Conditions: Lymphoma, Non-Hodgkin Lymphoma, Follicular Lymphoma, Mantle-Cell Lymphoma, Small-Cell Waldenstrom Macroglobulinemia Lymphoma, B-Cell, Marginal Zone
Keywords: Bendamustine Rituximab Vincristine sulfate Vincristine sulfate liposome injection Phase I Escalation With Overdose Control
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 11
Healthy volunteers: no

Brief summary:
This study evaluates addition of Vincristine Sulfate Liposome Injection (Marqibo®) to the standard regimen of Bendamustine and Rituximab in adult patients with indolent B-cell lymphoma. This is a dose-escalation study.

Detailed description:
Bendamustine-rituximab is a standard chemotherapy regimen for treatment of many indolent B-cell lymphomas, but most patients experience a recurrence of the lymphoma. Vincristine sulfate has been a traditional component of chemotherapy regimens in non-Hodgkin lymphoma and it is possible that adding it to the bendamustine-rituximab regimen might provide a better quality of remissions or longer duration of remissions with acceptable toxicity.

This is a phase 1, single-center, open-label, single-arm trial in patients with indolent B-cell non-Hodgkin lymphoma otherwise appropriate for bendamustine-rituximab as initial or subsequent line of therapy. Patients will receive the of rituximab and bendamustine in combination with escalating doses of vincristine sulfate liposome injection (Marqibo®). The objective of this study is to assess safety of this combination by establishing the maximum tolerated dose of vincristine sulfate liposome injection (Marqibo®) in the combination.

Arms:
arm 1: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. arm 2: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. arm 3: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. arm 4: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. arm 5: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. arm 6: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. arm 7: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. arm 8: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. arm 9: Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy.

Interventions: intervention 1: Rituximab intervention 2: Bendamustine intervention 3: Vincristine sulfate liposome injection
Intervention descriptions: intervention 1: 375 mg/m2 I.V. on Day 1 of each cycle intervention 2: 90 mg/m2 I.V. on Day 1 and 2 of each cycle intervention 3: Dose per dose escalation protocol, I.V. on Day 2 of each cycle

Protocol document:
Prot_SAP_ICF_000.pdf: 
1  
BrUOG 326: A Phase I Dose-Escalation Study of Vincristine Sulfate Liposome 
Injection (Marqibo®) in Combination with Bendamustine and Rituximab 
(BRiM) in Indolent non-Hodgkin Lymphoma (IIS-MAR-003) 
Coordinating Center: 
 
 
Brown University Research Oncology Group, Providence, RI 
Sponsor/Principal Investigator: 
Adam J. Olszewski, MD 
 
Comprehensive Cancer Center at Rhode Island Hospital 
 
593 Eddy St., George-353, Providence, RI, 02903 
 
Phone: (401) 444-5396 
 
Fax:  (401) 444-8918 
 
adam_olszewski@brown.edu 
Co-Investigators: 
John Reagan, MD 
 
Howard Safran, MD 
 
James Butera, MD 
 
 
 
Coordinating Center: 
Brown University Oncology Research Group 
233 Richmond Street Box G-R001 
Providence, Rhode Island 02903 
Phone: (401) 863-3000 
Fax: (401) 863-3820 
Email: BrUOG@brown.edu 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b) and IND exemption letter 
from the FDA.  IND exempt 125221 
Original date Amendment:   
5/1/2020 
 
Revision history:  
8/16/2016 
Submitted to Spectrum 
8/30/2016 
Approved by Spectrum 
9/1/2016 
9/2/2016 
Resubmitted 
9/16/2016 
10/17/2016 
Post-internal review edits 
10/17/2016 
Resubmitted  
1/6/2017 
 
 
2/1/2017 
With IB 12,  
6/2/2017 
Amendment #1 
2/16/2018 
Amendment #2 
8/3/18 
Amendment #3 
5/1/2020  
Amendment #4 
 
 


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PROTOCOL 
SYNOPSIS Title of 
Study: 
A Phase I Dose-Escalation Study of Vincristine Sulfate Liposome Injection 
(Marqibo®) in Combination with Bendamustine and Rituximab (BRiM) in Indolent 
non-Hodgkin Lymphoma 
Sponsor: 
Adam Olszewski, MD 
IND Number: 
Study Exempt from IND Requirements per 21 CFR 312.2(b) and IND exemption 
letter from the FDA.   
Study Centers: 
Brown University Oncology Research Group – Rhode Island Hospital 
Objectives: 
Primary objective: 
• 
To establish the maximum tolerated dose (MTD) and dose-limiting toxicity 
(DLT) of vincristine sulfate liposome injection (Marqibo®) in combination 
with bendamustine and rituximab (BRiM).  
• 
To establish the dose-limiting toxicities (DLT) of vincristine sulfate liposome 
injection (Marqibo®) in combination with bendamustine and rituximab 
(BRiM). 
Secondary objectives: 
• 
To evaluate cumulative rates of non-DLT toxicities of the BRiM combination 
in patients with non-Hodgkin lymphoma. 
• 
To evaluate tolerability, assessed by rate of completion of the planned six 
cycles of BRiM chemotherapy. 
• 
To evaluate response rate (RR) and complete response rate (CR) of the BRiM 
regimen in the study population of indolent non-Hodgkin lymphoma patients. 
Study Design: 
 
Phase 1, single-center, open-label, single-arm trial in 10 patients with indolent B-cell 
non-Hodgkin lymphoma otherwise appropriate for bendamustine-rituximab as initial 
or subsequent line of therapy. Patients will receive the BRiM regimen, consisting of 
rituximab and bendamustine (standard doses) in combination with vincristine sulfate 
liposome injection (Marqibo®)—at a patient-specific dose determined by the 
Escalation With Overdose Control (EWOC) protocol, from 1.8 mg/m2 to the ceiling 
dose of 2.4 mg/m2. The treatment will continue at the same dose for up to 6 cycles. 
Patients will be evaluated weekly during Cycle 1 to assess toxicity and identify dose-
limiting toxicities (DLT). During Cycle 2-6 patients will be followed every two 
weeks. The response to chemotherapy will be evaluated after Cycles 3 and 6 of 
treatment- see section 6. The maximum tolerated dose (MTD, recommended phase 
II dose) of Marqibo® in the BRiM combination will be defined upon completion of 
the trial as the median of the marginal posterior distribution of the MTD. The trial 
will be terminated if the first three patients experience a DLT or anytime the 
posterior probability that the DLT rate at the minimum dose exceeds 0.33 is 0.8 
or more. 
Dosing schema 
 
 
 
 
 
 
 


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Study Treatment 
Assignments 
• Rituximab at 375 mg/m2 intravenously over 3-5 hours on Day 1 
• Bendamustine at 90 mg/m2 intravenously over 10 to 30 minutes on Day 1, 2 
• Marqibo® at patient-specific dose, intravenously over 60 minutes on Day 2 
—every 28 days for up to six cycles. 
Number of Subjects: 
Ten (10) patients will be treated.  
Target Population: 
Adult subjects with indolent B-cell non-Hodgkin lymphoma otherwise appropriate 
for therapy with bendamustine-rituximab regimen according to current National 
Comprehensive Cancer Network (NCCN Guidelines®). The following subtypes are 
allowed: 
• 
Follicular lymphoma; 
• 
Mantle cell lymphoma;  
• 
Marginal zone lymphoma, not amenable to curative therapy; 
• 
Small lymphocytic lymphoma; 
• 
Lymphoplasmacytic lymphoma; 
• 
Other indolent B-cell lymphomas (including not otherwise specified, NOS); 
Patients may receive the protocol therapy as the initial or subsequent line of 
treatment, as long as bendamustine-rituximab is an otherwise clinically appropriate 
treatment option. 
Duration of  
Treatment: 
In the absence of clinical or radiographic progression or prohibitive toxicity, patients 
will continue therapy for up to six 28-day cycles.  
Discontinuation: 
Patients may be discontinued from the study treatment for the following reasons: 
• 
Occurrence of a DLT in the first cycle of treatment, 
• 
Disease progression, 
• 
The need for administration of therapy for lymphoma not specified in the 
protocol; this includes any form of chemotherapy, radiation therapy or biologic 
therapy; 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Adverse event(s) deemed unacceptable by the patient or the treating physician, 
• 
Patient decides to withdraw from the study for any reason, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
Diagnosis and Main 
Eligibility Criteria: 
 
• 
Eligibility criteria: Patients must have histologically confirmed indolent B-cell 
non-Hodgkin lymphoma, CD20-positive, previously treated or untreated-for 
which bendamustine-rituximab chemotherapy is clinically indicated; the 
following subtypes are allowed: Follicular lymphoma; Mantle cell lymphoma; 
Marginal zone lymphoma; Small lymphocytic lymphoma; Lymphoplasmacytic 
lymphoma, or Indolent B-cell lymphoma, NOS.  
• 
Radiological measurable disease, defined as any measurable lesion >15 mm on 
the staging CT or PET/CT. Patients with blood or bone marrow involvement 
only are ineligible. Splenomegaly is acceptable as a measurable site if enlarged 
on the initial CT scan (>13 cm in the cranio-caudal dimension). 
• 
Previous treatment for lymphoma is allowed, with the exception of use of 
bendamustine within 180 days of the date of the consent form, or any prior use 
of vincristine sulfate liposome injection (Marqibo®).  
• 
Age ≥18 years.   
• 
ECOG performance status 0 or 1 (see Appendix A). 
• 
Life expectancy of greater than 6 months. 
• 
Patients must have adequate organ and marrow function as defined below: 


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o 
leukocytes 
 
≥3,000/mm3 
o 
absolute neutrophil count 
≥1,000/mm3 
o 
platelets 
                     ≥75,000/mm3  
o 
total bilirubin 
within normal institutional limits 
o 
AST(SGOT)/ALT(SGPT) 
<2.5 × institutional ULN 
o 
creatinine 
 
<2.0 mg/mL 
o 
AND 
o 
creatinine clearance  
<50 mL/min/1.73 m2. 
calculated by method of Cockroft and Gault 
• 
Prevention of pregnancy. 
• 
The effects of bendamustine and vincristine on the developing human fetus are 
unknown.  For this reason and because Class D agents as well as other 
therapeutic agents used in this trial are known to be teratogenic, women and men 
of child-bearing potential must agree to use adequate contraception (hormonal 
or barrier method of birth control; abstinence; vasectomy) prior to study entry 
and up to 4 months after the last dose of study treatment.  
• 
Women of childbearing potential must have a negative serum or urine pregnancy 
test within 14 days prior to first treatment on study (Cycle 1, Day 1). Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.  
Postmenopausal women (after surgical menopause or no menses for >12 
months) do not need to have a pregnancy status, but their postmenopausal status 
must be documented.  
• 
Ability to understand and the willingness to sign a written informed consent 
document. 
 
Exclusion criteria: 
• 
History of any allergic reaction attributed to rituximab (with the exception of 
<grade 3 infusion reaction), bendamustine, vincristine sulfate, Marqibo®, 
mannitol, sodium phosphate injection or sphingomyelin/cholesterol liposome. 
• 
Patients who have had any lymphoma-directed radiotherapy, chemotherapy, 
biologic or experimental therapy, oral or intravenous, within 4 weeks (6 weeks 
for nitrosoureas or mitomycin C) prior to entering the study or those who have 
not recovered from adverse events due to agents administered more than 4 weeks 
earlier to ≤grade 1-with the exception of alopecia, which is allowed. 
• 
Any prior treatment with vincristine sulfate liposome injection (Marqibo®). 
• 
Prior treatment with bendamustine or vincristine sulfate within 180 days of 
enrollment. Prior treatment with rituximab is allowed. 
• 
Patients who are receiving any other investigational agents or anti-cancer 
therapy with the exception of endocrine therapy for breast or prostate cancer. 
• 
Patients with known central nervous system involvement (infiltration of the 
brain, meninges or cerebrospinal fluid) by the lymphoma are excluded from this 
clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. 
• 
Active peripheral sensory or motor neuropathy > grade 1. This is defined by the 
CTCAE as any neuropathy requiring intervention or limiting instrumental 
activities of daily life. 
• 
History of demyelinating form of Charcot-Marie-Tooth syndrome, acquired 
demyelinating disorders, or other demyelinating condition. 
• 
Documented positive test for the Human Anti-Chimeric Antibody (HACA). 
• 
Patients receiving any medications or substances that are strong inhibitors or 
inducers of CYP3A enzyme are ineligible.   


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• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection (that requires antibiotic use which is not prophylactic), symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements. In cases of uncertainty, the PI will decide whether an illness is 
considered prohibitive. Suppressive antiviral therapy with acyclovir, 
famciclovir, or valacyclovir for herpes simples or herpes zoster is allowed. 
• 
Prisoners. 
• 
Pregnant or breast-feeding women.  
• 
Known Human Immunodeficiency Virus (HIV) or active Hepatitis B infection 
(defined as presence of HBV DNA or hepatitis B S antigen in the blood).  
• 
Any prior or active cancer, which in the opinion of the investigator would 
preclude safe participation in this study. 
Study Procedures/ 
Frequency: 
Patients will undergo screening and registration procedures, including staging of 
their lymphoma using a CT scan or a PET/CT scan and, if clinically indicated, a bone 
marrow biopsy. 
Patients will receive the study regimen (BRiM), approximately every 28 days for up 
to 6 cycles. Patients will undergo clinical and laboratory evaluation on 
approximately Day 1, 8, 15 and 22 of Cycle-1 of therapy, and a on Day 1 and 15 of 
each subsequent cycle of treatment.  
Patients will undergo radiographic assessment of response using a CT scan or a 
PET/CT scan after Cycle-3 and Cycle-6 of therapy. Bone marrow aspiration and 
biopsy may be performed after completion of therapy if indicated to confirm 
complete remission. 
Test Product, Dose, 
and Mode of 
Administration: 
Commercially available preparation of bendamustine and rituximab will be used in 
this study, and administered as in general clinical practice. The drugs will be 
administered as outpatient, intravenously. 
VSCLI (Marqibo®) will be supplied as a single use, 3-vial kit designed to enable 
entrapment of vincristine in liposomes at the time of use.  
Patients will receive Marqibo® at a patient-specific dose determined at the time of 
registration by the EWOC algorithm, from 1.8 mg/m2 up to the ceiling dose of 2.4 
mg/m2 (maximal actual dose given to any study patient will be 2.3 mg/m2), as an 
intravenous infusion over 60 minutes on Day 2 of each cycle.  
Dose Escalation Schedule 
Dose Level 
Dose* 
Rituximab 
(mg/m2) 
Bendamustine 
(mg/m2) 
Marqibo® 
(mg/m2) 
Level 1 
375 (Day 1) 
90 (Day 1 and 2) 
1.80 
Levels 2-10 
375 (Day 1) 
90 (Day 1 and 2) 
EWOC-specified 
1.8 – 2.4 mg/m2 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than 
as a percentage. 
Criteria for 
Evaluation: 
Dose-limiting toxicity (DLT) will be defined as one of the following adverse 
reactions occurring during the first cycle of study therapy: 
• 
Grade 4 neutropenia (< 500/mm3) lasting  > 7 days 
• 
Grade 3 neutropenia (<1000/mm3) with fever or infection; 


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• 
Grade 4 thrombocytopenia (<25,000/mm3); 
• 
Grade 3 thrombocytopenia (<50,000/mm3) requiring transfusion; 
• 
Grade 3 or 4 treatment-related non-hematologic toxicity, excluding: 
− 
Alopecia.  
− 
Grade 3 nausea or vomiting if corrected to ≤ grade 2 within 48 hours.  
− 
Grade 3 or 4 infusion reactions if occurring on Day 1 of Cycle 1. 
• 
Delay of 2nd cycle of treatment for >14 days. 
Safety: 
Adverse events and laboratory results will be summarized as proportions of patients 
experiencing toxicity. Toxicity will be graded according to the NCI CTCAE v4.0. 
Efficacy: 
Response rate will be evaluated according to The Revised International Working 
Group Response Criteria for malignant lymphomas.  
Statistical Methods 
and Sample Size: 
 
The primary endpoint (Maximum tolerated dose, MTD) will be defined as the dose 
level of Marqibo® in the BRiM combination, that when administered to a patient 
results in a probability of 33% that a DLT will be manifest within the first cycle of 
treatment. For this purpose, consecutive patients will be treated with BRiM 
chemotherapy using escalating doses of Marqibo®. Subjects will be enrolled in 
cohorts of N=1 (i.e. the next subject will be enrolled only after the DLT status of all 
previous subjects have been resolved and a new dose level assigned). The dose 
escalation schema will use the Escalation With Overdose Control (EWOC) design 
and software—a Bayesian method permitting precise determination of the 
therapeutic working-dose while directly controlling the likelihood of an overdose. 
MTD will be determined after completion of the study using the EWOC algorithm. 
It will be calculated as the median of the marginal posterior distribution of the MTD, 
rounded to 0.05 mg/m2. 
The Marqibo® dose will be escalated from the starting dose (1.8 mg/m2). The 
maximum dose in the escalation scheme will be set at 2.4 mg/m2, but this dose is 
never actually administered to any patient. The maximum actual dose that might be 
administered in the absence of any DLT’s will be 2.3 mg/m2.  
The trial will be terminated if the first three patients experience a DLT or 
anytime the posterior probability that the DLT rate at the minimum dose 
exceeds 0.33 is 0.8 or more..  
The baseline rate of serious adverse events (SAE) with BR is assumed to be equal to 
19% (as derived from the STiL phase III trial, Rummel et al., Lancet. 
2013;381(9873):1203-10). The sample size of 10 subjects for the current study is 
chosen on the basis of a simulation of N=100 trials, assuming the target probability 
of DLT (θ) of 33%, probability of exceeding target dose (α) of 25% (with variable 
α increment of 5%), starting Marqibo® dose of 1.8 mg/m2, and maximal dose of 2.4 
mg/m2. The study will be able to correctly estimate the MTD in the range of 1.80 
mg/m2 to 2.20 mg/m2 with >80% of patients treated at ±10% of the optimal dose.  
A simulation of N=500 trials with the above parameters, with sample size varying 
between 10 and 30, demonstrates that for the range of true MTD from 1.85 mg/m2 
to 2.20 mg/m2, trials with sample size of 10 will deliver a reasonably precise estimate 
of MTD according to the operating characteristics described in Section 16. 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
AUCinf 
Area under the concentration vs. time curve extrapolated to  infinity 
BP 
Blood pressure 
BR 
Bendamustine and rituximab 
BRiM 
Bendamustine, rituximab and Marqibo®  
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CHOP 
Cyclophosphamide, doxorubicin, vincristine, prednisone 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete remission 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
Cyclophosphamide, vincristine and prednisone 
CYP3A4 
Cytochrome P450 3A4 
DA-EPOCH 
Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and 
doxorubicin 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
EWOC 
Escalation With Overdose Control  
FDG 
Fluorodeoxyglucose 
FL 
Follicular lymphoma 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug (Application) 
IRB 
Institutional review board 
IV 
Intravenous 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 


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LPL 
Lymphoplasmacytic lymphoma 
MCL 
Mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MTD 
Maximal tolerated dose 
MZL 
Marginal zone lymphoma 
NCCN 
National Comprehensive Cancer Network  
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s lymphoma 
nM 
Nanomolar 
PD 
Progressive disease 
PE 
Physical examination 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PR 
Partial remission 
PT 
Prothrombin time 
PVC 
Poly vinyl chloride 
RCHMP 
Rituximab, cyclophosphamide, doxorubicin, Marqibo® , prednisone 
RCHOP 
Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum glutamic oxalo-acetic transaminase (same as AST) 
SGPT 
Serum glutamic pyruvic transaminase (same as ALT) 
SPD 
Sum of the product of diameters 
US 
United States 
USP 
United States Pharmacopeia 
vs 
versus 
VSLI 
Vincristine sulfate liposome injection 
WBC 
White blood cell (count) 


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TABLE OF CONTENTS 
ABBREVIATIONS 7 
TABLE OF CONTENTS .................................................................................................................9 
1. 
OBJECTIVES 11 
1.1 
Primary Objectives.................................................................................................11 
1.2 
Secondary Objectives.............................................................................................11 
2. 
BACKGROUND ...............................................................................................................11 
2.1 
Therapy of Mature B-Cell Non-Hodgkin Lymphomas .........................................11 
2.2 
Bendamustine-Rituximab: Standard Front-Line Therapy in Indolent NHL ..........11 
2.3 
Combinations of Bendamustine (with or without Rituximab) with Other 
Cytotoxic Agents, Including Vincristine ...............................................................13 
2.4 
Vincristine Sulfate .................................................................................................13 
2.5 
Vincristine Sulfate Liposome Injection (VSLI, Marqibo® ) .................................14 
2.6 
Rationale for the BRiM combination .....................................................................17 
3. 
PATIENT ELIGIBILITY ..................................................................................................18 
3.1 
Eligibility Criteria ..................................................................................................18 
3.2 
Exclusion Criteria ..................................................................................................19 
3.3 
Inclusion of Women and Minorities ......................................................................20 
4. 
TREATMENT ...................................................................................................................21 
4.1 
Agent Administration.............................................................................................21 
4.2 
Criteria to initiate the next cycle ............................................................................21 
4.3 
Ancillary Therapy ..................................................................................................22 
4.4 
Prior and Concomitant Medications ......................................................................22 
4.5 
Duration of Therapy ...............................................................................................23 
5. 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ...............................23 
5.1 
Neutropenia ............................................................................................................24 
5.2 
Thrombocytopenia (CTCAE 4.0: Platelet count decreased)..................................24 
5.3 
Nausea and Vomiting .............................................................................................24 
5.4 
Constipation ...........................................................................................................25 
5.5 
Diarrhea..................................................................................................................25 
5.6 
Rituximab infusion and hypersensitivity reactions ................................................26 
5.7 
Other non-hematologic, treatment-related toxicities .............................................26 
6. 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR ............................................27 
6.1 
Dose-Limiting Toxicity (Definition) .....................................................................28 
6.2 
Disease Assessments ..............................................................................................28 
6.3 
Off Study Assessment ............................................................................................28 
7. 
RESPONSE ASSESSMENT .............................................................................................29 
7.1 
Definitions of response ..........................................................................................29 
8. 
REGISTRATION PROCEDURES ...................................................................................32 
8.1 
General Guidelines.................................................................................................32 
9. 
PHARMACEUTICAL INFORMATION ..........................................................................32 
9.1 
Rituximab (IDEC-C2B8) .......................................................................................33 


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9.2 
Bendamustine hydrochloride .................................................................................34 
9.3 
Vincristine sulfate liposomal injection (Marqibo®) ..............................................36 
10. 
AGENT ACCOUNTABILITY ..........................................................................................42 
10.1 
Agent Inventory Records .......................................................................................42 
10.2 
Treatment Compliance ...........................................................................................43 
11. 
ADVERSE DRUG REACTION REPORTING ................................................................43 
11.1 
Adverse Events and Potential Risks List ...............................................................43 
11.2 
Routine Adverse Event Reporting .........................................................................46 
11.3 
Serious Adverse Event Reporting ..........................................................................47 
11.4 
Overdosage ............................................................................................................48 
11.5 
Procedures in the Event of Pregnancy ...................................................................48 
12. 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ........................................49 
13. 
REGULATORY CONSIDERATIONS .............................................................................49 
14. 
DATA MONITORING, QUALITY ASSURANCE AND RECORD RETENTION .......49 
14.1 
Rationale for the study and subject selection .........................................................49 
14.2 
Data and Safety Monitoring Plan ...........................................................................49 
14.3 
Investigator Responsibilities ..................................................................................50 
14.4 
Drug Manufacturer’s Responsibilities ...................................................................52 
15. 
DATA SAFETY AND MONITORING BOARDS ...........................................................52 
16. 
STATISTICAL CONSIDERATIONS...............................................................................52 
16.1 
Study Design/Endpoints.........................................................................................52 
16.2 
EWOC Phase I design ............................................................................................54 
16.3 
Dose Escalation Procedure ....................................................................................55 
16.4 
Assignment of Marqibo® Dose Level ...................................................................55 
16.5 
Sample Size/Accrual Rate ......................................................................................56 
REFERENCES 
58 
APPENDIX A 
Performance status criteria .........................................................................63 
APPENDIX B 
List of Concomitant Medications Known to Interact with Cytochrome 
P450-3A4 Isoenzymes and/or P-glycoprotein (to be used with caution)+ ........................64 
APPENDIX C 
Registration checklist .................................................................................65 
APPENDIX D 
Model Informed Consent Form .................................................................67 
 
 


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1. OBJECTIVES 
1.1 
Primary Objectives 
• To establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of 
vincristine sulfate liposome injection (Marqibo®) in combination with bendamustine and 
rituximab (BRiM).  
• To establish the dose-limiting toxicities (DLT) of vincristine sulfate liposome injection 
(Marqibo®) in combination with bendamustine and rituximab (BRiM). 
1.2 
Secondary Objectives 
• To evaluate cumulative rates of non-DLT toxicities during the six planned cycles of the 
BRiM combination in patients with indolent non-Hodgkin lymphoma. 
• To evaluate tolerability, assessed by rate of completion of the planned six cycles of BRiM 
chemotherapy. 
• To evaluate response rate (RR) and complete response rate (CR) of the BRiM regimen in 
the study population of indolent non-Hodgkin lymphoma patients. 
2. BACKGROUND 
2.1 
Therapy of Mature B-Cell Non-Hodgkin Lymphomas 
Mature B-cell non-Hodgkin lymphomas (NHL) are a highly heterogeneous group of lymphoid 
malignancies, which comprise nearly 20 subtypes according to the most recent 2008 World Health 
Organization classification. They range from indolent lymphomas often managed by “watchful 
waiting” until symptomatic phase, to highly aggressive diseases associated with poor prognosis 
and immediate need for aggressive chemotherapy.1 B-cell NHL is typically treated with 
chemotherapy in combination with the monoclonal antibody rituximab.  
The treatment in aggressive B-cell NHL, such as diffuse large B-cell lymphoma (DLBCL) is 
curative and most commonly involves the RCHOP regimen (rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone). In contrast, therapy in “indolent NHL”, which include, 
among else, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma 
(MZL), lymphoplasmacytic lymphoma (LPL) and small lymphocytic lymphoma (SLL), is geared 
towards achieving a partial or complete remission, although most patients experience further 
recurrences of the disease and are not cured. 
For decades, regimens utilizing the alkylating agent cyclophosphamide and vincristine, such as 
CHOP/RCHOP and CVP/RCVP, have been the mainstay of therapy for B-cell NHL. A number of 
randomized studies have established RCHOP as the standard treatment for DLBCL.2-6 In indolent 
B-cell NHL, the acceptable front-line regimens included rituximab alone, RCHOP, RCVP and 
combinations of rituximab with fludarabine ± mitoxantrone—depending on patient characteristics, 
comorbidities and burden of the lymphoma.7-11 MCL is associated with poorer prognosis than other 
indolent NHLs and in recent trials more aggressive treatments are investigated for this disease.12 
These regimens are typically prescribed for 6 to 8 cycles, delivered every 21 days, with additional 
chronic maintenance therapy using single-agent rituximab in FL.9 
2.2 
Bendamustine-Rituximab: Standard Front-Line Therapy in Indolent NHL 
Bendamustine is an alkylating neoplastic agent. Rituximab is a monoclonal antibody against the 
CD20 molecule present on mature B-cells. In 2005 the combination of bendamustine with 


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rituximab has shown high activity in relapsed/refractory indolent NHL (FL and MCL). In a phase 
II trial of 63 patients, Rummel et al. achieved an overall response rate of 90% and complete 
remission rate of 60%, with a median progression-free survival (PFS) of 24 months.13 This regimen 
was notable for its tolerability: non-hematologic toxicities were limited to grade 1-2, with at 16% 
risk of grade 3/4 neutropenia, and only 3% rate of other grade 3-4 hematologic toxicities. These 
results were confirmed in a North American phase II study, with an overall response of 92%, CR 
rate of 41%, PFS of 23 months and 36% rate of grade 3-4 neutropenia and very rare non-
hematologic severe adverse events: febrile neutropenia 6%, infections 10%.14 The BR regimen is 
not associated with significant rates of peripheral neuropathy or ileus. 
Two subsequent large randomized trials have compared BR with RCHOP/RCVP as a front-line 
therapy in indolent NHL. The German Study Group for Indolent Lymphomas (StiL) trial 
randomized 549 patients with FL, MCL, MZL, LPL, SLL or other low-grade B-cell NHL (not 
otherwise specified, NOS) to 6 cycles of RCHOP or BR.15 At a median follow-up of 45 months, 
BR was associated with a significantly longer PFS (68.5 months vs 31.2 months, hazard ratio 0.58,  
95% CI 0.44-0.74), and significantly improved CR rate (40% vs 30%), despite similar overall RR 
(93% vs 91%). The overall survival did not differ between the treatment groups. In the BRIGHT 
study, 487 patients with indolent NHL were randomized to RCHOP/RCVP or BR.16 In this trial, 
BR was shown to be non-inferior to RCHOP/RCVP in the primary endpoint (CR, 31% vs 25%), 
as well as overall RR (97% vs 91%).  
In both studies, the toxicity of BR was significantly more favorable than that of RCHOP, and was 
generally quite manageable, with very low rates of non-hematologic grade 3-4 toxicities. 
Moreover, BR was shown to improve patients’ quality of life better than RCHOP/RCVP in the 
BRIGHT study.17 
Table 1. Rates of adverse events in phase III trials of BRin indolent NHL. 
Grade 3-4 adverse event 
Rate in StIL 
Rummel at al.15 
Rate in BRIGHT 
Flinn et al.16 
All grade 3-4 
19% 
Not reported 
Neutropenia 
29% 
39% 
Anemia 
3% 
0% 
Thrombocytopenia 
5% 
10% 
Infection 
Not reported 
12% 
Vomiting 
0% 
5% 
Fatigue 
0% 
4% 
Other (grade 1-4) 
 
 
Infection 
37% 
55% 
Paresthesiae 
7% 
9% 
Stomatitis 
6% 
3% 
Skin (erythema) 
16% 
 
Skin (allergic reaction) 
15% 
20% 
Sepsis 
<1% 
 
The results of those two randomized studies established BR as a standard front-line regimen in 
indolent B-cell lymphomas. Current US national guidelines from the National Comprehensive 
Cancer Network (NCCN Guidelines®) for the management of indolent NHL recommend BR as a 
top category 1 front-line treatment option for patients with FL (grade 1-2), MCL (for patients 
requiring less aggressive therapy), disseminated non-gastric MZL, and LPL.18 


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2.3 
Combinations of Bendamustine (with or without Rituximab) with Other Cytotoxic 
Agents, Including Vincristine 
Because of the excellent toxicity profile of BR, several studies have evaluated combinations of 
this regimen with additional chemotherapeutic agents. In a phase II study in 40 patients with MCL 
ineligible for more intense regimens, bendamustine (70 mg/m2 on Day 1, 2) with rituximab (375 
mg/m2 on Day 1) and cytarabine (MTD of 800 mg/m2 on Day 2, 3, 4) showed acceptable tolerance, 
with reversible myelosupression as the principal toxicity: 12% rate of febrile neutropenia, transient 
grade 3-4 thrombocytopenia in 87%, 35% rate of fatigue (5% grade 3), 15% rate of infection (12 
% grade 2-3), 15% rate of rash, 10% rate of elevated transaminases (2% grade 3) and 40% gamma-
glutamyltransferase elevation.19 This regimen was characterized by a highly encouraging 100% 
RR in previously untreated patients (80% in relapsed/refractory MCL). 
In relapsed/refractory indolent NHL, BR has been also combined with bortezomib—a proteasome 
inhibitor characterized by peripheral neuropathy and thrombocytopenia as the principal dose-
limiting toxicities.20 The regimen of bendamustine (90 mg/m2 on Day 1 and 4), rituximab (375 
mg/m2 on Day 1) and full-dose bortezomib (1.3 mg/m2 on Day 1, 4, 8, 11) was administered to 30 
patients, and most non-hematologic adverse events were grade 1-2 only with the rates of nausea 
50%, neuropathy 47%, fatigue 47%, constipation 40% and fever 40%. Eight patients (26%) 
experienced serious adverse effects, which included gr. 4 liver/renal failure, gr. 5 sepsis, gr.3 
peripheral neuropathy, fatigue, hypotension, herpes zoster and dehydration (in 1 or 2 cases each). 
This toxicity was deemed acceptable to proceed with a randomized study of BR with 
BR+bortezomib (NCT01216683). Another US phase II study (VERTICAL trial) of bortezomib 
and BR in 73 patients with relapsed/refractory FL also showed limited toxicity, with dose 
escalation of bendamustine from 50 mg/m2 to 90 mg/m2 (on Day 1, 2) without reaching the MTD.21 
The overall rate of  ≥ grade 3 toxicities was 77%, with 34% patients experiencing an SAE. The 
rates of grade 3-4 toxicities were: neutropenia 25%, thrombocytopenia 14%, fatigue 12%, diarrhea 
12%, neuropathy 11%, vomiting 8%, nausea 7%. The overall rate of peripheral neuropathy was 
44%, constipation 45% and fever 34%. 
Bendamustine had been previously combined with vincristine and prednisone and compared with 
an analogous regimen of cyclophosphamide, vincristine and prednisone in a phase III trial 
conducted in Germany in 2006—as a front-line therapy for patients with indolent NHL.22 The 
schedule of bendamustine in this trial differed from currently used standards (60 mg/m2 on Day 1, 
2, 3, 4 and 5—total 300 mg/m2 per cycle). The dose of vincristine was 2 mg (Day 1) and was not 
weight- or BSA-adjusted. The toxicity profile of this regimen was as follows: grade 3-4 leukopenia 
in 19%, anemia in 10%, thrombocytopenia 4%, infection 2% (all grades: 14%), peripheral 
neuropathy 1.2% (all grades: 35%), constipation 0.8% (all grades: 10%). The protocol initially 
specified bendamustine at 70 mg/m2 for 5 days (total dose per cycle 350 mg/m2), which was 
reduced after enrollment of the first 25 patients because of significant thrombocytopenia. There 
were no significant differences between those two arms in the rate of RR, CR, although PFS 
favored the bendamustine-based combination. 
Those results suggest that BR can be safely combined with other cytotoxic agents that may cause 
peripheral neuropathy or myelosupression, including vincristine sulfate. 
2.4 
Vincristine Sulfate 
Vincristine sulfate (22-oxovincaleukoblastine) is an alkaloid antineoplastic agent derived from the 
periwinkle plant (Vinca rosea Linn.), with a high activity against lymphoid neoplasms. Vincristine 


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is a cell-cycle-specific agent which causes mitotic arrest in the M-phase by binding tubulin, a 
protein component of microtubules, and disrupting cell division. Vincristine sulfate is a significant 
component of some of the most active chemotherapy regimens for NHL, including RCVP, RCHOP 
or DA-EPOCH. It is also an essential component of treatment in high-grade lymphoid 
malignancies such as acute lymphoblastic leukemia and lymphoblastic lymphoma. Vincristine is 
metabolized primarily by the liver and excreted in the bile and feces. Elimination half-life in adults 
varies widely between 164 and 5100 minutes, depending on the assay, dose and rate of 
administration.23 
The dose-limiting toxicity of vincristine sulfate is neurological.23,24 In its most common form it is 
dose-dependent, symmetrical, and manifests as peripheral sensory and motor neuropathy. It can 
be classified as early—within 1 week of administration (decreased deep tendon reflexes, jaw or 
thigh pain, ileus), intermediate—within 2-3 weeks (paresthesiae, sensory loss, constipation, 
bladder dysfunction, hyponatremia related to the syndrome of inappropriate antidiuretic hormone), 
and late—beyond 3 weeks: foot/wrist drop, postural hypotension and erectile dysfunction, 
ophthalmoplegia, dysphagia. Cranial nerve damage or encephalopathy are rare. Distal neuropathy 
may progress to severe pain, weakness, gait disturbance, motor and sensory impairment. 
Vincristine-induced  neuropathy is generally reversible although recovery may take months and is 
often incomplete. Because the toxicity was historically seen particularly in children treated with 
high doses (1.5-2.0 mg/m2 weekly), the dose of vincristine sulfate is typically capped at total 2 mg 
per dose in all currently used regimens.25 
Other toxicities associated with vincristine sulfate are rare and include alopecia, hyponatremia, 
constipation and colicky abdominal pain. These reflect a vincristine-induced autonomic nervous 
system dysfunction. Fatal adynamic ileus has been rarely observed. Vincristine sulfate is a vesicant 
and its extravasation can result in painful local inflammation. At conventional vincristine sulfate 
doses, myelosuppression is uncommon. 
2.5 
Vincristine Sulfate Liposome Injection (VSLI, Marqibo® ) 
Marqibo® 
(vincristine 
sulfate 
liposomes 
injection) 
is 
vincristine 
encapsulated 
in 
sphingomyelin/cholesterol liposomes. The lipid components in the liposome are sphingomyelin 
and cholesterol at a molar ratio of approximately 60:40 (mol:mol). Marqibo® was developed to 
improve activity, therapeutic index and pharmacokinetic profile of vincristine sulfate.26,27 Clinical 
pharmacokinetic studies have shown it to be a long-circulating, slow release formulation, which 
in adults is characterized by an initial 3 to 12 hours delay in clearance after administration. This 
results in total vincristine levels that remain relatively constant before declining with time. It 
contributes significantly to the greater plasma exposure of total vincristine that is observed after 
administration of Marqibo® as compared to vincristine sulfate. The pharmacokinetics of total 
vincristine was not altered significantly after repeated dosing of Marqibo® up to 3 cycles (2.0 
mg/m2 every 2 weeks=1 cycle). Liposomal encapsulation of vincristine sulfate does not alter its 
route of excretion from the body which is primarily biliary/fecal with urinary elimination 
comprising a minor pathway. Marqibo® has been administered to 809 subjects in 20 studies and 
2 compassionate use programs since program initiation. It is currently approved by the US Food 
and Drug Administration for use at a dose of 2.25 mg/m2 weekly in adults with Philadelphia 
chromosome-negative acute lymphoblastic leukemia in second or greater relapse or whose disease 
has progressed following two or more anti-leukemia therapies. 


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2.5.1 Pharmacokinetics 
The pharmacokinetics of Marqibo® was examined in a series of 7 clinical studies in adults with 
various solid and hematologic tumors, in hepatically impaired subjects, and in children with 
various tumors. The data are consistent and show that vincristine is retained in the plasma 
encapsulated in the liposomes for extended periods after administration of Marqibo®.28 Released 
vincristine is undetectable at most time points in all patients for whom this was evaluated. 
Therefore, the total vincristine measured in plasma reflects liposomally encapsulated drug that 
may not be immediately bioavailable and may not be directly comparable to plasma levels of 
vincristine after administration of standard vincristine sulfate injection, which provides the drug 
in an immediately bioavailable form. Interpatient variability is high; however plasma clearance 
profiles for individual patients are consistent upon repeated exposure to Marqibo®. No drug 
accumulation in plasma is apparent upon repeated exposure with a 14 day interval. No consistent 
change in AUC or clearance was observed between Cycles 1 and 3 of treatment at 2.0 mg/m2 every 
14 days. Following IV administration of Marqibo®, urinary excretion was a minor route of 
elimination for vincristine and a metabolite, N-desformylvincristine. Less than 8% of the 
administered dose was eliminated in urine over the 96 hour observation period. Total vincristine 
clearance and plasma exposure (AUCinf) did not appear to be influenced by gender, age, BSA, or 
cancer type. 
2.5.2 Efficacy and toxicity as a single agent in NHL 
In a phase I study of 25 patients with various solid tumors, the maximum tolerated dose of 
Marqibo® was established at 2.4 mg/m2 every 3 weeks and the recommended phase II dose was 
2.0 mg/m2.29 Myalgias and constipation were the DLT at the dose of 2.8 mg/m2. Early 
hypersensitivity with transient fever was reported in 60% of patients during the first infusion. 
Altogether in this study the rates of grade 3-4 toxicities were: constipation 12%, alopecia 8%, 
fatigue 8%, anemia 8%, other at 4%: nausea, neuropathy, fever, pain, myalgias, leukopenia, 
neutropenia (grade 4), and thrombocytopenia. 
Sarris et al. studied Marqibo® as a single-agent at the dose of 2.0 mg/m2 every 14 days in 51 
patients with relapsed NHL, all of whom had pre-existing grade 1-2 neuropathy.30 They observed 
no grade 3-4 nausea, vomiting, stomatitis, ileus, obstipation or hematologic toxicities. 31% of 
patients experienced worsening of neuropathy to grade 3, but it improved in all patients within 
weeks of discontinuation of Marqibo®. Febrile neutropenia occurred in 6% of patients, all of 
whom had a pre-existing neutropenia. Responses were seen in 41% of patients, particularly in 
aggressive or transformed NHL. Rodriguez et al. reported a phase II study of single-agent 
Marqibo® (2.0 mg/m2 every 2 weeks) in 119 patients with refractory aggressive NHL (primarily 
DLBCL).31 They observed a 25% RR, with very limited toxicities and predominantly grade 1/2 
adverse events, 24% rate of dose modifications and 20% rate of dose delays. Neuropathy was the 
predominant reason for treatment discontinuation or dose modification. Grade 3/4 neuropathy 
occurred in 32%, all of whom had baseline grade 2 neuropathy. Other grade 3/4 toxicities included: 
gastrointestinal (11%), dyspnea (5%), fatigue (7%), fever (2%), constipation (3%), pain (7%), 
weakness (18%), anemia (15%), neutropenia (27%), thrombocytopenia (12%). 
Single-agent Marqibo® was extensively studied as a treatment for refractory ALL. In a Phase II 
trial of Marqibo® at 2.0 mg/m2 every 2 weeks, the RR was 14%.32 The non-hematologic toxicity 
was minimal in that study, with two cases (12%) of grade 1 peripheral neuropathy, grade 2 
orthostasis and headaches. Subsequently, 65 adults with relapsed/refractory Philadelphia-negative 


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16 
ALL were treated with high-dose Marqibo® at 2.25 mg/m2 weekly in a pivotal phase II trial, which 
demonstrated a 35% RR.33 At this dose 86% of patients had a neuropathy-associated adverse 
effect, with 39% experiencing at least one ≥ grade 3 event, most commonly neuropathy-related 
(23%), constipation or abdominal pain (6%), fatigue, asthenia or fever (aggregate 8%). The rates 
of hematologic grade 3/4 adverse effects were: neutropenia 16%, anemia 5%, thrombocytopenia 
7%, febrile neutropenia 3%. 
2.5.3 Combinations with rituximab and/or cytotoxic agents 
Marqibo® has been used in combination with rituximab and with RCHOP-like regimen in B-cell 
NHL, without signals of increased or unexpected toxicities. Kaplan et al. combined Marqibo® at 
2.0 mg/m2 every 2 weeks with rituximab 375 mg/m2 in 22 patients with relapsed/refractory 
DLBCL or MCL in need of palliative therapy, reporting an overall RR of 59%, including 27% 
CR.34 The toxicity profile was consistent with single-agent experience for Marqibo® (Table 2). 
Hagemeister et al. used Marqibo® 2.0 mg/m2 as a substitute for vincristine sulfate in the RCHOP 
regimen (with standard doses of rituximab, cyclophosphamide, doxorubicin and prednisone, every 
21 days) for untreated DLBCL.35 This RCHMP regimen achieved a 96% response rate with 90% 
CR rate. The safety profile was not different than what would be expected with RCHOP in this 
population (Table 2).  
These two studies indicate that Marqibo® can be safely combined with rituximab and full-dose 
alkylating agents for the treatment of NHL, without unexpected toxicities. 
Table 2. Rates of adverse events in studies combining Marqibo® with rituximab or 
rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHMP). 
    
Rituximab-Marqibo®34  
  
 R-CHMP35  
    
All grades, 
% 
Gr. 3, 
% 
Gr. 4, 
% 
 
All grades, 
% 
Gr. 3, 
% 
Gr. 4, 
% 
Any event 
100 
59 
18 
  
100 
24 
53 
Neurologic 
87 
46 
- 
  
86 
11 
- 
  Headache 
9 
- 
- 
  
15 
3 
- 
  Numbness 
9 
- 
- 
  
39 
3 
- 
  Neuropathy 
 
 
 
  
36 
3 
- 
 
   Motor 
23 
18 
- 
 
 
 
 
 
   Sensory 
36 
18 
- 
 
 
 
 
 
   NOS 
23 
9 
- 
 
 
 
 
  Weakness 
18 
9 
- 
  
12 
3 
- 
Gastrointestinal 
55 
5 
- 
  
72 
6 
- 
  Constipation 
46 
5 
- 
  
15 
- 
- 
  Diarrhea 
- 
- 
- 
  
15 
1 
- 
  Nausea 
23 
- 
- 
  
53 
1 
- 
  Vomiting 
- 
- 
- 
  
35 
1 
- 
  Stomatitis 
- 
- 
- 
  
14 
1 
- 
Hematologic 
55 
23 
18 
  
83 
21 
53 
  Leukopenia 
27 
14 
5 
  
7 
1 
6 
  Neutropenia 
41 
14 
- 
  
72 
14 
50 
  Anemia 
18 
- 
- 
  
28 
4 
0 


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Rituximab-Marqibo®34  
  
 R-CHMP35  
  Thrombocytopenia 
18 
5 
- 
  
18 
13 
1 
  Febrile neutropenia 
9 
9 
- 
  
21 
18 
1 
Other 
64 
5 
- 
  
72 
4 
- 
  Fatigue 
46 
5 
- 
  
39 
1 
- 
  Mucosal 
inflammation 
- 
- 
- 
  
15 
- 
- 
  Pyrexia 
18 
- 
- 
  
31 
3 
- 
  Metabolic/nutrition 
14 
5 
- 
  
24 
7 
- 
  Dyspnea 
- 
- 
- 
  
17 
0 
- 
  Infection 
23 
5 
- 
  
 Not reported  
2.6 
Rationale for the BRiM combination 
The front-line therapy of indolent B-cell NHL has shifted from combinations of cyclophosphamide 
and vincristine (RCHOP, RCVP) to the alkylator-only regimen (BR), which has superior efficacy, 
but does not benefit from synergy of alkylating and microtubule-disrupting agents which are 
characterized by different mechanisms of action. Although bendamustine is a superior alkylating 
agent compared with cyclophosphamide, it has not advanced to therapy of aggressive lymphomas 
because of the need to safely introduce it into multi-agent regimens necessary for the cure of 
DLBCL. There is thus an unmet need for a bendamustine-based multi-agent chemotherapy 
combination that could incrementally improve therapy of indolent NHL and provide a backbone 
for novel curative regimens in DLBCL. Considering non-overlapping toxicities, BR-vincristine 
combination is a natural choice for this goal, reflecting the synergy utilized in 
cyclophosphamide/vincristine combinations. Marqibo®, a novel liposomal formulation allowing 
for improved pharmacokinetics and efficacy of vincristine sulfate, is a promising agent that could 
be combined with BR, potentially enhancing the effects of this regimen without additional toxicity.  
In front-line therapy of indolent B-cell NHL, BR provides 30-40% rate of complete remission.16 
The augmented regimen may be particularly beneficial for patients with indolent B-cell NHL who 
are classified as higher-risk. At present, patients with indolent NHL are treated as a homogeneous 
group with the standard BR regimen. However in FL significant heterogeneity in prognosis is 
recognized, captured by clinical prognostic scores such as FLIPI and FLIPI-2.36-38 About 27% of 
patients with FL can be classified as high-risk FLIPI-2 and these patients experience a PFS rate of 
only about 50% at 3 years and 19% at 5 years with standard therapy.37 An addition of a highly 
active agent such as Marqibo® to the front-line chemoimmunotherapy regimen may improve 
outcomes in this group without compromising safety. 
BR has also been widely used as a front-line therapy for patients with MCL who are ineligible for 
more aggressive strategies.15 However, MCL remains difficult to treat, with >50% of patients 
experiencing relapse within 3 years. Although the addition of cytarabine to BR may improve 
response rates and potentially duration of remission, it is associated with significantly increased 
toxicity (despite a lower dose of bendamustine, 70 mg/m2), particularly thrombocytopenia 
requiring transfusion (65% of cycles) which prevented any dose escalation in the trial.19 BRiM 
may offer a more tolerable alternative in this disease. 


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3. PATIENT ELIGIBILITY 
3.1 
Eligibility Criteria  
3.1.1 Documentation of disease. 
Patients must have histologically confirmed indolent B-cell non-Hodgkin lymphoma, 
CD20-positive, previously treated or untreated—for which bendamustine-rituximab 
chemotherapy is clinically indicated; the following subtypes are allowed: 
− 
Follicular lymphoma 
− 
Mantle cell lymphoma,  
− 
Marginal zone lymphoma,  
− 
Small lymphocytic lymphoma,  
− 
Lymphoplasmacytic lymphoma, or 
− 
Indolent B-cell lymphoma, NOS.  
BrUOG must receive the pathology report to confirm the diagnosis and the CD20-positive 
status, as well as documentation from the treating physician that bendamustine-rituximab 
chemotherapy is clinically indicated for the subject. 
3.1.2 Radiological measurable disease, defined as any measurable lesion >15 mm on the staging 
CT or PET/CT. Patients with blood or bone marrow involvement only are ineligible. 
Splenomegaly is acceptable as a measurable site if enlarged on the initial CT scan (>13 cm 
in the cranio-caudal dimension). 
3.1.3 Previous treatment for lymphoma is allowed, with the exception of use of bendamustine 
within 180 days of the date of the consent form, or any prior use of vincristine sulfate 
liposome injection (Marqibo®).  
3.1.4 Age ≥18 years.   
3.1.5 ECOG performance status 0 or 1 (see Appendix A). 
3.1.6 Life expectancy of greater than 6 months. 
3.1.7 Patients must have adequate organ and marrow function as defined below: 
− 
leukocytes 
 
≥3,000/mm3 
− 
absolute neutrophil count 
 
≥1,000/mm3 
− 
platelets 
 
≥75,000/mm3 (without a transfusion within 1 week) 
Note: if a transfusion was given, it must be documented with a date on the ConMed log 
− 
total bilirubin 
 
within normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
 
<2.5 × institutional upper limit of normal 
− 
creatinine 
 
≤2.0 mg/mL, AND 
− 
creatinine clearance 
 
≥50 mL/min/1.73 m2. 
calculated by method of Cockroft and Gault, using actual weight: 
CrCl (mL/min) = (140 - age in years)  x  actual weight (in kg)    x  0.85 (for female patients) 
  
 
72  x  serum creatinine (mg/dL) 


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3.1.8 Prevention of pregnancy. 
The effects of bendamustine and vincristine on the developing human fetus are unknown.  
For this reason and because Class D agents (bendamustine, vincristine) are known to be 
teratogenic, women and men of child-bearing potential must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence; vasectomy) prior 
to study entry and up to 4 months after the last dose of study treatment.  
3.1.9 Women of childbearing potential must have a negative serum or urine pregnancy test 
within 14 days prior to first treatment on study (Cycle 1, Day 1). Should a woman 
become pregnant or suspect she is pregnant while she or her partner is participating in 
this study, she should inform her treating physician immediately.  Postmenopausal 
women (after surgical menopause or no menses for >12 months) do not need to have a 
pregnancy status, but their postmenopausal status must be documented.  
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
The patient must be aware of the neoplastic nature of his/her disease and must willingly 
consent after being informed of the procedure to be followed, the experimental nature of 
the therapy, alternatives, potential benefits, side effects, risks, and discomforts.  
3.2 
Exclusion Criteria 
3.2.1 History of any allergic reaction attributed to rituximab (with the exception of <grade 3 
infusion reaction), bendamustine, vincristine sulfate, Marqibo®, mannitol, sodium 
phosphate injection or sphingomyelin/cholesterol liposome. 
3.2.2 Patients who have had any lymphoma-directed radiotherapy, chemotherapy, biologic or 
experimental therapy, oral or intravenous, within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C) prior to entering the study or those who have not recovered from adverse 
events due to agents administered more than 4 weeks earlier to ≤grade 1—with the 
exception of alopecia, which is allowed. 
3.2.3 Any prior treatment with vincristine sulfate liposome injection (Marqibo®). 
3.2.4 Prior treatment with bendamustine or vincristine sulfate within 180 days of enrollment. 
Prior treatment with rituximab is allowed. 
3.2.5 Patients who are receiving any other investigational agents or anti-cancer therapy with 
the exception of endocrine therapy for breast or prostate cancer. 
3.2.6 Patients with known central nervous system involvement (infiltration of the brain, 
meninges or cerebrospinal fluid) by the lymphoma are excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
3.2.7 Active peripheral sensory or motor neuropathy > grade 1. This is defined by the CTCAE 
as any neuropathy requiring intervention or limiting instrumental activities of daily life. 
3.2.8 History of demyelinating form of Charcot-Marie-Tooth syndrome, acquired 
demyelinating disorders, or other demyelinating condition. 
3.2.9 Documented positive test for the Human Anti-Chimeric Antibody (HACA). 
(Documentation must be sent to BrUOG) 


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3.2.10 Patients receiving any medications or substances that are strong inhibitors or inducers of 
CYP3A enzyme are ineligible. See Appendix B for the list of prohibited drugs. 
Note: Dexamethasone use as an anti-emetic according to the protocol is allowed. 
As part of the enrollment/informed consent procedures, the patient will be counseled on 
the risk of interactions with other agents, and what to do if new medications need to be 
prescribed or if the patient is considering a new over-the-counter medicine or herbal 
product. Grapefruit juice in particular has significant undesirable interactions.    
3.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
(that requires antibiotic use which is not prophylactic), symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations 
that would limit compliance with study requirements. In cases of uncertainty, the treating 
physician will request a review by BrUOG to decide whether an illness is considered 
prohibitive (planning should be used as review can take multiple days). Suppressive 
antiviral therapy with acyclovir, famciclovir, or valacyclovir for herpes simples or herpes 
zoster is allowed. 
3.2.12 Prisoners. 
3.2.13 Pregnant or breast-feeding women.  
Pregnant women are excluded from this study because bendamustine and vincristine are 
Class D agents with the potential for teratogenic or abortifacient effects.  Based on its 
mechanism of action and findings from animal studies, Marqibo® can cause fetal harm 
when administered to pregnant women. If this drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should be apprised of the 
potential hazard to a fetus. Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with bendamustine and/or 
vincristine, breastfeeding should be discontinued if the mother is treated with either agent. 
These potential risks may also apply to other agents used in this study. 
3.2.14 Known Human Immunodeficiency Virus (HIV) or active Hepatitis B infection (defined 
as presence of HBV DNA or hepatitis B S antigen in the blood).  
HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with Marqibo®. In addition, these patients are 
at increased risk of lethal infections when treated with marrow-suppressive therapy. 
Patients with active hepatitis B infection are included because of high risk of disease 
worsening during treatment with rituximab.  
3.2.15 Any prior or active cancer, which in the opinion of the investigator would preclude safe 
participation in this study. 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 


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4. TREATMENT 
4.1 
Agent Administration 
Patient must start protocol treatment within 7 days of registration on the study. Treatment 
will be delivered in 28-day courses, for no more than 6 cycles. In case of a holiday or other 
extenuating circumstances, Cycle 2-6 treatment may be initiated up to 1 day before or up to 5 days 
after that date (ie. on Day 27 to Day 33 of the cycle), provided that all Section 4.2 criteria are met. 
Other delays related to toxicity as provisioned in the protocol are allowed. No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the patient's malignancy. 
Regimen description 
Agent 
Premedications; Precautions 
Dose § 
Route 
Schedule 
Cycle  
Rituximab 
Premedicate with:  
− Acetaminophen 650 mg 
orally 
− Diphenhydramine 25 mg IV 
or orally  
375 mg/m2 
 
IV, see 
Section 9.1  
for infusion 
rate  
Day 1 
28 days  
 
 
 
Bendamustine Premedicate with: 
Day 1: 
− Palonosetron 0.25 mg IV 
− Dexamethasone 4-20 mg IV 
or orally 
− (optionally) Fosaprepitant 
150 mg IV 
Day 2: 
− Dexamethasone 4-20 mg IV 
or orally 
90 mg/m2 
 (each day) 
IV over 10 
to 30 
minutes 
Day 1  (after 
rituximab) and 
Day 2 (before 
Marqibo®) 
Marqibo® 
Only administer through a 
secure and free-flowing venous 
access line 
Instruct the patient on the 
bowel regimen 
** 
in 100mL 
NS as per 
package 
insert 
IV over 60 
minutes 
Day 2 
(after benda-
mustine) 
§   Dose should be adjusted during each cycle only if dose recalculated with an adjusted BSA differs by more 
than 10% of the dose during Cycle 1 
** Patient-specific dose calculated at registration, 1.8 to 2.4 mg/m2  
4.2 
Criteria to initiate the next cycle 
The following criteria must be met by Day 1 of a new cycle to initiate therapy: 
− 
absolute neutrophil count≥1,000/mm3 If ANC is <1,500/mm3 refer to section 5.1 and 
hold treatment if deemed related to study treatment. 
− 
platelets≥75,000/mm3 (without a transfusion within 1 week) 
− 
recovery from all non-hematologic toxicities (excluding alopecia and weight 
gain/loss) related to any of the agents administered on the protocol to <grade 2, or to 
patient’s baseline grade prior to starting therapy on protocol.  
Grade 2 toxicity that is continuing from baseline or is non-treatment related is allowed.  


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Any patient who experiences a DLT during cycle 1 must come off study. 
4.3 
Ancillary Therapy 
4.3.1 Hematopoietic Growth Factors 
Patients who meet criteria for primary prophylaxis of febrile neutropenia set by the American 
Society of Clinical Oncology may receive subcutaneous pegfilgrastim 6 mg on Day 3 or Day 4 of 
the treatment cycle, at least 24 hours after administration of study therapy.39 The high-risk factors 
that need to be considered when evaluating patient’s risk for febrile neutropenia include: age (>65 
years), poor performance or poor nutritional status, history of febrile neutropenia, open wounds or 
active infection, extensive prior treatment, cytopenias due to bone marrow involvement by tumor 
and other serious comorbidities. All patients >65 years old treated in this study protocol should 
receive primary prophylaxis with pegfilgrastim on Day 3, 4 or 5 of the cycle.  
Patients with neutropenic fever or infection must be hospitalized promptly for intravenous 
antibiotic therapy and may receive myeloid growth factors as appropriate.  
Erythropoiesis-stimulating agents such as epoetin alfa or darbepoetin alfa may not be used during 
study treatment. 
4.3.2 Blood and Platelet Transfusion 
Transfusions will be used at the Investigator’s clinical judgment. Red blood cell transfusions may 
be administered prophylactically for hemoglobin <8.0 g/dL or in case of severe symptomatic 
anemia. Platelet transfusions may be administered prophylactically for platelet counts ≤10,000 
/mm3 or therapeutically for low platelet counts. 
4.3.3 Infections 
Patients in this study will not receive any pre-specified infectious prophylaxis. In case of grade 4 
neutropenia (ANC<500/mm3), a prophylactic quinolone (ciprofloxacin 500 mg twice daily, 
levofloxacin 500 mg daily or moxifloxacin 400 mg daily) may be prescribed to prevent febrile 
neutropenia.  
Patients with history of herpes simplex or herpes zoster on suppressive therapy with acyclovir, 
famciclovir or valacyclovir may (but do not need to) continue therapy during the treatment on 
study. 
The concurrent administration of itraconazole with vincristine increases onset and severity of 
neuromuscular adverse effects of vincristine. If antifungal therapy is required during study 
treatment, alternative anti-fungals should be evaluated prior to considering any azoles.   
4.4 
Prior and Concomitant Medications 
The Investigator will be permitted to prescribe other treatment(s) at his or her discretion. These 
treatments, including any transfusions or prophylactic therapies, must be recorded on the CRF. 
However, any other standard or investigational treatments for lymphoma are not allowed. If such 
treatment is deemed necessary, the patient must discontinue treatment on this study. 
Medications known to interact with cytochrome P450-3A4 isoenzymes and/or P-glycoprotein are 
either prohibited (see Section 3.2, Exclusion Criteria), or should be administered with caution. 
A list of these medications can be found in Appendix B. Close monitoring is recommended for 


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subjects taking agents with narrow therapeutic indices and metabolized by the liver, such as 
warfarin, quinidine, and digoxin. 
All medications and supportive therapy that are administered within 14 days prior to the start of 
study drug administration through 30 days after the last dose of study treatment, including the start 
and stop date(s), dose/amount administered, and indication, must be recorded in the source 
documents and in the subject’s CRF. This includes any transfusions or prophylactic treatments. 
4.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment will continue for 6 cycles or 
until one of the following criteria applies: 
• Occurrence of a DLT in the first cycle of treatment, 
• Disease progression, 
• The need for administration of therapy for lymphoma not specified in the protocol; this 
includes any form of chemotherapy, radiation therapy or biologic therapy; 
• Intercurrent illness that prevents further administration of treatment, 
• Adverse event(s) deemed unacceptable by the patient or the treating physician, 
• Patient decides to withdraw from the study for any reason, or 
• General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
5. DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
All subjects must meet Criteria to initiate the next cycle according to Section 4.2 before receiving 
a next cycle of therapy.  
If a toxicity-related treatment delay is needed, the cycle should be delayed by up to 8 days. In case 
of delay exceeding 14 days, the patient must discontinue the study treatment. Further therapy for 
the lymphoma will be at the discretion of the treating physician. 
There will be no dose modifications for rituximab in this study. Dose modifications for 
bendamustine and Marqibo® will conform to the following dose levels: 
Dose level 
Dose 
Bendamustine 
Marqibo® 
0 
90 mg/m2 
100% patient-assigned dose 
-1 
50 mg/m2 
75% patient-assigned dose 
-2 
25 mg/m2 
50% patient-assigned dose 
Once a dose is reduced, it may not be re-escalated during the study treatment. Patients requiring 
>2 dose reductions must go off protocol therapy. 
The following guidelines apply to any toxicities attributed to treatment (understood as any agent 
administered on protocol). Baseline or disease-related toxicities will be managed according to the 
treating physician’s recommendations. 


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5.1 
Neutropenia 
Neutropenia 
Management/Next Dose for Bendamustine 
Management/Next Dose for Marqibo® 
≤ Grade 1 
(ANC ≥ 
1500/mm3) 
No change in dose 
No change in dose 
Grade 2 
(ANC 1000-
1499/mm3) 
Hold until ≤ Grade 1.  Resume at same dose 
level.  
Consider prophylactic pegfilgrastim in case of 
repeated delays. 
Hold until ≤ Grade 1.  Resume at same dose 
level. 
Consider prophylactic pegfilgrastim in case of 
repeated delays. 
Grade 3 
(ANC 500-
999/mm3) 
Hold until < Grade 2.  Resume at one dose 
level lower and consider prophylactic 
pegfilgrastim with the next cycle. 
Hold until < Grade 2.  Resume at one dose 
level lower and consider prophylactic 
pegfilgrastim with the next cycle. 
Grade 4 
(ANC < 
500/mm3) 
Hold and consider a prophylactic antibiotic 
until < Grade 2.   
Resume at one dose level lower and/or institute 
prophylactic pegfilgrastim with the next cycle 
Hold and consider a prophylactic antibiotic 
until < Grade 2.   
Resume at one dose level lower and/or institute 
prophylactic pegfilgrastim with the next cycle 
Recommended management:  Prophylactic antibiotics may include: ciprofloxacin 500 mg twice daily, 
levofloxacin 500 mg daily, or moxifloxacin 400 mg daily. 
5.2 
Thrombocytopenia (CTCAE 4.0: Platelet count decreased) 
Thrombocytopenia 
Management/Next Dose for 
Bendamustine 
Management/Next Dose for 
Marqibo® 
≤ Grade 1 (>75,000/mm3) 
No change in dose 
No change in dose 
Grade 2 (50-74,999/mm3) 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Hold until ≤ Grade 1.  Resume at same 
dose level. 
Grade 3 (25-49,999/mm3) 
Hold until < Grade 2.  Resume at one 
dose level lower, if indicated. 
Hold until < Grade 2.  Resume at one 
dose level lower, if indicated. 
Grade 4 (<25,000/mm3) 
Off protocol therapy 
Off protocol therapy 
5.3 
Nausea and Vomiting  
Patients must receive prophylaxis for chemotherapy-induced nausea and vomiting (Section 4.1).  
 
Nausea or 
vomiting 
Management/Next Dose for Bendamustine 
Management/Next Dose for Marqibo® 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose 
level. 
Hold until ≤ Grade 1.  Resume at same dose 
level. 
Grade 3 
Hold until < Grade 2.  Resume at one dose 
level lower, if indicated. 
Hold until < Grade 2.  Resume at one dose 
level lower, if indicated. 
Grade 4 
Off protocol therapy 
Off protocol therapy 
Recommended management:  Administer fosaprepitant or olanzapine with the next cycle (if not given). Use 
breakthrough antiemetics: prochlorperazine, metoclopramide, ondansetron, lorazepam, as indicated. 


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In case of grade 3 or 4 chemotherapy-induced nausea or vomiting, an aggressive outpatient or 
inpatient therapy with intravenous fluids, electrolyte replacement and anti-emetics should be 
instituted. If the nausea and/or vomiting resolve to grade 1-2 within 48 hours, such an event will 
not be considered a DLT. 
5.4 
Constipation 
Severe constipation may develop in subjects who receive Marqibo®. Decreased bowel motility 
due to intrabdominal disease, hypercalcemia, dehydration, use of opioids can also contribute to 
constipation. A diet high in bulk fiber, fruits and vegetables, and adequate fluid intake may help 
minimize constipation. All patients treated in this study should receive education on prophylactic 
bowel regimen. A suggested bowel regimen is as follows: 
1. Prophylactic laxatives 
a. Senna at bedtime (1-2 tablets, dose varies with the preparation), or  
b. Milk of Magnesia, 30 mL at bedtime 
2. If no bowel movement with the above, add: 
a. Lactulose, 20 gram (30 mL) up to 3 times a day, or 
b. Polyethylene glycol 3350 powder (MiraLax®) 17 gram dissolved in 4-8 oz. of 
water, once daily by mouth, or 
c. Biscodyl, 5 to 15 mg tablet by mouth or one 10 mg suppository, at bedtime. 
3. Other, more aggressive alternatives include: 
a. Magnesium Citrate, 150 mL by mouth, up to twice a day. 
Constipation 
Management/Next Dose for Bendamustine 
Management/Next Dose for Marqibo® 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose 
level. 
Hold until ≤ Grade 1.  Resume at same dose 
level. 
Grade 3 
Hold until < Grade 2.  Resume at one dose level 
lower, if indicated.** 
Hold until < Grade 2.  Resume at one dose level 
lower, if indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
Recommended management:  See above. 
5.5 
Diarrhea 
Diarrhea 
Management/Next Dose for Bendamustine 
Management/Next Dose for Marqibo® 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. Hold until ≤ Grade 1.  Resume at same dose 
level. 
Grade 3 
Hold until < Grade 2.  Resume at one dose level 
lower, if indicated 
Hold until < Grade 2.  Resume at one dose 
level lower, if indicated. 
Grade 4 
Off protocol therapy 
Off protocol therapy 
Recommended management:  Rule out infectious diarrhea. Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-free for 12 hours 
(maximum dosage:  16 mg/24 hours). Use flouroquinolones and/or octreotide according to the ASCO Guidelines 
for the Treatment of Cancer Treatment-Induced Diarrhea.40 


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5.6 
Rituximab infusion and hypersensitivity reactions 
• Interrupt rituximab for infusion reactions ≥ grade 1. Resume infusion when symptoms improve 
to < grade 1 at 50% of the previous infusion rate.  
• For grade 1 or 2 hypersensitivity reactions, interrupt rituximab infusion and manage according 
to institutional procedures. Resume infusion when symptoms improve to < grade 1 at 50% of 
the previous infusion rate.  
• For grade 3 or 4 hypersensitivity reactions, discontinue rituximab. 
5.7 
Other non-hematologic, treatment-related toxicities (excluding alopecia, weight 
gain/loss) 
Toxicity 
Management/Next Dose for Bendamustine 
Management/Next Dose for Marqibo® 
≤ Grade 1 No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose 
level. 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until < Grade 2.  Resume at one dose level 
lower, if indicated. 
Hold* until < Grade 2.  Resume at one dose level 
lower, if indicated. 
Grade 4 
Off protocol therapy 
Off protocol therapy 
 
 


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6. SCHEDULE OF EVALUATIONS / STUDY CALENDAR  
Evaluation 
Pre-Treatment Period 
Treatment Period 
Cycle 1 
Treatment 
Period 
Cycle 2-6 
Off 
Studye  
≤ 42 days  
before 
registration 
≤ 14 days  
before first 
treatment 
D1a 
D8d 
D15d 
D22d 
D1a,f 
D15d 
 
Clinical evaluation 
 
 
 
Signed informed consent 
Xg 
 
 
 
 
 
 
 
 
History and physical examination 
 
X 
Xa 
 
 
 
X 
 
X 
Vital signs: BP, pulse,  
respiratory rate, temperature 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
ECOG performance status 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
Height (baseline only), weight, BSA 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
Tumor measurements 
X 
 
 
 
 
 
Xb 
 
X 
Toxicity assessment 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
Concomitant medication log 
 
X 
Xa 
 
 
 
X 
 
X 
DLT determination 
 
 
 
X 
X 
X 
X(C2) 
 
 
Laboratory studies  
 
 
 
 
CBC with differential  
 
X 
Xa 
X 
X 
 
Xa 
 
X 
Electrolytes (Na, K, Cl, CO2. Ca, Mg, 
phosphorus), BUN, and creatinine 
 
X 
Xa 
X 
X 
 
Xa 
 
X 
Creatinine clearance (calculated) 
 
X 
Xa 
X 
X 
 
Xa 
 
X 
Bilirubin total, ALP, AST, ALT 
 
X 
Xa 
X 
X 
 
Xa 
 
X 
PT, APTT 
 
X 
Xa 
 
 
 
 
 
 
Serum or urine pregnancy test  
(women of child bearing potential only) 
 
X 
Xa 
 
 
 
Xa 
 
 
LDH 
 
X 
Xa 
X 
X 
 
Xa 
 
 
Uric acid 
 
X 
Xa 
X 
X 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
 
 
 
 
 
 
Urinalysis (WBC, blood, protein) 
 
X 
Xa 
 
 
 
Xa 
 
 
HIV, Hepatitis B S Ag 
 
X 
 
 
 
 
 
 
 
Disease assessment b 
 
 
 
 
CT (chest-abomen-pelvis) or PET-CT  
X 
 
 
 
 
 
Xb 
 
Xb 
Bone marrow aspirate / biopsy c 
Xc 
 
 
 
 
 
 
 
Xc 
Treatment 
 
 
 
 
BRiM chemotherapy 
 
 
Xh 
 
 
 
Xh 
 
 
a. 
Laboratory values and clinical assessments may be obtained within 72 hours prior to Day 1 of each cycle. Pre-registration assessments may be 
used for Cycle 1/Day 1 assessment if obtained within 7 days before treatment. Treatment must start within 7 days of registration. 
b. 
CT must be with IV contrast unless there is a documented contraindication. Imaging studies and tumor measurements should be obtained: 
• 
After Cycle 3:  
between Day 22 and Day 28 of Cycle 3 and  
• 
After Cycle 6: 
within 28-42 days after the last treatment  
Ct scan at “off study” is not required for patients who terminate study therapy early and have received fewer than 3 cycles of treatment, or had a 
restaging CT scan within 1 month prior to discontinuation of study therapy.  
c.      Bone marrow aspirate and biopsy is not required, unless it is clinically necessary for staging in the judgment of the investigator, within ≤42 
days of the first treatment and within 28-42 days after the last administered study treatment, if needed to document a complete remission.  
d.  
± 1 day 
e. 
Off Study Assessment visit should occur between Day 30 and Day 42 of the last treatment cycle. 
f. 
Cycle 2 to 6 may be delivered up to 1 calendar day before (Day 28 of the previous cycle), to 5 days after the scheduled date in case of holidays 
or other extenuating circumstances, and not accounting for delays as mandated by toxicity. 
g. 
Consent must be signed within 30 days of Day 1 of treatment. Otherwise the subject must be reconsented. 


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h. 
Including chemotherapy administration on Day 2 per protocol. 
6.1 
Dose-Limiting Toxicity (Definition) 
Dose-limiting toxicity (DLT) will be defined as one of the following AEs occurring during Cycle 
1 of study therapy (with a final determination on Day 1 of Cycle 2), after administration of any 
study medication listed in Section 4.1: 
• Grade 4 neutropenia (< 500/mm3) lasting  > 7 days 
• Grade 3 neutropenia (<1000/mm3) with fever or infection; 
• Grade 4 thrombocytopenia (<25,000/mm3); 
• Grade 3 thrombocytopenia (<50,000/mm3) requiring transfusion; 
• Grade 3 or 4 treatment-related non-hematologic toxicity, excluding: 
− 
Alopecia.  
− 
Grade 3 nausea or vomiting if corrected to ≤ grade 2 within 48 hours.  
− 
Grade 3 or 4 infusion reactions if occurring on Day 1 of the first cycle. 
− 
Grade 3 or 4 electrolyte (sodium, potassium, magnesium, calcium, chloride, 
phosphorus) abnormality, unless corrected to <grade 2 within 48 hours. 
• Delay of 2nd cycle of treatment for >14 days. 
Any patient who experiences a DLT must come off study. The trial will be terminated if the 
first three patients experience a DLT or anytime the posterior probability that the DLT 
rate at the minimum dose exceeds 0.33 is 0.8 or more. Toxicities occurring prior to 
administration of any study medications will not be considered DLT. 
6.2 
Disease Assessments 
For the purpose of the study, the disease will be assessed and tumor measurements performed at 
three time points: 
• During pre-treatment period, within 42 days prior to registration (Section 8.1) 
• After Cycle-3 chemotherapy, between Day-22 and Day-28 of the cycle 
• After Cycle-6 chemotherapy (or the last treatment, if therapy is discontinued earlier). 
CT scan is not required for patients who terminate study therapy early and have received fewer 
than 3 cycles of treatment, or had restaging CT scan within 1 month prior to discontinuation of 
study therapy. 
For patients who undergo a pre-treatment staging bone marrow evaluation, the procedure must be 
repeated if complete remission (CR) is assigned as the final tumor response. A repeat procedure is 
not necessary otherwise. Any assessment for disease that is performed between the date of 
informed consent signature and off-study assessment date must be submitted to BrUOG. 
6.3 
Off Study Assessment 
The patient will undergo Off Study Assessment during a visit scheduled between Day 30 and Day 
42 of the last cycle of study treatment they receive. The visit will entail the following evaluations: 
• History and physical examination, including vital signs, ECOG performance status, weight, 
BSA, and concomitant medication log.  
• Toxicity grading assessment, including determination of all cumulative toxicities for the 
purpose of the study. 


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• Assessment of final response to treatment using the International Working Group Revised 
Response Criteria for Malignant Lymphoma (see Section 7.1)41. This assessment should be 
finalized after the results of disease assessment tests become available. 
7. RESPONSE ASSESSMENT 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard International Working Group criteria for Malignant Lymphomas, as 
revised in 2007.41  
Patients will be assessed for response to treatment after Cycle 3 and Cycle 6 of therapy on study 
(see Section 6.2). Earlier assessment may be performed in case of suspected clinical progression 
of disease. A CT scan or a PET-CT scan can be used for response assessment in this study, 
according to Investigator’s preference guided by the histologic subtype of the lymphoma. For the 
purpose of study evaluation, all relevant measurable nodal and extranodal sites of disease ≥1 cm 
in size should be recorded in the baseline scan and followed until resolution. If CT is utilized for 
response assessment, it should be performed with IV contrast unless there is a documented 
contraindication (such as chronic kidney disease or hypersensitivity to contrast agent). 
7.1 
Definitions of response 
7.1.1 Complete remission 
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
2. FDG-avid lymphoma: in patients with no pretreatment PET scan or when the PET scan was 
positive before therapy, a post-treatment residual mass of any size is permitted as long as it is 
PET negative. 
3. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment PET 
scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have 
regressed on CT to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 
cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long axis and 
more than 1.0 cm in their short axis before treatment must have decreased to ≤ 1.0 cm in their 
short axis after treatment. 
4. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should disappear. 
However, determination of splenic involvement is not always reliable because a spleen 
considered normal in size may still contain lymphoma, whereas an enlarged spleen may reflect 
variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes other 
than lymphoma. 
5. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made 
must be adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is negative by 
immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow 
cytometry will be considered a CR. 


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7.1.2 Partial remission 
1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest 
dominant nodes or nodal masses. These nodes or masses should be selected according to all of 
the following: they should be clearly measurable in at least 2 perpendicular dimensions; if 
possible they should be from disparate regions of the body; and they should include mediastinal 
and retroperitoneal areas of disease whenever these sites are involved. 
2. No increase should be observed in the size of other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, in the 
greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was positive 
before treatment. However, if positive, the cell type should be specified (eg, large-cell 
lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria, but 
who have persistent morphologic bone marrow involvement will be considered partial 
responders. 
6. When the bone marrow was involved before therapy and a clinical CR was achieved, but with 
no bone marrow assessment after treatment, patients should be considered partial responders. 
7. No new sites of disease should be observed. 
8. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET scan 
was positive before therapy, the post-treatment PET should be positive in at least one 
previously involved site. 
9. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, CT criteria should be used. 
10. In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only indicated 
with one or at most two residual masses that have regressed by more than 50% on CT; those 
with more than two residual lesions are unlikely to be PET negative and should be considered 
partial responders. 
7.1.3 Stable disease 
1. A patient is considered to have SD when he or she fails to attain the criteria needed for a CR 
or PR, but does not fulfill those for progressive disease. 
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with no 
new areas of involvement on the post-treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan or if the pretreatment PET was negative, there must be no change in the size of the 
previous lesions on the post-treatment CT scan. 
7.1.4 Progressive disease 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of the 
short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal 
if its short axis is more than 1.0. Lymph nodes ≤ 1.0 × ≤ 1.0 cm will not be considered as abnormal 


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for progressive disease. 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected 
site should only be considered relapsed or progressive disease after confirmation with other 
modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules 
identified by CT are mostly benign. Thus, a therapeutic decision should not be made solely on 
the basis of the PET without histologic confirmation. 
2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single 
involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered 
progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must 
increase by ≥ 50% and to a size of 1.5 × 1.5 cm or more than 1.5 cm in the long axis. 
3. At least a 50% increase in the longest diameter of any single previously identified node more 
than 1 cm in its short axis. 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was 
PET positive before therapy unless the lesion is too small to be detected with current PET systems 
(< 1.5 cm in its long axis by CT). 
 
Table 4: International Working Group Criteria for response to therapy in NHL 
 
 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
(a) FDG-avid or PET positive prior to therapy; 
mass of any size permitted if PET negative  
(b) Variably FDG-avid or PET negative; 
regression to normal size on CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate by 
morphology, IHC 
should be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
≥ 50% decrease in SPD of up to 6 largest 
dominant masses; no increase in size of other 
nodes  
(a) FDG-avid or PET positive prior to therapy; 
one or more PET positive at previously 
involved site (b) Variably FDG-avid or PET 
negative; regression on CT 
≥50% decrease 
in SPD of 
nodules; no 
increase in liver 
or spleen size 
Irrelevant if 
positive prior to 
therapy;  
cell type should be 
specified 
SD 
Failure to 
attain CR/PR 
or PD 
(a) FDG-avid or PET positive prior to therapy; 
PET positive at prior sites of disease and no 
new sites on CT or PET 
(b) Variably FDG-avid or PET negative; no 
change in size of previous lesions on CT 
 
 
PD 
Any new 
lesion or 
increase by ≥ 
50% of 
previously 
involved sites 
from nadir 
Appearance of a new lesion(s) > 1.5 cm in any 
axis, ≥ 50% increase in SPD of more than one 
node, or ≥ 50% increase in longest diameter of 
a previously identified node > 1 cm in short 
axis. 
Lesions PET positive if FDG-avid lymphoma 
or PET positive prior to therapy 
> 50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 
 
 
 


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8. REGISTRATION PROCEDURES 
8.1 
General Guidelines 
All patients will be registered through the Brown University Oncology Research Group Central 
Office. The following documents must be faxed to the BrUOG Central Office, Fax: (401) 863-
3820, at the time of registration and prior to patient treatment: 
• Eligibility checklist with supporting original source documentation 
• On-study form 
• Signed patient consent form. 
Details of patient’s study participation will be documented in the institutional electronic medical 
record. The Brown University Oncology Research Group will provide case report forms, included 
in the appendix, for the recording and collection of data. In the event of corrections, each correction 
will be initialed and dated by the person making the correction. The investigator will sign the case 
reports to indicate that, to his/her knowledge, they are complete and accurate. Case report forms, 
flow sheets, off-study forms and follow-up forms should be mailed / faxed to:  
Brown University Oncology Research Group, 
Brown University 
Box G-R 001 
Providence, RI 02912 
Fax: 401-863-3820 
Phone: 401-863-3000 
BrUOG@brown.edu 
All supporting data must be sent in with the corresponding BrUOG forms. It is the treating 
physician’s responsibility to review all data submitted to the BrUOG Central Office for accuracy 
and completeness and he/she must sign the on-study form. It is required that source documentation 
be submitted to support all eligibility criteria (inclusion and exclusion) and also the schedule of 
evaluations table for prior to registration. 
A next subject can be registered for this study only after the DLT status of all prior subjects have 
been resolved and a new dose level is assigned according to the procedures outlined in Section 16. 
9. PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the agents administered in this study 
can be found in Section 11.1.  
The Investigator and the trial site are responsible for the investigational product accountability. 
All clinical trial supplies will be delivered to and be the responsibility of a suitably qualified and 
authorized person such as a hospital pharmacist, who will document study drug disposition and 
accountability for the duration of the trial. 
Acrotech Biopharma, LLC will provide Marqibo® as the investigational agent. Patients will 
receive commercially available preparations of bendamustine (Treanda®, Belrapzo®, or 
Bendeka®) and rituximab (Rituxan®). 


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9.1 
Rituximab (IDEC-C2B8) 
9.1.1 Product description 
Rituximab is a CD20-directed chimeric monoclonal antibody. It is indicated for treatment of: 
relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; 
previously untreated follicular, CD20-positive, B-cell NHL in combination with first line 
chemotherapy and as single-agent maintenance therapy; non-progressing (including stable 
disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP 
chemotherapy; and previously untreated diffuse large B-cell, CD20-positive NHL in combination 
with CHOP or other anthracycline-based chemotherapy regimens. 
A comprehensive product information and list of adverse effects is available in the Rituxan® 
package insert, available at: 
http://www.gene.com/download/pdf/rituxan_prescribing.pdf 
9.1.2 Availability 
The commercial, FDA-approved formulation of rituximab (Rituxan®, Genentech, Inc, South San 
Francisco, CA) will be used in this study. Rituximab is available in 10 mL and 50 mL single-use 
vials containing 100 mg or 500 mg of rituximab solution, respectively, at a concentration of 10 
mg/mL. 
9.1.3 Storage and stability 
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4 mg/mL) are 
stable for 24 hours under refrigeration, and for an additional 24 hours at room temperature. 
9.1.4 Preparation 
The desired dose of rituximab should be diluted in 0.9% NaCl or D5W to a final concentration of 
1-4 mg/mL. Mix by inverting the bag gently. 
9.1.5 Dosage and Administration 
Rituximab will be administered by IV infusion at the dose of 375 mg/m2 on Day 1 of each study 
treatment. Patients must be pretreated with acetaminophen and diphenhydramine on each day of 
antibody treatment.  
Do not administer rituximab IV push or bolus. For the initial infusion, start at a rate of 50 mg/hour; 
if there is no reaction, increase the rate by 50 mg/hour increments every 30 minutes, to a maximum 
rate of 400 mg/hour. For subsequent infusions, if the patient tolerated the initial infusion, start at a 
rate of 100 mg/hour; if there is no reaction, increase the rate by 100 mg/hour increments every 30 
minutes, to a rate of 400 mg/hour. If the patient did not tolerate the initial infusion, follow the 
initial infusion guidelines. If a reaction occurs, slow or stop the infusion. If the reaction abates, 
restart infusion at 50% of the previous rate. 
If the subject did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 
90-minute infusion can be administered during Cycle 2. Initiate at a rate of 20% of the total dose 
to be given in the first 30 minutes and the remaining 80% of the total dose over the next 60 minutes. 
If the 90-minute infusion is tolerated during Cycle 2, the same rate can be used during all 
subsequent cycles. Patients who have clinically significant cardiovascular disease or who have a 
circulating lymphocyte count ≥5000/mm3 before Cycle 2 should not be administered the 90-
minute infusion. 


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9.1.6 Toxicity 
The most serious adverse events associated with rituximab include severe infusion reactions, tumor 
lysis syndrome, and severe mucocutaneous reactions. Severe infusion reactions consisting of 
hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation or cardiogenic shock may be fatal. Most reported fatal reactions occurred 
within 24 hours of the first dose of rituximab. Because severe infusion reactions have been noted 
more frequently in patients with high leukocyte counts, such patients should be observed closely.  
Tumor lysis syndrome resulting in renal failure has been described, and occasional fatalities noted. 
Tumor lysis syndrome is more likely in patients with high numbers of circulating malignant cells.  
Severe mucocutaneous reactions associated with rituximab include Stevens-Johnson syndrome 
and toxic epidermal necrolysis. The onset of these reactions has been from 1-3 weeks.  
Less severe infusion reactions are common with rituximab. These include fever, chills, and 
dyspnea. The mechanism of rituximab infusion reactions is thought to be the release of cytokines.  
Hepatitis B reactivation with fulminant hepatitis, hepatic failure and death in some patients with 
hematologic malignancies treated with rituximab have been reported. The majority of these 
patients received rituximab in combination with chemotherapy. The median time to diagnosis of 
hepatitis was approximately 4 months after starting rituximab and approximately 1 month after the 
last dose.  
Exacerbation or reactivation of other viral infections has also been reported with rituximab. JC 
virus reactivation leading to progressive multifocal leukoencephalopathy in patients who were 
receiving rituximab has been reported. Patients presenting with new neurologic findings (e.g., 
major changes in vision, unusual eye movements, loss of balance or coordination, confusion) 
should be evaluated for progressive multifocal leukoencephalopathy. An increase in fatal infection 
in HIV-related lymphoma patients when rituximab was used in combination with CHOP 
chemotherapy, as compared to CHOP alone has been reported.  
For a comprehensive list of adverse events, refer to the Rituxan® package insert. 
9.1.7 Drug interactions 
Rituximab does not have any known clinically significant interactions with other study drugs. 
9.2 
Bendamustine hydrochloride 
9.2.1 Product description 
Bendamustine hydrochloride is an alkylating antineoplastic drug which is a bifunctional 
mechlorethamine derivative containing a purine-like benzimidazole ring. It is indicated for 
treatment of patients with CLL or with an indolent B-cell non-Hodgkin lymphoma (NHL) that has 
progressed during or within six months of treatment with rituximab or a rituximab-containing 
regimen. 
Bendamustine is available as two formulations: Treanda® and Bendeka®. Both are acceptable for 
this study. A comprehensive product information and list of adverse effects is available in the 
Treanda® and Bendeka® package inserts, available at: 
http://www.treandahcp.com/pdf/TREANDA_final_PI.pdf and 
http://bendeka.com/Pdf/PrescribingInformation.PDF 


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9.2.2 Availability 
Treanda® (Cephalon, Inc. Frazer, PA) is supplied as a single-use vial containing 100 mg 
bendamustine HCL as white to off-white lyophilized powder. Bendeka® (Teva Oncology, North 
Wales, PA) is supplied in individual cartons of 5 mL clear multiple-dose vials containing 100 mg 
of bendamustine hydrochloride as a clear, and colorless to yellow ready-to-dilute solution. 
9.2.3 Storage and stability 
Treanda® may be stored up to 25° C (77°F) with excursions permitted up to 30°C (86°F). 
Bendeka® should be stored in a refrigerator, 2°-8°C (36°- 46°F). Retain in original package until 
time of use to protect from light.  
9.2.4 Preparation 
9.2.4.1 
Treanda® 
• Aseptically reconstitute each 100 mg bendamustine HCl (Treanda®) vial with 20 mL of only 
Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution 
with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should 
completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product 
should not be used. 
• Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL 
concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride 
Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP 
(normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, 
USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion 
bag should be within 0.2 – 0.6 mg/mL. The reconstituted solution must be transferred to the 
infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the 
contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow 
solution. 
Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride 
Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined 
above. No other diluents have been shown to be compatible. 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration whenever solution and container permit. Any unused solution should be 
discarded according to institutional procedures for antineoplastics. 
9.2.4.2 
Bendeka® 
Follow the procedure according to FDA-approved Prescribing Information: 
• Aseptically withdraw the volume needed for the required dose from the 25 mg/mL solution 
and immediately transfer the solution to a 50 mL infusion bag of one of the following diluents: 
− 0.9% Sodium Chloride Injection, USP; or − 2.5% Dextrose/0.45% Sodium Chloride 
Injection, USP; or − 5% Dextrose Injection, USP. The resulting final concentration of 
bendamustine hydrochloride in the infusion bag should be within 1.85 mg/mL – 5.6 mg/mL. 
After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a 
clear, and colorless to yellow solution. 


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• Bendeka® injection contains no antimicrobial preservative. The admixture should be prepared 
as close as possible to the time of patient administration. If diluted with 0.9% Sodium Chloride 
Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture 
is stable for 24 hours when stored refrigerated (2-8°C or 36-46°F) or for 6 hours when stored 
at room temperature (15-30°C or 59-86°F) and room light. Administration of diluted 
Bendeka® injection must be completed within this period of time. In the event that 5% 
Dextrose Injection, USP is utilized, the final admixture is stable for 24 hours when stored 
refrigerated (2-8°C or 36-46°F) or for only 3 hours when stored at room temperature (15-30°C 
or 59-86°F) and room light. Administration of diluted BENDEKA must be completed within 
this period of time. 
9.2.5 Dosage and Administration 
Treanda®  is administered by intravenous route over 30 minutes in 500 mL of 0.9% Sodium 
Chloride (or 2.5% Dextrose/0.45% Sodium Chloride). Bendeka® is administered by intravenous 
route over 10 minutes in 50 mL of 0.9% Sodium Chloride, or 0.45% Sodium Chloride /2.5% 
Dextrose or 5% Dextrose . 
Bendamustine will be administered in this study at the dose of 90 mg/m2 each day on Days 1 and 
2 of each cycle. 
9.2.6 Toxicity 
The most common side effect is bone marrow suppression. Most common non-hematologic 
adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, 
constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. Most 
common hematologic abnormalities (frequency ≥15%) are lymphopenia, anemia, leukopenia, 
thrombocytopenia, and neutropenia. For a comprehensive list of adverse events, refer to Treanda® 
or Bendeka® package insert. 
9.2.7 Drug interactions 
Concomitant CYP1A2 inducers or inhibitors have the potential to affect the exposure of 
bendamustine. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase 
plasma concentrations of bendamustine and decrease plasma concentrations of active metabolites. 
Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma 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. 
9.3 
Vincristine sulfate liposomal injection (Marqibo®) 
9.3.1 Product description 
Marqibo® is a vinca alkaloid indicated for the treatment of adult patients with Philadelphia 
chromosome-negative acute lymphoblastic leukemia in second or greater relapse or whose disease 
has progressed following two or more anti-leukemia therapies. The drug substance and active 
ingredient is the chemotherapeutic agent, vincristine sulfate. Vincristine Sulfate is supplied as 
Vincristine Sulfate Injection, USP which is a component of the Vincristine Sulfate Liposome 
Injection (0.16 mg/mL) (Marqibo®) kit. Vincristine Sulfate Liposome Injection (Marqibo®) binds 
to microtubular protein of the mitotic spindle causing metaphase arrest. 


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A comprehensive product information and list of adverse effects is available in the Marqibo® 
package insert, available at: 
http://marqibo.com/pi 
Additional information about VSLI is provided in Section 2.5. 
9.3.2 Availability 
Marqibo® is supplied as a single-use, 3-vial kit designed to enable entrapment of vincristine in 
sphingomyelin/cholesterol liposomes at the time of use. The active agent consists of vincristine 
sulfate as an aqueous solution and the vehicle consists of sphingomyelin/cholesterol liposomes 
with a sodium phosphate buffer as described in the 3-vial kit component table below. 
Table 5: 
Vincristine Sulfate Liposomes Injection (0.16 mg/mL) 3-vial Kit Components1 
Component 
No. of 
Vials/Kit 
Description 
Active 
1 
Vincristine Sulfate Injection, USP (1 mg/mL, 5 mL) 
Liposomes 
1 
Sphingomyelin/Cholesterol Liposomes Injection (103 mg/mL, 1 mL) 
Buffer 
1 
Sodium Phosphate Injection (14.2 mg/mL, 25 mL) 
1Kit also includes: 1) 1 floatation ring, 2) 1 infusion bag label, 3) 1 Marqibo® overlabel, 4) 1 set of constitution instructions. 
Vincristine is encapsulated into the sphingomyelin/cholesterol liposomes during the constitution 
procedure. Vincristine sulfate injection, sphingomyelin/cholesterol liposomes, and buffer are 
combined and warmed to 65 ± 2° C for 10 minutes. The sphingomyelin/cholesterol liposomes have 
an internal pH of ~4.0. When the sodium phosphate buffer and vincristine sulfate injection are 
added, the solution outside the liposomes has a pH of ~7.3. The pH gradient induces vincristine to 
migrate across the sphingomyelin/cholesterol liposome membrane, which becomes more 
permeable upon heating. Returning to room temperature, the sphingomyelin/cholesterol liposome 
membrane loses its permeability with the vincristine encapsulated inside. 
Figure 1:  
Marqibo® Encapsulation Process 
 
 
 
 
9.3.3 Storage and stability 
Marqibo® kits are to be stored in a controlled refrigerator (2-8ºC; 36-46ºF) until the time of 
constitution; refrigeration temperature logs (or equivalent records) should be maintained. Retain 
vials in carton until time of use. DO NOT FREEZE. 
Constitution should take place under strict aseptic conditions following detailed instructions 
included in the kit. After constitution of Marqibo, the constituted product should be stored in the 
constitution vial or diluted, according to the instructions, in the infusion bag. 
The constituted product should be stored at controlled room temperature (15-30ºC; 59-86ºF) and 
must be administered within 12 hours of the constitution start time. 


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All unused Marqibo® kits will be returned to the drug manufacturer or delegate at the end of the 
study or destroyed at the site as per local pharmacy’s cytotoxic agent destruction procedures and 
according to applicable regulations. Destruction on site should only occur with prior drug 
manufacturer’s authorization. Documentation of local Marqibo® destruction must be provided to 
the drug manufacturer. Marqibo® is an investigational drug. Drugs supplied for clinical 
investigation should be given by or under the supervision of the Investigators throughout this 
study. 
9.3.4 Preparation and Constitution  
The illustrated constitution procedure for the 3-vial Marqibo® kit is located in the study procedures 
manual. 
One Marqibo® kit will adequately supply sufficient constituted Marqibo® at a dose of  
2.25 mg/m2 for a BSA of ≤ 2.1 m2. A BSA of > 2.1 m2 will require two Marqibo® kits. 
The reliability of the preparation procedure for Marqibo® from the 3-vial kit can be performed in 
a high degree of confidence with small variations having minimal or no effect on product quality 
and performance. 
9.3.4.1 
Items Required by the Pharmacy to Prepare Marqibo®  
Either water bath or block heater can be used for preparation of the Marqibo® infusion: 
• Marqibo® Kit  
• Water bath (for water bath processing) or Dri-Block heater (for block heater processing) 
• Calibrated thermometer  (0°C to 100°C)  
• Calibrated electronic timer 
• Sterile venting needle or other suitable device equipped with a sterile 0.2 micron filter  
• 1 mL or 3 mL sterile syringe with needle, and  
• 5 mL sterile syringe with needle. 
• Tongs 
9.3.4.2 
Preparation Instructions for Marqibo® (vinCRIStine sulfate LIPOSOME 
injection), 5 mg/31 mL (0.16 mg/mL)  
Procedures for handling and disposal of anticancer drugs should be followed. 
Call 1-888-292-9617 if you have questions about the preparation of Marqibo®. Marqibo® takes 
approximately 60 to 90 minutes to prepare. The preparer should have dedicated uninterrupted time 
to prepare Marqibo® due to the extensive monitoring of temperature and time required for the 
preparation.  
Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present 
in Marqibo®. The preparation steps of Marqibo® that involve mixing the Sodium Phosphate 
Injection, Sphingomyelin/Cholesterol Liposome Injection, and Vincristine Sulfate Injection must 
be done in a biological safety cabinet or by established pharmacy safety procedures for the 
preparation of sterile injectable formulations and hazardous drugs. If using the water bath, the 
preparation steps that involve placement of the vial in the water bath must be done outside of the 
sterile area.  
Do not use with in-line filters. Do not mix with other drugs. 
Please note the kit instructions will include details on the use of the water bath and the heat block. 


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Water bath:  
1. 
Fill a water bath with water to a level of at least 8 cm (3.2 inches) measured from the bottom and maintain this minimum water 
level throughout the procedure. The water bath must remain outside of the sterile area.  
2. 
Place a calibrated thermometer in the water bath to monitor water temperature and leave it in the water bath until the procedure 
has been completed.  
3. 
Preheat water bath to 63°C to 67°C. Maintain this water temperature until completion of the procedure using the calibrated 
thermometer.  
4. 
Visually inspect each vial in the Marqibo® Kit for particulate matter and discoloration prior to preparation, whenever solution 
and container permit. Do not use if a precipitate or foreign matter is present.  
5. 
Remove all the caps on the vials and swab the vials with sterile alcohol pads.  
6. 
Vent the Sodium Phosphate Injection vial with a sterile venting needle equipped with a sterile 0.2 micron filter or other suitable 
venting device in the biological safety cabinet. Always position venting needle point well above liquid level before adding 
Sphingomyelin/Cholesterol Liposome Injection and VinCRIStine Sulfate Injection.  
7. 
Withdraw 1 mL of Sphingomyelin/Cholesterol Liposome Injection.  
8. 
Inject 1 mL of Sphingomyelin/Cholesterol Liposome Injection into the Sodium Phosphate Injection vial.  
9. 
Withdraw 5 mL of VinCRIStine Sulfate Injection.  
10. Inject 5 mL of VinCRIStine Sulfate Injection into the Sodium Phosphate Injection vial.  
11. Remove the venting needle and gently invert the Sodium Phosphate Injection vial 5 times to mix. DO NOT SHAKE.  
12. Fit Flotation Ring around the neck of the Sodium Phosphate Injection vial.  
13. Confirm that the water bath temperature is at 63°C to 67°C using the calibrated thermometer. Remove the Sodium Phosphate 
Injection vial containing VinCRIStine Sulfate Injection, Sphingomyelin/Cholesterol Liposome Injection, and Sodium 
Phosphate Injection from the biological safety cabinet and place into the water bath for 10 minutes using the calibrated 
electronic timer. Monitor the temperature to ensure the temperature is maintained at 63°C to 67°C.  
14. IMMEDIATELY after placing the Sodium Phosphate Injection vial into the water bath, record the constitution start time and 
water temperature on the Marqibo® Overlabel.  
15. At the end of the 10 minutes, confirm that the water temperature is 63°C to 67°C using the calibrated thermometer. Remove 
the vial from the water bath (use tongs to prevent burns) and remove the Flotation Ring.  
16. Record the final constitution time and the water temperature on the Marqibo® Overlabel.   
17. Dry the exterior of the Sodium Phosphate Injection vial with a clean paper towel, affix Marqibo® (vinCRIStine sulfate 
LIPOSOME injection) Overlabel, and gently invert 5 times to mix. DO NOT SHAKE.  
18. Permit the constituted vial contents to equilibrate for at least 30 minutes to controlled room temperature (15°C to 30°C, 59°F 
to 86°F).  
19. Marqibo® (vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate. One prepared, 
store at controlled room temperature (15°C to 30°C, 59°F to 86°F) for no more than 12 hours.  
20. Swab the top of the vial now containing Marqibo® with a sterile alcohol pad and return the vial back into the biological safety 
cabinet.  
21. Calculate the patient’s Marqibo® dose based on the patient’s actual body surface area (BSA) and remove the volume 
corresponding to the patient’s Marqibo® dose from an infusion bag containing 100 mL of 5% Dextrose Injection or 0.9% 
Sodium Chloride Injection.  
22. Inject the dose of Marqibo® into the infusion bag to result in a final volume of 100 mL.  
23. Complete the information required on the Infusion Bag Label and apply to the infusion bag.  
24. Finish administration of the diluted product within 12 hours of the initiation of Marqibo® preparation.  
25. Empty, clean, and dry the water bath after each use.  
26. Deviations in temperature, time, and preparation procedures may fail to ensure proper encapsulation of vincristine sulfate into 
the liposomes. In the event that the preparation deviates from the instructions in the above steps, the components of the kit 
should be discarded and a new kit should be used to prepare the dose.  
Block Heater: 
1. 
Arrange the three heater blocks in the Block Heater such that the block holding the constitution vial is centered between 
the two other blank heater blocks. 
2. 
Place a calibrated thermometer in the block opening adjacent to the vial well to monitor the temperature. Leave the 
thermometer in the block opening until the procedure has been completed. 
3. 
Turn on the Block Heater and set the controller to 75°C. Verify the block temperature by checking that the thermometer 
inserted in the block reads 75 ±2°C. Equilibrate the heating block at 75 ±2°C for 15 minutes. Maintain this block 
temperature until completion of the procedure using the calibrated thermometer. 
4. 
Visually inspect each vial in the MARQIBO Kit for particulate matter and discoloration prior to preparation, whenever 
solution and container permit. Do not use if a precipitate or foreign matter is present. Note that 
Sphingomyelin/cholesterol 


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liposomes are a white to off-white homogeneous suspension, essentially free of visible foreign matter and aggregates. 
5. 
Remove all the caps on the vials and swab the vials with sterile alcohol pads. 
6. 
Vent the Sodium Phosphate Injection vial with a sterile venting needle equipped with a sterile 0.2-micron filter or other 
suitable venting device in the biological safety cabinet. Always position venting needle point well above liquid level 
before adding Sphingomyelin/Cholesterol Liposome Injection and VinCRIStine Sulfate Injection. 
7. 
Withdraw 1 mL of Sphingomyelin/Cholesterol Liposome Injection. 
8. 
Inject 1 mL of Sphingomyelin/Cholesterol Liposome Injection into the Sodium Phosphate Injection vial. 
9. 
Withdraw 5 mL of VinCRIStine Sulfate Injection. 
10. Inject 5 mL of VinCRIStine Sulfate Injection into the Sodium PhosphateInjection vial. 
11. Remove the venting needle and gently invert Sodium Phosphate Injection vial 5 times to mix. DO NOT SHAKE. 
12. Confirm that the Block Heater temperature is at 73°C to 77°C using the calibrated thermometer. Remove the Sodium 
Phosphate Injection vial containing VinCRIStine 
Sulfate Injection, Sphingomyelin/Cholesterol Liposome Injection, and Sodium Phosphate Injection from the biological 
safety cabinet and place into the Block 
Heater for 18 minutes using the calibrated electronic timer. Monitor the temperature to ensure the temperature is 
maintained at 73°C to 77°C. 
13. IMMEDIATELY after placing the Sodium Phosphate Injection vial into the Block 
Heater, record the constitution start time and Block Heater temperature on the MARQIBO Overlabel. Use only the 
calibrated thermometer inserted in the block to monitor temperature. 
14. At the end of the 18 minutes using the Block Heater, confirm that the Block Heater temperature is 73°C to 77°C using 
the calibrated thermometer. Remove the vial from the Block Heater (use tongs to prevent burns). 
15. Record the final constitution time and the Block Heater temperature on the MARQIBO Overlabel. 
16. Affix MARQIBO (vinCRIStine sulfate LIPOSOME injection) Overlabel, and gently invert 5 times to mix. DO NOT 
SHAKE. 
17. Permit the constituted vial contents to equilibrate for at least 30 minutes to controlled room temperature (15°C to 30°C, 
59°F to 86°F). 
18. MARQIBO (vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate. ONCE 
PREPARED, STORE AT CONTROLLED ROOM 
TEMPERATURE (15°C to 30°C, 59°F to 86°F) FOR NO MORE THAN 12 HOURS. 
19. Swab the top of the vial now containing MARQIBO with a sterile alcohol pad and 
return the vial back into the biological safety cabinet. 
20. Calculate the patient’s MARQIBO dose based on the patient’s actual body surface area (BSA) and remove the volume 
corresponding to the patient’s Marqibo dose from an 
infusion bag containing 100 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. 
21. Inject the dose of MARQIBO into the infusion bag to result in a final volume of 100 mL. 
22. Complete the information required on the Infusion Bag Label and applyto the infusion bag. 
23. Finish administration of the diluted product within 12 hours of the initiation of MARQIBO preparation. 
24. Deviations in temperature, time, and preparation procedures may fail to ensure proper encapsulation of vincristine sulfate 
into the liposomes. In the event that the preparation deviates from the instructions in the above steps, the components of 
the kit should be discarded and a new kit should be used to prepare the dose. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit. Do not use if a precipitate or 
foreign matter is present. 
9.3.5 Dosage and Administration 
Marqibo® will be administered at a patient-specific dose established for each patient at the time 
of registration (see Section 4.3 and Section 5.1). The dose will be given intravenously over 60 
minutes (±10 minutes) on Day 2 of each treatment cycle.  
Marqibo® may be infused through a free running peripheral or central venous catheter, without 
the use of an inline filter, using an infusion pump. For peripheral venous access, a minimum 21-
gauge catheter or butterfly should be used. It is extremely important that the intravenous needle or 
catheter be properly positioned before any Marqibo® is administered. Leakage into surrounding 
tissue during intravenous administration of Marqibo® may cause local irritation. If extravasation 
occurs, the injection should be discontinued immediately and managed per institutional 


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procedures. Any remaining portion of the dose should be introduced into another vein. 
Marqibo® should be administered only by intravenous infusion and by individuals experienced 
with the administration of vincristine sulfate. 
Marqibo® should not be mixed with or diluted with other drugs or solutions for infusion. It is 
recommended that the infusion bag and tubing be constructed from medical grade PVC. There is 
currently no compatibility data available for material other than medical grade PVC.  It is not 
required that the Marqibo® dose be corrected for obese subjects. 
9.3.6 Toxicity 
Marqibo® has a safety profile comparable to conventional vincristine. Neurotoxicity is the dose 
limiting toxicity of Marqibo, mostly peripheral sensory neuropathy. The severity of neuropathy 
worsens with cumulative dose but this occurs gradually. Myelosuppression is evident from 
Marqibo® treatment but significant myelotoxicity occurs infrequently and can be managed with 
the concomitant use of colony stimulating factors. Fatigue was commonly observed but severe 
infections, infusion-related pyrexia, severe gastrointestinal symptoms, and alopecia were seen 
infrequently. Other common or important adverse effects reported in clinical experience with 
Marqibo® include: 
• General: chills, pain, mucosal inflammation and infusion site leakage 
• Hematologic: neutropenia, febrile neutropenia and thrombocytopenia 
• Gastrointestinal: abdominal pain, hemorrhage, weight loss, vomiting, ulceration, swelling 
in mouth/colon/stomach 
• Metabolism: dehydration, change in chemistries, elevation of liver enzymes 
• Musculoskeletal: weakness, jaw pain- notes as common 
• Neurologic: peripheral neuropathy, urinary retention 
• Respiratory: shortness of breath with potential for respiratory failure 
• Cutaneous: alopecia, rash 
• Cardiovascular: hypertension, hypotension 
For a comprehensive list of adverse events, refer to Marqibo® package insert. 
9.3.7 Drug Accountability 
All study drug supplies must be kept in a locked limited access room. The study drug must not be 
used outside the context of the protocol. Under no circumstances should the Investigator or other 
site personnel supply study drug to other Investigators, subjects, or clinics, or allow supplies to be 
used other than directed by this protocol without prior authorization from the Sponsor and the drug 
manufacturer. 
The pharmacist will maintain complete drug accountability records as described in Section 12.3.6. 
Periodically throughout the study, and again at the end of the study, BrUOG will require 
submission of the drug accountability record providing a complete accounting of the receipt and 
disposition of each vial of study drug and the total number of vials dispensed to each subject. This 
will occur again at the closure of the study. 
9.3.8 Drug Handling 
As with other potentially toxic anticancer agents, care should be exercised in the handling and 
preparation of infusion solutions with Marqibo®. The use of gloves and protective garments is 


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recommended during Marqibo® preparation. Preparation should occur in a vertical laminar flow 
biological hood using proper aseptic technique. Disinfect vertical laminar flow biological hood by 
wiping surfaces with 70% isopropyl alcohol or by established pharmacy procedures. If a solution 
of Marqibo® contacts the skin, wash immediately and thoroughly with soap and water. If 
Marqibo® contacts the mucous membranes, flush thoroughly with water. Dispose of all anticancer 
agents according to institutional policy.  
9.3.9 Spillage/Contamination 
Wear gloves, mask, and protective clothing. Treat spilled liquid with sodium hypochlorite solution. 
Carefully absorb solution with gauze pads or towels, wash area with water and absorb with gauze 
or towels again. 
Place the gauze pads or towels in a plastic bag, seal, double bag and mark as hazardous waste. 
Dispose of waste by incineration or by other methods approved for hazardous materials. 
Personnel involved in clean up should wash with soap and water. 
9.3.10 Disposal 
Avoid contact with skin by using gloves. All needles, syringes, vials, and other materials that have 
come in contact with vincristine sulfate should be segregated in plastic bags, sealed, and marked 
as hazardous waste. Incinerate at 1000°C or higher. Sealed containers may explode if a tight seal 
exists. 
If incineration is not available, sodium hypochlorite (household bleach) may be added to the vial(s) 
to detoxify the vincristine sulfate. Care must be taken to vent the vial(s) to avoid a pressure build-
up of chlorine gas generated. Decomposition occurs within 10 minutes. Dispose of detoxified vials 
in a safe manner. 
Dispose all components of the Vincristine Sulfate Liposomes Injection Marqibo® Kit that did not 
come into contact with vincristine sulfate as per established pharmacy procedures for non-
biohazardous waste. 
The water bath can be destroyed on site, per institutional policy.  
The destruction of all materials is required to be documented via the drug accountability log, 
except for used vials. Prior to destroying drug or any materials (such as the water bath etc), 
BrUOG must be made aware and obtain approval from Acrotech Biopharma, LLC. Once 
approved by Acrotech Biopharma, LLC, BrUOG will then approve site destruction of all 
materials including drug, before destruction occurs. This does not include the destruction of used 
vials. 
10. AGENT ACCOUNTABILITY 
10.1 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received from manufacturer using a Drug 
Accountability Record Form. Sites must submit to BrUOG accountability logs during the study 
and prior to destruction. To be able to destroy drug, sites must contact BrUOG who will obtain 
approval from Acrotech Biopharma, LLC  prior to destruction.  


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10.2 
Treatment Compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted. 
All drugs will be administered to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).  The pharmacist will maintain records of drug receipt drug 
preparation, and dispensing, including the applicable lot numbers. Any discrepancy between the 
calculated dose and dose administered and the reason for the discrepancy must be recorded in the 
source documents. 
11. ADVERSE DRUG REACTION REPORTING 
11.1 
Adverse Events and Potential Risks List 
11.1.1 Adverse event (definition) 
An adverse event (AE) will be defined as any untoward medical occurrence in a patient enrolled 
in the study, which may or may not have a causal relationship with this treatment. AEs will include: 
• any unfavorable and unintended sign, symptom, or disease, whether or not considered related 
to the study therapy; 
• pre-existing events or illnesses which increase in frequency or severity or change in nature 
during or as a consequence of study treatment; 
• pre- or post-treatment complications that occur as a result of protocol-mandated procedures. 
Any AE with an onset date between the date the subject signs the informed consent for this 
trial and the date of End-of-study Assessment should be recorded as an AE in the patient files. 
AEs do not include disease progression. Any events that are unequivocally due to progression of 
disease must not be reported as AEs, unless they result in the death of the patient. 
11.1.2 Serious adverse events 
A serious adverse event (SAE) will be any AE occurring during the time on study that results in 
any of the following outcomes: 
• Death; 
• Life-threatening adverse event; 
• An AE that results in an inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours; 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions; 
• Congenital anomaly/birth defect in the offspring of a subject who received study drug; 
• Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
 “Life-threatening” means that the patient is at immediate risk of death from the event as it 
occurred. This definition does not encompass an event that might have led to death, if it had 
occurred with greater severity. Complications that occur during hospitalizations are AEs. If a 
complication prolongs hospitalization, it is an SAE.  


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11.1.3 Lists of adverse events associated with study agents 
For comprehensive lists of potential risks and adverse events for each of the study agents refer to 
the FDA-approved package inserts, available at: 
Rituximab:  
http://www.gene.com/download/pdf/rituxan_prescribing.pdf 
Bendamustine: 
http://treanda.com/PDF/TREANDA_final_PI.pdf or 
http://www.treandahcp.com/pdf/TREANDA_final_PI.pdf 
Vincristine sulfate liposome injection (Marqibo®): 
http://marqibo.com/ 
The most commonly encountered and most significant adverse effects associated with each agent 
are listed below. 
Drug 
Adverse effects 
Rituximab 
Common: 
Cardiovascular: Hypotension (non-Hodgkin lymphoma, 10%; chronic lymphocytic 
leukemia, 2% ), Peripheral edema (Wegener granulomatosis or microscopic polyangiitis, 
16% ) 
Dermatologic: Night sweats (non-Hodgkin lymphoma, 15% ), Pruritus (non-Hodgkin 
lymphoma, 14% ), Rash (non-Hodgkin lymphoma, 15%; Wegener granulomatosis or 
microscopic polyangiitis, 10% ) 
Gastrointestinal: Abdominal pain (non-Hodgkin lymphoma, 14%; rheumatoid arthritis, 2% 
), Diarrhea (non-Hodgkin lymphoma, 10%; Wegener granulomatosis and microscopic 
polyangiitis, 17% ), Nausea (non-Hodgkin lymphoma, 23%; Wegener granulomatosis and 
microscopic polyangiitis, 18% ), Vomiting (non-Hodgkin lymphoma, 10% ) 
Hematologic: Anemia, All grades (non-Hodgkin lymphoma, 8% to 35%; Wegener 
granulomatosis or microscopic polyangiitis, 16% ) 
Musculoskeletal: Arthralgia (non-Hodgkin lymphoma, 10%; Wegener granulomatosis or 
microscopic polyangiitis 13% ), Backache (non-Hodgkin lymphoma, 10% ), Myalgia (non-
Hodgkin lymphoma, 10% ) 
Neurologic: Asthenia (non-Hodgkin lymphoma, 26%; rheumatoid arthritis, 2% ), Dizziness 
(non-Hodgkin lymphoma, 10% ), Headache (non-Hodgkin lymphoma, 19%; Wegener 
granulomatosis and microscopic polyangiitis, 17% ), Sensory neuropathy (non-Hodgkin 
lymphoma, 30% ) 
Respiratory: Increasing frequency of cough (non-Hodgkin lymphoma, 13% ), Rhinitis 
(non-Hodgkin lymphoma, 12% ) 
Other: Fever (non-Hodgkin lymphoma, 53% ), Infectious disease (non-Hodgkin lymphoma, 
31%; rheumatoid arthritis, 39%; Wegener granulomatosis or microscopic polyangiitis, 62% 
), Pain (non-Hodgkin lymphoma, 12% ), Shivering (non-Hodgkin lymphoma, 33%; 
rheumatoid arthritis, 3% ) 
Rare but serious: 
Cardiovascular: Cardiac dysrhythmia, Cardiogenic shock, Heart failure, Myocardial 
infarction, Supraventricular arrhythmia, Supraventricular tachycardia 
Dermatologic: Lichenoid dermatitis, Pemphigus paraneoplastica, Stevens-Johnson 
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Gastrointestinal: Bowel obstruction, Gastrointestinal perforation, Regional ileocolitis 
Hematologic: Anemia, Grade 3 and 4 (non-Hodgkin lymphoma, 3% ), Aplastic anemia, 
Transient, Cytopenia, Grade 3 and 4 (non-Hodgkin lymphoma, 48% ), Febrile neutropenia, 
Grade 3 and 4 (chronic lymphocytic leukemia, 9% to 15% ), Hemolytic anemia, Leukopenia, 
Grade 3 and 4 (non-Hodgkin lymphoma, 4%; chronic lymphocytic leukemia, 23%), 
Lymphocytopenia, Grade 3 and 4 (non-Hodgkin lymphoma, 40% ), Neutropenia, All grades 
(non-Hodgkin lymphoma, 8% to 14% ), Neutropenia, Grade 3 and 4 (non-Hodgkin 
lymphoma, 4% to 6%; chronic lymphocytic leukemia, 8.5% to 49% ), Thrombocytopenia 
(non-Hodgkin lymphoma, all grades, 12%; grades 3 and 4, 2% to 9%; chronic lymphocytic 
leukemia, 11% ) 
Hepatic: Fulminating type B viral hepatitis, acute, Hepatitis B, Liver failure, Relapsing type 
B viral hepatitis 
Immunologic: Infusion reaction, All grades (non-Hodgkin lymphoma, 77%; rheumatoid 
arthritis, 32%; Wegener granulomatosis or microscopic polyangiitis, 12% ), Infusion 
reaction, Grade 3 and 4 (non-Hodgkin lymphoma, 1.1% to 3.5%; chronic lymphocytic 
leukemia, 7% to 9% ) 
Neurologic: Progressive multifocal leukoencephalopathy (rheumatoid arthritis, rare ) 
Ophthalmic: Peripheral ulcerative keratitis 
Renal: Nephrotoxicity 
Respiratory: Dyspnea (Wegener granulomatosis or microscopic polyangiitis, 10% ), 
Obliterative bronchiolitis, Pneumocystis pneumonia, Pneumonitis, Pulmonary fibrosis 
Other: Angioedema (non-Hodgkin lymphoma, 11% ), Infectious disease, Serious (non-
Hodgkin lymphoma, 4%; rheumatoid arthritis, 2%; Wegener granulomatosis or microscopic 
polyangiitis, 11% ), Tumor lysis syndrome 
Bendamustine 
Common: 
Dermatologic: Injection site pain (6% ), Pruritus (5% to 6% ), Rash (all grades, 8% to 16%; 
grade 3 or 4, less than 1% to 3% ) 
Endocrine metabolic: Weight loss (all grades, 7% to 18%; grade 3 or 4, 2% ) 
Gastrointestinal: Constipation (all grades, 29%; grade 3 or 4 less than 1% ), Diarrhea (all 
grades, 9% to 37%; grade 3 or 4, 1% to 3% ), Loss of appetite (all grades, 23%; grade 3 or 
4, 2%), Nausea (all grades, 20% to 75%; grade 3 or 4, less than 1% to 4% ), Stomatitis (all 
grades, 15%; grade 3 or 4, less than 1% ), Vomiting (all grades, 16% to 40% ; grade 3 or 4, 
less than 1% to 3% ) 
Neurologic: Headache (21% ) 
Respiratory: Cough (all grades, 4% to 22%; grade 3 or 4, less than 1% ), Dyspnea (all 
grades, 16%; grade 3 or 4, 2% ) 
Other: Dehydration (all grades, 14%; grade 3 or 4, 5% ), Fatigue (all grades, 9% to 57%; 
grade 3 or 4, 1% to 11%), Fever (all grades, 24% to 34%; grade 3 or 4, 2% to 4% ) 
Rare but serious: 
Cardiovascular: Hypertensive crisis 
Dermatologic: Dermatologic toxicity, Injection site extravasation, Stevens-Johnson 
syndrome, Toxic epidermal necrolysis 
Endocrine metabolic: Hyperuricemia (all grades, 7%; grade 3 or 4, 2% ) 


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Hematologic: Acute myeloid leukemia, Anemia (all grades, 88% to 89%; grade 3 or 4, 11% 
to 13% ), Febrile neutropenia (6% ), Leukopenia (all grades, 61% to 94%; grade 3 or 4, 28% 
to 56% ), Lymphocytopenia (all grades, 68% to 99%; grade 3 or 4, 47% to 94% ), 
Myelodysplastic syndrome, Myeloproliferative disorder, Myelosuppression, grade 3 and 4 
(98% ), Neutropenia (all grades, 75% to 86%; grade 3 or 4, 43% to 60%), Thrombocytopenia 
(all grades, 77% to 86%; grade 3 or 4, 11% to 25% ) 
Immunologic: Anaphylaxis, Hypersensitivity reaction (all grades, 5%; grade 3 or 4, 1% ), 
Infectious disease, Sepsis, Septic shock 
Renal: Renal failure 
Respiratory: Squamous cell carcinoma of bronchus 
Other: Myelodysplastic syndrome, Tumor lysis syndrome 
Vincristine sulfate 
liposome injection 
(Marqibo®) 
Common: 
Gastrointestinal: Constipation (57% ), Decrease in appetite (33% ), Diarrhea (37% ), 
Nausea (52% ) 
Hematologic: Anemia (34% ), Febrile neutropenia (38% ) 
Neurologic: Insomnia (32% ), Peripheral nerve disease (39% ) 
Other: Fatigue (41% ), Fever (43% ) 
Rare but serious: 
Cardiovascular: Cardiac arrest (6% ), Hypotension, Grade 3 or greater (6% ) 
Gastrointestinal: Constipation, Grade 3 or greater (4.8% ), Pseudo-obstruction of 
gastrointestinal tract, Grade 3 or greater 
Hematologic: Anemia, Grade 3 or greater (16.9% ), Febrile neutropenia, Grade 3 or greater 
(31.3% ), Neutropenia, Grade 3 or greater (18.1% ), Thrombocytopenia, Grade 3 or greater 
(16.9% ) 
Hepatic: AST/SGOT level raised, Grade 3 or greater (6% to 11% ), Hepatotoxicity 
Immunologic: Immune hypersensitivity reaction, Septic shock, Grade 3 or greater (6% ), 
Staphylococcal infectious disease, Grade 3 or greater (6% ) 
Neurologic: Peripheral motor neuropathy, Grade 3 or greater (16.7% to 31% ) 
Respiratory: Pneumonia, Grade 3 or greater (8.4% ), Respiratory distress, Grade 3 or greater 
(6% ), Respiratory failure, Grade 3 or greater (4.8% ) 
Other: Fever, Grade 3 or greater (14.5% ), Tumor lysis syndrome 
 
11.2 
Routine Adverse Event Reporting 
All AEs, whether serious or non-serious, related or unrelated, will be reported from the time the 
signed and dated informed consent form is obtained until the date of Off Study Assessment, 
or until the subject withdraws consent from study participation, or at the time the patient is deemed 
ineligible for the study, whichever occurs first.  AEs will be graded, assessed by the Investigator, 
and recorded on the CRF. All AEs must be reported in routine study data submissions.  The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. These are available at: 


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http://evs.nci.nih.gov/ftp1/CTCAE/About.html    
and 
https://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx 
AEs occurring during Cycle 1 of study treatment will be used for DLT designation if they meet 
the DLT definition (Section 6.3). AEs occurring during Cycle 1 through 6 will be recorded and 
used for determination of secondary outcomes (cumulative toxicity). 
During each study assessment, all new AEs as well as previously occurred, unresolved AEs will 
be recorded. For each AE, the following items will be recorded: 
11.3 
Serious Adverse Event Reporting 
All SAEs and deaths occurring within the AE reporting timeframe must be reported to BrUOG, 
the drug manufacturer and the IRB. The process of reporting is initiated by the Investigator 
according to the guideline below. 
11.3.1 Investigator’s responsibilities. 
11.3.1.1 
Telephone/email report to BrUOG:  
Investigator (or designee at the site) must notify BrUOG within 24 hours of learning of the event 
by phone: 401-863-3000 or email. Investigator (or designee at the site) must provide 24-hour 
notification prior to submitting SAE to BrUOG (unless event is a death, for which site is to 
provide notification more expeditiously). 
11.3.1.2 
Written report to BrUOG.  
Investigator (or designee at the site) must provide a written signed report using the MedWatch 
3500A form, within 4 calendar days of the event (or as soon as they are aware of the event), to the 
BrUOG Central Office by email or fax: 
Brown University Oncology Research Group 
Phone: (401) 863-3000 
 
Fax: (401) 863-3820 
Email: BrUOG@brown.edu  
 
All deaths during treatment or within 30 days following completion of active protocol therapy 
must be reported within 4 calendar days or as soon as the investigator is made aware of the event. 
If the death is thought to be related to the study drug, deaths must be reported within 24 hours of 
the investigator being made aware of the event. 
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product, if available. Information not 
available at the time of the initial report must be documented on a follow-up report.  
MedWatch 3500A reporting guideline: In addition to completing appropriate patient 
demographic and suspect medication information, the report should include the following 
information within the Event Description (section 5) of the MedWatch 3500A form: 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description and number: BrUOG 326 and IIS-MAR-003 
• Description of event, severity, treatment, and outcome, if known 
• Expectedness (determined by investigator based on Investigator Brochure, protocol and 
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• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to investigational product 
(Marqibo®), bendamustine, rituximab, disease, or any suspect medication. 
Additional follow-up information: 
For any follow-up SAE report, submit a new MedWatch 3500A report; do not resubmit the initial 
report with any additions. The follow-up report must be submitted to BrUOG with subject 
identifiers (subject number, initials, and date of birth), protocol description and number (BrUOG 
326 and IIS-MAR-003), suspect drug, a brief summary of previously reported SAE information, 
and any new information, including modification of prior events, causality, new serious events, 
discharge date, etc. 
A final report documenting discharge date from the hospital is required. 
11.3.1.3 
Investigator’s report to the IRB 
The Investigator is required to notify his/her Institutional Review Board (IRB) of a serious adverse 
event according to institutional policy. 
11.3.2 BrUOG responsibilities. 
BrUOG must inform: 
• the FDA, Fax: 1-800-FDA-0178 (1-800-332-0178) 
• the Principal Investigator (via email),  
• all participating sites (via email), and  
• Acrotech Biopharma, LLC at: 
o Email: DrugSafety@acrotechbiopharma.com 
of any SAE, in writing using a signed MedWatch 3500A form submitted by the Investigator (or 
designee at the site), no later than 1 business day after BrUOG’s receipt of the information (signed 
form) from the site. A copy of the email transmission of the SAE report to Acrotech Biopharma, 
LLC  will be attached to the SAE and retained with the study records at BrUOG. 
11.4 
Overdosage 
There are currently no data available regarding overdosage of Marqibo® or rituximab. The 
treatment of AEs associated with overdosage should be supportive for the underlying adverse 
symptoms. Management of overdosage of bendamustine should include general supportive 
measures, including monitoring of hematologic parameters and electrocardiogram. Signs and 
symptoms of an overdose that meet the criteria of serious should be reported as a SAE and be 
documented as clinical sequelae to an overdose. 
11.5 
Procedures in the Event of Pregnancy 
Marqibo® can cause fetal harm when administered to a pregnant woman. There are no 
adequate and controlled studies of Marqibo® or vincristine sulfate conducted in pregnant women. 
Vincristine sulfate is a known teratogen in animals. Therefore women and men of child bearing 
potential must use adequate methods of birth control while participating in the study, from the 
registration through 4 months after the last dose of study treatment. 
Pre-menopausal women of childbearing potential must inform the Investigator immediately if they 
become pregnant during the study, and must be immediately removed from the protocol if a 
pregnancy occurs. The Investigator will counsel the patient and discuss the risk and the possible 


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effects on the fetus. Monitoring of the patient will continue until conclusion of the pregnancy. 
If a female partner of a male subject on the study product becomes pregnant, the male subject 
should notify the Investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately. 
Treatment on study must be discontinued immediately in the event of a pregnancy. The pregnancy 
must be reported to BrUOG by the investigator within 1 working day of learning about it on the 
Medwatch 3500A form, and BrUOG will in turn report it to Acrotech Biopharma, LLC  within 1 
working day of receiving the documentation from the investigator. Pregnancies and suspected 
pregnancies (including a positive pregnancy test regardless of age or state of the disease) of a 
female subject occurring within the AE reporting window are considered immediately reportable. 
12. REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
Patients will be removed from study when any of the criteria listed in Section 4.5 applies.  The 
reason for study removal and the date the patient was removed must be documented in the CRF. 
Patients who discontinue the study treatment should undergo the End-of-study Assessment within 
30 to 42 days after their last treatment. Documentation of all SAEs and AEs are to be collected up 
to the date of the End-of-study Assessment.  
13. REGULATORY CONSIDERATIONS 
This research study is sponsored by the Principal Investigator, Dr. Adam J. Olszewski, in 
collaboration with Brown University Oncology Research Group (BrUOG), which will serve as the 
central coordinating office for the study.  
14. DATA MONITORING, QUALITY ASSURANCE AND RECORD RETENTION 
14.1 
Rationale for the study and subject selection 
Most indolent B-cell lymphomas, including the follicular, mantle cell, marginal zone, and 
lymphoplasmacytic subtypes, are at present incurable in the majority of patients. The goals of 
treatment include relief (palliation) of symptoms and achievement of remission from the 
lymphoma. Currently available standard regimens, such as bendamustine-rituximab (BR), have a 
limited potential to achieve these goals, and are associated with recurrences of the disease in a 
majority of patients. Development of more active regimens, which would provide improved 
response rates and duration of remission, without compromising the toxicity profile and patients’ 
quality of life, is an important research goal. For example, current NCCN guidelines® for 
treatment of follicular lymphoma recommend consideration of investigational therapy as first line 
of treatment given incurability with conventional therapy.18 
Patients eligible for this study must be otherwise good candidates for the standard BR regimen as 
would be administered in routine clinical practice and supported by current NCCN guidelines®. 
All patients must read, comprehend, and sign the IRB-approved Informed Consent prior to 
engaging in any study-related procedures. 
14.2 
Data and Safety Monitoring Plan 
This study will treat 10 subjects. Patients who experience a DLT during the first cycle of therapy 
will be removed from the study and their further treatment will be at the managing physician’s 
discretion. If the first three patients experience a DLT or anytime the posterior probability that the 


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DLT rate at the minimum dose exceeds 0.33 is 0.8 or more, the study regimen will be considered 
too toxic and the study will be terminated. 
All AEs occurring during the study treatment will be recorded in the study data files (Section 11), 
All SAEs will be immediately reported to BrUOG, who will then report them to Acrotech 
Biopharma, LLC  (Section 11.3). The Principal Investigator will be responsible for reviewing the 
toxicities in all study participants, identifying, reporting and resolving any potential issues related 
to the study conduct, observed AEs and data management and safety. 
Protocol deviations and violations will be managed and reported according to BrUOG’s Standard 
Operating Procedures. 
14.3 
Investigator Responsibilities 
14.3.1 Good Clinical Practice 
The Investigator will ensure that this study is conducted in full compliance with the principles of 
the Declaration of Helsinki (as amended in Tokyo, Venice, Hong Kong, and South Africa), ICH 
guidelines, and with the United States laws and regulations, whichever affords the greater 
protection to the study subject. The Investigator will ensure that the basic principles of “Good 
Clinical Practice,” as outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and 
Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, are adhered to. The protocol 
has been written, and the study will be conducted according to the ICH Harmonized Tripartite 
Guideline for Good Clinical Practice. 
14.3.2 Institutional Review Board (IRB) Approval 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, information sheets, or descriptions of the study used to obtain informed consent) 
will be submitted, by the Investigator, to the IRB. The IRB’s approval opinion must be obtained 
before starting the study and should be documented in a letter to the Investigator. 
Any modifications made to the protocol after receipt of IRB approval must also be submitted to 
the IRB for approval/favorable opinion prior to implementation. 
14.3.3 Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and prior to undertaking any study-related procedures. The 
Investigator must utilize a current IRB consent form for documenting written informed consent. 
Each informed consent will be appropriately signed and dated by the subject and the person 
obtaining consent.  
Subjects will be treated and/or compensated for any study-related illness/injury pursuant to the 
information provided in the Compensation for Injury section of the Sample Informed Consent. 
BrUOG must receive and approve all consent forms, including the initial form, prior to IRB 
submission, and throughout the duration of the study, any time the consent document is amended. 
14.3.4 Confidentiality 
The Investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials and an identification code 


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(i.e., not names) should be recorded on any form submitted to the drug manufacturer and IRB. The 
Investigator must keep a subject identification code list showing codes, names, and addresses for 
all subjects enrolled in the trial. 
The Investigator agrees that all information received from Acrotech Biopharma, LLC or agent, 
including but not limited to the Investigator’s Brochure, the investigational new drug, and any 
other study information are and remain the sole and exclusive property of Acrotech Biopharma, 
LLC. This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Acrotech Biopharma, LLC. The Investigator further agrees to take all reasonable precautions to 
prevent the disclosure by any employee or agent of the study site to any third party or otherwise 
into the public domain. 
14.3.5 Study Files and Retention of Records 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
The Brown University Oncology Research Group, as coordinator of this study, is responsible for 
ensuring proper conduct of the study with regard to protocol adherence and the validity of the data 
recorded on the case report forms. The Principal Investigator (Adam J. Olszewski, M.D.) and 
Brown University Oncology Research Group will monitor this study. The case report forms will 
be monitored for accuracy, completeness, adherence to the protocol and regulatory compliance.  
U.S. FDA (21CFR§312.62[c]) states that an Investigator shall retain the required records: 
a) 
for a period of two years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or  
b) 
if no application is to be filed or if the marketing application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified. 
If neither a) or b) applies, then the Investigator shall retain the required records for a minimum of 
fifteen (15) years after the completion or discontinuation of the study.  
14.3.6 Drug Accountability 
The Investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), and subject dispensing records. Dispensing records will 
document quantities received from Acrotech Biopharma, LLC and quantities dispensed to subjects, 
including lot number, date dispensed, subject identifier number, subject initials, and the initials of 
the person dispensing the study drug. 
In addition, for each dose of Marqibo® constituted, the study drug records must include: 
• the start time of the constitution of each dose of Marqibo, and 
• the name(s) of the responsible pharmacy staff who performed the constitution. 
14.3.7 Protocol Compliance and Revisions 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
All revisions to the protocol must be created and provided by BrUOG to the participating 
Investigators.  The Investigators will not implement any deviation or change to the protocol 
without prior review and documented approval/favorable opinion from BrUOG, except where 


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necessary to eliminate an immediate hazard(s) to study patients. When applicable, documentation 
of approval signed by the chairperson or designee of the IRB must be sent to BrUOG.  If the 
revision is an Administrative Letter, Investigator must inform the IRB. 
14.4 
Drug Manufacturer’s Responsibilities 
14.4.1 Drug provision 
This study is conducted with support of Acrotech Biopharma, LLC, the manufacturer of 
Marqibo®. The drug manufacturer will provide Marqibo® for the current study, with a sufficient 
number of reconstitution kits to treat each enrolled patient for all cycles of study therapy, and 
allowing for timely administration of treatment according to this protocol. In case of damage or 
expiry of a kit, a replacement kit will be provided. 
15. DATA SAFETY AND MONITORING BOARDS 
This BrUOG study is subject to oversight by the Data Safety Monitoring Board (DSMB). The 
BrUOG DSMB meets two times per year with additional meetings scheduled when needed. The 
DSMB responsibilities are as follows: 
• Familiarize the DSMB members with the research protocol. 
• Review trial performance information including accrual information.   
• Review interim analyses of outcome data and cumulative toxicity data summaries to determine 
whether the trial should continue as originally designed, should be changed, or should be 
terminated based on these data.   
• Determine whether and to whom outcome results should be released prior to the reporting of 
study results. 
• All adverse events are reviewed by the committee, with assurances that these have been in fact 
sent for review to all pertinent IRBs. 
• Review of reports of related studies to determine whether the monitored study needs to be 
changed or terminated. 
• Review major proposed modifications to the study prior to their implementation (e.g., 
termination, dropping an arm based on toxicity results or other reported trial outcomes, 
increasing target sample size). 
• Following each DSMB meeting, provide the study leadership with written information 
concerning findings for the trial as a whole related to cumulative toxicities observed and any 
relevant recommendations related to continuing, changing, or terminating the trial.  
The DSMB leadership will provide information on cumulative toxicities and relevant 
recommendations to the local principal investigators to be shared with their IRB’s. 
16. STATISTICAL CONSIDERATIONS 
16.1 
Study Design/Endpoints 
This is a Phase 1, single-center, open-label, single-arm trial evaluating escalating doses of 
Marqibo® in combination with standard doses of bendamustine-rituximab (BRiM) in adult 
patients with indolent B-cell non-Hodgkin lymphoma, for whom bendamustine-rituximab is 
otherwise clinically indicated as initial or subsequent line of therapy. 


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16.1.1 Primary endpoint 
The primary endpoint in this study is the Maximum Tolerated Dose (MTD) of Marqibo® in the 
BRiM combination.  
MTD is defined to be the dose level of Marqibo® that when administered to a patient in the BRiM 
combination results in a probability of θ = 33% that a DLT will be manifest within the first cycle 
of treatment. It will be synonymous with the recommended phase II dose for this regimen. 
Upon completion of the trial, the primary endpoint will be calculated as the median of the marginal 
posterior distribution of the MTD, rounded to 0.05 mg/m2. The MTD and the 95% highest 
posterior density credible interval estimate of the MTD will be reported, as calculated by the 
Investigator in cooperation with the study statistician. Data from all enrolled patients will be used 
for the calculation.  
The computation of the dose to be administered to each patient and the 95% highest posterior 
density credible interval estimate of the MTD will be carried out by the Investigator in cooperation 
with statistician consultant, using the Web-EWOC computer software, available at:42 
http://biostatistics.csmc.edu/ewoc/ 
In case of unavailability of the Web-EWOC interface, the stand-alone EWOC Version 3.1 will be 
used. The results of all simulations, calculations and dose determinations will be recorded in the 
study files and signed by the Investigator.  
The DLT will be described as the CTCAE terms for the recorded DLT’s, and the dose level at 
which they occurred. The trial will be terminated after ten patients are evaluated, or if the 
first three patients experience a DLT or anytime the posterior probability that the DLT rate 
at the minimum dose exceeds 0.33 is 0.8 or more. 
16.1.2 Secondary endpoints 
The secondary endpoints of the study include:  
• Tolerability of the BRiM regimen, assessed by proportion of enrolled patients completing 6 
cycles of study treatment. 
• Proportions of patients experiencing cumulative toxicities with the BRiM combination during 
the study treatment. 
• Proportion of patient achieving partial remission (PR) or complete remission (CR) after 
completion of the study treatment 
The secondary endpoints will be calculated using data from Off Study Assessments for all enrolled 
patients. Proportions of patients with cumulative toxicities will be calculated as the total numbers 
of patients experiencing each of the recorded toxicities at each grade. Each AE will be counted 
once per patient, at the worst grade experienced during treatment. 
16.1.3 Analysis population 
The endpoints will be assessed in the population of all registered patients. 
16.1.4 Treatment regimen 
The dose of Marqibo® will be determined specifically for each patient at the time of registration, 
from the starting dose of 1.8 mg/m2, up to the convergence ceiling dose of 2.4 mg/m2. The 
computation of the dose to be administered to each patient and the 95% highest posterior density 


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credible interval estimate of the MTD will be carried out by the Principal Investigator with the 
EWOC-Web software. The Principal Investigator will provide BrUOG with the dose-assignment 
trees (as in Figure 3 below) for the first 5 patients before the first patient is registered on the study. 
The Principal Investigator will then generate a dose-assignment tree for 4 subsequent patients 
when subject #4 is registered (see Section 16.4 for details). 
Patients will be evaluated weekly during the first cycle to assess clinical and laboratory toxicity 
and to identify any DLT. Patients will be followed every two weeks during subsequent cycles, 
until completion of six cycles of therapy or discontinuation of treatment.  
The response to chemotherapy will be evaluated after 3 cycles and 6 cycles of treatment. The 
cumulative toxicities will be evaluated at each visit. The radiographic responses will be assessed 
according to the International Working Group criteria.41  
16.2 
EWOC Phase I design 
The dose escalation will follow a Bayesian method permitting precise determination of the 
therapeutic working-dose while directly controlling the likelihood of an overdose. The method, 
known as EWOC (Escalation With Overdose Control), has been used to design many dose finding 
clinical trials.43-50 Babb et al. provided a comparison of EWOC with alternative phase I design 
methods.51 They showed that up-and-down designs treated only 35% of patients at optimal dose 
levels, versus 55% for EWOC, i.e., more patients are treated with doses outside the therapeutic 
window by up-and-down than by EWOC designs. Babb and Rogatko provide a summary of 
Bayesian phase I design methods and Tighiouart et al. studied the performance of EWOC under a 
rich class of prior distributions for the MTD.52,53 Tighiouart and Rogatko showed that EWOC is 
coherent.54 
EWOC was the first dose-finding procedure to directly incorporate the ethical constraint of 
Figure 2: Treatment schema. 


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minimizing the chance of treating patients at unacceptably high doses.  Its defining property is that 
the expected proportion of patients treated at doses above the MTD is equal to a specified value 
α, the feasibility bound. This value is selected by the clinician and reflects his/her level of concern 
about overdosing. Zacks et al. showed that among designs with this defining property, EWOC 
minimizes the average amount by which patients are under-dosed.55 This means that EWOC 
approaches the MTD as rapidly as possible, while keeping the expected proportion of patients 
overdosed less than the value α. Zacks et al. also showed that, as a trial progresses, the dose 
sequence defined by EWOC approaches the MTD (i.e., the sequence of recommended doses 
converges in probability to the MTD). Eventually, all patients beyond a certain time would be 
treated at doses sufficiently close to the MTD. 
16.3 Dose Escalation Procedure 
The dose of Marqibo® for the first patient in this trial will be 1.8 mg/m2, which is considered to 
be safe in view of feasibility of 2.0 mg/m2 dose in the R-CHMP combination with full-dose 
rituximab and cyclophosphamide.35 The dose for each subsequent patient will be determined so 
that, on the basis of all available data, the probability that it exceeds the MTD is equal to a pre-
specified value α.  In this trial, we set α = 25%, with an increase α in small increments of 5% until 
α = 50%, this value being a compromise between the therapeutic aspect of the agent and its toxic 
side effects.  
The dose selected for every patient in the trial will be between the minimum dose of 1.8 mg/m2 
and the maximum allowable dose 2.4 mg/m2. This maximum dose serves only as a convergence 
value for the algorithm and will never be actually administered to any patient. The maximum dose 
that could be administered to a patient during the dose escalation portion, in the absence of any 
DLT, would be 2.3 mg/m2. The trial will be terminated if the first three patients experience a 
DLT or anytime the posterior probability that the DLT rate at the minimum dose exceeds 
0.33 is 0.8 or more. Figure 3 shows all the possible dose sequences that could be realized for the 
first 5 patients, assuming that the first patient is treated at dose level 1.8 mg/m2 and does not 
experience a DLT.   
16.4 Assignment of Marqibo® Dose Level 
The determination of the patient-specific dose of Marqibo® to be delivered as part of the study 
regimen will be performed solely by the BrUOG central office using the pre-populated dose-
Figure 3. Distribution of doses (in mg/m2) for patients 
2-5 in the study according to the EWOC protocol 
(assuming the first patient is treated at dose 1.8 mg/m2 
and does not experience a DLT). 


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assignment trees generated by the Principal Investigator. The doses will be calculated using the 
EWOC-web software, available at:42 
http://biostatistics.csmc.edu/ewoc/ 
When creating the dose-assignment trees, the Investigator will input a data matrix containing 
information about all study patients for whom DLT information is available at the time of 
calculation. The following parameters will be set for the software: 
- Target Probability of Dose Limiting Toxicity =  
0.33  
- Probability of Exceeding Target Dose =  
 
0.25  
- Minimum Dose =  
 
 
 
1.8  
- Maximum Dose =  
 
 
 
2.4  
- Minimum Dose Increment =  
 
 
0.01  
- Bayesian Confidence Interval Percentage =  
 
95  
- Number of Patients =  
 
 
 
1  
- Variable Alpha Increment =  
 
 
0.05  
- Prior Distribution =  
 
 
 
Uniform  
- Uniform Lower =  
 
 
 
0  
- Uniform Upper =  
 
 
 
0.33  
Only N=1 patient per cohort is allowed, i.e. a new subject may be registered for the study 
only after all previous subjects resolve their DLT assessment period.  
At no time will there be more than one subject on the study with unresolved DLT status. 
The calculated dose will be patient-specific and will not be adjusted during subsequent cycles 
(except for toxicity, as delineated in Section 5).  
16.5 
Sample Size/Accrual Rate 
The planned sample size for this study is 10 treated patients with a planned accrual rate of 5 patients 
per year.  
Procedure for determining the number of patients needed in a dose finding trial using a Bayesian 
framework depends on the investigators, goal and sets of criteria such as precision of the estimate 
of the MTD and frequency of DLTs.  The investigators conducted extensive simulations under 
several scenarios, with true values of the MTD ranging from 1.85 mg/m2 to 2.20 mg/m2, and 
probability of toxicity at the initial dose (20%) and target probability of DLT (θ = 33%) set at the 
levels assumed for the study using prior literature. Table 3 presents results of simulations of N=100 
trials consisting of 10 patients, assuming different levels of true MTD. The results indicate that the 
study will estimate reasonably precise MTD within a range of MTD 1.80 mg/m2 to 2.20 mg/m2. 
Table 3. Results of simulation of N=100 trials of 10 patients with true MTD ranging from 
1.81 mg/m2 to 2.25 mg/m2, conducted according to the current trial’s design. 
True 
MTD 
level  
(mg/m2) 
Estimated 
MTD 
(mg/m2) 
Estimated root 
mean standard 
error  (mg/m2) 
Patients treated at 
±10% of the 
optimal dose, % 
Patients 
overdosed, 
% 
DLT’s 
observed,  
% 
1.81 
1.82 
0.01 
100 
0 
58 
1.90 
1.98 
0.08 
88 
12 
43 
2.00 
2.08 
0.13 
83 
17 
33 


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2.10 
2.12 
0.11 
98 
0 
28 
2.20 
2.15 
0.12 
89 
0 
26 
2.25 
2.15 
0.15 
87 
0 
25 
Figure 4 shows the results of a simulation of N=500 trials with varying sample size (10 to 30) and 
true MTD (1.80, 2.00, and 2.25 mg/m2), with resulting estimated MTD and mean root standard 
errors. The simulation indicates acceptable performance and precision of the estimates even with 
the smallest sample size, if the MTD is rounded to 0.05 mg/m2.   
 
 
Figure 4. Simulation of N=500 trials with varying sample size conducted according 
to the current study design, with a true MTD of 1.85, 2.00 or 2.20 mg/m2 


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lymphoma or mantle cell lymphoma in need of palliative therapy. Clin Lymphoma Myeloma Leuk. 
2014;14(1):37-42. 
35. 
Hagemeister F, Rodriguez MA, Deitcher SR, Younes A, Fayad L, Goy A, et al. Long term 
results of a phase 2 study of vincristine sulfate liposome injection (Marqibo((R)) ) substituted for non-
liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without 
rituximab for patients with untreated aggressive non-Hodgkin lymphomas. Br J Haematol. 
2013;162(5):631-8. 
36. 
Smith SM. Dissecting follicular lymphoma: high versus low risk. Hematology: the Education 
Program of the American Society of Hematology. 2013;2013:561-7. 
37. 
Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, et al. 
Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma 
developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 
2009;27(27):4555-62. 
38. 
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lymphoma international prognostic index. Blood. 2004;104(5):1258-65. 
39. 
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 update 
of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice 
guideline. J Clin Oncol. 2006;24(19):3187-205. 
40. 
Benson AB, 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, Jr., et 
al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 
2004;22(14):2918-26. 
41. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-86. 
42. 
Rogatko A TM, Cook-Wiens G. Escalation with overdose control. User's guide. Version 3.1., 
2012. 
43. 
Angevin E, Lopez-Martin JA, Lin CC, Gschwend JE, Harzstark A, Castellano D, et al. Phase 
I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic 
renal cell carcinoma. Clin Cancer Res. 2013;19(5):1257-68. 
44. 
Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, dose-
escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J 
Clin Oncol. 2012;30(3):282-90. 
45. 
DeAngelo DJ, Spencer A, Bhalla KN, Prince HM, Fischer T, Kindler T, et al. Phase Ia/II, 
two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in 
patients with advanced hematologic malignancies. Leukemia. 2013;27(8):1628-36. 
46. 
Harvey RD, Owonikoko TK, Lewis CM, Akintayo A, Chen Z, Tighiouart M, et al. A phase 1 
Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor 
malignancies. Br J Cancer. 2013;108(4):762-5. 
47. 
Lonial S, Kaufman J, Tighiouart M, Nooka A, Langston AA, Heffner LT, et al. A phase I/II 
trial combining high-dose melphalan and autologous transplant with bortezomib for multiple myeloma: a 
dose- and schedule-finding study. Clin Cancer Res. 2010;16(20):5079-86. 
48. 
Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC, et al. Phase I safety, 
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inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol. 2012;23(9):2399-408. 
49. 
Sharma S, Beck J, Mita M, Paul S, Woo MM, Squier M, et al. A phase I dose-escalation 
study of intravenous panobinostat in patients with lymphoma and solid tumors. Invest New Drugs. 
2013;31(4):974-85. 
50. 
Sinha R, Kaufman JL, Khoury HJ, Jr., King N, Shenoy PJ, Lewis C, et al. A phase 1 dose 
escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified 
vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas. 
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52. 
Babb JS, Rogatko A. Patient specific dosing in a cancer phase I clinical trial. Stat Med. 
2001;20(14):2079-90. 
53. 
Tighiouart M, Rogatko A, Babb JS. Flexible Bayesian methods for cancer phase I clinical 
trials. Dose escalation with overdose control. Stat Med. 2005;24(14):2183-96. 
54. 
Tighiouart M, Rogatko, A. Dose Finding with Escalation with Overdose Control (EWOC) in 
Cancer Clinical Trials. Statistical Science. 2010;25(2):217-26. 
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Zacks S, Rogatko A, Babb J. Optimal Bayesian-feasible dose escalation for cancer phase I 
trials. Stat Prob Ltrs. 1998;38:215-20. 
 
 
 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry 
out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
LIST OF CONCOMITANT MEDICATIONS KNOWN TO INTERACT WITH 
CYTOCHROME P450-3A4 ISOENZYMES AND/OR P-GLYCOPROTEIN (TO BE USED WITH 
CAUTION)+ 
 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Amiodarone 
Cordarone 
Miconazole 
(systemic) 
Lotrimin, Monistat 
Atazanavir§ 
Reyataz 
Modafinil§ 
Provigil 
Atorvastatin 
Lipitor 
Nefazodone§ 
Serzone 
Azithromycin 
Zithromax 
Nelfinavir§ 
Viracept 
Barbiturates§ 
(including phenobarbital) 
Amytal, Fioricet, Fiorinal, Illocalm, 
Mebaral, Brietal, Nembutal, Seconal, 
Pentothal 
Nevirapine§ 
Viramune 
Bromocriptine 
Parlodel 
Nicardipine 
Cardene 
Buprenorphine/naloxone§ 
Suboxone 
Norfloxacin 
Noroxin 
Carbamazepine§ 
Tegretol, Tegretol-XR 
Omeprazole 
Prilosec 
Cerivastatin 
Baycol 
Orphenadrine 
Norflex 
Chlorpheniramine 
Chlor-Trimeton 
Oxcarbazepine§ 
Trileptal 
Cimetidine 
Tagamet 
Paroxetine 
Paxil 
 
 
Phenytoin§ 
Dilantin 
Ciprofloxacin 
Cipro 
Posaconazole 
Noxafil 
Clarithromycin§ 
Biaxin 
Progesterone 
Progestasert, 
Prometrium, Crinone, 
Corluvite 
Clotrimazole* 
Mycelex, Lotrimin* 
Quinine 
Legatrin, Quinamm 
Quinine sulfate 
Cyclosporine 
Neoral, Sandimmune 
Ranitidine 
Zantac, Tritec 
Danazol* 
Danocrine* 
Rapamycin 
Rapamune 
Delavirdine 
Rescriptor 
Rifabutin§ 
Mycobutin 
Dexamethasone§ 
Decadron 
Rifampin§ 
Rifadin, Rimactane 
Diltiazem 
Cardizem 
Rifapentine 
Priftin 
Digoxin 
Lanoxin 
Ritonavir§ 
Novir, Kaletra 
Efavirenz§ 
Sustiva 
Rosiglitazone 
Avandia 
Ergotamine 
Ergomar, Ergostat 
Saquinavir§ 
Invirase, Fortovase 
Erythromycin 
E-Mycin, EES, Ilosone, Pediazole 
Sertraline 
Zoloft 
Fluconazole* 
Diflucan* 
Simvastatin 
Zocor 
Grapfruit juice 
NA 
St. John’s Wort§ 
NA 
Haloperidol 
Halodol 
Tacrolimus 
Prograf 
Indinavir§ 
Crixivan 
Tamoxifen 
Nolvadex 
Isoniazid 
INH, Nydrazid, PMS-Isoniazid 
Telithromycin§ 
Ketek 
Itraconazole§ 
Sporanox* 
Toremifene 
Fareston 
Ketoconazole§ 
Nizoral* 
Trazodone 
Desyrel 
 
 
Troglitazone§ 
Rezulin, Resulin, 
Romozin, Noscal 
Lidocaine 
Xylocaine 
Troleadomycin 
TAO 
Lovastatin 
Mevacor 
Verapamil 
Calan 
Methadone 
Dolophine, Diskets 
Voriconazole 
Vfend 
Metronidazole* 
Flagyl* 
Zafirlukast 
Accolate 
 + Not a comprehensive listing 
* Must have Sponsor’s and drug manufacturer’s approval prior to use 
§ Prohibited in his protocol. Patients taking this medication are not eligible for participation. 
Dexamethasone use as an anti-emetic according to the protocol is allowed. 


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APPENDIX C 
REGISTRATION CHECKLIST 
Inclusion Criteria 
___ Yes 
Histologically confirmed indolent B-cell non-Hodgkin lymphoma, CD20-positive, previously treated or 
untreated—for which bendamustine-rituximab chemotherapy is clinically indicated; the following 
subtypes are allowed (check or circle applicable): 
− 
Follicular lymphoma 
− 
Mantle cell lymphoma,  
− 
Marginal zone lymphoma,  
− 
Small lymphocytic lymphoma,  
− 
Lymphoplasmacytic lymphoma, or  
− 
Indolent B-cell lymphoma, NOS. 
Note: BrUOG must receive the pathology report to confirm the diagnosis and the CD20-positive status, as well as 
documentation from the treating physician that bendamustine-rituximab chemotherapy is clinically indicated for 
the subject. 
___ Yes 
Radiological measurable disease, defined as any measurable lesion >15 mm  
Patients with blood or bone marrow involvement only are ineligible.  
Splenomegaly is acceptable as a measurable site if enlarged on the initial CT scan (>13 cm in the 
cranio-caudal dimension). 
___ Yes 
Previous treatment for lymphoma is allowed, with the exception of use of bendamustine within 180 
days of the date of the consent form, or any prior use of vincristine sulfate liposome injection 
(Marqibo®). 
___ Yes 
Age ≥18 years.   
___ Yes 
ECOG performance status 0 or 1 
___ Yes 
Life expectancy of greater than 6 months. 
___ Yes 
White blood cell count 
 
≥3,000/mm3  
Date _________ 
___ Yes 
Absolute neutrophil count  
≥1,000/mm3  
Date _________ 
___ Yes 
Platelets 
 
 
≥75,000/mm3 
Date _________ 
Note: platelet transfusion within 1 week before registration is not allowed; note the date of a prior 
platelet transfusion on the ConMed log 
___ Yes 
Total bilirubin within normal institutional limit 
 
Date _________ 
___ Yes 
AST(SGOT)/ALT(SGPT) <2.5x normal institutional limit  
Date _________ 
___ Yes 
Creatinine 
 
 
≤2.0 mg/mL   
Date_________ 
___ Yes 
Creatinine clearance  
 
≥50 mL/min/1.73 m2.  
Date_________ 
Note: calculate by Cockroft-Gault equation, using actual weight 
___ Yes 
Subject is a women of child-bearing potential or a man, and agrees to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and up to 4 months after 
the last dose of study treatment. 
___ Yes 
 
___ Yes 
Subject is a woman of childbearing potential and has a negative serum or urine pregnancy test. 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she agrees to inform her treating physician immediately.   
Postmenopausal women (after surgical menopause or no menses for >12 months) do not need to 
have a pregnancy status, but their postmenopausal status must be documented. Males with a 
vasectomy also must be documented. 
___ Yes 
Subject is able to understand and the willingness to sign a written informed consent document. 


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Exclusion criteria 
___ No 
History of any allergic reaction attributed to rituximab (with the exception of <grade 3 infusion 
reaction), bendamustine, vincristine sulfate, Marqibo®, mannitol, sodium phosphate injection or 
sphingomyelin/cholesterol liposome. 
___ No 
Any lymphoma-directed radiotherapy, chemotherapy, biologic or experimental therapy, oral or 
intravenous, within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study, or 
subject has not recovered from adverse events due to agents administered more than 4 weeks 
earlier to ≤grade 1—with the exception of alopecia, which is allowed. 
___ No 
Any prior treatment with vincristine sulfate liposome injection (Marqibo®). 
___ No 
Prior treatment with bendamustine or vincristine sulfate within 180 days of enrollment.  
Prior treatment with rituximab is allowed. 
___ No 
Subject is receiving any other investigational agents or anti-cancer therapy with the exception of 
endocrine therapy for breast or prostate cancer. 
___ No 
Known central nervous system involvement (infiltration of the brain, meninges or cerebrospinal fluid) 
by the lymphoma  
___ No 
Active peripheral sensory or motor neuropathy > grade 1. This is defined by the CTCAE as any 
neuropathy requiring intervention or limiting instrumental activities of daily life. 
___ No 
History of demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, 
or other demyelinating condition. 
___ No 
Documented positive test for the Human Anti-Chimeric Antibody (HACA).  
___ No 
Subject is receiving any medications or substances that are strong inhibitors or inducers of CYP3A 
enzyme are ineligible. 
___ No 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (that requires 
antibiotic use), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.  
Note: Suppressive anti-HSV/VZV therapy with acyclovir, famciclovir, or valacyclovir is allowed. 
___ No 
Prisoner. 
___ No 
Pregnant or breast-feeding woman. 
___ No 
___ No 
 
Known Human Immunodeficiency Virus (HIV) or active Hepatitis B infection (defined as presence of 
HBV DNA or hepatitis B S antigen in the blood). 
Any prior or active cancer, which in the opinion of the investigator would preclude safe participation 
in this study. 
Signed informed consent: 
___ Yes 
The patient is aware of the neoplastic nature of his/her disease and willingly consents after being 
informed of the procedure to be followed, the experimental nature of the therapy, alternatives, 
potential benefits, side effects, risks, and discomforts. 
Support documentation enclosed: (NOTE: all must be faxed to BrUOG for registration) 
___ Yes Demographics Form 
___ Yes Pathology Report 
___ Yes CT or PET-CT report(s) 
___ Yes Treating oncologist’s note (documenting that bendamustine-rituximab is clinically indicated) 
___ Yes Lab Source Document         
___ Yes ICF signature page 
___ Yes Others, please list: 
 
 
 
 
 
 
 
 
 
IRB approval date of protocol:  
 
     Hospital where patient will be treated: __________ 
Date patient will begin treatment:  
 
     Treating oncologist:   
 
 
 
Your signature:  
 
 
 
 
Date:  
 
 
The support documentation, consent form, and this checklist, must be faxed to BrUOG at the time of registration. Source 
documents to support each inclusion and prove the subject does not meet each exclusion criteria are required. Source 
document for each element in Section 6 must also be sent.  


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APPENDIX D 
MODEL INFORMED CONSENT FORM 
AGREEMENT TO PARTICIPATE IN A RESEARCH STUDY AND AUTHORIZATION FOR USE AND 
DISCLOSURE OF INFORMATION 
BrUOG 326: A Phase I Dose-Escalation Study of Vincristine Sulfate Liposome Injection 
(Marqibo®) in Combination with Bendamustine and Rituximab (BRiM) in Indolent non-
Hodgkin Lymphoma 
 
You are being asked to take part in a research study.  All research studies carried out at <INSERT 
HOSPTIAL NAME> are covered by rules of the Federal government as well as rules of the State 
and <INSERT HOSPTIAL NAME>.  Under these rules, the researcher will first explain the study, 
and then he or she will ask you to participate.  You will be asked to sign this agreement that states 
that the study has been explained, that your questions have been answered, and that you agree to 
participate. 
The researcher will explain the purpose of the study. He or she will explain how the study will be 
carried out and what you will be expected to do.  The researcher will also explain the possible risks 
and possible benefits of being in the study.  You should ask the researcher any questions you have 
about any of these things before you decide whether you wish to take part in the study.  This 
process is called informed consent. 
This form also explains the research study.  Please read the form and talk to the researcher about 
any questions you may have.  Then, if you decide to be in the study, please sign and date this 
form in front of the person who explained the study to you. You will be given a copy of this form 
to keep. 
Nature and Purpose of the Study      
Your doctors are participating in this research study sponsored by the Principal Investigator, Dr. 
Adam Olszewski, in collaboration with Brown University Oncology Research Group (BrUOG), 
which will serve as the central coordinating office for the study 
You have been asked to participate in this study, because you have been diagnosed with a 
lymphoma for which your doctor has recommended treatment with rituximab and bendamustine 
chemotherapy.  
The combination of rituximab and bendamustine is one of the treatment options for patients with 
indolent (slow-growing) lymphomas. Although other chemotherapy regimens exist, 
rituximab/bendamustine is often used because it is both effective (works well) and is well tolerated 
by patients when compared with other combinations. Many patients with indolent lymphomas who 
receive rituximab/bendamustine chemotherapy for the first time experience shrinking of their 
lymphoma. However, some patients with indolent lymphomas do not respond to this treatment, 
and while over half of the patients who do respond are alive and have not had recurrence of their 
lymphoma more than 5 years after this treatment, in most patients the lymphoma does eventually 
regrow. Also, about 1 in 5 patients treated with rituximab/bendamustine experience a serious side 
effect (toxicity) during therapy. New treatments are needed to see if new combinations of 
treatments are well tolerated and might work better.  
The purpose of this study is to find the maximum tolerated dose of the drug Marqibo® (vincristine 


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sulfate liposome injection) that can be given in combination with rituximab and bendamustine for 
patients with certain types of lymphoma. This will be determined by looking at the side effects 
that occur during the treatment with the combination. In this study, your doctors hope to show that 
rituximab and bendamustine can be safely combined with Marqibo® in your type of lymphoma, 
called non-Hodgkin lymphoma (NHL). Two previous studies indicated that Marqibo® can be 
safely combined with rituximab and full-dose alkylating agents (similar to Bendamustine, which 
belongs to this same class of drugs) for the treatment of NHL without unexpected side effects. 
Marqibo® is already approved by Food and Drug Administration (FDA) for the treatment of acute 
lymphoblastic leukemia that has relapsed after at least two other lines of therapy. Acute 
lymphoblastic leukemia is a very aggressive kind of lymphoma that involves blood and bone 
marrow. Marqibo® has been combined with rituximab and other chemotherapy drugs for treatment 
of other kinds of lymphoma in some studies. The active ingredient of Marqibo® (vincristine) is 
commonly used in chemotherapy combinations for many kinds of lymphoma,  but Marqibo® is 
not at present FDA-approved for the treatment of your type of non-Hodgkin lymphoma.  
 
The use of Marqibo® in combination with rituximab/bendamustine in this study is experimental. 
The doses and schedules of rituximab and bendamustine in this study are the same as those used 
for patients in routine clinical practice. The dose of Marqibo® will be decided on for each patient 
participating in the study, depending on side effects seen in all previous patients enrolled in this 
study. Because in this study Marqibo® is used in combination with rituximab/bendamustine, the 
doses of Marqibo® used in this study are lower than the FDA-approved dose for acute 
lymphoblastic leukemia. 
 
Approximately 10 patients will be treated on this study. 
Explanation of Procedures   
What will happen if I take part in this research study?  
If the following exams, tests and procedures show that you can be in the study, and you choose 
to take part, then you will need the following tests, while on the study.  They are part of regular 
cancer care.  
• Medical history 
• A physical examination with performance status, toxicity assessment, weight, vitals, and an 
assessment of the medications you are taking 
• Blood and urine tests, including blood counts, kidney and liver function, a pregnancy test (if 
you are a woman who can become pregnant) and tests for the HIV and hepatitis viruses; many 
of these tests will be repeated during the study; approximately three tablespoons of blood will 
be taken; 
• An electrocardiogram—a simple test that involves putting electrode stickers on your chest to 
record the heart’s electrical activity; 
• A scan to obtain measurements of any lymphoma tumors inside your body. This may be a CT 
(Computed Tomography) scan or a PET-CT (Positron Emission Tomography and Computed 
Tomography) scan.  


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• If your doctor feels it is necessary, a bone marrow aspirate and biopsy will be performed. This 
is a procedure performed by a physician that involves collecting a sample of the marrow from 
the hip bone to find out if it contains lymphoma cells.  
While on study: 
Different doses of Marqibo® are being tested in this study and each patient will be registered to 
their own dose based on how well previous patients did in the study (ranging from the smallest 
dose of 1.8 mg of drug per square meter of body surface area to the highest dose of 2.4 mg of drug 
per square meter of body surface area).. Patients will be treated to determine the highest safe dose 
of Marqibo® in combination with bendamustine and rituximab.  
The Brown University Oncology Research Group, the group coordinating this trial, will calculate 
the dose of Marqibo® to be used for your treatment. This calculation will take into consideration 
information about any side effects that happened to any patients previously treated in the study, in 
order to lower the risk of side effects. Neither you nor your doctor can choose which dose you will 
receive and your dose will not be increased. 
Once your dose has been calculated, you will start the study treatment. The treatment will be given 
in “cycles” of four weeks (28 days) for a maximum of 6 cycles (about 6 months). It will involve 
chemotherapy with rituximab, bendamustine and Marqibo®, given intravenously (through a vein) 
according to the schedule below. 
On Day 1 of each treatment cycle (your visit is expected to last about 6 hours): 
• You will undergo a physical examination including vital signs, ECOG performance status, 
height, weight, and recording of all medications you take. 
• Laboratory tests before the treatment to confirm normal blood counts, kidney and liver function 
(approximately 2 tablespoons of blood). 
• Urinalysis  
• If you are a woman of childbearing potential you will also have a pregnancy test 
You will then receive: 
• Medications to prevent allergic reactions and nausea (by mouth or intravenously). These are 
routinely given (they are standard) to patients receiving rituximab or bendamustine. 
On Day 1 of each treatment cycle you will receive: 
• Rituximab as an intravenous infusion, which may take up to 4-5 hours to complete. 
• Bendamustine as an intravenous infusion, over approximately 10 to 30 minutes. 
On Day 2 of each treatment cycle (your visit is expected to last about 2 hours) you will receive: 
• Bendamustine as an intravenous infusion, over approximately 10 to 30 minutes. 
• Marqibo® as an intravenous infusion, at a dose calculated for you at the time of enrollment, 
over approximately 60 minutes. 
If your doctor recommends it, you may also receive an additional medication (pegfilgrastim) on 
Day 3 or 4 of each cycle. Pegfilgrastim is given as an injection under the skin for patients who are 
at higher risk of serious infections during chemotherapy. It lowers the risk of infections by 
increasing the number of a type of white blood cells called neutrophils, which may drop during 
chemotherapy. 


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During cycle 1: 
During the first cycle of treatment, you will come in for three weekly checkup visits after treatment 
on; day 8, day 15 and day 22. Each of these visits is expected to last about 1 hour.  You will have 
the following done: 
• Vital signs, ECOG performance status, and weight  
• Toxicity assessment  
• Laboratory tests, approximately 2 tablespoons of blood 
During Cycles 2-6: 
You will be assessed prior to day 1 of cycles 2-6 as explained above. You will then receive 
treatment on Day 1 and 2 as explained above.  
Day 15: You will also be seen on day 15 of cycles 2-6 (each or these visits are expected to last 
about 1 hour) for the following: 
• Vital signs, ECOG performance status, weight 
• Toxicity assessment 
• A scan to obtain measurements of any lymphoma tumors inside your body using a CT 
(Computed Tomography) scan or a PET-CT (Positron Emission Tomography and Computed 
Tomography) scan will be done after cycle 3 and after cycle 6 or when you come off study. 
• If your doctor feels it is necessary, a bone marrow aspirate and biopsy may be performed if 
your doctor feels your cancer is responding. This is a procedure performed by a physician that 
involves collecting a sample of the marrow from the hip bone to find out if it contains 
lymphoma cells.  
For all patients, treatment on study will be given in cycles of every 4 weeks (28 days) for a 
maximum of 6 cycles.  
End of study treatment 
Between 30- 42 days after your last treatment you will undergo the following: 
• History and physical examination, including vital signs, ECOG performance status, weight, 
and recording of all medications you take.  
• Toxicity assessment. If there are any important side effects, your doctor will continue to follow 
your condition until they stabilize or resolve. 
• A scan to obtain measurements of any lymphoma tumors inside your body may also be done 
(as noted above) if you come off prior to completing all your treatment. 
How long will I be in this study? 
You will receive the study treatment for 6 months.  
 
 


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Can I stop being in this study? 
Yes. You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping 
or decide to stop.  He or she will tell you how to stop safely.   
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
discontinuation of treatment can be evaluated by your doctor.  Another reason to tell your doctor 
that you are thinking about stopping is to discuss what follow-up care and testing could be most 
helpful for you.  
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
Costs of participating in this study 
Acrotech Biopharma, LLC, the maker of Marqibo®, will provide Marqibo® at no charge while 
you take part in this study. All other services you will receive during this research study are 
considered to be “routine clinical services” that you would have received even if you were not 
participating in the research study. These include all study doctor visits, blood tests, urine tests, 
bendamustine and rituximab, drugs and administration costs, drugs used to reduce side effects, CT 
scans, PET scans, EKGs and bone marrow biopsies.  Therefore, all of the services listed in this 
paragraph will be billed to your health insurance company, but you will be responsible for paying 
any deductibles, co-payments, or co-insurance that are a normal part of your health insurance plan. 
If you do not have health insurance or your insurance does not cover these services, you will be 
responsible for those costs. 
Risks or Discomforts: 
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for side effects.  However, doctors don’t know all the side effects that may happen.  Side 
effects may be mild or very serious. Your health care team may give you medicines to help lessen 
side effects. Many side effects go away soon after you stop the chemotherapy. In some cases, side 
effects can be serious, long lasting, or may never go away. There also is a risk of death.  You 
should talk to your study doctor about any side effects that you have while taking part in the study.  
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
VINCRISTINE SULFATE LIPOSOME INJECTION (MARQIBO®) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Marqibo®, more than 20 and up to 100 may have (>20%): 
• Constipation, diarrhea, nausea, vomiting, belly pain 
• Loss of appetite and weight loss 
• Anemia which may require blood transfusions 
• Infection, especially when white blood cell count is low 
• Difficulty sleeping  
• Chills, Fever, tiredness 
• Numbness and tingling of the arms and legs, weakness and difficulty walking 
• Hair loss 


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VINCRISTINE SULFATE LIPOSOME INJECTION (MARQIBO®) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Marqibo®, more than 20 and up to 100 may have (>20%): 
• Headache, jaw pain/and or muscle pain 
• Low platelets, which may increase risk of bleeding 
• Pain and redness at the site of injection 
• Swelling of lower legs 
• Dehydration 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Marqibo®, from 4 to 20 may have (4-20%): 
• Heart stops beating 
• Low blood pressure, which may cause feeling faint 
• High blood pressure 
• Bruising, bleeding 
• Severe blood infection 
• Muscle weakness 
• Difficulty emptying bladder or urinating 
• Sores in stomach or bowel 
• Damage to the lungs, which may cause shortness of breath 
• Hoarseness  
 
RARE, AND SERIOUS 
In 100 people receiving Marqibo®, 3 or fewer may have (<3%): 
• Liver damage 
• Kidney damage which may require dialysis 
• Allergic reaction which may cause rash, wheezing, swelling of the face or throat 
• Seizure or changes in consciousness 
 
RITUXIMAB 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab, more than 20 and up to 100 may have (>20%): 
• Nausea 
• Chills, fever 
• Allergic reaction during or following infusion of the drug 
• Infection, especially when white blood cell count is low 
• Anemia (low blood count) which may require blood transfusions 
• Numbness and tingling  
• Tiredness 
 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab, from 4 to 20 may have (4-20%): 
• Bruising, bleeding 
• Abnormal heartbeat 
• Heart attack or heart failure which may cause shortness of breath, swelling of ankles, 
and tiredness 
• Sores in eye 
• A tear or a hole in the stomach that may require surgery 
• Diarrhea, vomiting 
• Pain 
• Swelling of the body 
• Hepatitis which may cause yellow eyes and skin 
• Dizziness, headache 
• Kidney damage which may require dialysis 
• Cough, scarring of the lungs 
• Stuffy nose 
• Blockage of internal organs which may cause shortness of breath, wheezing, vomiting 
• Increased sweating 
• Itching, rash, blisters on the skin 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of 
the body 
• Low blood pressure which may cause feeling faint 
 
RARE, AND SERIOUS 
In 100 people receiving Rituximab, 3 or fewer may have (<3%): 
• Damage to the brain caused by a virus which may result in tiredness, weakness, 
changes in thinking, and disability.  This is called progressive multifocal 
leukoencephalopathy (PML). 
• Heart stops beating, death 
 
BENDAMUSTINE 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Bendamustine, more than 20 and up to 100 may have (>20%): 
• Anemia which may cause tiredness, or may require blood transfusions 
• Constipation, diarrhea, nausea, vomiting 
• Fever, tiredness 
• Bruising, bleeding 
• Infection, especially when white blood cell count is low 
• Loss of appetite 
• Headache 
• Cough 
 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Bendamustine, from 4 to 20 may have (4-20%): 
• Sores in mouth which may cause difficulty swallowing 
• Pain at the site of injection 
• Swelling and redness at the site of the medication injection 
• Weight loss 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Severe blood infection 
• Dehydration 
• A new cancer resulting from treatment of earlier cancer 
• Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions 
• Kidney damage which may cause swelling, may require dialysis 
• Blisters on the skin 
• Itching, rash 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body 
• High blood pressure which may cause dizziness, blurred vision 
• Shortness of breath 
 
RARE, AND SERIOUS 
In 100 people receiving Bendamustine, 3 or fewer may have (<3%): 
• None 
Reproductive risks: You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby. Women should not breastfeed a 
baby while on this study.  It is important you understand that if you are a man or woman of 
childbearing potential you must use birth control while on this study and for up to 4 months 
post the last dose of study treatment. Appropriate methods of birth control include 
abstinence, oral contraceptives, implantable hormonal contraceptives (Norplant), or double 
barrier method (diaphragm plus condom). Check with your study doctor about what kind 
of birth control methods to use and how long to use them. Women will be asked to have a 
pregnancy test before starting this study. In case of a pregnancy, you must report it to your 
study doctor immediately. The drugs used in the study may also make you unable to have 
children in the future. If you wish to re-start breastfeeding after treatment, you should 
discuss the appropriate timing with your physician. 
For more detailed information about risks and side effects, ask your study doctor. 
By signing this document you are acknowledging that you understand and agree to the information 
presented in this Reproductive Risk section. 
Medications to prevent nausea and infusion reactions: As part of the treatment you will receive 
medications to prevent nausea and allergic infusion reactions, which are routinely given to patients 
who receive bendamustine and rituximab. These medications have few side effects, although 


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medications used to prevent nausea and vomiting may cause drowsiness, dry mouth, diarrhea, 
constipation, headache, restlessness, agitation, anxiety, dizziness, involuntary tremors, skin rash, 
and possible allergic reaction. 
Venipuncture (inserting a needle into a vein to obtain blood or give medication): May cause 
inflammation, pain, bruising, bleeding, or infection. 
When you receive chemotherapy by vein, there is a slight risk that some of the drug may leak out 
around the needle at the injection site. A skin burn may result. Most skin burns are treatable and 
heal well. 
In order to monitor the side effects, your physician will examine you frequently and obtain 
laboratory tests (blood tests, chest x-rays, or CT scans as needed) to determine the effects of your 
treatment and alter the drug dosages if necessary. 
Risk of CT imaging: CT imaging uses x-rays. The radiation dose associated with this procedure 
is estimated to be a small fraction of the annual permissible dose to an x-ray technologist. There 
is no significant risk from this amount of radiation. 
There may be other side effects that have not been reported. If you have any unusual symptoms, 
you should report them immediately to your doctor or nurse. 
Benefits: 
You may receive no direct benefit from your participation in this study. Your lymphoma might 
respond to the treatment better or for longer if the study treatment is more effective than standard 
chemotherapy, but this is not known at this time. We do know that the information from this study 
will help doctors learn more about the way that combined chemotherapy drugs work together as a 
treatment for cancer.  This information could help future cancer patients. 
Alternatives: 
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual treatment approach described above 
• you may choose to take part in a different study, if one is available 
• or you may choose not to be treated for the lymphoma, but receive comfort care to relieve 
symptoms. 
Talk to your doctor about your choices before you decide if you will take part in this study. 
Refusal/Withdrawal 
It is up to you whether you want to be in the study.  You are not required to enroll or participate.  
If you decide to participate, you can always change your mind and quit at any time.  If you decide 
not to be in the study, or if you quit later, you will still be able to get the health care services you 
normally get.  If you join, but later on the researcher or your doctor feels being in the study is no 
longer good for you, they may choose to take you out of the study before it is over.  If new 
information becomes available that might change your mind about whether you want to stay in the 
study the researcher will share this information with you as soon as possible. 


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If you make the decision to withdraw from this study (stop taking study medication) for any reason, 
tell your doctor immediately. You will be asked to sign a form indicating whether you give your 
permission for your doctor and the research staff to continue to collect and submit follow-up 
information on your health status from your physicians and medical record. After signing the form, 
you still have the right to change your mind, at any time, regarding follow-up after withdrawal. 
Compensation in Case of Injury:  
A research injury is any physical or mental injury or illness caused by being in the study. If you 
are injured by a medical treatment or procedure you would have received even if you were not in 
the study that is not a research injury. To help avoid research injury and added medical expenses, 
it is very important to follow all study directions carefully. If you do experience a research injury, 
<INSERT HOSPITAL NAME> or the study doctor can arrange medical treatment for you. Such 
treatment will be paid for as described below.  
Medical treatment will be available if you suffer a research related injury; however, you and/or 
your health insurance company will be charged for this treatment. The study will not pay for this 
medical treatment. Neither Dr. Adam Olszewski nor BrUOG, the coordinating center, have money 
set aside to reimburse you for medical bills from treatment of a research related injury or otherwise 
compensate you in the event of a study-related injury.  
If you have insurance and have a research injury that is not covered by the study, it is possible that 
some or all of the cost of treating you could be billed to your insurer. If your health insurance will 
not cover such costs, it is possible you would have to pay out of pocket. In some cases, <INSERT 
HOSPITAL NAME>  might be able to help you pay if you qualify for free care under <INSERT 
HOSPITAL NAME>  policy. However, <INSERT HOSPITAL NAME>  has no policy to cover 
payment for such things as lost wages, expenses other than medical care, or pain and suffering. 
Rights and Complaints 
Signing this form does not take away any of your lawful rights. If you have any complaints about 
this study, or would like more facts about the rules for research studies, or the rights of people who 
take part in research studies you may contact <INSERT CONTACT NAME OF IRB> 
Confidentiality 
Your research records will be treated as private health care records and will be protected according 
to <INSERT HOSPITAL NAME> privacy practices and policies that are based on state and federal 
law. In particular, federal law requires us to get your permission to use or disclose (release your 
information to someone outside of <INSERT HOSPITAL NAME>) your health information for 
research purposes. If you sign this form you agree to be in this research study and you permit the 
use and disclosure of your health information for the purpose of conducting the research, providing 
treatment, collecting payment and running the business of the hospital. This permission has no 
expiration date. You may withdraw from the study at any time. However, if you do not want the 
researchers to use or disclose any further information in this study you must cancel permission in 
writing and may do so at any time. If you cancel your permission, you will stop taking part in the 
study and no new information will be collected about you. However, if you cancel your permission, 
it will not apply to actions already taken or information already collected about you by the hospital 


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or the researchers before you canceled your permission. 
Generally, the entire research record and any medical records held by the hospital may be used 
and released for research purposes. The following people or businesses/companies might use, 
release, or receive such information:  
• The researcher and their support staff;  
• The study sponsor: Dr. Adam Olszewski and BrUOG, The Brown University Oncology 
Research Group and its representatives. Acrotech Biopharma, LLC, maker of the drug being 
used in this study and the financial supporter. 
• Doctors, nurses, laboratories and others who provide services to you in connection with this 
study;  
• The company or section of the U.S. government that is paying for the study and others they 
hire to oversee, administer, or conduct the research;  
• The United States Food and Drug Administration, the Department of Health and Human 
Services, the Office of Inspector General, and the Office of Civil Rights;  
• People who volunteer to be patient advocates or research volunteer protectors;  
• Members of the hospital's administrative staff responsible for reviewing, approving and 
administering clinical trials and other healthcare or research activities.  
There are times when the law might require or permit <INSERT HOSPITAL NAME>  to release 
your health information without your permission. For example, <INSERT STATE> law requires 
researchers and health care workers to report abuse or neglect of children to the Department of 
Children, Youth and Families (DCYF) and to report abuse or neglect of people age 60 and older 
to the Department of Elderly Affairs.  
All researchers and health care providers are required to protect the privacy of your health care 
information. Other people and businesses/organizations that are not health care providers are not 
required by law to do that so it is possible they might re-release your information.  
You have the right to refuse to sign this form and not participate in the research. Your refusal 
would have no effect on your treatment, charges billed to you, or benefits at any Rhode Island 
Hospital health care site. If you do not sign, you will not be able to enroll in the research study and 
will not receive treatment as a study participant.  
If you decide to quit the study after signing this form no new information will be collected about 
you unless you gave us permission to do so. However, the hospital or the researchers may continue 
to use information that was collected before you quit the study to complete analysis and reports of 
this research. 
You will not be allowed to see or copy the information described in this form as long as the research 
study is open.  You may see and copy the information when the study is completed. 
Additionally, a description of this clinical trial will be available on the website 
http://www.ClinicalTrials.gov, as required by U.S. law. This Web site will not include information 
that can identify you. At most, the Web site will include a summary of the results. You can search 
this Web site at any time.  
If after you have signed this form you have any questions relating to your rights, please contact 


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<INSERT IRB CONATACT INFORMATION> 
For more detail about your privacy rights see the <INSERT HOSPITAL NAME> which has or will 
be given to you  
Research authorization for use and disclosure of information.   
The purpose of this section of the document is to provide you with some more information about 
how the information learned about you during the study will be used and shared. 
We understand that your medical information is very personal and we will work hard to keep it 
private. If you sign this form you consent to participate in this research study and are giving us 
permission to use and share your personal health information in the ways described in this form.   
Understandings and notifications 
The main purpose of permitting the use and release of your information is to allow the research 
project to be conducted and to ensure that the information relating to that research is available to 
all parties who may need it for research purposes.  Your information may also be used as necessary 
for your research-related treatment, to collect payment for your research-related treatment (when 
applicable), and to run the business operations of the hospital. 
All health care providers are required to protect the privacy of your information.  However, most 
persons or entities (i.e., businesses, organizations) that are not health care providers are not bound 
by law to protect the privacy of your information.  You understand that if the person or entity that 
receives your information is not a health care provider bound to protect your privacy, such person 
or entity might re-release your health information.  
You have the right to refuse to sign this form.  If you do not sign this form, none of your health 
care outside the study, or the payment for your health care, or your health care benefits will be 
affected.  However, if you do not sign this form, you will not be able to enroll in the research study 
described in this form, and you will not receive treatment as a study participant.  
If you sign this consent form, you may withdraw from the study at any time.  However, if you do 
not want the researchers to use or disclose any further information in this study you must cancel 
permission in writing and may do so at any time. If you cancel your permission, you will stop 
taking part in the study and no new information will be collected about you.  However, if you 
cancel your permission, it will not apply to actions already taken or information already collected 
about you by the hospital or the researchers before you canceled your permission.  This information 
or action may be needed to complete analysis and reports of this research. This permission will 
never expire unless you cancel it.  To cancel this permission, please write to Adam Olszewski, MD 
c/o the Medical Oncology Clinical Research Office at Rhode Island Hospital, 593 Eddy Street, 
APC Building Rm. 131, Providence, RI 02903. 
If after you have signed this form you have any questions relating to your rights, please contact 
<INSERT IRB CONTACT> 
Uses and releases covered by this authorization (permission) 
Who will release, receive, and/or use your information?   
This form will allow the following person(s), class(es) of persons, and/or organization(s)* to 
release,  use, and receive the information listed below in connection with this Study, or as required 


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by law: 
 Every research site for this study, including this hospital, and including each site's research 
staff and medical staff 
 Health care providers who provide services to you in connection with this study 
 Laboratories and other individuals and organizations that analyze your health information in 
connection with this study, in accordance with the study’s protocol 
 The following research sponsors and the people and companies that they use to oversee, 
administer, or conduct the research: The Principal Investigator Adam Olszewski, MD and BrUOG, 
the group coordinating the study, Acrotech Biopharma, LLC, the maker of the drug Marqibo being 
used in this study, and the financial supporter of this trial. 
 The United States Food and Drug Administration, the Department of Health and Human 
Services, the Office of Inspector General, and the Office of Civil Rights 
 The members and staff of the Institutional Review Board(s) or Ethics Committee(s) that 
approves this study 
 Principal Investigator and other Investigators 
 Study Coordinator 
 Additional members of the Research Team 
 The Patient Advocate or Research Volunteer Protector: _____________________ 
 Members of the hospital's administrative staff responsible for administering clinical trials and 
other research activities 
 Contract Research Organization (A contract research organization is an independent 
organization that agrees to oversee and make possible, various aspects of the clinical research 
process for the research sponsor.) 
 Data and Safety Monitoring Boards and others that monitor the conduct of the Study, for 
example a Clinical Events Committee 
 The members and staff of the hospitals affiliated Privacy Board (if such a board is used) 
 Others: _____________________________ 
 
 
* If, during the course of the research, one of the companies or institutions listed above merges with or is 
purchased by another company or institution, this permission to use or release protected health information 
in the research will extend to the new company or institution.  
 The entire research record and any medical records held by the hospital may be used and 
released.   
 The following information: _____________________________________________ 
 
 
 
 
 
 


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SIGNATURE 
I have read this informed consent and authorization form.  ALL OF MY QUESTIONS HAVE 
BEEN ANSWERED, AND I WANT TO TAKE PART IN THIS RESEARCH STUDY. 
By signing below, I give my permission to participate in this research study and for the described 
uses and releases of information.  I also confirm that I have been now or previously given a copy 
of the <INSERT HOSPITAL NAME> Privacy Notice 
 
 
 
The Researcher is required to provide a copy of this consent to you.  
 
 
 
_________________________________________  
 
________          ____________ 
 Signature of study volunteer/authorized representative* Date         and    Time when signed 
I was present during the consent PROCESS AND signing of this agreement by the study 
volunteer or authorized representative 
 
 
 
__________________________________________ 
 
 
 
______________ 
Signature of witness (required if consent  
 
 
 
 
 
 
Date 
is presented orally or at the request of the IRB)  
 
 
 
 
 
 
 
 
 
 
__________________________________________ 
 
______________ 
Signature of Translator 
 
 
 
Date 
 
 
 
___________________________________________ ________          __________ 
 Signature of researcher or designate  
 
 
 
Date         and    Time when signed 
* If signed by agent other than study volunteer, please explain below. 
______________________________________________________________________________ 
This informed consent document expires on ______________.   
DO NOT sign this document after this expiration date