x K/mm3 (without G-CSF support in the 
previous 14 days)  
 Platelets ≥ 75 x K/mm3 (without platelet transfusion in the previous 14 days) 
 LVEF >45% corrected by MUGA scan or echocardiogram.   
 Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
 AST ≤ 2.5 x ULN 
 ALT ≤ 2.5 x ULN 
 
Serum creatinine < 3.0 mg/dL  
EVALUATION 
CRITERIA 
Responses will be based on a modified International Myeloma Working Group 
criteria18, and defined as outlined below:  
 
Response* 
Definition 
Complete Response (CR) 
Negative for monoclonal protein by immunofixation 
on the serum and urine, and 
Disappearance of any soft tissue plasmacytomas, and 
<5% plasma cells in bone marrow 
Stringent complete response 
(sCR) 
CR as defined above, plus  
Normal free light chain ratio, and 
Absence of clonal cells in bone marrow by flow-
cytometry 
Near complete response 
(nCR) 
Meeting criteria for CR, except with persistence of 
original monoclonal protein by IF while absence by 
serum or urine protein electrophoresis. 
Very good partial response 
(VGPR) 
90% or more reduction in serum M-protein plus  
urine M-component <100 mg/24 hours 
Partial response (PR) 
50% or more reduction in serum M-protein and 
90% or more reduction in urine M-protein or to <200 
mg/24hours 
 
If serum and urine M-protein are immeasurable, a 
50% or more reduction in free light chain level is 
required in place of M-protein criteria. 
 
In addition to the above criteria, if present at baseline, 
a 50% or more reduction in the size of soft tissue 
plasmacytomas is required. 
 
For patients with free light chains as their only 
measurable disease, a 50% or greater decrease in the 
difference between involved and uninvolved free light 
chain levels. 
Minimal response (MR) 
25-49% reduction in serum M-protein, and 
 
If present, a 50-89% reduction in 24 hour light chain 
excretion, which exceeds 200 mg/24 hours, and 
 
No increase in the size or number of lytic bone lesions 


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(development of compression fracture does not 
exclude response) 
Stable disease (SD) 
Not meeting criteria for CR, VGPR, MR, PR or 
progression of disease. 
Progressive disease (PD) 
Any one of the following criteria: 
- 
Increase of 25% or more in serum or urine M-
protein from baseline. 
- 
Serum M-protein and/or the absolute increase 
must be ≥0.5 g/dL 
- 
Urine M-protein and/or absolute increase must be 
≥200 mg/24 hours 
- 
Development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of 
existing bone lesions or soft tissue plasmacytomas 
- 
Development of hypercalcemia (corrected serum 
Ca++ >11.5 mg/dL) that can be attributed solely to 
the plasma cell proliferative disease. 
 
In patients who have achieved CR or sCR: 
- 
Reappearance of serum or urine M-protein by IF 
or electrophoresis. 
- 
Development of 5% or more clonal plasma cells in 
the bone marrow 
- 
Appearance of any other sign of progression (i.e., 
new plasmacytoma, lytic bone lesions, or 
hypercalcemia). 
* All response categories require two consecutive assessments made any time before 
the institution of any new therapy.  Repeat of radiographic studies and bone marrow 
evaluation are not required to satisfy these responses. 
STATISTICAL 
CONSIDERATIONS 
Although bendamustine has been combined with mitoxantrone, etoposide, and 
Idarubicin with acceptable toxicity, there is currently no data of its appropriate dosing in 
combination with pegylated liposomal doxorubicin and bortezomib. Therefore, we will 
investigate the combination in two phases: 
 
Phase I component 
The primary objective in the phase I component is to determine the MTD of 
bendamustine in combination with bortezomib and pegylated liposomal doxorubicin 
(with growth factor support) to gain a better idea of safe dosing before proceeding with 
the second phase to assess efficacy.  
 
A standard 3 + 3 design will be used to determine the MTD.  Three patients will be 
enrolled at dose level 1. If no patient experiences dose limiting toxicities (DLTs), 
escalation to the next dose level will occur.  If 1 of 3 patients at any dose level 
experiences a DLT, 3 additional patients will be enrolled at that dose level. If only 1 of 6 
patients experiences a DLT, dose escalation will be permitted. If 2 or more patients at 
any dose level experienced a DLT, then the previous dose with at most 1 out of 6 DLT 
will be considered the maximum tolerated dose (MTD).  If myelosuppression is dose 
limiting, we will add an additional dose level at the MTD with growth factor (G-CSF; 


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filgrastim) support (dose level +3). Dose escalation will not occur beyond level 3. 
Therefore, we will need at most 18 patients in phase I. 
 
Phase II component 
The primary objective in the Phase II component is to determine the overall response 
(CR+PR) at the MTD of bendamustine in combination with bortezomib and pegylated 
liposomal doxorubicin.  Note that here CR includes all categories of sCR, CR, nCR and 
PR includes all categories of VGPR and PR defined in Section 8.1.  A min/max optimal 
two-stage design will be followed.  Patients will be considered evaluable for response if 
they have received at least 2 cycles of therapy or if they have had disease progression 
before 2 cycles are completed.  If a patient does not finish at least 2 cycles (except for 
disease progression), we will recruit a new patient to replace him/her. An overall 
response rate of 60% or more will be acceptable, while an overall response rate of less 
than 40% will be considered unacceptable.  In statistical terms, we will test the null 
hypothesis H0: p0<0.4 versus the alternative hypothesis H1: p1 >0.6, where p is the 
probability of overall response.  Type I and type II errors will be both set at 0.1. In the 
first stage, we will enroll 28 evaluable patients. If less than 12 patients respond, the trial 
will be stopped and we will conclude in favor of the null hypothesis.  If 12 or more 
patients respond, we will proceed with the second stage by enrolling an additional 13 
evaluable patients for a maximum sample size of 41 evaluable patients.  If more than 20 
patients achieve at least a partial response, we will conclude in favor of H1: p1> 0.6.  
The probability of early termination under the null hypothesis is 0.55. We expect only 
80% of enrolled patients to be evaluable. Therefore, overall, we will have to enroll 51 
patients if the stage 2 is conducted to achieve 41 evaluable samples.  
Analysis 
 Phase I Component 
Patients’ characteristics will be summarized using mean, median, and standard 
deviation for continuous variables, and tables for discrete variables. Toxicity 
profile (for all patients) will be presented by rate of overall toxicity and rates of 
grade 3 or 4 toxicities analyzed separately and combined.  Adverse events will be 
summarized in phase I and accompanied by 95% confidence intervals using 
binomial distribution.  Response rates will be summarized.  
 
 Phase II Component 
Descriptive analysis of patients’ characteristics will be summarized in a similar 
way as Phase I. 
 
Primary analysis 
The primary objective in phase II is to assess the overall response rate (CR+PR) 
of treatment at the MTD level found in phase I. Overall response rate will be 
evaluated and accompanied by 95% confidence intervals using the binomial 
distribution. Response rate by categories will be calculated with 95% confidence 
intervals. 
 
Secondary analysis 
Toxicity profile (for all phase II patients) will be presented by rate of overall 
toxicity and rates of grade 3 or 4 toxicities analyzed separately and combined. 
The toxicity analysis may also be performed for the patients with and without 


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autologous stem cell transplantation separately due to the potential higher 
hematological toxicity in transplanted patients. Time to progression will analyzed 
using Kaplan-Meier survival analysis and accompanied with 95% confidence 
interval. Similar analysis will be applied to the progression-free survival, 
duration of response, and overall survival. Median survival time will be 
calculated with 95% confidence interval for each of the time-to-event outcome. 
 
Correlative analysis 
The bendamustine pharmacokinetics parameters (Cmax, t1/2, and AUC) at cycle 1 
(and cycle 2) will be correlated with response by comparing their means between 
the responders (CR +PR) and those respond (non-responders) otherwise using 
two-sample t tests. Appropriate transformation of the pharmacokinetics 
parameters will be done to fit the normal distribution assumption. Similar 
analysis will be used to correlate them with toxicity (grade 3-4).  
The DNA damage/repair at day 1 of cycle 1 and day 4 of cycle 2 will be 
compared using a paired t test. AUC for the extent of DNA damage will be 
correlated with response by comparing their means between responders and non-
responders. AUC will be correlated with response duration using a proportional 
hazards model, and plasma AUC using Pearson’s correlation coefficient. 
  
Modifications in the August 2014 amendment  
The amendment introduces a lower dose level of bendamustine, which if passing 
the study will be the recommended dose level for future studies. This low dose 
will be used for the remaining first stage, and second stage. The same rule will be 
used for the first stage. For the second stage, the response rate at the low dose 
will be evaluated first. If this rate is no less than the response rate of the high 
dose by 10% and no less than 50%, the two dose levels will be combined in 
analyses following the original rule, i.e. if more than 20 patients achieve at least 
a partial response, we will conclude in favor of H1: p1> 0.6.  Otherwise, the 
response rate will be evaluated and its 95% confidence intervals will be 
calculated separately for the two dose levels. It is argued from the scientific point 
of view that the low dose will have at least the same or even higher response rate 
as the high dose. Consequently, the power level will be at least the same as the 
original designed. For the secondary and correlative analyses, they will be 
performed both separately for the two dose levels and in the combined manner. 
 


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A Phase I/II trial of Bendamustine in Combination with Bortezomib and Pegylated 
Liposomal Doxorubicin in Patients with Relapsed or Refractory Multiple Myeloma: Hoosier 
Cancer Research Network MM08-141 
 
 
INDEX  
 
SECTION                                                                                                                 
PAGE 
 
 
 
SCHEMA ........................................................................................................................................ 10 
1.0 
BACKGROUND & RATIONALE .................................................................................... 12 
2.0 
OBJECTIVES ..................................................................................................................... 16 
3.0 
ELIGIBILITY CRITERIA ................................................................................................ 16 
4.0 
PATIENT REGISTRATION ............................................................................................. 18 
5.0 
TREATMENT PLAN ......................................................................................................... 19 
6.0 
DOSE MODIFICATIONS ................................................................................................. 24 
7.0 
STUDY CALENDAR & EVALUATIONS ......................... ……………………………..29 
8.0 
CRITERIA FOR DISEASE EVALUATION ................................................................... 33 
9.0 
BIOLOGICAL CORRELATIVES ................................................................................... 35 
10.0 CTM INFORMATION & ADVERSE EVENTS MANAGEMENT .............................. 36 
11.0 REPORTING ADVERSE EVENTS & SERIOUS ADVERSE EVENTS ..................... 46 
12.0 STATISTICAL CONSIDERATIONS .............................................................................. 49 
13.0 TRIAL MANAGEMENT ................................................................................................... 51 
14.0 REFERENCES .................................................................................................................... 55 
 
 
 
 
 
 


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SCHEMA 
 
A Phase I/II trial of Bendamustine in Combination with Bortezomib and Pegylated 
Liposomal Doxorubicin in Patients with Relapsed or Refractory Multiple Myeloma: Hoosier 
Cancer Research Network MM08-141 
 
 
Phase I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol therapy may continue for up to 8 cycles in the absence of disease progression or 
unacceptable toxicity. 
 
 
Treatment:  
Cycle = 28 days 
 Bortezomib (D 1, 4, 8, 11) 
 pegylated liposomal doxorubicin (D 4) 
 Bendamustine, dose escalation (D1, 4) 
MTD 
Registration 
Evaluation of Eligibility Criteria 
Phase II 


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Phase II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol therapy may continue for up to 8 cycles in the absence of disease progression or 
unacceptable toxicity.  
Treatment:  
Cycle = 28 days 
 Bortezomib (D 1, 4, 8, 11) 
 Pegylated liposomal 
doxorubicin(D 4) 
 Bendamustine at MTD (D1, 4) 
<12 responses 
≥ 12 responses 
Stop study 
Continue the study 
Enroll 28 evaluable patients 
Registration 
Evaluation of Eligibility Criteria 


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1.0 
BACKGROUND & RATIONALE 
 
Multiple myeloma is a clonal disorder affecting terminally differentiated B-cells, with 
accumulation of plasma cells in the bone marrow. The annual incidence of MM is 
approximately 4 per 100,000, and is particularly common in the elderly population with a 
median age of 65 years; only 3% of patients with MM are < 40 years old.   
 
Therapy for MM remains unsatisfactory and is essentially palliative.  Although cytotoxic 
chemotherapy prolongs the survival of symptomatic patients, the prognosis of treated 
patients with MM remains poor. While high-dose chemotherapy with stem cell support 
increases the proportion of complete responses, the effect on prolongation of overall 
survival remains relatively modest, and all patients invariably relapse1,2.  Intensifying 
treatment with tandem cycles of high-dose alkylating agents (with or without total body 
radiation) have improved outcome in some3,4, but not all studies5.  For patients who 
progress after primary chemotherapy therapy, including autologous stem cell 
transplantation, further chemotherapy is generally of limited benefit. Overall, the results 
of conventional cytotoxic chemotherapy in MM suggest that a plateau has been reached, 
indicating the need for novel therapies.  
 
Recently, the novel agents, thalidomide, lenalidomide, and bortezomib have been 
investigated with promising results6,7.  In recent trials, a further improvement in response 
rates and time to progression is observed when these agents are combined with 
corticosteroids and conventional cytotoxic agents8,9,10.  The novel regimen of bortezomib 
and pegylated liposomal doxorubicin (PLD) has recently been shown to result in a 
complete response (CR) rate of 36%, overall response of 73%, and a time to progression 
(TTP) of 9.3 months in patients with relapsed and refractory MM11. Furthermore, the 
regimen was shown to be superior to bortezomib alone in a phase III trial12, supporting 
the preclinical studies indicating synergism between bortezomib and DNA damaging 
agents13.  In spite of the excellent outcomes reported, the majority of patients still relapse 
indicating a need to continue to develop novel regimens. The bortezomib and pegylated 
liposomal doxorubicin regimen represents a good platform on which to combine other 
active and non-cross-reactive agents.    
 
1.1 
Bendamustine 
 
Bendamustine is a DNA alkylating agent with a unique mechanism of action, including 
the ability to cause cross-linking between DNA and proteins and proteins alone. With 
short exposure, bendamustine also induces the onset of apoptosis as well as ATP 
depletion, and these effects are sustained. Experiments have demonstrated that 
bendamustine has only partial cross resistance with other alkylating agents and has in 
vitro activity in cells that are resistant to a variety of anti-tumor agents. In preclinical 
studies, bendamustine toxicity was predominantly bone marrow suppression, 
gastrointestinal toxicity, fever, dermal hypersensitivity reactions, glomerulitis, prostatic 
atrophy, and alopecia.  
 
Bendamustine has been shown to be clinically efficacious in non-Hodgkin’s lymphoma, 
CLL, breast cancer, and MM.  In a phase III trial comparing bendamustine (150 mg/m2 
on days 1 and 2) plus prednisone (BP) and melphalan (15 mg) plus prednisone (MP) in 


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patients with MM, BP resulted in significantly more patients achieving complete 
remission (CR) (32% vs. 11%, P=0.009), and longer remission duration (18 months vs. 
12 months, P=0.017)14. Bendamustine has been investigated in combination with a 
number of classic cytotoxic agents, including etoposide, Idarubicin, and mitoxantrone in 
a variety of lymphoid disorders with acceptable toxicity and tolerability. 
 
However, one published study using lymphoma cell lines has suggested that the 
combination of bendamustine with doxorubicin (or mitoxantrone) is antagonistic in 
vitro15, discouraging the investigation of bendamustine/ doxorubicin combination 
therapy in MM.  To establish whether similar antagonism occurs in MM cells and study 
the effect of addition of bendamustine (B) to doxorubicin (D) and bortezomib (V), we 
(Farag Laboratory, Indiana University School of Medicine) evaluated cellular 
cytotoxicity using the different drug combinations in H929 and MM1R myeloma cell 
lines using the MTS ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-
sulfophenyl)-2H-tetrazolium, inner salt) assay. The effect of the combination in terms of 
additive, antagonistic, or synergistic activity was assessed by Valeriote and Lin’s 
method16. In repeated experiments, bendamustine alone induced MM cell death in a time 
and dose-dependent manner, with a bendamustine concentration that was lethal to 50% 
of cells (LC50) of 34.9± 3.4 µg/ml after 48 hours of drug exposure. Further, when 
combined with doxorubicin, bendamustine showed no antagonistic effect. Indeed, the 
measured cell survival for the combination of B+D was similar to the calculated 
expected cell survival based on individual drug activity, indicating an additive effect 
(Figure 1). In addition, bendamustine showed an additive effect when combined with 
bortezomib, and as previously shown doxorubicin and bortezomib (D+V) were 
synergistic (Figure 1). To test the effect of the combination of all three drugs, cells were 
cultured with bendamustine (15 μg/ml) and doxorubicin (0.03 μg/ml) for 48 hours, and 
bortezomib (2.5 nmol/l) was added in the last 24 hours, and cytotoxicity was assayed. 
The expected cell survival for the combination of B+(D+V) is lower than the product of 
the effects of B and D+V, indicating a synergistic effect of bendamustine when 
combined added to the combination of doxorubicin and bortezomib (Figure 1). These 
results provide pre-clinical rationale for clinically testing the efficacy of combining 
bendamustine with the established combination of pegylated liposomal doxorubicin and 
bortezomib, which may be a highly effective regimen in the treatment for MM.   


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Figure 1. Representative experiment showing synergistic cytotoxic activity of bendamustine when 
combined with doxorubicin and bortezomib in H929 cells. B, 15μg/ml bendamustine; D, 0.03μg/ml 
doxorubicin; V, 2.5nmol/L bortezomib; B+D, 15μg/ml bendamustine and 0.03μg/ml doxorubicin; B+V, 
15μg/ml bendamustine and 2.5nmol/L bortezomib; D+V, 0.03μg/ml doxorubicin and 2.5nmol/L 
bortezomib; B+D+V, the combination of 15μg/ml bendamustine with 0.03μg/ml doxorubicin and 
2.5nmol/L bortezomib. Synergy of the drug combination was defined when the measured cell survival was 
lower than the product of the effect of each single drug. 
 
In humans, bendamustine follows first order pharmacokinetics over a wide range of 
doses (120 to 280 mg/m2)14. Following a 30-minute IV infusion, Cmax is achieved in 30-
35 minutes; elimination from plasma occurs in a biphasic fashion with a distribution half 
life of approximately 10 minutes and an elimination half-life of about 30-36 minutes14.  
About 20% of bendamustine is excreted in the urine, mainly as bendamustine HCl, γ-
hydroxy bendamustine, the relatively inactive mono- and di-2-chloroethyl amine 
bendamustine derivatives, and as yet to be identified polar metabolites14. A small amount 
(8.7%) of bendamustine HCl is excreted via bile. Importantly, in patients with hepatic 
tumor involvement or with renal dysfunction (including those requiring dialysis) the 
clearance of bendamustine is not significantly different than clearance in subjects with 
none of these findings14. Therefore, bendamustine is quite suitable for use in MM 
patients where renal insufficiency is not uncommon due to disease progression.  
 
In phase I clinical trials in human, the maximum tolerated dose (MTD) of a single 
intravenous infusion of bendamustine was established as 215 mg/m2, with non-
hematological dose-limiting toxicity (DLT) being predominantly anti-cholinergic effects, 
including dry mouth, cardiac tachyarrhythmia, somnolence and constipation17.  None of 
these DLTs overlap with those of those of bortezomib and pegylated liposomal 
doxorubicin.  
 
As bendamustine appears to be non-cross resistant to other alkylating agents, has potent 
anti-myeloma activity, and has DLT that is not overlapping with bortezomib and 


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pegylated liposomal doxorubicin, we postulate that the combination of bendamustine 
into the bortezomib and pegylated liposomal doxorubicin regimen may be an effective, 
well-tolerated preparative regimen for MM patients. While an increase in 
myelosuppression is a possibility, this may be mitigated successfully with myeloid 
growth factors. 
 
1.2 
Rationale for study 
 As reviewed above, the combination of bortezomib and pegylated liposomal 
doxorubicin has been shown to have synergistic activity against myeloma cells, and has 
also been shown to be a clinically effective regimen in MM patients compared to 
bortezomib alone in a randomized phase III trial.  We have also shown that the addition 
of bendamustine to the combination of bortezomib and doxorubicin shows further 
synergy against MM cell lines in pre-clinical studies, providing pre-clinical rationale to 
test the three drug combination clinically.   
 
Although bendamustine has been combined with mitoxantrone, etoposide, and idarubicin 
with acceptable toxicity, there is currently no data of its appropriate dosing in 
combination with pegylated liposomal doxorubicin and bortezomib. Therefore, we will 
investigate the combination in two phases: 
 
(1) 
In the first phase, we will perform a limited phase I study to determine the MTD of 
bendamustine in combination with bortezomib and pegylated liposomal 
doxorubicin to gain a better idea of safe dosing before proceeding with the second 
phase to assess efficacy.  As myelosuppression may be a dose-limiting effect that 
could be overcome with growth factor support, we will also test the MTD of the 
combination with myeloid growth factor support. 
 
(2) 
At the MTD, we will expand to a phase II trial to assess efficacy of the combination 
in terms of overall response rate (complete and partial responses). 
 
1.3 
Rational for MTD reduction in Phase II 
 
In the course of the phase II portion of the study, an excess of cumulative myelotoxicity 
was observed that occurred beyond the first cycle. Of 22 patients treated, 8 patients came 
off study because of prolonged grade 3-4 myelotoxicity (neutropenia and/or 
thrombocytopenia), which occurred beyond the third cycle of treatment.  As patients 
came off study, the planned course of treatment was not delivered which could have 
compromised the potential maximal response.  As this was not observed in the first 
cycle, it was not evident in the phase I component of the trial when the MTD was 
determined. Based on this observation, the study is amended to dose reduce 
bendamustine and allow longer period for recovery of counts before patients came off 
study provided clinical benefit is observed (see Sections 5.2 and 6.2). 
 


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2.0 
OBJECTIVES 
 
2.1 
Primary Objectives: 
 
2.1.1 
Determine the maximum tolerated dose of bendamustine in association with bortezomib 
and pegylated liposomal doxorubicin in patients with relapsed or refractory MM. 
 
2.1.2 
Assess the overall response rate (CROP) of bendamustine in association with bortezomib 
and pegylated liposomal doxorubicin in patients with relapsed or refractory MM.   
 
2.2 
Secondary Objectives: 
 
2.2.1 
Describe the toxicity of the combination of bendamustine with bortezomib and pegylated 
liposomal doxorubicin. 
 
2.2.2 
Evaluate the time to progression, overall survival, progression free survival, and duration 
of response of MM patients treated with bendamustine, bortezomib and pegylated 
liposomal doxorubicin. 
 
2.2.3 
Correlate bendamustine pharmacokinetics parameters (Cmax, t1/2, and AUC) at cycle 1 
(and cycle 2) with patients’ responses and correlate the DNA damage/repair at day 1 of 
cycle 1 and day 4 of cycle 2 with patients’ responses. 
 
 
3.0 
ELIGIBILITY CRITERIA 
 
3.1 
Written informed consent, HIPAA authorization for release of personal health 
information, ability to understand the requirements of the study, abide by the study 
restrictions and agree to return for the required assessments. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained 
separately. 
 
3.2 
Age > 18 years at the time of consent. 
 
3.3 
ECOG Performance Status of 0-2 within 21 days prior to registration for protocol 
therapy. 
 
3.4 
A histologically established diagnosis of multiple myeloma with evidence of relapse or 
refractory disease. 
 
NOTE: Relapsed myeloma is defined in patients as at least a 25% increasing 
monoclonal (M)-protein in serum or urine or in the size of a plasmacytoma compared to 
a best response reached after a previous therapy. 
NOTE: Refractory myeloma is defined as failure to achieve at least a minor response 
(patient achieved stable disease as his/her best response) or progression of disease on 
current therapy or within 60 days of last dose of current therapy.   
 


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3.5 
Must have a detectable serum or urine M-Protein by protein electrophoresis that is at 
least 500 mg/dL (serum) or 1 gm/24 hours (urine), respectively. For patients without 
measurable disease by serum or urine protein electrophoresis as defined above, patients 
who have detectable serum free light chain >100 mg/l will be eligible.  
NOTE: Patients with non-secretory myeloma or plasmacytoma only will be excluded. 
 
3.6 
Must have received at least one (1) prior line of systemic treatment that has included 
either lenalidomide or thalidomide.  
NOTE: Patients may have undergone prior autologous stem cell transplantation (stem 
cell transplant with high dose induction chemotherapy with/without planned maintenance 
therapy will be considered one line of therapy).  Patients who have received prior 
bortezomib, pegylated liposomal doxorubicin, or the combination are eligible.  Patients 
who have received prior bendamustine for the treatment of MM are also eligible if this 
was not combined with bortezomib or pegylated liposomal doxorubicin. 
 
3.7 
Must not have received an excessive cumulative dose of anthracycline.  
NOTE: Permissible prior exposure is doxorubicin  240 mg/m2 (or anthracycline 
equivalent calculated as 1 mg doxorubicin = 1 mg Doxil = 1.8 mg epirubicin = 0.25 
idarubicin = 0.3 mg mitoxantrone) 
 
3.8 
Females of childbearing potential and males must be willing to use an effective method 
of contraception (hormonal or barrier method of birth control; abstinence) from the time 
consent is signed until 30 days after treatment discontinuation.  
 
3.9 
Females of childbearing potential must have a negative pregnancy test within 7 days 
prior to registration for protocol therapy.    
NOTE:  Females are considered not of child bearing potential if they are surgically 
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. 
 
3.10 
Females must not be breastfeeding.   
 
3.11 
Must be willing to provide correlative blood samples.  
 
3.12 
No ≥ grade 2 peripheral neuropathy. 
 
3.13 
No cytotoxic chemotherapy within 30 days prior to registration for protocol therapy. 
NOTE: This interval may be reduced to 14 days for thalidomide, lenalidomide, 
bortezomib, or corticosteroids, provided other entry criteria are met. 
 
3.14 
No autologous stem cell transplant within 6 months prior to registration for protocol 
therapy.  
 
3.15 
No prior radiation therapy to ≥ 25% of bone marrow forming bones (i.e., pelvis) within 
30 days prior to registration for protocol therapy.  See Study Procedures Manual to 
calculate percent of prior radiation. 
 


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3.16 
No current corticosteroid therapy in doses greater than 10 mg daily of prednisone (or 
equivalent) if given for management of co-morbid conditions. 
 
3.17 
No known central nervous system involvement by myeloma. 
 
3.18 
No poorly controlled intercurrent illness including, but not limited to, ongoing or active 
infection, poorly controlled diabetes, symptomatic congestive heart failure, cardiac 
arrhythmia, or psychiatric illness/social climate that in the opinion of the investigator 
would limit compliance with study requirements. 
 
3.19 
No unstable angina pectoris or recent myocardial infarction (within 6 months). 
 
3.20 
No patients known to be positive for HIV, or active Hepatitis A, B, or C. 
 
3.21 
No major surgery within 30 days prior to registration for protocol therapy.  Placement of 
a venous access device within 30 days prior to registration for protocol therapy is 
allowed. 
 
 
NOTE:  Organ and marrow function must be assessed within 21 days prior to registration for 
protocol therapy.   
3.22 
Absolute neutrophil count (ANC) ≥ 1.2 x K/mm3 (without G-CSF support in the previous 
21 days)  
 
3.23 
Platelets ≥ 75 x K/mm3 (without platelet transfusion in the previous 21 days) 
 
3.24 
LVEF >45% corrected by MUGA scan or echocardiogram.   
 
3.25 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
 
3.26 
AST ≤ 2.5 x ULN 
 
3.27 
ALT ≤ 2.5 x ULN 
 
3.28 
Serum creatinine < 3.0 mg/dL  
 
 
4.0 
PATIENT REGISTRATION  
 
4.1  
All patients must be registered through the Hoosier Cancer Research Network’s database 
system.   
 
 
Patients must be registered prior to starting protocol therapy and begin therapy within 5 
working days of registration.   
 
4.2 
Blinding 
 
 


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The study treatment is not blinded to the patient or the investigator 
 
 
5.0 
TREATMENT PLAN 
 
The protocol and treatment plan will be conducted in two components: 
1) A dose-escalation, phase I study to determine the MTD of bendamustine in 
combination with bortezomib and pegylated liposomal doxorubicin.  
2) 
A phase II study at the MTD of bendamustine to assess efficacy of the combination 
in terms of overall response rate. 
 
5.1 
Phase I component   
The primary objective is to determine the MTD of bendamustine when combined with 
bortezomib and pegylated liposomal doxorubicin. All patients will receive the same 
doses of bortezomib and pegylated liposomal doxorubicin. The dose of bendamustine 
will be escalated in successive cohorts of patients.  Using a standard dose escalation 
design, successive cohorts of 3 patients will be treated with escalating doses of 
bendamustine as outlined in Section 5.1.1 (see also dose-escalation rules Section 5.1.3).  
At the MTD (or highest dose-level if the MTD is not reached), patients will then be 
treated on the Phase II component of the study. 
 
5.1.1 
Treatment schedule 
After informed consent and collection of baseline tests and samples, patients will receive 
study drugs according to the following schedule.  The order of administration will be left 
to the investigator’s discretion.  Each cycle will be 28 days.  Patients will continue 
treatment for a total of 8 cycles.   
 
Table 1: Phase I Treatment Administration 
REGIMEN DESCRIPTION 
Agent 
Dose 
Route 
Schedule 
Cycle 
length 
Bortezomib  
1.3 mg/m2 
IV bolus 
Days 1, 4, 8, and 11 
28 days 
Pegylated liposomal 
doxorubicin  
30 mg/m2 
IV over 1 
hour 
Day 4 
Bendamustine* 
escalating 
cohorts 
IV over 1 
hour 
Days 1 and 4 
* NOTE: The dose of bendamustine will be escalated in phase I of the protocol in 
successive cohorts according to the following dose levels: 
 
Table 2: Phase I Dose levels 


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Cohort 
n 
Bendamustine 
(mg/m2) 
Bortezomib 
(mg/m2) 
Pegylated 
liposomal 
doxorubicin 
(mg/m2) 
Filgrastim 
1 
3-6 
60 
1.3 
30 
- 
+1 (start) 
3-6 
90 
1.3 
30 
- 
+2 
3-6 
120 
1.3 
30 
- 
+3 
3-6 
120 (or MTD) 
1.3 
30 
5 µg/kg 
 
 
Patients will initially be enrolled on dose level +1 (i.e., bendamustine 90 mg/m2).  
 
At any dose level, three (3) patients will be treated. If no dose-limiting toxicity [DLT] is 
observed (see Section 5.1.2 for definition), the next cohort of three (3) patients is treated 
at the next higher dose level. If 1 of the 3 patients demonstrates DLT in a given dose 
level, an additional 3 patients are treated at that dose level. If only 1 of the 6 shows DLT, 
the next cohort of three patients is entered at the next dose level. If 2 or more of the 6 
demonstrate DLT at the first dose level, we will deescalate to dose level 1. At 
subsequent dose levels, the MTD is defined as the previous dose level where no more 
than 1 of 6 patients experiences DLT.  
 
5.1.1.1 Dose Level +3: 
If only myelosuppression is dose limiting at any given dose level, we will add an 
additional dose level at the MTD with growth factor (G-CSF; filgrastim) support (dose 
level +3).   
 
Filgrastim will be administered as 5 µg/kg/day SC starting day 6 until neutrophil 
recovery to ANC ≥1000.   
 
Dose escalation will occur only when all patients in the given cohort have completed 
the first cycle.  The MTD will be based on DLT in the first cycle. Patients can 
continue with repeated cycles at the same dose level of the drugs until progression 
up to a maximum of 8 cycles.  Dose modification in subsequent cycles will be 
performed according to toxicity. 
 
5.1.2 
Dose-Limiting Toxicity (DLT) in Phase I Component of Trial 
The National Cancer Institute Common Terminology Criteria for Adverse events 
(CTCAE) version 3.0 (http://ctep.cancer.gov) will used to characterize toxicities. 
 
DLT is defined as adverse events (AE) related to study treatment occurring in the first 
cycle of treatment with an attribution of possible, probably, or definite and fulfilling one 
of the following criteria: 
 
Grade 4 neutropenia and thrombocytopenia that persists for greater than 7 days, and 
which is not due to underlying disease. 
 
Grade 4 fatigue or a two-point decline in ECOG performance status. 


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 
Any grade 3 or 4 non-hematologic/organ toxicity (except rash, alopecia, nausea and 
vomiting controllable with anti-emetic therapy, and correctable biochemical 
abnormalities). 
 
Treatment delays exceeding 14 days due to toxicity during the first cycle of 
treatment will constitute DLT. 
 
5.1.3  
Maximum Tolerated Dose (MTD) and Dose Escalation Rules in Phase I Component 
To define the Maximum Tolerable Dose (MTD), patients will be evaluated for DLT in 
the first cycle of treatment. The MTD is the dose level at which less than 2 out of 6 
patients experience DLT. The MTD becomes the recommended dose for the phase II 
component of the study. 
 
Patients will initially be enrolled onto dose level +1 (see Section 5.1.1).  Three to six 
patients will be enrolled at each dose level.  All patients assigned to a dose level must be 
followed at least until day 28 before dose escalation to the next cohort level can begin. 
The following rules will be followed: 
Table 3: Dose Escalation Rules 
Number of 
patients with 
DLT at given 
dose level 
Escalation decision 
0 out of 3 
Enter 3 patients at the next dose level 
≥ 2 out of 3 
Dose escalation will be stopped.  This dose level will be declared the 
maximum administered dose.  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were treated 
previously at that next lowest dose level. 
1 out of 3 
Enter at least 3 more patients at this dose level 
 
If 0 of these additional 3 patients experience DLT, proceed to next 
dose level. 
 
If 1 or more of these additional 3 patients experience DLT, then dose 
escalation is stopped, and this dose is declared the maximum 
administered dose.  Three (3) additional patients will be entered at the 
next lowest dose level if only 3 patients were treated previously at 
that dose.    
≤ 1 out of 6 at 
highest dose level 
below the 
maximum 
administered 
dose 
This will be defined as the MTD.  This dose level will be expanded to 
enrolment as the Phase II component of the study. 
 
5.1.4  
Second Cycle and Subsequent Cycles 
Patients may continue receiving treatment in the absence of disease progression or 
unacceptable toxicity for a total of 8 cycles.  Filgrastim may be used at the investigator’s 
discretion.  Dose modifications will be made according to section 6.0. 
 
5.2 
Phase II component 
NOTE: Based on the participant rate of myelosuppression observed in the first 20 
number of participants in the Phase II part of this study, the MTD established during the 


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Phase I is reduced from 120mg/ m2 to 90mg/ m2. Please refer to Section 1.3 Rational for 
MTD reduction in Phase II. 
 
The phase II component will determine the response rate to the combination. Patients 
will receive study drugs according to the following schedule: 
 
Table 4: Phase II Treatment Administration 
REGIMEN DESCRIPTION 
Agent 
Dose 
Route 
Schedule 
Cycle 
length 
Bortezomib  
1.3 mg/m2 
IV bolus 
 
or 
 
SQ 
injection* 
Days 1, 4, 8, and 
11 
28 days 
Pegylated liposomal 
doxorubicin  
30 mg/m2 
IV over 1 
hour 
Day 4 
Bendamustine  
90mg/ m2 
IV over 1 
hour 
Days 1 and 4 
         *Reconstitution volumes for IV and SQ injection should be: 
    
 INTRAVENOUS: 
 
Route of 
Administration  
Bortezomib (mg/vial) 
Diluent (0.9% 
sodium chloride) 
Final 
Concentration 
Intravenous 
3.5mg 
3.5mL 
1.0mg/ml 
 
   
SUBCUTANEOUS: 
 
Route of 
Administration  
Bortezomib (mg/vial) 
Diluent (0.9% 
sodium chloride) 
Final 
Concentration 


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Subcutaneous 
3.5mg 
1.4 mL 
2.5mg/ml 
 
INTRAVENOUS AND SUBCUTANEOUS ROUTE OF ADMINISTRATION HAVE 
DIFFERENT RECONSTITUTED CONCENTRATIONS. CAUTION SHOULD BE USED 
WHEN CALCULATING THE VOLUME TO BE ADMINISTERED. 
Each cycle will be 28 days.  Patients will continue treatment for up to 8 cycles.  
 
NOTE: 
 
In the absence of excessive toxicity, patients will receive a minimum of 2 cycles of 
therapy before being evaluated for response/progression.  Patients whose disease 
has progressed (>25% increase in serum or urine M protein) will be taken off 
therapy and failure of therapy declared. Patients whose disease has not progressed 
will be eligible to continue therapy. 
 
Patients will continue treatment until disease-progression, development of 
unacceptable toxicity, or for up to 8 cycles.   
 
Dose modifications will be made according to the guidelines in Sections 6.1 and 
6.2 
 
Patients will be evaluated for toxicity after each cycle. 
 
Patients will be evaluated for response/disease progression every 2 cycles (i.e., 
every 6 weeks) or earlier if clinically indicated.   
 
5.3 
Duration of Therapy in Phase II component 
Patients will remain on study for up to 8 cycles as long as there is no grade 3 or 4 non-
hematological toxicity (see below), and there is no progression of disease as assessed by 
evaluation after a minimum of 2 cycles. 
 
Patients will be removed from study if they are not able to comply with treatment, if the 
patient withdraws consent, or if the investigator or agencies involved in the study 
administration discontinue the study. 
 
5.4  
Supportive care 
 
5.4.1 
Prophylactic antiemetic therapy will be left to the discretion of the treating physician 
and/or institutional guidelines.   
 
5.4.2  
Bisphosphonates may be used at the discretion of the treating physician. 
 
5.4.3  
Erythropoietin preparations may be used for anemia at the discretion of the treating 
physician. 
 
5.4.4  
Palliative radiation therapy may be employed at the discretion of the treating physician 
for the treatment of intractable pain due to myeloma, pathological fracture, or 
compressive lesions caused by plasmacytomas.   
 


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5.4.5 
Other medications and supportive measures to maintain the patient’s baseline condition 
or to treat intercurrent conditions may be administered at the discretion of the 
investigator. 
 
5.4.6 
It is recommended that patients receive prophylaxis for herpes zoster infection (e.g., 
acyclovir, valacyclovir)  
 
5.4.7 
Premedication with antihistamines, antipyretics, and/or corticosteroids for patients with a 
previous grade 1 or 2 infusion reaction to bendamustine should be considered. 
 
NOTE:  Dosing on Days 1 & 4 may be critical for efficacy of the combination.  All 
efforts should be made to maintain the treatment schedule. However, Day 1 infusions 
may be given ±3 days for reasons such as observed holidays, inclement weather, 
scheduling conflicts, etc.  This should be clearly documented in patient’s chart and case 
report forms.  
 
5.4.8 
Filgrastim or pegfilgrastim is strongly encouraged and may be used at the discretion of 
the treating physician unless deemed necessary per section 6.2.1. 
 
 
6.0 
DOSE MODIFICATIONS  
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 will 
be used to grade adverse events. 
   
Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study as specified in 
section 7.0 
 
Patients will be evaluated for adverse events (all grades), serious adverse events, and 
adverse events requiring study drug interruption or discontinuation at each study visit for 
the duration of their participation in the study.   
 
Patients who complete 8 cycles of treatment or who discontinue for reasons other than 
disease progression (but haven’t started another treatment) will be evaluated at least 30 
days after the last dose of study drug. 
 
If patients require discontinuation of any drug due to adverse event (as described below) 
patients should be taken of study. 
 
6.1  
Phase I component 
 
6.1.1 
No dose modification of any of the drugs will be made during cycle 1 of treatment in the 
phase I component of the study. 
 
6.1.2 
In second and subsequent cycles, the guidelines outlined for dose adjustments for the 
phase II component of the protocol should be followed (Section 6.2) 
 


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6.2 
Phase II component 
 
Patients will be monitored for toxicity.  Appropriate adjustment of dose, delay or 
discontinuation of drugs will be made as outlined below for each drug: 
 
6.2.1 
Hematological Toxicity 
 A cycle of treatment should not start unless the absolute neutrophil count (ANC) is 
1.0 x K/mm3 and the platelet count is 75 x K/mm3 at least 28 days after the start 
of the previous cycle. If blood counts are below these levels, treatment should be 
delayed for 1 week.  After 1 week, the peripheral blood counts are reassessed and 
treatment again delayed for an additional week if the ANC is <1.2 x K/mm3 and the 
platelet count is <75 x K/mm3.  If counts have recovered, filgrastim or 
pegfilgrastim is strongly recommended and should then be used prophylactically in 
subsequent cycles if this has not been used in cycle 1 (i.e., level 3 dosing; see 
section 5.1.1).  
 
 If marrow recovery (ANC is 1.2 x K/mm3, platelet count is 75 x K/mm3) does 
not occur after a two-week delay, the patient should be taken off study treatment. 
However, if responding to treatment and treatment delayed > 2 weeks due to 
myelosuppression only, the patient may remain on study treatment with pegylated 
liposomal doxorubicin and bendamustine reduced by 33%. If > 4 week delay is 
required the patient should be taken off study treatment. 
 If grade 4 neutropenia and/or thrombocytopenia occurred in the previous cycle 
and/or treatment delayed > 1 week in spite of filgrastim or pegfilgrastim, the doses 
of pegylated liposomal doxorubicin and bendamustine should be reduced by 33% 
in subsequent cycles. 
  
 If grade 4 neutropenia (ANC <0.5x K/mm3) lasting 5 days or more, or 
neutropenic fever has occurred with a cycle of therapy even if delay in 
subsequent dosing has not occurred, filgrastim or pegfilgrastim should be used 
prophylactically with the next cycle of treatment (if it has not been used in cycle 
1; i.e., level 3 dosing; see section 5.1.1). 
 
6.2.2 
Dose reduction for pegylated liposomal doxorubicin (PLD) 
 
The dose of pegylated liposomal doxorubicin should be reduced by 33% for 
myelosuppression that occurs in spite of growth factor support (see Section 6.2.1) 
 
 
The dose of pegylated liposomal doxorubicin should be reduced by 50% if the total 
bilirubin is 1.2 to 3 mg/dL, and by 75% if the bilirubin is >3 mg/dL (in the 
absence of proven hemolysis).  Subsequently, the dose should be increased to the 
original dose if hepatic function improves (bilirubin <1.2 mg/dL).  If the patient 
does not improve after the initial dose reduction, there will be no further 
reductions.  
 
The dose will not be modified for renal impairment.   
 
 
For patients developing signs of significant cardiac toxicity (ECG voltage criteria; 
clinically significant arrhythmias) or cardiac failure, pegylated liposomal 


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doxorubicin should be discontinued.  Patients requiring discontinuation of 
pegylated liposomal doxorubicin will be removed from protocol. 
 
 
Palmar-plantar erythrodysesthesia (PPE) syndrome.  Treatment with pegylated 
liposomal doxorubicin is associated with higher risk of PPE.  The following 
grading of PPE and dose adjustment of pegylated liposomal doxorubicin will be 
used: 
 
   Table 5:  Dose Adjustments for Palmar-Plantar syndrome 
PALMAR - PLANTAR ERYTHRODYSESTHESIA SYNDROME 
Toxicity Grade 
Dose Adjustment 
1 
(mild erythema, swelling, or desquamation 
not interfering with daily activities) 
Redose unless patient has experienced 
previous Grade 3 or 4 toxicity.  If so, delay 
up to 2 weeks and decrease dose by 25%.  
Return to original dose interval. 
2 
(erythema, desquamation, or swelling 
interfering with, but not precluding normal 
physical activities; small blisters or 
ulcerations less than 2 cm in diameter.) 
Delay dosing up to 2 weeks or until 
resolved to Grade 0-1.  If after 2 weeks 
there is no resolution pegylated liposomal 
doxorubicin should be discontinued and 
patient removed from protocol. 
3 
(blistering, ulceration, or swelling interfering 
with walking or normal daily activities; 
cannot wear regular clothing) 
Delay dosing up to 2 weeks or until 
resolved to Grade 0-1.  Decrease dose by 
25% and return to original dose interval.  If 
after 2 weeks there is no resolution 
pegylated liposomal doxorubicin should 
be discontinued and patient removed from 
protocol. 
4 
(diffuse or local process causing infectious 
complications, or a bed ridden state or 
hospitalization) 
Delay dosing up to 2 weeks or until 
resolved to Grade 0-1.  Decrease dose by 
25% and return to original dose interval.  If 
after 2 weeks there is no resolution, 
pegylated liposomal doxorubicin should 
be discontinued and patient removed from 
protocol. 
 
 


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 
Stomatitis.  The dose of pegylated liposomal doxorubicin should be adjusted as 
follows for stomatitis: 
 
 
Table 6: Dose Adjustments for Stomatitis 
STOMATITIS 
Toxicity Grade 
Dose Adjustment 
1 
(painless ulcers, 
erythema, or mild 
soreness) 
Redose unless patient has experienced previous Grade 3 or 
4 toxicity.  If so, delay up to 2 weeks and decrease dose by 
25%.  Return to original dose interval. 
2 
(painful erythema, 
edema, or ulcers, but 
can eat) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  If 
after 2 weeks there is no resolution, pegylated liposomal 
doxorubicin should be discontinued and patient removed from 
protocol. 
3 
(painful erythema, 
edema, or ulcers, and 
cannot eat) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  
Decrease dose by 25% and return to original dose interval.  If 
after 2 weeks there is no resolution, pegylated liposomal 
doxorubicin should be discontinued and patient removed from 
protocol. 
4 
(requires parenteral or 
enteral support) 
 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  
Decrease dose by 25% and return to original dose interval.  If 
after 2 weeks there is no resolution, pegylated liposomal 
doxorubicin should be discontinued and patient removed from 
protocol. 
 
6.2.3 Bortezomib  
NOTE: Patients with prior thalidomide therapy and persistent peripheral neuropathy are 
at increased risk for development of grade 2-3 peripheral neuropathy when treated with 
bortezomib, although this is not a contraindication to treatment with bortezomib.  
The dose of bortezomib should be reduced for development of peripheral neuropathy as 
follows: 
 
Table 7: Dose Adjustments for Peripheral Neuropathy 
PERIPHERAL NEUROPATHY 
Toxicity Grade 
Dose Adjustment 
Grade 1: Paresthesia without pain or loss of function  
No dose change 
Grade 1 with pain, or  
 
Grade 2 interfering with function but not activities of daily 
living 
Reduce to 1 mg/m2 
Grade 2 with pain, or 
 
Grade 3 interfering with activities of daily living 
Discontinue 
bortezomib and 
remove patient from 
protocol 
 


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6.2.4 
Bendamustine 
 
The dose of bendamustine should be reduced by 33% for myelosuppression that 
occurs in spite of growth factor support (see Section 6.2.1) 


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7.0 
STUDY CALENDAR & EVALUATIONS 
 
Study Day 
Pre-study 
Cycles3 
End of 
treatment visit4 
Follow 
up5 
-21 
days 
-7 
days 
Day 1 
Day 4 
Day 8 
Day 11 
(30 ± 7 days 
post last 
treatment) 
 
REQUIRED 
ASSESSMENTS 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
X 
 
BP, weight 
X 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
X 
 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 
 
MUGA or Echo  
X 
 
 
 
 
 
 
 
CBC with differential 
X 
 
X 
X 
X 
X 
X 
 
Complete metabolic panel1 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
Adverse event and 
concomitant medication 
assessment 
X 
 
X 
 
 
 
X 
 
DISEASE 
ASSESSMENT 
 
 
 
 
 
 
 
 
Serum β2-microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum immunoglobulins 
(IgG, IgA, IgM) 
X 
 
Every 2 cycles or as clinically 
indicated 
X 
 
Serum protein 
electrophoresis (SPEP) and 
immunofixation (IF)2 
X 
 
Every 2 cycles or as clinically 
indicated 
X 
 
Serum free light chains2 
X 
 
Every 2 cycles or as clinically 
indicated 
X 
 
24-hour urine for M-
protein2 
X 
 
Every 2 cycles or as clinically 
indicated 
X 
 
Skeletal survey 
X6 
 
If progression is suspected 
 
 
Bone marrow aspirate and 
core biopsy 
X7 
 
For confirmation of complete 
remission or as clinically indicated10 
X11 
 
TREATMENT 
 
 
 
 
 
 
 
Bortezomib 
 
X 
X 
X 
X 
 
 
Pegylated Liposomal 
Doxorubicin  
 
 
X 
 
 
 
 
Bendamustine 
 
X 
X 
 
 
 
 
CORRELATIVE 
STUDIES - Mandatory 
 
 
 
 
 
 
 
 
Pharmacokinetics (PK) 
 
 
X8 
 
 
 
 
 
Pharmacodynamics (PD) 
 
 
X9 
X9 
 
 
 
 
FOLLOW- UP 
 
 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
 
X 
Disease progression 
 
 
 
 
 
 
 
X 


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1 Complete metabolic panel (CMP) to include creatinine, BUN, albumin, AST, ALT, alkaline phosphatase 
and total bilirubin.   
 
2 SPEP, IF, serum free light chains, and 24-hour urine for M-protein are performed every 2 cycles (i.e., 
before cycle 3, 5, 7, etc.) to assess disease response/progression, and when the patient is taken off treatment 
(see footnote #4) if not performed in the previous 4 weeks.  Disease evaluation may also be performed at 
other times as clinically indicated if disease progression is suspected.   
 
3 Dosing on Days 1 & 4 may be critical for efficacy of the combination.  All efforts should be made to 
maintain the treatment schedule. However, Day 1 infusions may be given ±3 days for reasons such as 
observed holidays, inclement weather, scheduling conflicts, etc.   
 
4 All patients, including those who discontinue protocol therapy early, should be evaluated 30 ± 7 days post 
last dose for the end of treatment visit.  End of treatment evaluation of disease status will be performed 
only for patients who complete 8 cycles of treatment or who discontinue for reasons other than disease 
progression (but haven’t started another treatment).  See section 7.4. 
 
5 All patients who receive study drug will be followed for disease progression and survival every 3 months 
for 2 years from registration for protocol therapy, every 6 months for years 3 - 5, and annually thereafter. 
 
6 Skeletal survey: If not performed within 3 months prior to registration for protocol therapy. 
 
7 Bone marrow aspirate and core biopsy: If not performed within 6 months prior to registration for protocol 
therapy. 
 
8 Mandatory PK studies for bendamustine will be performed only in cycles 1 and 2. Blood will be drawn 
(5-8 ml) at baseline (i.e., before drug administration and 24-hours after the start of the infusion. Please see 
the Study Procedure Manual for collection, processing and shipping instructions. 
 
9 Mandatory PD studies will be performed in cycles 1 and 2 only.  In cycle 1, blood (15 ml) will be drawn 
at baseline (i.e., before drug administration and 24 hours after the start of the infusion on day 1 (i.e., 
bendamustine and bortezomib).  In cycle 2, blood will be drawn at baseline (i.e., before drug administration 
and 24 hours after the start of the infusion on Day 4. Please see the Study Procedure Manual for collection, 
processing and shipping instructions. 
 
10 A bone marrow aspirate and core biopsy should be performed (including flow cytometry) to confirm 
complete remission. 
 
11 End of treatment bone marrow aspirate and core biopsy will be performed only as clinically indicated. 
 
 
 


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7.1 
BASELINE/SCREENING 
  
7.1.1 
Within 21 days prior to registration for protocol therapy: 
 
History and Physical examination, and assessment of ECOG performance status  
 
Height, blood pressure, weight 
 
Twelve-lead ECG 
 
Cardiac ejection fraction (by MUGA scan or echocardiography).   
 
Adverse event and concomitant medication assessment 
 
Serum protein electrophoresis (SPEP) and quantification of M-protein, and 
immunofixation 
 
24-hour urine for protein electrophoresis and immunofixation 
 
Serum free light chains 
 
Serum immunoglobulins (IgG, IgA, IgM) 
 
Serum β2-microglobulin 
 
CBC and differential 
 
Complete metabolic panel (CMP) to include creatinine, BUN, albumin, AST, ALT, 
alkaline phosphatase and total bilirubin.   
 
Skeletal survey (if not performed within previous 3 months) 
 
Bone marrow aspirate and core biopsy (including cytogenetics and FISH studies) if 
not performed in the previous 6 months.  
 
7.1.2 
Within 7 days of registration for protocol therapy: 
 
Pregnancy test for women of childbearing potential 
 
7.2 
ON TREATMENT 
 
7.2.1 
Day 1 of each cycle (within 3 days prior): 
Note: Cycle 1 Day 1 testing need not be repeated if completed within 7 days of 
starting protocol therapy. 
 
 
History and Physical examination, and assessment of ECOG performance status 
 
CBC with differential 
 
Complete metabolic panel (CMP) to include creatinine, BUN, albumin, AST, ALT, 
alkaline phosphatase and total bilirubin.  . 
 
Adverse event and concomitant medication assessment 
 
Bortezomib administration 
 
Bendamustine administration 
 
Day 1 of Cycle 1 and 2 only: 
 
Mandatory PK studies:  Blood will be collected at baseline (i.e., before drug 
administration) and 24-hours after the start of the infusion. 
 
Day 1 of Cycle 1 only: 
 
Mandatory PD studies:  Blood will be collected at baseline (i.e., before drug 
administration) and 24 hours after the start of the infusion on day 1 (i.e., 
bendamustine and bortezomib).   


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7.2.2 
Day 4 of each cycle (within 1 day prior): 
 
CBC with differential 
 
Complete metabolic panel (CMP) to include creatinine, BUN, albumin, AST, ALT, 
alkaline phosphatase and total bilirubin.   
 
Bortezomib administration 
 
pegylated liposomal doxorubicin administration 
 
Bendamustine administration 
 
Day 4 of Cycle 2 only: 
 
Mandatory PD studies:  Blood will be collected at baseline (i.e., before drug 
administration) and 24 hours after the start of the infusion on day 4. 
 
7.2.3 
Day 8 of each cycle (within 1 day prior): 
 
CBC with differential 
 
Complete metabolic panel (CMP) to include creatinine, BUN, albumin, AST, ALT, 
alkaline phosphatase and total bilirubin.   
 
Bortezomib administration 
 
7.2.4 
Day 11 of each cycle (within 1 day prior): 
 
CBC with differential 
 
Complete metabolic panel (CMP) to include creatinine, BUN, albumin, AST, ALT, 
alkaline phosphatase and total bilirubin.   
 
Bortezomib administration 
 
7.2.5 
Disease Assessment 
Every 2 cycles or as clinically indicated: 
 
Serum protein electrophoresis (SPEP) and immunofixation (IF) 
 
Serum free light chains 
 
24 hour urine for M-protein 
 
If progression is suspected: 
 
Skeletal survey 
 
Serum protein electrophoresis (SPEP) and immunofixation (IF) 
 
Serum free light chains 
 
24 hour urine for M-protein 
 
For confirmation of complete remission or as clinically indicated: 
 
Bone marrow aspirate and core biopsy (including flow cytometry) 
 
7.3 
TREATMENT DISCONTINUATION 
A patient will be discontinued from the treatment under the following circumstances: 
 
If there is evidence of progressive disease.  
 
If the attending physician thinks a change of therapy would be in the best interest of 
the patient. 
 
If the patient requests discontinuation. 
 
If the drug(s) exhibit(s) unacceptable adverse event. 
 
If a patient becomes pregnant. 


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 
Treatment interruption for greater than (or equal to) 14 days due to treatment 
related adverse event, except in the case of patient responding and 
myelosuppression causing delay of > 2 weeks but ˂ 4 weeks. Please see Section 6.0 
for additional information.  
 
Patients can stop participating at any time. However, if they decide to stop 
participating in the study, patients will continue to be followed for disease 
progression and survival (if haven’t withdrawn consent).  
 
7.4 
END OF TREATMENT EVALUATIONS: 30 days post last dose of study therapy 
(± 7 days) 
 
All patients, including those who discontinue protocol therapy early, should be evaluated 
30 days post last dose for the end of treatment visit.  The end of treatment evaluations 
should not be performed prior to 21 days after the last dose.   
 
End of Treatment evaluations will include: 
 
History and Physical examination, and assessment of ECOG performance status 
 
Adverse event and concomitant medication assessment 
 
CBC with differential 
 
Complete metabolic panel (CMP) to include creatinine, BUN, albumin, AST, ALT, 
alkaline phosphatase and total bilirubin.   
 
Evaluation of disease status will be performed only for patients who complete 8 
cycles of treatment or who discontinue for reasons other than disease progression 
(but haven’t started another treatment).  Disease assessment will include: SPEP and 
IF, serum free light chains, 24-hour urine evaluation for M-protein and bone 
marrow biopsy (as clinically indicated; see Section 7.0). 
 
7.5 
FOLLOW-UP: 
All patients who receive study drug will be followed for disease progression and survival 
every 3 months for 2 years from registration for protocol therapy, every 6 months for 
years 3 - 5, and annually thereafter.   
 
Completion of the off-study eCRF in  the database is required once follow-up is 
completed. 
 
8.0 
CRITERIA FOR DISEASE EVALUATION 
 
Responses will be based on a modified International Myeloma Working Group criteria18, 
and defined as outlined below:   
 


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8.1 
Definitions  
 
Table 8:  Response Criteria 
Response* 
Definition 
Complete Response (CR) 
Negative for monoclonal protein by immunofixation on the 
serum and urine, and 
Disappearance of any soft tissue plasmacytomas, and 
<5% plasma cells in bone marrow 
Stringent complete response 
(sCR) 
CR as defined above, plus  
Normal free light chain ratio, and 
Absence of clonal cells in bone marrow by flow-cytometry 
Near complete response (nCR) 
Meeting criteria for CR, except with persistence of original 
monoclonal protein by IF while absence by serum or urine 
protein electrophoresis. 
Very good partial response 
(VGPR) 
90% or more reduction in serum M-protein plus  
urine M-component <100 mg/24 hours 
Partial response (PR) 
50% or more reduction in serum M-protein and 
90% or more reduction in urine M-protein or to <200 
mg/24hours 
 
If serum and urine M-protein are immeasurable, a 50% or 
more reduction in free light chain level is required in place 
of M-protein criteria. 
 
In addition to the above criteria, if present at baseline, a 
50% or more reduction in the size of soft tissue 
plasmacytomas is required. 
 
For patients with free light chains as their only measurable 
disease, a 50% or greater decrease in the difference 
between involved and uninvolved free light chain levels. 
Minimal response (MR) 
25-49% reduction in serum M-protein, and 
 
If present, a 50-89% reduction in 24 hour light chain 
excretion, which exceeds 200 mg/24 hours, and 
 
No increase in the size or number of lytic bone lesions 
(development of compression fracture does not exclude 
response) 
Stable disease (SD) 
Not meeting criteria for CR, VGPR, MR, PR or 
progression of disease. 


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Progressive disease (PD) 
Any one of the following criteria: 
- 
Increase of 25% or more in serum or urine M-protein 
from baseline. 
- 
Serum M-protein and/or the absolute increase must be 
≥0.5 g/dL 
- 
Urine M-protein and/or absolute increase must be ≥200 
mg/24 hours 
- 
Development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of 
existing bone lesions or soft tissue plasmacytomas 
- 
Development of hypercalcemia (corrected serum Ca++ 
>11.5 mg/dL) that can be attributed solely to the plasma 
cell proliferative disease. 
 
In patients who have achieved CR or sCR: 
- 
Reappearance of serum or urine M-protein by IF or 
electrophoresis. 
- 
Development of 5% or more clonal plasma cells in the 
bone marrow 
- 
Appearance of any other sign of progression (i.e., new 
plasmacytoma, lytic bone lesions, or hypercalcemia). 
* All response categories require two consecutive assessments made any time before the 
institution of any new therapy.  Repeat of radiographic studies and bone marrow 
evaluation are not required to satisfy these responses.  
 
 
 
9.0 
BIOLOGICAL CORRELATIVES 
 
 
Please see the Study Procedure Manual for collection, processing and shipping 
instructions. 
 
The following laboratory correlative studies will be performed: 
 
9.1  
Bendamustine pharmacokinetics.  
Blood levels of bendamustine will be assayed only after the first dose (day 1) of cycles 1 
and 2 of treatment. The maximum concentration (Cmax), half-life (t1/2), and area under 
the curve (AUC) will be determined according to standard techniques and correlated with 
response to treatment, grades 3-4 toxicities, and pharmacodynamic activity (see below).  
Mandatory samples will be collected at baseline and at 24 hours after start of infusion.   
 
9.2  
Pharmacodynamic activity.   
It has been previously shown that DNA repair is an important mechanism mediating 
resistance to alkylator therapy in MM19. Furthermore, the measurement of DNA adduct 
formation/repair in peripheral blood mononuclear cells (PBMC) is a valid surrogate 
tissue for evaluating alkylator therapy in MM20.  In this protocol, we will investigate the 
extent of DNA damage and kinetics of repair in PBMC as a possible predictor of 
response in patients treated with bendamustine in combination with bortezomib and 
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Specifically, we will compare the molecular endpoints of DNA damage/repair in PBMC 
after receiving bendamustine with bortezomib (day 1 of cycle 1) and after receiving 
bendamustine, pegylated liposomal doxorubicin, and bortezomib (day 4 of cycle 2), and 
correlate the AUC for the extent of DNA damage associated with each assessment with 
response and response duration, and with plasma AUC of drug. 
 
Mandatory blood samples will be collected at baseline in cycle 1 and 2.  In cycle 1, blood 
samples will be also collected at 24 hours after the start of the infusion on day 1 to assess 
the effect of bendamustine and bortezomib.  In cycle 2, blood samples will be collected 
at 24 hours after the start of the infusion on day 4 to assess the effect of the 
bendamustine, pegylated liposomal doxorubicin and bortezomib combination. The 
following molecular endpoints will be measured: 
 
Total amount of DNA damage over time as measured using the COMET assay and 
the ARP assay kits (Kamiya Biomedical, Seattle, WA), and represented by the 
AUC during 0-24 hours of blood sampling in each of cycles 1 and 2 as described 
above.  The AUC of DNA damage/repair will be calculated using an adaptation of 
previously reported methods20,21,22,23. 
 
The assays will be performed in Dr. Farag’s laboratory. 
 
The AUC for DNA damage/repair following bendamustine and bortezomib will be 
compared to that following bendamustine, pegylated liposomal doxorubicin, and 
bortezomib to evaluate any incremental effect on DNA damage when the three drugs are 
utilized in vivo.  In addition, the AUC for DNA damage/repair in responders and non-
responders will be compared, and correlated with PK parameters of Cmax and AUC of 
plasma levels of bendamustine.  
 
 
10.0 
CTM INFORMATION & ADVERSE EVENTS MANAGEMENT 
 
10.1  
Bortezomib (VelcadeTM) 
Classification:  Proteasome inhibitor 
 
Mode of Action: Bortezomib inhibits proteasomes, enzyme complexes that regulate 
protein homeostasis within the cell. Specifically, it reversibly inhibits chymotrypsin-like 
activity at the 26S proteasome, leading to activation of signaling cascades, cell-cycle 
arrest and apoptosis.   
 
Pharmacodynamic/kinetics:  
Protein binding: ~83%  
Metabolism: Hepatic via CYP 1A2, 2C9, 2C19, 2D6, 3A4; forms metabolites (inactive)  
Half-life elimination: 9-15 hours 
 
Formulation: Bortezomib is supplied as a powder for reconstitution (preservative free): 
3.5 mg per vial (contains mannitol 35 mg). See Section 5.2 for specifications regarding 
reconstitution volume for IV vs. subcutaneous injection. 
 


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Administration: Rapid IV push (i.e., 3-5 seconds) or subcutaneous injection   
 
Dosing: The dose of Bortezomib in this protocol is 1.3 mg/m2 with dose adjustment as 
outlined in Section 6.2. There are no specific guidelines available for dosing in patients 
with renal impairment, although MM patients with renal failure have been successfully 
treated without significant toxicity. Studies, however, did not include patients with 
Creatinine clearance <13 ml/min and patients on hemodialysis. 
Specific guidelines are not available for patients with liver impairment, although the 
clearance of the drug may be decreased. 
 
Side effects and toxicity: 
The following adverse events have been reported to occur with bortezomib: 
 
Most Common side effects: 
The most common risks are those that have occurred in greater than or equal to 30% of 
patients who have received bortezomib: 
 Feeling weak, tired, and generally uncomfortable  
 Gastrointestinal effects such as constipation, diarrhea, nausea, vomiting, and loss of 
appetite.  These may result in dehydration and/or weight loss. 
 Fever commonly with shaking chills 
 Painful feelings or numbness and tingling in hands and feet (neuropathy), which 
may not get better after stopping bortezomib. Uncommonly, the nerves that control 
things like heart rate, gut movement and urinary bladder may be affected. 
 Lowered platelets;  this may increase the chance of bleeding  
 Lowered red cells or anemia which may result in feeling tired 
 
Very Common side effects: 
The very common risks are those that have occurred in 10-29% of patients who have 
received bortezomib: 
 
 Lowered white blood cells called neutrophils that may increase risk of infection 
and is uncommonly associated with fever; commonly patients may have lowered 
white blood cells called lymphocytes or have lowered red blood cells, white blood 
cells and platelets at the same time  
 Flu-like symptoms and other upper respiratory tract infections, such as chills, sore 
throat, and runny nose and sinus and throat infections 
 Abdominal (belly) pain  
 Aches and pains in muscles and joints pain in bones and in arms and legs 
 Swelling or fluid build-up in the arms and legs, and feeling dizzy and weight gain.  
Patients should not drive or operate any dangerous tools or machines if they have 
these or any other symptoms  
 Cough, feeling short of breath, lung infections including pneumonia and commonly 
bronchitis   
 Headache   
 Skin rash with itching and redness.  An uncommon risk is a severe, life-threatening 
or deadly rash with skin peeling and mouth sores.     


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 Herpes virus such as shingles (herpes zoster) that can sometimes cause local pain 
that does not go away for a while and herpes simplex virus.  Shingles can 
sometimes spread over large parts of the body.  Both may also affect the eyes or 
brain, but this is uncommon. 
 Feeling anxious  
 Problems sleeping (insomnia)   
 
Common side effects: 
Common risks are those that have occurred in 1-9% of patients who have received 
bortezomib:  
 Lowered blood pressure that can commonly cause feelings of light headedness or 
fainting when standing up  
 Changes in heart rate and heart beat that can feelings of light-headedness, dizziness, 
fainting, shortness of breath, and/or chest pain.  This may also cause patients to feel 
confused.  An uncommon risk is a possible life threatening abnormal heart beat 
 New or worsening heart failure, which can show up as feeling short of breath, 
swelling in the legs, and/or chest pain, or decreased heart function and can 
uncommonly, be severe.  If patients have heart failure or other diseases that put 
them at risk of getting heart failure, they should tell their doctor.  
 Fluid buildup around the lungs 
 Infection and/or inflammation of the eye or eyelids 
 Blurred vision  
 Painful sores of the mouth and/or throat, which may make swallowing difficult  
 Heartburn, acid reflux  and stomach bloating 
 Severe bleeding, including bleeding in the stomach and intestines (gut) that may be 
linked with low platelet counts, and blood clotting changes.  Uncommonly, this 
bleeding may cause bloody diarrhea and/or bloody vomit.   
 Nosebleeds  
 Kidney function that gets worse  
 Infections of the bladder, sinuses, throat, stomach and intestines (gut), skin and at 
the area of skin where the catheter is placed  
 Fungal infections in the mucous membrane such as the mouth and throat and 
uncommonly in the skin and nails  
 Life-threatening infections in the blood (sepsis) 
 Changes in blood sugar have been reported in a few diabetic patients who took oral 
anti-diabetic medicine.  If patients are taking oral anti-diabetic medicines they may 
need blood sugar levels watched more closely.   
 Blood in the urine  
 Feeling confused   
 Changes in the way things taste 
 Abnormal liver tests and decreased protein in the blood    
 Lowered amount of potassium and sodium in the blood and increase in the amount 
of calcium in the blood  
 Muscular weakness 
 Redness at injection site 
 Itching at injection site 
 


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Uncommon side effects: 
Uncommon risks are those that have occurred in less than 1% of patients who have 
received bortezomib: 
 Inflammation and fluid buildup in the lungs, or pus build up between the layers 
surrounding the lungs that may cause breathing problems, and can be life-
threatening or lead to death. Increased blood pressure in the lungs, called 
pulmonary hypertension, has also been reported.  This can cause breathing 
problems and can be life-threatening.    
 Inflammation of the layers surrounding the heart or collection of fluid around the 
heart may cause chest pain or breathing problems and can be life-threatening or 
lead to death.    
 Hepatitis and liver failure (in patients who also got many drugs and had other 
serious medical problems). 
 Pain, redness, swelling and infection in the area of the skin where bortezomib is 
injected into the vein  
 Pain in the mouth and throat when swallowing  
 Loss of hearing  
 Intestinal obstruction (blockage in the gut) that may get better on its own and not 
need surgery and inflammation of the intestines, pancreas or stomach   
 Coughing up blood  
 Bleeding in the brain and subdural hematoma which is bleeding between the skull 
and your brain 
 Fast death of cancer cells that may let toxins into the blood and injure organs, such 
as the kidneys  
 Allergic reactions that may include skin swelling and/or swelling of the face or 
throat and could be severe or life threatening  
 Severe muscle weakness and paralysis (not being be able to move the arms and 
legs) 
 Changes to the brain that may cause convulsions and confusion 
 Posterior reversible encephalopathy syndrome (PRES) affects the brain and may 
cause headaches, changes in vision, changes in mental status, or seizures (fits), but 
is usually reversible  
 Loss of some to all vision affecting one or both eyes, which may be caused by 
damage to the nerve in the eye.  Loss of vision may or may not be reversible. 
 Progressive multifocal leukoencephalopathy (PML); PML is a rare, serious 
infection of the brain that is caused by a virus already in the body at the time of 
treatment onset. Persons with a weakened immune system may develop PML. PML 
can result in death or severe disability. Monitor for symptoms that include: 
confusion or problems thinking, loss of balance or problems walking, difficulty 
speaking, decreased strength or weakness on one side of your body, blurred vision 
or loss of vision. 
 
Contraindications: Hypersensitivity to bortezomib, boron, mannitol, or any component 
of the formulation.  
Pregnancy: Adverse effects were observed in animal studies. There are no adequate and 
well-controlled studies in pregnant women. Effective contraception is recommended for 
women of childbearing potential. 


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Lactation: Excretion in breast milk is unknown and breast feeding is not recommended.  
Drug Interactions: 
 
CYP3A4 inhibitors: Serum level and/or toxicity of bortezomib may be increased. 
Inhibitors include amiodarone, cimetidine, clarithromycin, erythromycin, delavirdine, 
diltiazem, disulfiram, fluoxetine, fluvoxamine, grapefruit juice, nefazodone, nevirapine, 
propoxyphene, quinupristin/dalfopristin, verapamil, zafirlukast, zileuton.  
 
CYP3A4 inducers: Serum levels and/or efficacy of bortezomib may be decreased. Some 
common inducers include amiodarone, carbamazepine, nevirapine, phenobarbital, 
phenytoin, rifampin. 
 
Warnings/Precautions: The U.S. Food and Drug Administration (FDA) currently 
recommends that procedures for proper handling and disposal of antineoplastic agents be 
considered. Bortezomib may cause peripheral neuropathy, risk may be increased with 
previous use of neurotoxic agents or pre-existing peripheral neuropathy; adjustment of 
dose and schedule may be required. May cause orthostatic/postural hypotension; use 
caution with dehydration, history of syncope or medications associated with hypotension. 
Use caution with hepatic or renal impairment. Safety and efficacy have not been 
established in pediatric patients. 
 
Procurement: Commercial supplies for bortezomib will be used in this study and billed 
to third party payers or the patient.  Bortezomib is approved by the FDA for patients with 
relapsed MM.  
 
10.2 Doxorubicin HCL liposome injection (Doxil®) 
Classification:  Doxil® (doxorubicin HCl liposome injection) is doxorubicin 
hydrochloride (HCl) encapsulated in long-circulating STEALTH® liposomes for 
intravenous administration. The active ingredient of Doxil® is doxorubicin HCl, a 
cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. 
STEALTH® Liposomes are microscopic vesicles composed of a phospholipid bilayer 
that are capable of encapsulating active drugs. The STEALTH® liposomes of Doxil® are 
formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often 
referred to as pegylation, to protect liposomes from detection by the mononuclear 
phagocyte system (MPS) and to increase blood circulation time. 
 
Mode of Action: The mechanism of action of doxorubicin HCl is related to its ability to 
bind DNA and inhibit nucleic acid synthesis.  Cell structure studies have demonstrated 
rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic 
activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal 
aberrations. 
 
Formulation: Doxil® (doxorubicin HCl liposome injection) is supplied as a sterile, 
translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials. Each 10-
mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/ml. Each 30-mL vial 
contains 50 mg doxorubicin HCl at a concentration of 2 mg/ml.  
 


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Drug Storage and Stability:  Refrigerate unopened vials of Doxil® at 2C to 8C (36F 
to 46F).  Avoid freezing.  Prolonged freezing may adversely affect liposomal drug 
products; however, short-term freezing (less than 1 month) does not appear to have a 
deleterious effect on Doxil®.  Caution should be exercised in the handling and 
preparation of Doxil®. The use of gloves is required.  
 
Administration: The appropriate dose of Doxil®, up to a maximum of 90 mg, must be 
diluted in 250 ml of 5% Dextrose Injection, USP prior to administration. Aseptic 
technique must be strictly observed since no preservative or bacteriostatic agent is 
present in Doxil®. Diluted Doxil® should be refrigerated at 2°C to 8°C (36°F to 46°F) 
and administered within 24 hours.  
Doxil® should be considered an irritant and precautions should be taken to avoid 
extravasation. With intravenous administration of Doxil®, extravasation may occur with 
or without an accompanying stinging or burning sensation, even if blood returns well on 
aspiration of the infusion needle. If any signs or symptoms of extravasation occur, the 
infusion should be immediately terminated and restarted in another vein. The application 
of ice over the site of extravasation for approximately 30 minutes may be helpful in 
alleviating the local reaction. Doxil® must not be given by the intramuscular or 
subcutaneous route. 
 
Dosing: In this protocol, Doxil® should be administered intravenously at a dose of 30 
mg/m2 (doxorubicin HCl equivalent) at an initial rate of 1 mg/min to minimize the risk of 
infusion reactions.  If no infusion-related reactions are observed, the rate of infusion can 
be increased to complete administration of the drug over one hour. If Doxil® comes into 
contact with skin or mucosa, immediately wash thoroughly with soap and water.  The 
dose of Doxil® should be reduced based on toxicity according to the guidelines in 
Section 6.2.2. 
 
Side Effects and Toxicity: The major toxic effects of doxorubicin are nausea and 
vomiting, alopecia, mucositis, and phlebitis at the site of drug administration.  In 
addition, the following toxicities may occur: 
 
Myelosuppression, predominantly neutropenia, occurs with a nadir at 10-14 days, with 
recovery in 21 days. Patients with obstructive liver disease have more severe 
myelosuppression due to impaired drug excretion, and dose reduction is usually required 
(see Section 6.2).  Renal excretion is minimal, although is sufficient to turn the urine 
color red.  Renal impairment does not result in increased toxicity, and no dose reductions 
are required. 
 
Radiation recall reactions may occur patients who have received prior or are receiving 
concurrent radiation therapy with reactivation or exacerbation of radiation dermatitis.   
 
Cardiac toxicity, manifested as acute left ventricular failure, congestive heart failure due 
to cardiomyopathy, arrhythmia, or rarely sudden death, occurs predominantly in patients 
who receive cumulative doses in excess of 550 mg/m2.   
Other side effects are much less common and include fever on the day of administration, 
chills, facial flushing, anaphylaxis, conjunctivitis, and lacrimation.  
 


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Procurement: Commercial supplies of Doxil® will be used in this study and billed to 
third party payers or the patient.  Doxil® in combination with Bortezomib is approved by 
the FDA for use in patients with relapsed MM.  
 
10.3 
Doxorubicin Hydrochloride Liposome (Lipo-Dox®) 
 Clasification:  doxorubicin hydrochloride encapsulated in long circulating pegylated 
Liposomes. Liposomes are microscopic vesicles composed of a phospholipid bilayer that 
are capable of encapsulating active drugs. The pegylated Liposomes of doxorubicin are 
formulated with surface bound methoxypolyethylene glycol (MPEG), a process often 
referred to as pegylation, to protect liposomes from detection by the mononuclear 
phagocyte system (MPS) and to increase blood circulation time. Pegylated liposomes 
have a half-life of approximately 55 hours in humans. They are stable in blood and direct 
measurement of liposomal doxorubicin shows that at least 90% of the drug remains 
liposome encapsulated during circulation. It is hypothesized that because of their small 
size and persistence in the circulation, the pegylated doxorubicin liposomes are able to 
penetrate the altered and often compromised vasculature of tumors. Once the pegylated 
liposomes distribute to the tissue compartment, the encapsulated doxorubicin HCL 
becomes available. The exact mechanism of release is not understood. 
 
Mode of Action:  The exact mechanism of the antitumor activity of doxorubicin is not 
known. It is generally believed that inhibition of synthesis of DNA, RNA and protein is 
responsible for the majority of the cytotoxic effects. Liposomal doxorubicin penetrates 
the cells rapidly, binds to chromatin and inhibits nucleic acid synthesis by intercalation 
between adjacent base pairs of the DNA double helix thus preventing their unwinding for 
Replication. 
 
Formulation:  Each Lipo-Dox® vial contains pegylated liposomal doxorubicin HCl 2 
mg/ml and delivers 10ml (20mg) in a concentrate for single dose intravenous infusion 
and is presented as a sterile, translucent, and red suspension. The active ingredient of 
Lipo-Dox® is doxorubicin HCl, a cytotoxic anthracycline antibiotic obtained from 
Streptomyces peucetius var. caesius 
 
Drug Storage and Stability:  Refrigerate unopened vials at 2°C to 8°C. Avoid freezing. 
After dilution with Dextrose 5% in Water, the diluted Lipo-Dox® solution should be used 
immediately or stored at 2°C to 8°C for not longer than 24 hours. Discard the partially 
used vials. 
 
Administration:  The appropriate dose of liposomal doxorubicin up to a maximum of 90 
mg must be diluted in 250 ml of 5% Dextrose Injection USP prior to administration. 
Doses exceeding 90 mg should be diluted in 500 ml of 5% dextrose injection USP prior 
to administration. Aseptic technique must be strictly observed since no preservative or 
bacteriostatic agents are present in LipoDox. Diluted liposomal doxorubicin should be 
refrigerated at 2°C to 8°C and administered within 24 hours. LipoDox should not be used 
with in line filters and should not be mixed with other drugs. It should not be used with 
any other diluent other than Dextrose injection 5%. Partially used vials should be 
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Dosing:  LipoDox should be administered 2 intravenously at a dose of 30 mg/m2 at an 
initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related 
adverse events are observed, the rate of infusion can be increased to complete 
administration of the drug over one hour. 
 
Side effects and Toxicity:  It is recommended that all patients receiving liposomal 
doxorubicin routinely undergo frequent ECG monitoring. Transient ECG changes such 
as, T-wave flattening, S-T segment depression and benign arrhythmias are not 
considered mandatory indications for the suspension of liposomal doxorubicin therapy. 
However, reduction of the QRS complex is considered more indicative of cardiac 
toxicity. If this change occurs, the most definitive test for anthracycline myocardial 
injury i.e., endomyocardial biopsy, must be considered. Acute infusion related reactions 
characterized by flushing, shortness of breath, facial swelling, headache, chills, chest 
pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, 
cyanosis, syncope, bronchospasm, asthma, apnea and/or hypotension have been reported 
with liposomal doxorubicin. In most patients, these reactions resolve over the course of 
several hours to a day once the infusion is terminated or when the rate of infusion is 
slowed. 
 
Liposomal doxorubicin should be administered at the initial rate of 1 mg/min to 
minimize the risk of infusion reactions. 
Moderate and reversible myelosuppression has been observed in ovarian and breast 
cancer patients who received liposomal doxorubicin with anemia being the most 
common hematologic adverse event followed by leucopenia, thrombocytopenia and 
neutropenia. 
Dosage should be reduced in patients with impaired hepatic function. Prior to liposomal 
doxorubicin administration evaluation of hepatic function is recommended using 
conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase and 
bilirubin.  
Radiation induced toxicity to the myocardium, mucosae, skin and liver have been 
reported to be increased by the administration of doxorubicin HCl. 
 
10.4 
Bendamustine (Treanda®) 
 
Classification: Alkylating agent.  
 
Mode of Action: Bendamustine is a DNA alkylating agent with a unique mechanism of 
action, including the ability to cause cross-linking between DNA and proteins and 
proteins alone. With short exposure, bendamustine also induces the onset of apoptosis as 
well as ATP depletion, and these effects are sustained. Bendamustine has only partial 
cross-resistance with other alkylating agents and has in vitro activity in cells that are 
resistant to a variety of anti-tumor agents. 
 
Bendamustine’s active metabolites, gamma-hydroxy bendamustine (M3) and N-
desmethylbendamustine (M4) are formed via cytochrome P450 CYP1A2. Inhibitors of 
CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma 
concentration of bendamustine and decrease plasma concentrations of active metabolites. 
Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma 


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concentrations of bendamustine and increase plasma concentrations of its active 
metabolites. Caution should be used, or alternative treatments considered if concomitant 
treatment with CYP1A2 inhibitors or inducers is needed.  
 
Formulation: Bendamustine is available as powder in 100 mg vials for reconstitution.  
 
Drug Storage and Stability: Bendamustine is stable in normal saline (NS), and 
Dextrose 2.5 in ½ NS. 
 
Administration: Bendamustine is infused over 60 minutes in this protocol. 
Premedication with antihistamines, antipyretics, and/or corticosteroids for patients with a 
previous grade 1 or 2 infusion reaction to bendamustine should be considered. 
 
Dosing: The dose of Bendamustine should be reduced based on toxicity according to the 
guidelines in Section 6.2. 
 
Side Effects and Toxicity: 
 
Tumor Lysis Syndrome: 
Tumor lysis syndrome associated with bendamustine treatment has been reported in 
patients in clinical trials and in spontaneous reports. The onset tends to be within the first 
treatment cycle of bendamustine and, without intervention, may lead to acute renal 
failure and death. Preventive measures include maintaining adequate volume status, and 
close monitoring of serum chemistry, particularly potassium and uric acid levels. 
Allopurinol has also been used prior to or at the beginning of bendamustine therapy. 
However, there may be an increased risk of severe skin toxicity when bendamustine and 
allopurinol are administered concomitantly. 
 
Skin Reactions: 
Skin reactions have been reported in clinical trials and postmarketing spontaneous 
reports. These events have included rash, toxic skin reactions, and bullous exanthema. 
Some events occurred when bendamustine was given in combination with other 
anticancer agents, so the precise relationship of the skin reactions to bendamustine 
treatment is uncertain. 
 
In a study of bendamustine (90 mg/m2) in combination with rituximab (study SDX-105-
02), 1 case of TEN occurred. TEN has been associated with treatment with rituximab. 
Spontaneous reports of SJS and TEN, some fatal, have been reported when bendamustine 
was administered concomitantly with allopurinol and other medications known to cause 
these syndromes. The relationship to bendamustine cannot be determined. 
When skin reactions occur, they may be progressive and increase in severity with further 
treatment. Therefore, patients with skin reactions should be monitored closely. If skin 
reactions are severe or progressive, bendamustine treatment should be withheld or 
discontinued. 
 
The following side effects and toxicities have been reported to occur in >10% of patients: 
Hypersensitivity/infusion reactions: Infusion reactions, which may include chills, fever, 
pruritus, and rash, are common. Rarely, anaphylactic and anaphylactoid reactions have 


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occurred particularly with the second or subsequent cycle(s). In general, patients who 
experienced grade 3 or 4 allergic reactions were not rechallenged in previously reported 
clinical trials. Consider premedication with antihistamines, antipyretics and/or 
corticosteroids for patients with a history of grade 1 or 2-infusion reaction. Discontinue 
for severe allergic reaction; consider discontinuation with grade 3 or 4 infusion reaction. 
 
Cardiovascular: Peripheral edema (≤13%) 
 
Central nervous system: Fatigue (9% to 57%), fever (24% to 34%), headache (≤21%), 
chills (6% to 14%), dizziness (≤14%), insomnia (≤13%) 
 
 
Dermatologic: Rash (8% to 16%; grades 3/4: ≤3%) 
Endocrine & metabolic: Dehydration (≤14%) 
 
Gastrointestinal: Nausea (20% to 75%), vomiting (16% to 40%), diarrhea (9% to 37%), 
constipation (≤29%), anorexia (≤23%), weight loss (7% to 18%), stomatitis (≤15%), 
abdominal pain (5% to 13%), appetite loss (≤13%), dyspepsia (≤11%) 
 
Hematologic: Myelosuppression (nadir: in week 3), lymphopenia (68% to 99%; grades 
3/4: 47% to 94%), leukopenia (61% to 94%; grades 3/4: 28% to 56%), anemia (88% to 
89%; grades 3/4: 11% to 13%), thrombocytopenia (77% to 86%; grades 3/4: 11% to 
25%), neutropenia (75% to 86%; grades 3/4: 43% to 60%) 
 
Hepatic: Bilirubin increased (≤34%; grades 3/4: 3%) 
 
Neuromuscular & skeletal: Back pain (≤14%), weakness (8% to 11%) 
 
Respiratory: Cough (4% to 22%), dyspnea (≤16%) 
 
The following toxicities have been reported to occur in 1% to 10% of patients: 
Cardiovascular: Tachycardia (≤7%), hypotension (≤6%), chest pain (≤6%), hypertension 
aggravated (≤3%) 
 
Central nervous system: Anxiety (≤8%), depression (≤6%), pain (≤6%) 
Dermatologic: Pruritus (5% to 6%), dry skin (≤5%) 
Endocrine & metabolic: Hypokalemia (≤9%), hyperuricemia (≤7%; grades 3/4: 2%), 
hyperglycemia (grades 3/4: ≤3%), hypocalcemia (grades 3/4: ≤2%), hyponatremia 
(grades 3/4: ≤2%) 
 
Gastrointestinal: Gastroesophageal reflux disease (≤10%), xerostomia (9%), taste 
alteration (≤7%), oral candidiasis (≤6%), abdominal distention (≤5%) 
 
Genitourinary: Urinary tract infection (≤10%) 
 
Hematologic: Febrile neutropenia (3% to 6%) 


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Hepatic: ALT increased (grades 3/4: ≤3%), AST increased (grades 3/4: ≤1%) 
 
Local: Infusion site pain (≤6%), catheter site pain (≤5%) 
 
Neuromuscular & skeletal: Arthralgia (≤6%), bone pain (≤5%), limb pain (≤5%) 
 
Renal: Creatinine increased (grades 3/4: ≤2%) 
 
Respiratory: Upper respiratory infection (10%), sinusitis (≤9%), pharyngolaryngeal pain 
(≤8%), pneumonia (≤8%), nasopharyngitis (6% to 7%), wheezing (≤5%), nasal 
congestion (≤5%) 
 
Miscellaneous: Herpes infection (3% to 10%), infection (≤6%; grades 3/4: 2%), 
hypersensitivity (≤5%; grades 3/4: 1%), diaphoresis (≤5%), night sweats (≤5%) 
 
Rare important or life-threatening toxicities, reported in <1% of patients include: 
Acute renal failure, alopecia, anaphylaxis, bullous exanthema, cardiac failure, dermatitis, 
erythema, hemolysis, infusion reaction, injection/infusion site reaction (irritation, 
pruritus, swelling), malaise, mucosal inflammation, myelodysplastic syndrome, 
pulmonary fibrosis, sepsis, septic shock, skin necrosis, somnolence, toxic epidermal 
necrolysis, toxic skin reactions, tumor lysis syndrome. 
 
Procurement: Cephalon, Inc. will provide bendamustine at no cost in this protocol. 
 
 
 
11.0 
REPORTING ADVERSE EVENTS & SERIOUS ADVERSE EVENTS 
 
11.1  
Definitions of Adverse Events 
 
11.1.1 
Adverse Event (AE) 
 
 Any untoward medical occurrence in a patient or clinical trial subject administered an 
investigational product and which does not necessarily have a causal relationship with 
the treatment.  An adverse event (AE) can, therefore, be any unfavorable and unintended 
sign (including an abnormal finding), symptom, or disease temporally associated with 
the use of an investigational product, whether or not related to the investigational 
product. 
 
11.1.2 
Serious Adverse Event (SAE) 
 
“Serious Adverse Event or Adverse Drug Reaction (AE/ADR)” means any AE/ADR 
occurring at any dose that results in any of the following outcomes: 
 
a) Death 
b) A life-threatening AE/ADR (i.e., the patient/subject was, in the view of the initial 
reporter/investigator, at immediate risk of death from the AE/ADR as it occurred.  It 
does not refer to an AE/ADR that hypothetically might have caused death if it were 
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c) Inpatient hospitalization or prolongation of existing hospitalization (i.e., 
hospitalization was required to treat or diagnose the AE/ADR; excludes 
hospitalization for unrelated reasons); 
d) A persistent or significant disability or incapacity (disability here means that there is a 
substantial disruption of a person’s ability to conduct normal life functions); 
e) A congenital anomaly/birth defect 
f) An important medical event (i.e., AEs/ADRs that might not be immediately life-
threatening, or result in death or hospitalization might be considered serious when,  
based upon appropriate medical and scientific judgment, they might jeopardize the 
patient/subject or might require medical or surgical intervention to prevent one of the 
other serious outcomes listed in the definition above).   
g) Any suspected transmission via a medicinal product of an infectious agent 
 
11.1.3 
Unexpected Adverse Event 
An adverse event not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the Investigator's Brochure or 
package insert. 
 
11.2 
Adverse Event (AE) Reporting 
Adverse events (AEs) will be recorded from the time of consent and for at least 30 days 
after treatment discontinuation, regardless of whether or not the event(s) are considered 
related to trial medications.  All AEs considered related to trial medication will be 
followed until resolution, return to baseline, or deemed clinically insignificant, even if 
this occurs post-trial. 
 
11.3 
Serious Adverse Event (SAE) Reporting 
 
11.3.1 
Study Center (Site) Requirements for Reporting SAEs 
Investigators and other site personnel must report any SAEs occurring during the course 
of the study within one business day of discovery of the event.  This includes events 
both related and unrelated to the investigational product.   
 
The definition of “related” being that there is a reasonable possibility the drug caused the 
adverse experience.  Sponsor-Investigator shall use his/her judgment to determine the 
relationship between the Serious Adverse Drug Experience and the Study Drug. 
 
Table 9: Definition or Relationship of AE to Study Medication  
Unrelated 
The Adverse Event is clearly not related to the investigational agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event  may be related to the investigational agent(s) 
Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 
The completed SAE Report Form (see Study Procedure Manual) must be faxed to 
Hoosier Cancer Research Network within 1 business day of discovery of the event.   
The investigator is responsible for informing the IRB and/or the Regulatory Authority of 
the SAE as per local requirements. 
 


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11.3.2 
Death and Immediately Life-Threatening Events  
Any death and immediately life-threatening event from any cause while a patient is 
receiving trial treatment on this protocol or up to 30 days after the last dose of trial 
treatment, or any death and immediately life-threatening event occurring more than 30 
days after trial treatment has ended but which is felt to be treatment related must be 
reported within one business day of discovery of the event.  All deaths must be reported 
primarily for the purposes of SAE reporting; however, deaths due unequivocally to 
progression are not SAEs.   
 
The site’s local IRB should be notified and the local reporting procedures followed.  The 
completed SAE Reporting Form should be faxed to Hoosier Cancer Research Network 
within one business day of discovery of the event. 
 
11.3.3 
HCRN Requirements for Reporting SAEs 
 
Institution (HCRN) shall notify Cephalon within one (1) business day, by facsimile, 
upon learning of the occurrence during the Study of: 
 
(a) All Serious AE/ADRs, regardless of causality; 
(b) Any exposure of a pregnant Study participant to the Study Drug within thirty (30) 
days of exposure; 
(c) A female partner of a male Study participant becoming pregnant within thirty (30) 
days of exposure;  
(d) Any medical event which may reasonably be believed to impair the integrity, 
validity or ongoing viability of the Study. 
 
The Hoosier Cancer Research Network will report any SAE to Cephalon, Inc. (from the 
time of first dose until 30 days post discontinuation) within one business day of receipt 
of the SAE Transmittal Form and will report to regulatory authorities (FDA) per federal 
guidelines.   
 
All such occurrences listed in this section shall be reported to Cephalon using the SAE 
Transmittal Form provided by Cephalon. 
The Hoosier Cancer Research Network will fax the SAE Transmittal Form to Cephalon 
and will provide follow-up information as reasonably requested. 
 
Cephalon, Product Safety:  
Fax: 610-738-6396 
 
All HCRN Institutional Participants shall notify their IRB, as appropriate as per 
institutional policy.  
 
In the event the IRB requests additional safety information from Sponsor Investigator, 
Institution shall notify Cephalon of such request within one (1) business day. 
 
11.4 
IND Safety Reports Unrelated to This Trial 


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IND safety reports not occurring on this trial but involving the study intervention 
(outside SAEs) received from outside sources will be reviewed by the Sponsor 
Investigator and will be forwarded to participating sites for submission to their 
Institutional Review Boards per their guidelines.   
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
Although bendamustine has been combined with mitoxantrone, etoposide, and Idarubicin 
with acceptable toxicity, there is currently no data of its appropriate dosing in 
combination with pegylated liposomal doxorubicin and bortezomib. Therefore, we will 
investigate the combination in two phases: 
 
12.1  
Phase I component 
The primary objective in the phase I component is to determine the MTD of 
bendamustine in combination with bortezomib and pegylated liposomal doxorubicin 
(with growth factor support) to gain a better idea of safe dosing before proceeding with 
the second phase to assess efficacy.  
 
A standard 3 + 3 design will be used to determine the MTD.  Three patients will be 
enrolled at dose level 1. If no patient experiences dose limiting toxicities (DLTs), 
escalation to the next dose level will occur.  If 1 of 3 patients at any dose level 
experiences a DLT, 3 additional patients will be enrolled at that dose level. If only 1 of 6 
patients experiences a DLT, dose escalation will be permitted. If 2 or more patients at 
any dose level experienced a DLT, then the previous dose with at most 1 out of 6 DLT 
will be considered the maximum tolerated dose (MTD).  If myelosuppression is dose 
limiting, we will add an additional dose level at the MTD with growth factor (G-CSF; 
filgrastim) support (dose level +3). Dose escalation will not occur beyond level 3. 
Therefore, we will need at most 18 patients in phase I. 
 
12.2   
Phase II component 
The primary objective in the Phase II component is to determine the overall response 
(CR+PR) at the MTD of bendamustine in combination with bortezomib and pegylated 
liposomal doxorubicin.  Note that here CR includes all categories of sCR, CR, nCR and 
PR includes all categories of VGPR and PR defined in Section 8.1.  A min/max optimal 
two-stage design will be followed.  Patients will be considered evaluable for response if 
they have received at least 2 cycles of therapy or if they have had disease progression 
before 2 cycles are completed.  If a patient does not finish at least 2 cycles (except for 
disease progression), we will recruit a new patient to replace him/her. An overall 
response rate of 60% or more will be acceptable, while an overall response rate of less 
than 40% will be considered unacceptable.  In statistical terms, we will test the null 
hypothesis H0: p0<0.4 versus the alternative hypothesis H1: p1 >0.6, where p is the 
probability of overall response.  Type I and type II errors will be both set at 0.1. In the 
first stage, we will enroll 28 evaluable patients. If less than 12 patients respond, the trial 
will be stopped and we will conclude in favor of the null hypothesis.  If 12 or more 
patients respond, we will proceed with the second stage by enrolling an additional 13 
evaluable patients for a maximum sample size of 41 evaluable patients.  If more than 20 
patients achieve at least a partial response, we will conclude in favor of H1: p1> 0.6.  


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The probability of early termination under the null hypothesis is 0.55.  We expect only 
80% of enrolled patients to be evaluable. Therefore, overall, we will have to enroll 51 
patients if the stage 2 is conducted to achieve 41 evaluable samples.  
 
12.3 
Analysis 
 
12.3.1  Phase I Component 
Patients’ characteristics will be summarized using mean, median, and standard deviation 
for continuous variables, and tables for discrete variables. Toxicity profile (for all 
patients) will be presented by rate of overall toxicity and rates of grade 3 or 4 toxicities 
analyzed separately and combined.  Adverse events will be summarized in phase I and 
accompanied by 95% confidence intervals using binomial distribution.  Response rates 
will be summarized.  
 
12.3.2 
Phase II Component 
Descriptive analysis of patients’ characteristics will be summarized in a similar way as 
Phase I. 
 
Primary analysis 
The primary objective in phase II is to assess the overall response rate (CR+PR) of 
treatment at the MTD level found in phase I. Overall response rate will be evaluated and 
accompanied by 95% confidence intervals using the binomial distribution. Response rate 
by categories will be calculated with 95% confidence intervals. 
 
Secondary analysis 
Toxicity profile (for all phase II patients) will be presented by rate of overall toxicity and 
rates of grade 3 or 4 toxicities analyzed separately and combined. The toxicity analysis 
may also be performed for the patients with and without autologous stem cell 
transplantation separately due to the potential higher hematological toxicity in 
transplanted patients. Time to progression will analyzed using Kaplan-Meier survival 
analysis and accompanied with 95% confidence interval. Similar analysis will be applied 
to the progression-free survival, duration of response, and overall survival. Median 
survival time will be calculated with 95% confidence interval for each of the time-to-
event outcome. 
 
Correlative analysis 
The bendamustine pharmacokinetics parameters (Cmax, t1/2, and AUC) at cycle 1 (and 
cycle 2) will be correlated with response by comparing their means between the 
responders (CR +PR) and those respond (non-responders) otherwise using two-sample t 
tests. Appropriate transformation of the pharmacokinetics parameters will be done to fit 
the normal distribution assumption. Similar analysis will be used to correlate them with 
toxicity (grade 3-4).  
 
The DNA damage/repair at day 1 of cycle 1 and day 4 of cycle 2 will be compared using 
a paired t test. AUC for the extent of DNA damage will be correlated with response by 
comparing their means between responders and non-responders. AUC will be correlated 
with response duration using a proportional hazards model, and plasma AUC using 
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12.4 
Time to event endpoint 
 
12.4.1 
Time to progression (TTP) 
 
The time from the start of treatment (i.e., first dose) to disease progression, with disease 
progression and death due to disease progression as events and deaths due to causes other 
than progression as censored.  Censoring date will be the last disease evaluation date for 
patient without progression/death or date of death due to other diseases for patients’ 
deaths due to other causes.  
 
12.4.2 
Progression-free survival (PFS) 
The time from the start of treatment to disease progression or death (regardless of cause 
of death), whichever comes first.   Censoring date will be the last disease evaluation date. 
 
12.4.3 
Duration of response (DOR) 
Duration from first date of at least partial response to the time of progression or death 
due to disease progression as events, with disease progression and death due to disease 
progression as events and deaths due to causes other than progression as censored.  
Censoring date will be the last disease evaluation date or date of death due to other 
causes as appropriate.  
 
12.4.4 
Overall survival (OS) 
The time from the start of treatment to death from any cause with last date known alive 
as censoring date. 
 
12.5 Modifications in the August 2014 amendment 
This amendment introduces a lower dose level of bendamustine, which if passing the study 
will be the recommended dose level for future studies. This low dose will be used for the 
remaining first stage, and second stage. The same rule will be used for the first stage. For 
the second stage, the response rate at the low dose will be evaluated first. If this rate is no 
less than the response rate of the high dose by 10% and no less than 50% in general, the 
two dose levels will be combined in analyses following the original rule, i.e. if more than 
20 patients achieve at least a partial response, we will conclude in favor of H1: p1> 0.6.  
Otherwise, the response rate will be evaluated and its 95% confidence intervals will be 
calculated separately for the two dose levels. It is argued from the scientific point of view 
that the low dose will have at least the same or even higher response rate as the high dose. 
Consequently, the power level will be at least the same as the original designed. For the 
secondary and correlative analyses, they will be performed both separately for the two dose 
levels and in the combined manner. 
 
13.0 
TRIAL MANAGEMENT 
 
13.1 
 Quality Controls and Quality Assurance 
 
13.1.1  
Study Monitoring 
Monitoring visits to the trial sites will be made periodically during the trial, to ensure all 
aspects of the protocol are followed.  Source documents will be reviewed for verification 


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of agreement with data as submitted via the data collection system.  The 
investigator/institution guarantee access to source documents by HCRN or its designee 
and appropriate regulatory agencies. 
 
The trial site may also be subject to quality assurance audit by Cephalon, Inc. or its 
designee as well as inspection by appropriate regulatory agencies. 
 
It is important for the investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 
13.1.2  
Data and Safety Monitoring Plan 
HCRN data safety monitoring activities include: 
 
Review of clinical trial conducted for progress and safety 
 
Review of all adverse events requiring expedited reporting as defined in the 
protocol 
 
Review of reports generated by data quality control review process  
 
Notification of the Sponsor Investigator of recommended action 
 
Notification of sites coordinated by the HCRN of adverse events requiring 
expedited reporting and subsequent committee recommendations for study 
modifications 
 
13.1.3 
Data/Safety Monitoring and Reporting Guidelines 
The HCRN will compile data summary reports for this trial and submit these reports to 
the Sponsor-investigator.  The HCRN will submit data summary reports to the Indiana 
University Simon Cancer Center (IUSCC) Clinical Trial Monitoring Committee 
(CTMC) for review per the HCRN’s standard operating procedures (SOP) and the study-
specific data monitoring plan (DMP).  
 
13.2  
Data Handling and Record Keeping 
 
13.2.1 
Case Report Forms 
An electronic case report form (eCRF) is required and must be completed for each 
included patient.  The completed dataset is the sole property of HCRN and should not be 
made available in any form to third parties, except for authorized representatives of 
appropriate Health/Regulatory Authorities, without written permission from HCRN. 
 
13.2.2 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records; e.g., hospital records), all original signed informed consent 
forms, copies of all eCRFs, and detailed records of drug disposition.  To comply with 
international regulations, the records should be retained by the investigator in 
compliance with regulations. 
 
During data entry, range and missing data checks will be performed on-line.  The checks 
to be performed will be documented in the Data Monitoring Plan for the study.  A 
summary report (QC Report) of these checks together with any queries resulting from 
manual review of the eCRFs will be generated for each site and transmitted to the site 


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and the site monitor.  Corrections will be made by the study site personnel.  This will be 
done on an ongoing basis. 
 
13.3 
Changes to the Protocol 
 
Study procedures will not be changed without the mutual agreement of the Sponsor 
Investigator,  Hoosier Cancer Research Network, and Cephalon, Inc. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version 
of the study protocol (amended protocol) will be generated by the Hoosier Cancer 
Research Network and must be approved by each IRB, Cephalon, Inc., and if applicable, 
also the local regulatory authority.  Local requirements must be followed. 
 
If a protocol amendment requires a change to the Written Informed Consent Form, then 
the IRB must be notified.  Approval of the revised Written Informed Consent Form by 
the IRB is required before the revised form is used.  
 
The principal investigator is responsible for the distribution of these documents to his or 
her IRB, and to the staff at his or her center.  The distribution of these documents to the 
regulatory authority will be handled according to local practice. 
 
Cephalon’s willingness to supply study drug is predicated upon the review of the 
protocol.  The Hoosier Cancer Research Network agrees to provide written notice to 
Cephalon, Inc. of any modifications to the protocol or informed consent. 
 
13.4  
Ethics 
 
13.4.1 
Ethics Review 
The final study protocol, including the final version of the Written Informed Consent 
Form, must be approved or given a favorable opinion in writing by an IRB.  The 
investigator must submit written approval to the HCRN office before he or she can 
enroll any patient into the study.   
 
The principal investigator is responsible for informing the IRB of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by 
the IRB annually, as local regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be 
provided to the IRB according to local regulations and guidelines. 
 
The investigator is also responsible for providing the IRB with reports of any serious 
adverse drug reactions from any other study conducted with the investigational product.  
Cephalon, Inc. will provide this information to the Sponsor Investigator.  These reports 
will be reviewed by the Sponsor Investigator and those considered unexpected and 
possibly related to protocol therapy plus all deaths within 30 days of discontinuing 
treatment will be forwarded to participating sites for submission to their Institutional 


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Review Boards per their guidelines.  All other events will be held and submitted to the 
sites for continuing review. 
 
13.4.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH/Good Clinical Practice, and 
applicable regulatory requirements. 
 
13.5  
Written Informed Consent 
The investigator will ensure the patient is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Patients 
must also be notified they are free to discontinue from the study at any time.  The patient 
should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
 
The patient’s signed and dated informed consent must be obtained before conducting 
any procedure specifically for the study.  The investigator must store the original, signed 
Written Informed Consent Form.  A copy of the signed Written Informed Consent Form 
must be given to the patient. 
 
 
 


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14.0 
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