Dose-Intense Yttrium-90 Ibritumomab Tiuxetan (Zevalin)-Containing Non-Myeloablative Conditioning for Allogeneic Stem Cell Transplantation in B-cell Malignancies
Phase: PHASE2
Conditions: Leukemia, Lymphoma
Sponsor: M.D. Anderson Cancer Center

2011-0393
September 2, 2014
Abstract - Page 1
Protocol Abstract Page
Dose-Intense Yttrium-90 Ibritumumab Tiuxetan (Zevalin)-Containing 
Non-Myeloablative Conditioning for Allogeneic Stem Cell Transplantation in 
B-cell Malignancies
2011-0393
Core Protocol Information
Study Chairman: 
Issa F. Khouri
Department:
Stem Cell Transplantation and Cellular Therapy
Phone:
713-792-8750
Unit:
0423
Full Title: 
Dose-Intense Yttrium-90 Ibritumumab Tiuxetan (Zevalin)-Containing Non-Myeloablative 
Conditioning for Allogeneic Stem Cell Transplantation in B-cell Malignancies
Protocol Phase:
Phase II
Version Status:
Terminated 04/26/2019
Version:
19
Document Status:
Final
Abstract
Objectives:
Primary Objectives:
1)  To characterize the safety of yttrium-90 ibritumumab tiuxetan calculated to deliver up 
to 10 Gy to critical organs, when administered in conjunction with fludarabine and 
bendamustine as non-myeloablative preparative regimen for allogeneic stem cell 
transplantation
 
Secondary Objectives:
1)  To estimate the efficacy of this strategy (overall survival and event-free survival) in 
patients with b-cell lymphoid malignancies
2)  To determine survival rates by histology subtype
3)  To correlate blood radioactivity level and time to neutrophil and platelet recovery
Rationale: (Be as concise as possible)
Allogeneic non-myleoblative stem cell transplantation (NST) with fludarabine 
bendamustine and rituximab has been a successful strategy for patients with 
lymphomas and CLL who had a chemosensitive relapse (Protocol 2008-0246). Results, 
however, need to be improved upon in patients who had refractory disease or are in 

2011-0393
September 2, 2014
Abstract - Page 2
kinetic failure at the time of transplantation. Intensification of the preparative regimen 
has been associated with increased toxicity with no improvement in outcomes. 
Immunomanipulation with donor lymphocytes or rapid immune suppression withdrawal 
has been associated with an increased risk of graft-versus-host disease without 
documented improvement in survival.
The anti-CD20 radioimmunoconjugates (RIC) (
90Y) ibritumomab tiuxetan and iodine-131 
(
131I) tositumomab produce durable remissions in previously treated patients who have 
relapsed or refractory, low-grade, follicular or transformed lymphoma. The standard 
dose of (
90Y) ibritumomab tiuxetan is based on weight and is equal to 0.4 mCi/kg. 
Protocol (ID01-233), involving the use of this radiolabeled antibody together with 
fludarabine and cyclophosphamide as NST conditioning, has shown adequate 
engraftment and time to  recovery of counts. Results also suggest that the addition of 
RIC can overcome the negative prognostic impact of PET+ in NST transplantation, and 
that it can be curative for patients with refractory, relapsed follicular lymphoma.
 Results 
remained suboptimal, however for patients with other histologies, such as mantle cell 
and diffuse large cell lymphoma.  Optimizing drug delivery may improve outcomes.
Because myelosuppression is the major toxicity of anti-CD20 RICs, they are ideal 
candidates for dose-escalation with stem cell support. Phase I/II studies have 
demonstrated that anti-CD20 RICs may be dose escalated with limited toxicity and that 
higher radiation doses are associated with improved clinical outcomes.
Conventional, therapeutic-dose 
131 tositumomab or (
90Y) ibritumomab tiuxetan has been 
added to the most commonly used high-dose chemotherapy program (i.e., carmustine, 
etoposide, cytarbine, melphalan [BEAM]) to intensify the regimen for NHL, but the 
combination has not been shown to be superior to high dose BEAM alone. More 
recently, the RIC was combined with BEAM
  with the goal of administering the highest 
possible dose of RIC without increasing toxicity. 
The dose of RIC was patient-specific, was based on dosimetry rather than weight, and 
was calculated to deliver cohort-defined  radiation-absorbed doses (RADs) to critical 
organs, excluding bone marrow and spleen. Fifteen Gy proved to be the 
maximum-tolerated RAD to critical organs. When doses were calculated according to 
weight, there was considerable variability among patients, which justified the 
dosimetry-based approach. Patient specific activity doses calculated to deliver a 
cohort-defined RAD to the critical organ varied widely. For example, the (90Y) 
ibritumomab tiuxetan doses administered to deliver an estimated 15 Gy to the liver in six 
patients ranged from 0.50 to 1.39 mCi/kg. Although eight patients safely received doses 
of 0.8 mCi/kg or greater, a weight-based strategy at twice the conventional 0.4 mCi/kg 
dose would have resulted in a wide range of RAD (median, 13 Gy; range, 4 to 31). 
Forty-four patients were treated. 
Thirty percent of patients had achieved less than a partial remission to their most recent 
therapy and would not have been eligible for autologous transplantation at most 
centers. Results were encouraging with an estimated 3-year PFS and Os rates of 43% 

2011-0393
September 2, 2014
Abstract - Page 3
and 60%, respectively. 
Eligibility: (List All Criteria)
Inclusion:
1)
18 to 70 years of age.
2)
Patients with the following CD20+ lymphoid malignancies who are eligible for allogeneic 
transplantation: a. Relapsed or refractory follicular lymphoma; b. Relapsed or refractory or high risk 
mantle cell lymphoma (hi ki67; blastic); c. Recurrent or refractory marginal zone; d. Recurrent or 
refractory CLL/small lymphocytic lymphoma; e. Double-hit lymphoma; f. Diffuse large B cell lymphoma; g. 
Richter's patients; or h. Refractory or recurrent Burkitts.

2011-0393
September 2, 2014
Abstract - Page 4
3)
Patients who meet criterion #2 or have any of the following are eligible: a. Less than PR to salvage 
chemotherapy; b. Kinetic failure; c. Having received more than 3 lines of therapy; d. Failure to mobilize 
autologous stem cell; e. 10% or more marrow involvement; f. 6 months post autologous stem cell 
transplant.
4)
Patients must have a fully-matched related donor or a matched unrelated donor identified. Double 
cord (at least 4/6 matched) can be used if no adult matched donor is available.
5)
Performance score of at least 80% by Karnofsky or 0 to 2 ECOG.
6)
Left ventricular EF >/= 45% with no uncontrolled arrythmias or symptomatic heart disease.
7)
FEV1, FVC >/= 60% and corrected DLCO >/= 60%.
8)
Serum creatinine </=1.6 mg/dL. Serum bilirubin < 2 mg/dL (unless due to Gilbert's Syndrome).
9)
SGPT < 2 X upper limit of normal.
10)
Men and women of reproductive potential must agree to follow accepted birth control methods (i.e., 
a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or 
abstinence) for the duration of the study.
11)
Negative Beta HCG test within 30 days in a woman with child bearing potential defined as not 
post-menopausal for 12 months or no previous surgical sterilization). Pregnancy testing is not required for 
post-menopausal or surgically sterilized women.
Exclusion:
1)
Patient with active CNS involvement with lymphoid malignancy.
2)
Known infection with HIV, HTLV-I, Hepatitis B, or Hepatitis C.
3)
Patients with other malignancies diagnosed within 2 years prior to study registration. Skin 
squamous or basal cell carcinoma are exceptions.
4)
Active bacterial, viral or fungal infections.
5)
History of stroke within 6 months prior to study registration.
6)
A prior allogeneic stem cell transplant.
7)
Patient has received other investigational drugs within 3 weeks before study registration.
8)
Presence of circulating malignant lymphoid cells or bone marrow with lymphoma that constituted 
more than 25% of the cellular elements.
9)
Serious nonmalignant or malignant disease or psychiatric illness, which, in the opinion of the 
investigator would compromise protocol objectives or interfere with participation.
10)
Patients who are breast-feeding.
Are patients <18 years of age eligible to participate in this study?  
Yes
No
Studies that include children must meet the criteria for inclusion.
http://www.fda.gov/ohrms/dockets/AC/04/briefing/4028B1_05_NIH-Inclusion%20of%20Children.doc

2011-0393
September 2, 2014
Abstract - Page 5
http://www.hhs.gov/ohrp/policy/populations/children.html
Studies that exclude children must have appropriate justification.  Please select all that 
apply:
Other:
Please Specify:
There is limited safety profile of radioimmunotherapy or bendamustine in patients who are 
younger than age 18 or older than 70 years of age.
Are participants >65 years of age eligible to participate in this study?  
Yes
No
Are pregnant women eligible to participate in this study?
Yes
No
Will the recruitment population at M. D. Anderson include persons who are incarcerated at time of 
enrollment (e.g., prisoners) or likely to become incarcerated during the study?
Yes
No
Disease Group:
Leukemia, Lymphoma
Treatment Agents/Devices/Interventions:
111In-ibritumomab tiuxetan, 90Y-ibritumomab tiuxetan, Allogeneic Stem Cell Transplant, Antithymocyte 
Globulin, Bendamustine HCl, Fludarabine, Rituximab
Proposed Treatment/Study Plan:
Is treatment assignment randomized?
Yes
No
Is this a blinded or double-blinded study?
Yes
No
The transplant day is referred as day zero (D0), treatment plan activities prior or after 
D0 are denominated as day minus (D-) or day plus (D+).
Within 3 weeks prior to start treatment, D-22, patients must be off any prior biological 
therapy, chemotherapy, radiotherapy, or other investigational therapy. 
Chemotherapy agent doses and administration
D-22 and -14, Rituximab will be given at 250 mg/m
2  (based on actual body weight) 
preceding 
111In Ibritumumab and  (
90Y) ibritumumab tiuxetan administration, respectively. 
Rituximab infusion will follow SCT&CT department standard practice. 
D-22, 
111In Ibritumumab Administration. 
111In Ibritumumab (5.0 mCi +/- 10% of 
111In) will 
be used for quantitative radionuclide imaging. The imaging dose of 
111In Ibritumumab will 
be administered by a slow IV push infusion immediately following the infusion of 

2011-0393
September 2, 2014
Abstract - Page 6
rituximab. 
111In Ibritumumab may be directly infused by stopping the flow from the IV bag 
and injecting the radiolabeled antibody directly into the line. A 0.22 micron filter must be 
on line between the patient and the infusion port. The line will be flushed with at least 10 
mL normal saline after 
111In Ibritumumab has been infused. 
D-22, -21 to -16, Imaging. Planar scintigraphy whole-body imaging will be started on 
D-22 post  
111In Ibritumumab infusion prior to voiding. Imaging will be repeated 3-6 hours 
later.  Whole-body planar scintigraphy imaging will be repeated between 22-26 hours, 
then between 70-74 hours, and later between 142-146 hours post 
111In Ibritumumab 
injection.  
D-15, Dosimetry. This trial requires patient-specific activities of (
90Y) ibritumumab 
tiuxetan to deliver a maximum radiation-absorbed dose (RAD) of 10 Gy to vital organs, 
including liver, lungs, and kidneys. The methodology for estimating the RAD will be 
based on quantitative whole-body planar (2D) radionuclide imaging of (
111In) 
ibritumumab tiuxetan pretreatment diagnostic tracer at multiple time points (5 in this 
proposal). The time-activity curves (TAC) of radiopharmaceutical uptake for different 
organs will be calculated and used as input to the FDA-approved OLINDA/EXM 1.1 
model-based internal radionuclide dosimetry software for calculation of 
radiation-absorbed dose to critical organs. The RAD estimates will be corrected for 
critical organ mass that will be calculated from CT-based volume measurements. 
D-14, (
90Y) ibritumumab tiuxetan Administration. (
90Y) ibritumumab tiuxetan will be given 
post rituximab, as described above.  While each patient will be receiving a mCi/kg 
Zevalin dosage based on patient-specific radiation dosimetry, an attempt to homogenize 
the dosage will be undertaken.  For this purpose, the dosage will be rounded to one of 
the following values:  0.5 mCi/kg, 0.75 mCi/kg, 1.0 mCi/kg, 1.25 mCi/kg, 1.5mCi/kg.  
 
Each patient’s dosage will be rounded to the highest mCi/kg level that maintains the 
absorbed dose estimated from the dosimetry nearest, but not below 10 Gy to the critical 
organs (liver, lungs and kidneys). Dose will not be allowed to exceed 12 Gy to critical 
organs, as this has been shown in a previous published study to be well tolerated by 
those organs without additional toxicity.  If the dose nearest to but not below 10 Gy 
exceeds 12 Gy, the patient will be treated at the mCi/kg one level below. Patients who 
would be estimated to receive > 12 Gy to any of the critical organs at the 0.5 mCi/kg 
level will be treated at standard dosage (0.4 mCi/kg up to 32 mCi).
D-5, -4 and -3, Fludarabine and Bendamustine will be administered following SCT&CT 
department standard practice. These will be dosed per adjusted body weight for 
patients weighing > 20% above their ideal body weight.  For patients less than or equal 
to 20% above their ideal body weight, the actual body weight is used.
Fludarabine will be administrated at a dose of 30 mg/m2 intravenously followed by 
Bendamustine at a dose of 130 mg/m
2  intravenously.   

2011-0393
September 2, 2014
Abstract - Page 7
Optional Research Blood Samples:
D0, Measurement of Peripheral-Blood Radioactivity. A peripheral blood sample will be 
obtained prior to stem cell transplantation on D0 for measurement of residual (
90Y) 
radioactivity level in the blood. 
Duplicate, 1.0-mL whole-blood aliquots will be drawn on day 0.  A 1.0 mL ( 
90Y) standard 
will be prepared from a decayed, known, (
90Y) activity sample prepared on day -14. 
Blood, standard, and background samples will each be counted for 1 minute with a wide 
energy window in a thallium-doped sodium iodide crystal gamma scintillation well 
counter interfaced to a multichannel analyzer. After background correction, patient 
blood sample results will be expressed as mean microCi (
90Y)/mL in whole blood.
Supportive Treatment. All patients will receive Graft Versus Host Disease (GvHD) 
prophylaxis, infections disease prophylaxis, growth factors, blood and platelet 
transfusion and other supportive treatment as per standard practice in patients receiving 
allogeneic transplant. 
Study Enrollment:
The study population for this research will consist of participants from:
Only at MDACC
Estimated Accrual:
Total Accrual at MDACC:
20
Estimated monthly accrual at MDACC:
1
Accrual Comments:
None
Is this an NCI-Cancer Therapy Evaluation Protocol (CTEP)?
No
Is this an NCI-Division of Cancer Prevention Protocol (DCP)?
Yes
Please send the Approval Letter in a PDOL generic memo to:  "CRC PBHSRC Help Desk"
Statistical Considerations:
Statistical section - patient sample size and analysis plan:
This is a Phase II study of high-dose (
90Y) ibritumumab tiuxetan added to fludarabine 
and bendamustine in patients undergoing stem cell transplantation.  The study will enroll 
a maximum of 20 patients. Patients will be enrolled in one of three histologies: follicular 
+ other indolent histologies, mantle-cell lymphoma, and diffuse large B-cell lymphoma.  
We wish to ensure that at least 10 patients are enrolled in each histology.  With a true 
incidence rate of 25%, the probability that we enroll at least 10 out of 20 patients in a 

2011-0393
September 2, 2014
Abstract - Page 8
particular histology is greater than 95%. 
The primary endpoint of the protocol is safety and feasibility. Several studies, including 
protocol ID01-233 (ASH 2011, abstract 662) are showing a similar safety profile 
between matched sibling and matched unrelated donor transplants. We believe that the 
safety profile will be similar in this study as well. However, we will report the results 
within each category, and we have added as a secondary analysis that we will repeat 
the primary analyses of event-free and overall survival stratified by transplant graft 
source.
Monitoring:
Two statistical monitoring rules are used to monitor the rate of TRM in all patients and 
the rate of engraftment failure/acute grade 4 GVHD in patients who receive a cord blood 
transplant.
TRM (All Patients):
We will use the method of Thall, Simon, and Estey to monitor the TRM rate in all 
patients within the first 100 days during the course of the trial.  We will assume a 
Beta(0.40, 1.60) prior distribution for the 100-day TRM rate, which has a mean of 20%.
The following decision rule will be used: stop accrual if at any time during the course of 
the trial 
Pr{100-day TRM rate > 20% | data from patients evaluated} > 0.975
In other words, if at any time during the study we determine that there is at least a 
97.5% chance that the 100-day TRM rate is at greater than 20%, we will stop enrollment 
into the study.  For logistical reasons, patients will be monitored in cohorts of 5.  
Stopping boundaries corresponding to this probability criterion are as follows: stop if:
[# of patients with TRM at day 100/ # of patients evaluated at day 100]
>/= 4/5, 6/10, 7/15, or 9/20
The operating characteristics for this rule are found in the table below.  If the true 
100-day TRM rate is less than the maximum targeted rate of 20%, the trial will stop 
early less than 6% of the time.
Engraftment Failure/Acute Grade 4 GVHD (Cord Blood Patients):

2011-0393
September 2, 2014
Abstract - Page 9
Because patients who receive a transplant from umbilical cord blood are at higher risk 
of engraftment failure and GVHD, we will also monitor the rate of engraftment failure or 
acute grade 4 GVHD in these patients.  We expect no more than 10 patients will receive 
a cord blood transplant.
We will use the method of Thall, Simon, and Estey to monitor the combined engraftment 
failure/grade 4 acute GVHD rate in cord blood patients within the first 100 days during 
the course of the trial.  We will assume a Beta(0.60, 1.40) prior distribution for the 
100-day rate, which has a mean of 30%.
The following decision rule will be used: stop accrual in cord blood patients if at any time 
during the course of the trial 
Pr{100-day engraftment failure/grade 4 acute GVHD rate > 20% | 
data from cord blood patients evaluated} > 0.975
In other words, if at any time during the study we determine that there is at least a 
97.5% chance that the 100-day engraft failure/grade 4 acute GVHD rate is greater than 
20%, we will stop enrollment into cord blood patients.  Stopping boundaries 
corresponding to this probability criterion are as follows: stop if:
[# of cord blood patients with engraft failure or grade 4 acute GVHD at day 100/ 
# of cord blood patients evaluated at day 100]
>/= 3/3, 5/6, 6/8, 7/10, 8/12, 9/14, 10/17, or 11/19
The table below presents the operating characteristics for this rule.
True Failure
Rate
Probability of
Stopping Early
P25
Median
P75
10%
0.1 %
20
20
20
20%
1.8 %
20
20
20
30%
7.8 %
20
20
20
40%
25.6 %
18
20
20
50%
54.5 %
7
16
20
60%
81.5 %
5
9
16
70%
96.2 %
3
5
9

2011-0393
September 2, 2014
Abstract - Page 10
Data Safety Monitoring Board / DSMB at MDACC:
Select the name of the data safety monitoring board (DSMB) monitoring this protocol:
Not Applicable
Please explain:
This study is not randomized nor blinded.
Protocol Monitoring:
Does this protocol have a schedule for interim and final analysis?
No
Provide a rationale for no interim analysis.
This is a non-randomized trial. Will follow the operating characteristics described within the statistical 
considerations section.

2011-0393
September 2, 2014
Abstract - Page 11
Protocol Monitoring Plan:
See Statistical Considerations section.
Intellectual Property:
1.
Does this study include any agents, devices, or radioactive compound (or 
drug) manufactured at  MD Anderson Cancer Center or by a contract 
manufacturer?
No
Investigational New Drugs (IND):
Does this protocol require an IND?
Yes
Who is the IND Holder/Regulatory Sponsor?
MDACC
IND Number:
113934
Please "Compose" an Investigator’s Brochure Cover Letter.  For technical assistance, contact the PDOL 
Help Desk, 713-745-7365.
Investigational Device (IDE):
Does this study utilize an Investigational Device?
No
Sponsorship and Support Information:
Does the Study have a Sponsor, Supporter or Granting Agency?
Yes
Sponsor Name:
Spectrum Pharmaceuticals
Support Type:
Industry Funding
Agent Name(s): Ibritumumab Tiuxetan
This Sponsor/Supporter/Granting Agency will receive data.
Radioactive Material:
Does this study involve the administration of radioisotopes or a
radioisotope labeled agent?
Click here  for help
Yes
M.D. Anderson’s Radioactive Material Authorization:
Authorized User:  Aaron Jessop, M.D.
Authorization Number (or state that Authorization Application is under Radiation Safety Committee 
review):  1412

2011-0393
September 2, 2014
Abstract - Page 12
Does this protocol include the administration of a radioactive compound (or drug) 
to a patient intended to obtain basic information regarding metabolism (including 
kinetics, distribution, and localization) of the drug or regarding human physiology, 
pathophysiology, or biochemistry, but not intended for immediate therapeutic, 
diagnostic, or similar purposes or to determine the safety and effectiveness of the 
drug in humans for such purposes (i.e. to carry out a clinical study)?
No
Is the radioactive compound (or drug) FDA approved and/or commercially available? No
Name the facility where the investigational agent is labeled or bound to the radioisotope (include the 
name of the laboratory at MDACC or the name of the company if outside MDACC):  
N/A
Biosafety:
Does this study involve the use of Recombinant DNA Technology? 
No
Does this study involve the use of organisms that are infectious to humans?
No
Does this study involve human/animal tissue other than blood derived 
hematopoietic stem cells?
No
Questions should be addressed to the Transfusion Medicine Tissue Coordinator at 713-792-8630.
Laboratory Tests:
Is there any biomarker testing in this study being used to determine patient/participant eligibility, 
treatment assignment, or management of patient/participant care?
Yes
No
Not Applicable For This Protocol
Manufacturing:
Will you manufacture in full or in part (split manufacturing) a drug or biological 
product at the M. D. Anderson Cancer Center for the proposed clinical study?
No
Student/Trainee Information:
Is this research being conducted as a partial fulfillment for completion of a degree?
No