Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) Added to Fludarabine, Bendamustine and Rituximab and Allogeneic Transplantation for CD22 Positive-Lymphoid Malignancies
Phase: PHASE1
Conditions: Hematopoietic and Lymphoid Cell Neoplasm
Sponsor: M.D. Anderson Cancer Center

Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) Added to 
Fludarabine, Bendamustine and Rituximab and Allogeneic Transplantation for 
CD22 Positive-Lymphoid Malignancies 
1 The University of Texas MD Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department 
2 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
3 The University of Texas MD Anderson Cancer Center, Pharmacy Department 
4 The University of Texas MD Anderson Cancer Center, Leukemia Department 
Institution Study Number: 
2012-0265 
IND Holder: 
MD Anderson Cancer Center 
IND Number: 
116121 
Financial Supporter: 
Pfizer, Inc. 
Principal Investigator: 
Issa F. Khouri, M.D.  
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy Department 
1515 Holcombe Blvd, Unit 0423 
Houston, TX 77030 
Telephone: 713-745-0049 
Fax: 713-792-4902 
ikhouri@mdanderson.org 
Collaborators: 
Qaiser Bashir, M.D.1 
Roland L. Bassett, Jr.2 
Richard E. Champlin, M.D.1 
Alison Gulbis, PharmD3
Elisa Jabbour, M.D.4
Partow Kebriaei, M.D.1 
Betul Oran, M.D.1
Uday Popat, M.D.1 
Gabriela Rondon, M.D.1 
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Table of Contents 
 
1.0 
Objectives ............................................................................................................................... 3 
2.0 
Background ............................................................................................................................. 3 
3.0 
Patient Eligibility ...................................................................................................................... 6 
4.0 
Treatment Plan ........................................................................................................................ 7 
5.0 
Evaluation During Study .......................................................................................................... 9 
6.0 
Background Drug Information .................................................................................................10 
7.0 
Statistical Considerations .......................................................................................................14 
8.0 
Study Definitions ....................................................................................................................16 
9.0 
Criteria for Removal from the Study ........................................................................................18 
10.0 
Reporting Requirements .........................................................................................................18 
11.0 
References .............................................................................................................................22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Body 
 
1.0 Objectives 
1.1 
Primary Objectives: 
 
1.1.1 
To characterize the safety of anti-CD22 immunoconjugate inotuzumab 
ozogamicin (CMC-544), when administered in conjunction with fludarabine, 
bendamustine, and rituximab as non-myeloablative preparative regimen for 
allogeneic stem cell transplantation for CD22-positive lymphoid malignancies. 
 
1.2 
Secondary Objectives: 
1.2.1 
To estimate tumor response. 
1.2.2 
To determine overall and event-free survival rates by histology subtype. 
2.0 Background 
2.1 
Non-myeloablative Allogeneic Stem Cell Transplantation for Lymphoid 
Malignancies. 
 
In conventional transplants, high-dose chemotherapy plus radiation, is 
used to destroy as many lymphoma cells as possible. However, these high dose 
associated with conventional stem cell transplantation. This has restricted the 
use of conventional transplantation to younger patients who may be more able to 
undergo this treatment. 
In a European Bone Marrow Transplantation Group study in which the 
majority of patients received total body irradiation-based preparative 
(pre-transplant) regimens, the treatment-related mortality for the allogeneic group 
was 25% compared with 11% for the autologous group.
1   Another multicenter 
analysis of allogeneic transplantation in 113 patients with advanced low-grade 
lymphoma reported a treatment-related mortality of 40%.
2    A similar high mortality 
has been seen using the chemotherapy conditioning regimen of 
cyclophosphamide, carmustine and etoposide.
3
 
Non-myeloablative allogeneic stem cell transplantation (NST) was 
developed following the observation that leukemia/lymphoma patients, who had 
received allogeneic transplantation and then subsequently relapsed, went back 
into remission following infusions of donor lymphocytes.
4   This and other findings 
confirmed that a graft-versus-tumor effect, where donor lymphocytes recognize 
cancer cells as foreign and then destroy them, is responsible for at least part of 
the efficacy of allogeneic bone marrow transplantation. If donor lymphocytes can 
control, or even eradicate malignant cells that have proved resistant to high-dose 
chemotherapy and irradiation, then these highly toxic therapies may not be 
necessary for the success of allogeneic stem cell transplantation strategies. 
 
Evidence for a graft-versus-lymphoma (GVL) effect includes the 
observation that patients who develop chronic graft-versus-host-disease 
(cGVHD) following allogeneic transplantation, where the donor’s immune cells 
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attack the patient’s normal tissue, have a lower probability of relapsing than 
patients who do not develop cGVHD. Chopra, et. al. demonstrated a lower 
incidence of relapse in patients who acquired cGVHD (0% relapse with cGVHD  
versus 35% relapse with no cGVHD). Perhaps the most direct data supporting 
the evidence and clinical significance of GVL comes from small studies and case 
reports whereby patients with progressive disease after allogeneic 
transplantation undergo withdrawal of drugs to suppress their immune system 
and induce cGVHD, which is often accompanied by a simultaneous decrease in 
the size of their lymphomas. Van-Besien demonstrated that of 9 patients who 
relapsed after allogeneic transplantation, 4 (44%) responded to withdrawal of 
immunosuppression drugs (2 complete remissions, 2 partial remissions), with 
responses that lasted nearly 2 years. 
The aim of NST is to establish immunological tolerance between the 
patient’s immune system and the new stem cells from the donor, and to use this 
as a platform for immunotherapy involving the activation of immune cells, with 
donor lymphocytes as the active agent. In NST, the patient receives low doses 
of chemotherapy and radiation, as well as drugs to suppress the immune system 
in order to prevent rejection of the donor stem cells. The donor stem cells are 
then infused into the patient. The patient’s suppressed immune system allows 
the donor cells to travel to the bone marrow where they produce replacement 
blood cells. This process is known as engraftment. Once engraftment occurs, 
the patient’s new blood and immune systems, resulting from the donor cells, 
have the ability to recognize and eradicate both the patient’s remaining stem 
cells and the lymphoma cells. 
Therefore, although NST was initially designed to decrease transplant 
related morbidity so that elderly patients, patients with other serious conditions, 
and patients relapsing from prior autologous transplants could be more safely 
treated, it is now seen as an effective form of immunotherapy for possibly all 
lymphomas. 
 
 
2.2 
Preparative Regimens for Non-myeloablative Transplantation for Lymphoid 
Malignancies. 
 
The low-dose transplant regimen must (a) produce suppression of the 
patient's immune system to prevent rejection of the donor cells and (b) suppress 
the lymphoma sufficiently to prevent marked progression of the tumor and allow 
time for the GVL effect to occur. 
 
2.2.1 FCR regimen. 
 
Our initial studies at MD Anderson involved a combination of fludarabine, 
cyclophosphamide and rituximab (FCR) as a conditioning regimen for patients 
who had chemosensitive disease (Protocol ID99-035) and who were to receive a 
transplant from a compatible sibling donor.
7 A recent update reported an overall 
survival (OS) rate of 85% and progression-free survival (PFS) rates of 83% in 
patients with follicular lymphoma patients. Median follow-up time was 5 years. 
While NST with FCR has been a successful strategy for patients with indolent 
lymphomas who had a chemosensitive relapse, results in patients who 
aggressive histologies or had refractory disease or were in kinetic failure at the 
time of transplantation need to be improved upon. The 5-year OS and PFS rates 
5
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in mantle cell lymphoma were 53% and 46%, respectively. 
8 Results were poorer 
in diffuse large cell lymphoma. 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 GVHD without 
documented improvement in survivals. 
 
2.2.2 Bendamustine-based regimen (FBR). 
 
Bendamustine is an alkylating agent with a unique structure containing 
both a nitrogen mustard group and a benzimidazole ring. It has been shown to be 
active against cell lines that are resistant to other alkylating agents in pre-clinical 
experiments in vitro. Its activity profile, when compared with other commercially 
available chemotherapeutics in the NCI human 60 cell line assay, appears 
unique. Studies are underway to further elucidate the possible existence of a 
unique mechanism of action, including potential contribution of the purine-like 
structure of the agent. There were 13 published reports of combination therapy 
with bendamustine for the treatment of low-grade NHL. In the publications that 
included only patients with NHL, overall response rates ranged from 66% to 96%, 
CR rates ranged from 20% to 60%, and PR rates ranged from 30% to 53%.There 
were 8 published reports of combination therapy with bendamustine for the 
treatment of high-grade NHL (N=72); overall response rates in these studies 
were 50%. 
Patients with lymphoid malignancies who are considered for allogeneic 
transplantation usually have had multiple relapses and have been thus rendered 
resistant to cyclophosphamide, the backbone of most conventional treatment 
regimens for NHL. In vitro studies suggest that there is no cross-resistance 
between cyclophosphamide and bendamustine, and that the latter may 
overcome the resistance to cyclophosphamide with lesser toxicities. Some other 
studies have also suggested recently a synergy between bendamustine and 
purine analogs. 
We have recently initiated a phase I/II trial of NST with bendamustine 
(maximum dose of 130 mg/m2/day x3) together with fludarabine and rituximab 
for patients with relapsed lymphoid malignancies (Protocol 2008-0246). 
Twenty-four patients have been treated. No DLT was observed. 
Myelosuppression was minimal (80% of patients did not require platelet 
transfusions, and 61% did not have a neutrophil nadir of below 500) and only one 
death occurred (ASH 2011, abstract # 894, oral presentation) This regimen is 
now replacing the FCR as a backbone for our NST regimens, and can be used 
as a platform for combination with additional agents to increase efficacy 
especially in patients with aggressive histologies and/or refractory disease. 
 
2.3 
Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544). 
 
CMC-544 is a humanized antibody conjugated to calicheamicin, a 
cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of 
B-cell NHL and in more than 80% of acute lymphocytic leukemia (ALL). 
CMC-544 alone and in combination with rituximab has demonstrated efficacy and 
tolerability in indolent and aggressive NHL patients including diffuse large B-cell 
lymphoma
12,13  , and more recently a 57% response rate was seen in relapsed 
10,11 
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ALL. The recommended dose in the phase 2 studies was 1.8 mg/m2 every 3-4 
weeks. Most common side effects were hematologic, and thrombocytopenia was 
a dose-limiting toxic effect, which can be minimized after an allogeneic NST. 
 
2.4 
Proposed Study. 
 
Because of the above properties, CMC-544 would be an ideal candidate 
for dose-escalation, as part of a non-myeloablative nontoxic conditioning (such 
as FBR) and allogeneic NST. We propose to treat cohorts of patients in an 
escalating dose of 0.6, 1.2 and 1.8 mg/m2. CMC-544 would be given on D-13 in 
order to decrease the risk of veno-occlusive disease or unforeseen additive 
toxicity to the conditioning. We propose the FBR as conditioning due to its well 
known favorable safety profile. We hope that this unique strategy will further 
decrease the relapse rate, especially in patients with aggressive histologies. 
3.0 Patient Eligibility 
3.1 
Inclusion Criteria: 
 
1. 
Age 18 to 70 years of age. 
 
2. 
Patients with B-cell hematological malignancies who are eligible for 
allogeneic transplantation. 
 
3. 
Patients must have a fully-matched sibling donor or a matched unrelated 
donor identified. 
 
4. 
Performance score of at least 80% by Karnofsky or 0 to 2 ECOG. 
 
5. 
Left ventricular EF > 45% with no uncontrolled arrhythmias or 
symptomatic heart disease. 
 
6. 
FEV1, FVC > 50% and corrected DLCO > 50%. 
 
7. 
Serum creatinine <1.6 mg/dL. Serum bilirubin < 2 mg/dL upper limit of 
normal (unless due to Gilbert's Disease; patient with this disease should 
have a right upper quadrant ultrasound evaluation before treatment). 
 
8. 
SGPT < 2 X upper limit of normal. 
 
9. 
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. 
 
10. 
Negative Beta HCG test in a woman with child bearing potential defined 
as not post-menopausal for 12 months or no previous surgical 
sterilization) or currently breast-feeding. Pregnancy testing is not 
required for post-menopausal or surgically sterilized women. 
 
 
 
 
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3.2 
Exclusion Criteria: 
 
1. 
Patient with active CNS involvement. 
 
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. 
 
6. 
History of biliary colic attack. 
 
7. 
A prior autologous transplant within 3 months of study entry or 
allogeneic stem cell transplant. 
 
8. 
Serious medical or psychiatric illness likely to interfere with participation in 
this clinical study. 
 
9. 
Patient has received other investigational drugs within 3 weeks before 
study registration. 
 
10. 
Serious nonmalignant disease which, in the opinion of the investigator 
would compromise protocol objectives. 
 
11. 
Prior exposure to CMC-544 within past 6 months. 
 
12. 
Established refractoriness to CMC-544. 
4.0 Treatment Plan 
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-13, patients must be off any prior 
biological therapy, chemotherapy, radiotherapy, or other investigational therapy. 
 
 
Prior to advancing dose levels a cohort summary must be completed and 
submitted to the Clinical Research Medical Monitor (IND Office). 
 
4.1 Chemotherapy agent doses and administration. 
 
D-13, CMC-544 will be infused intravenously (IV) as outpatient. Dose per 
cohort: 0.6,1.2 or 1.8 mg/m . Dose is based on actual body weight. Patients 
receive 650 mg Tylenol orally, 25 mg diphenhydramine, and 25 mg 
hydrocortisone IV, before inotuzumab ozogamicin. 
 
D-5, -4 and -3, Fludarabine and Bendamustine will be administered IV following 
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2 
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 IV followed by 
Bendamustine at a dose of 130 mg/m IV. 
 
Patients with CD20+ disease will also receive rituximab IV at 375 mg/m (based 
on actual body weight) on D-6, D+1 and D+8. Rituximab infusion will follow 
SCT&CT department standard practice. 
 
D0, Transplant. Fresh or cryopreserved bone marrow or peripheral blood 
progenitor cells will be infused on day 0. Depending on arrival time, patients 
who receive a graft from an unrelated donor might have one day delayed from 
D0. 
 
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 departmental standard 
practice in patients receiving allogeneic transplant. 
 
D-2 and D-1, Thymoglobulin 1 mg/kg (based on actual body weight) will be 
administrated IV to patients receiving a matched unrelated donor (MUD). 
Premedicate each dose with methylprednisolone and diphenhydramine per 
standard practice. 
 
D-2, Tacrolimus will start on D-2 administered at starting dose of 0.015 mg/kg 
(ideal body weight) as a 24 hour continuous infusion daily adjusted to achieve a 
therapeutic level of 5-15 ng/ml. Tacrolimus is changed to oral dosing when 
tolerated and can be tapered off after 6 months if no GVHD is present. 
 
D+1, +3 and +6, Methotrexate 5 mg/m2 will be administered IV for all patients. 
Patients receiving an unrelated graft will also be given methotrexate on D+11 
after the transplant. 
 
G-CSF (filgrastim-sndz, Zarxio) will be administered at a dose of 5 mcg/kg/day 
(rounded up the nearest vial size) subcutaneously beginning on D+7 for 
patients receiving related and MUD. G-CSF will continue until the absolute 
neutrophil count (ANC) is > 500 x 10/L for 3 consecutive days. 
 
In order to avoid liver toxicity related to antifungal agents, patients should 
receive caspofungin up until day +30 after which time therapy could be changed 
to an azole per SCT standard of care if LFTs are within normal limits. 
 
 
 
 
 
 
 
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5.0 Evaluation During Study 
5.1 Assessment and documentation of adverse events present at time of 
treatment initiation. 
5.2 Disease assessment prior to start treatment (baseline): 
Studies listed below will be done prior to start treatment only if 
these were not done before study entry either as part of diagnostic 
or routine pre-transplant workup. 
 
1. 
Unilateral bone marrow biopsy and aspiration. 
2. 
Disease specific PCR only if previously detected (mbr, mcr, and/or 
JH for follicular), BCL-1, and/or JH for Mantle cell 
Lymphoma-MCL), (JH for others). 
3. 
Cytogenetics and flow cytometry. 
4. 
Disease specific fluorescence in situ hybridization (FISH) only if 
previously detected (14, 18 for follicular) (11, 14 for MCL). 
5. 
Immunophenotyping. 
6. 
PET only if previously positive. 
7. 
Chest x-ray. 
8. 
CT neck, chest, abdomen and pelvis. 
9. 
Laboratory studies: CBC with differential, platelet count, PT, PTT, 
creatinine, ALT, bilirubin, LDH, alkaline phosphatase Beta 2 
microglobulin level, Hepatitis serology, HIV, HTLV-1, quantitative 
serum immunoglobulins, baseline peripheral CD4/CD8 counts and 
immunodeficiency panel. 
10. 
Patients with history of Gilbert's Disease: Right upper quadrant 
abdominal ultrasound. 
 
5.3 Evaluation During Study: 
 
Evaluations during this study follow our standard practice, if 
clinically indicated these studies may be done at other time points 
which can replace the nearest planned timepoint. After 12 months, 
follow-up testing to determine disease status will be done annually 
around years 2 and 3 as clinically indicated. 
1. 
To be performed around engraftment time: 
a) 
Chimerism studies from peripheral blood performed on 
separated T-cells and myeloid cells. After engraftment 
patients that have 100% donor cells, chimerism studies will 
be done every 3 months during the first year and then 
every 6 months while the patient is on study. 
 
2. 
To be performed as clinically indicated: 
a) 
Physical examination and adverse event assessment 
including GvHD assessment. 
b) 
Laboratory: 
1) Complete blood count with differential 
2) Standard Chemistries including LFT, BUN, Cr, albumin. 
 
3. 
Disease assessment to be performed around 1, 3, 6 and 12 
months post transplant: 
a) 
Unilateral bone marrow aspiration and biopsy. As clinically 
indicated if this was negative pre-transplant. 
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TM 
b) 
PCR (mbr, mcr, and/or JH for follicular), (BCL-1, and/or JH 
for CL), (JH if previously + for others) (repeat these only if 
a positive history) 
c) 
Cytogenetics, flow cytometry. 
d) 
FISH (14,18 for foll), (11,14 for MCL), XX/XY for 
sex mismatched donors only 
e) 
CT scans of neck. chest, abdomen and pelvis. 
f) 
PET if it was positive any time in the past. PET would not 
be repeated once CR is documented after transplant 
unless there are suspicious lymph nodes by CT. 
g) 
Quantitative serum immunoglobulins levels. 
h) 
PB CD4/CD8, immunodeficiency panel (only repeat in pts 
with recurrent infections). 
 
Patients who do not achieve CR or who progress will receive 
immunomodulation with rituximab and donor lymphocyte infusion 
(DLI) as per SCT&CT department standard practice. Those who 
progress after DLI will be taken off study. 
6.0 Background Drug Information 
6.1 
Bendamustine 
 
Description: Bendamustine is a bifunctional alkylating agent containing a 
purine-like benzimidazole ring. Bendamustine forms covalent bonds with DNA 
causing both single and double-strand DNA breaks leading to cell death. 
 
Preparation and stability: BENDEKA (Bendamustine) is supplied as 100mg/4mL 
(25 mg/mL) as a clear and colorless to yellow ready-to-dilute solution in a 
multiple-dose vial. Bendamustine hydrochloride 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 bendamustine hydrochloride 
(BENDEKATM) 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. Retain the partially used vial in original package to protect from 
light and store refrigerated (2-8°C or 36-46°F) if additional dose withdraw from 
the same vial is intended. 
 
Stability of Partially Used Vials (Needle Punched Vials): 
Bendamustine hydrochloride (BENDEKA
TM) is supplied in a multiple-dose vial. 
Although it does not contain any antimicrobial preservative, it is bacteriostatic. 
The partially used vials are stable for up to 28 days when stored in its original 
carton under refrigeration (2-8°C or 36-46°F). Each vial is not recommended for 
more than a total of six (6) dose withdrawals. After first use, the partially used vial 
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should be stored in the refrigerator in the original carton at 2°C to 8°C or 36-46°F 
and then discarded after 28 days. 
 
Aseptically withdraw the volume needed for the required dose from the 25 mg/mL 
solution as per Table (available in the package insert) 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. 
 
Administration: Administer each bendamustine dose intravenously over 30 to 60 
minutes. 
 
Adverse reactions: myelosuppression, infection, infusion reactions (rarely 
anaphylaxis), extravasation, skin reactions such as mild rash/itching or rarely 
toxic epidermal necrolysis, tumor lysis syndrome, diarrhea, nausea/vomiting, 
fatigue, and rarely secondary malignancies such as myelodysplastic syndrome or 
acute leukemia. 
 
Storage: BENDEKA (bendamustine hydrochloride) Injection should be stored in 
refrigerator, 2° to 8°C (36° to 46°F). Retain in original carton until time of use to 
protect from light. 
 
See the current package insert for additional information. 
 
 
6.2 
Rituximab 
 
Description: Rituximab is a monoclonal antibody targeted against CD20 primarily 
found on B lymphocytes. Rituximab causes cell lysis through complement 
mediated cytotoxicity and antibody-dependent cytotoxicity. 
 
Preparation and stability: Dilute with NS or D5W to a final concentration of 
1-4mg/mL. Solution is stable at 2-8 degrees C for 24 hours and additional 24 
hours at room temperature. Rituximab is supplied as 100mg and 500mg vials. 
 
Administration: Administer according to institutional standards. 
 
Adverse reactions: infusion reactions (fever, chills, hypotension), rarely 
anaphylaxis, acute respiratory distress syndrome, arrhythmias, lymphopenia, 
infection, hepatitis B reactivation, rarely progressive multifocal 
leukoencephalopathy, skin rash, tumor lysis syndrome, nausea/vomiting, 
arthralgias, myalgias, and severe mucocutaneous reactions (including 
Stevens-Johnson Syndrome and toxic epidermal necrolysis). 
 
Storage: Diluted solutions of Rituximab should be stored refrigerated at 2-8 
degrees C. Rituximab vials should be stored at 2-8 degrees C. and protected 
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from direct sunlight. Do not freeze or shake. 
See package insert for additional information. 
6.3 
Fludarabine 
 
Therapeutic classification: Fluorinated nucleoside analog 
 
Pharmaceutical data: Each vial contains 50 mg lyophilized drug, to be 
reconstituted prior to its use. Reconstitute each vial with 2 ml sterile water, each 
ml of solution will contain 25 mg of fludarabine phosphate. Vials should be stored 
refrigerated at 2-8 degrees C. 
 
Solution Preparation: mix each vial with 100mL NS and infuse over 30 minutes. 
Reconstituted solution should be used within 8 hours. 
 
Side effects: Pancytopenia, immunosuppression, autoimmune hemolytic anemia 
has (rarely) been reported, and recurred when patients were retreated with the 
drug. 
 
Nausea, vomiting, anorexia, weakness. 
 
From the CNS: Agitation, visual disturbances, confusion, coma, peripheral 
neuropathies have been reported. With high dose use confusion, blindness, 
coma and death have been reported. 
 
Special Precautions: As for other antineoplastic agents Fludarabine should be 
handled by trained personnel using procedures for proper handling. The use of 
gloves and protective glasses is recommended to avoid exposure upon 
accidental spillage. 
 
Mechanism of action: After phosphorylation to fluoro-ara-ATP the drug appears 
to incorporate into DNA and inhibit DNA polymerase alpha, ribonucleotide 
reductase and DNA primase, thus inhibiting DNA synthesis. 
 
Human safety and pharmacology: The half-life of the activated compound is 
approximately 10 hours, but the pharmacology is incompletely understood. 
Excretion is impaired in patients with impaired renal function. 
 
See package insert for additional information. 
 
6.4 
CMC-544 (inotuzumab ozogamicin) 
 
Description: CMC544 is a humanized monoclonal antibody target to CD22 and 
conjugated to calicheamicin. It is supplied as amber vials with white, 
unpreserved, lyophilized cake. Each vial contains 4mg. 
 
Preparation and stability: Allow vials to reach room temperature prior to 
reconstitution. Reconstitute each vial with 4mL sterile water for injection for a 
concentration of 1mg/mL. Gently swirl each vial to dissolve. Do not shake 
vigorously. Dilute reconstituted solution (entire dose) with 0.9% sodium chloride 
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to a final volume of 50mL. Infusion must be completed within 8 hours of 
reconstitution. Bags made of PVC or polyolefin are recommended. Unused or 
expired drug will be destroyed per institutional policy. 
 
Administration: Each dose should be administered at 50mL/hr. Flush line with 
22mL 0.9% sodium chloride after infusion is complete. Protect from light during 
preparation and administration. 
 
Adverse events: common and expected are thrombocytopenia and neutropenia, 
low grade liver function tests, increased risk of infections due to neutropenia and 
depletion of B-cells, nausea, vomiting, abdominal pain, constipation, diarrhea, and 
decreased appetite. 
 
Less common but serious and sometimes fatal are venoocclusive liver 
disease/sinusoidal obstructive syndrome (VOD/SOS), nodular regenerative 
hyperplasia, hepatic fibrosis / biliary cirrhosis, hepatic failure, ascites, 
hyperbilirubinemia, cytolytic hepatitis, hepatitis/hepatitis acute, and abnormal 
hepatic function. 
 
Fatigue and asthenia are common and sometimes severe. Chills, headache, 
pyrexia, and epistaxis have also been reported. 
 
No serious prolongation of QTc although no well characterized have been 
observed. 
 
Storage: Vials should be refrigerated (2-8°C) and protected from light. 
For additional information, please see the current investigator’s brochure . 
 
6.5 
Antithymocyte globulin (ATG) (Rabbit) (Thymoglobulin®) 
 
Description: Antithymocyte globulin is a polyclonal IgG against human 
T-lymphocytes causing profound immunosuppression 
 
Preparation and stability: Reconstitute each vial of antithymocyte globulin with 
5mL of sterile water. The final concentration will be 5mg/ml of Thymoglobulin. 
May further dilute with either D5W or NS. The recommended final concentration 
is 0.5mg/mL. Diluted solutions should be used immediately as there are no 
preservatives in the vials. The solution is stable at room temperature for 24 
hours; however, this is not recommended. Antithymocyte globulin is supplied as 
25mg vials. 
 
Administration: Administer each dose over 4-6 hours. Administer via in-line 0.22 
micron filter. Premedication with corticosteroids, acetaminophen, and 
antihistamines are recommended to reduce infusion related reactions. 
 
Adverse reactions: infusion reactions (fever, chills, hypotension), serum sickness, 
rash, infection, myelosuppression, allergic reactions including anaphylaxis, 
post-transplant lymphoproliferative disorders, and acute respiratory distress 
syndrome. 
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Storage: Antithymocyte globulin (Thymoglobulin) is supplied as 25 mg vials 
which should be stored refrigerated 2-8 degrees C. Protect from freezing. Protect 
from light. 
 
See package insert for additional information. 
 
7.0 Statistical Considerations 
Statistical section - patient sample size and analysis plan: 
 
7.1 
The study design developed by Ji, Li, and Bekele (2007) will be used to determine the 
MTD of CMC-544 targeting a toxicity rate not greater than 30% using a prior 
beta(0.5, 0.5). Three doses of CMC-544 will be studied (0.6, 1.2, 1.8 mg/m2). The 
dose-limiting toxicity (DLT) is defined as grade III or IV renal, hepatic, intestinal, 
neurologic, pulmonary or cardiac adverse events, as well as any graft failure or 
treatment-related death at any time from first CMC-544 administration (D-13) through 
30 days post transplant (D30). 
 
Patients will be enrolled in cohorts of two, beginning at 0.6 mg/m2. Each cohort of two 
must be fully evaluated for toxicity through D30 before enrolling the next cohort. The trial 
monitoring chart is displayed in Table 1. This table describes when a dose is declared 
too toxic and should be de-escalated or is safe and can be escalated or chosen as the 
MTD. The MTD is defined as the highest dose for which the probability of toxicity is 
closest to 30%. A legend is displayed below the table. Prior to advancing dose levels a 
cohort summary must be completed and submitted to the Clinical Research Medical 
Monitor (IND Office). 
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2 
2 
 
 
 
If the current dose is 1.8 mg/m and the decision rule from Table 1 is E (escalate), then 
future patients will be treated at 1.8 mg/m . We will terminate the trial when the maximum 
sample size (n=30) is reached. 
 
Table 2 presents the operating characteristics of the proposed design for this trial based 
on 2000 simulations using 5 scenarios with varying toxicity rates for each of the three 
doses. The first two scenarios contain safe toxicity rates for all doses (<30%) and the 
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17 
last scenario contains unsafe toxicity rates for all doses (>30%). 
 
 
Secondary Outcomes 
 
We will estimate the objective overall response (CR+PR) with a 95% confidence interval 
in the dose that is declared the MTD. We will use logistic regression to assess the 
association between response and disease and clinical characteristics of interest. 
 
Kaplan-Meier survival curves will be used to estimate overall survival and 
recurrence-free survival. We will use Cox proportional hazards regression methodology 
to assess the association between disease and clinical characteristics and the survival 
outcomes. We will use the method of Gooley et al to estimate the cumulative incidence 
of acute and chronic GVHD. 
 
8.0 Study Definitions 
8.1 
Treatment periods: 
Active treatment administration is defined from the first day of treatment 
administration as outlined in the treatment plan through D0. 
 
Active treatment period is defined from the first day of treatment administration 
through Day +30. 
 
Follow-up period is defined from BMT Day +31 until one year of treatment 
completion. 
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8.2 
Disease Response is defined according to disease specific criteria as per the CIBMTR. 
 
Complete Response (CR): 
1. No clinical or radiological evidence of disease. 
a) Negative bone marrow biopsy 
b) No palpable liver or spleen 
c) Negative scans 
 
Partial Remission (PR): 
1. 
Equal or more than 50% reduction in lymphadenopathy, liver and or spleen 
if abnormal at pre-treatment. 
2. 
No new site of disease. 
 
Stable Disease (SD): 
No change in disease status from baseline, no evidence of new sites of 
disease. 
 
Disease Progression: 
1. More than 50% increase in lymph nodes size. 
2. Evidence of new sites of disease (lymph nodes, bone marrow or other 
sites). 
3. If previously positive increased in PET uptake. 
 
8.3 Engraftment is defined as the evidence of donor derived cells (more than 95%) by 
chimerism studies in the presence of neutrophil recovery by D+ 28 post stem cell 
infusion. 
 
8.3.1 Other definitions used to assess engraftment: 
Neutrophil recovery is defined as a sustained absolute neutrophil count (ANC) 
> 0.5 x 10
9/L for 3 consecutive days. 
Engraftment date is the first day of three (3) consecutive days that the ANC 
exceeds 0.5 x10
9/L. 
Delayed engraftment is defined as the evidence of engraftment beyond D+28, 
as above, achieved after the administration of therapeutic (high dose) 
hematopoietic growth factors. 
Primary Graft failure is defined as failure to achieve an ANC > 0.5 x 10
9/L for 3 
consecutive days by D+ 28, as above, with no evidence of donor derived cells by 
bone marrow chimerism studies and no evidence of persistent or relapsing 
disease. 
Secondary graft failure is defined as a sustained declined of ANC <0.5 x 10
9/L 
for 3 consecutive days after initial documented engraftment with no evidence of 
disease progression. 
Autologous reconstitution is defined by the presence of ANC > 0.5 x 10
9/L 
without evidence of donor-derive cells by bone marrow chimerism studies. This 
can occur at initial engraftment or later after initial engraftment has been 
documented. 
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9.0 Criteria for Removal from the Study 
1. 
Patient withdrawal of the informed consent. 
2. 
Patient not being compliant or fails to return for follow-up. 
3. 
An increasing or unexpected pattern of toxicity observed deemed 
unacceptable by the Study Chairman. 
4. 
Disease progression after donor lymphocyte infusion. 
5. 
Investigator judgment when the well being and best interest of the patient is 
compromised. 
6. 
After 3 years of study completion. 
10.0 Reporting Requirements 
PDMs/CORe will be used as the electronic case report form (eCRF) for this protocol and 
protocol specific data including adverse events will be entered into PDMs/CORe. 
 
Severity of the adverse events (AEs). 
The severity of the adverse events (AEs) will be graded according to the Common 
Terminology Criteria v4.0 (CTCAE). Events not included in the CTCAE chart will be scored as 
follows: 
General grading: 
Grade 1: Mild: discomfort present with no disruption of daily activity, no 
treatment required beyond prophylaxis. 
Grade 2: Moderate: discomfort present with some disruption of daily activity, 
require treatment. 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding 
to first line treatment. 
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
 
Grading for specific syndromes: 
Veno-occlusive disease (VOD): 
Grade 3: Bili >2mg/dl with at least two of the following: increased weight >4% 
from baseline, ascites or hepatomegaly 
Grade 4: pulmonary and or renal failure 
 
Pulmonary events not caused by CHF (interstitial pneumonitis (IP), pulmonary 
hemorrhage (DAH): 
Grade 1: CXR showing mild infiltrates or interstitial changes 
Grade 2: mild SOB 
Grade 3: requires supplemental oxygen, or is a documented infection 
Grade 4: requires intubation 
 
Thrombotic thrombocytopenic purpura (TTP): 
Grade 1: No treatment required 
Grade 2: Requires steroids and/or plasma transfusions 
Grade 3: Requires plasma exchange 
 
Cytokine storm or engraftment syndrome: 
Grade 1: No treatment required 
Grade 2: Treatment required 
Grade 3: Organ dysfunction 
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Grade 4: Total Bilirubin >5 
 
Hemorrhagic Cystitis: 
Grade 1: minimal or microscopic bleeding/pain 
Grade 2: gross bleeding/pain and spasms 
Grade 3: transfusion/irrigation required 
Grade 4: dialysis required 
 
Causality Assessment. 
For the purpose of this study common adverse events of Fludarabine, 
Bendamustine and Rituximab as preparative regimen for allogeneic stem cell 
transplantation are known and well described. Therefore an increased pattern 
of frequency and or severity of these events will be assessed and reported as 
definitive related to the preparative regimen in combination of CMC-544. 
 
When the relationship of the adverse event cannot be ruled out with certainty 
the AE may be considered probable or possible related. 
 
Adverse events known to be related to drugs used for supportive treatment will 
be scored as unrelated. 
 
The principal investigator will be the final arbiter in determining the casualty 
assessment. 
 
List of most common expected AEs related to high dose chemotherapy followed by 
allogeneic stem cell transplantation: 
1. Infections in the presence or absence of neutropenia: fungal, bacterial and 
or viral infections. 
2. Fever: Non-neutropenic or neutropenic without infection 
3. Acute graft versus host disease (aGVHD): most commonly manifested by 
skin rash, diarrhea and abnormal liver function tests could also present with 
some degree of fever, upper gastrointestinal symptoms (nausea and vomiting) 
mucositis and eye dryness. 
4. Gastrointestinal (GI tract): the GI tract manifestations could be not only due 
to direct damage from the preparative regiment but also be a manifestation of 
GVHD or infections. Therefore, the time, course, and its presentation are 
crucial when assessing these as adverse events. Nausea/vomiting, mucositis, 
and diarrhea when presented within first 7 to 10 days most likely will be related 
to the preparative regimen. 
5. Skin rash: not related to GVHD could be caused by chemotherapy used for 
the preparative regimen or antibiotics used as supportive treatment. 
6. Transaminitis: liver function test elevation. 
7. Pulmonary events: not related to CHF most likely caused by drug injury or 
infection. These could present with a pneumonitis pattern manifested with 
shortness of breath, pulmonary infiltrates on chest radiograph, sometimes 
accompanied by fever and cough and progress to acute respiratory 
insufficiency and a diffuse bilateral alveolar pattern. 
8. Cytokine Storm/ engraftment syndrome: most likely caused by released 
cytokines. 
9. Hemorrhagic cystitis: not related to chemotherapy agents used in the 
proposed preparative regimen is most likely caused by viral infection. 
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10. Thrombotic thrombocytopenic purpura (TTP). 
11. Veno-occlusive Disease of the Liver (VOD): known to have a higher 
incidence in patients undergoing high dose chemotherapy. Some 
antimicrobial agents have been also incriminated in its development. 
12. Fluid overload due to hydration required for conditioning regimen, blood 
product transfusions and or IV alimentation 
13. Graft failure. 
14. Chronic GVHD. 
15. For the purpose of this study the following events would not be considered 
adverse events and would not be recorded in the database: 
1. 
Flu-like symptoms not associated with infection 
3. 
Abnormal laboratory findings considered associated to the original 
disease 
4. 
Isolated changes in laboratory parameters such as electrolyte, 
magnesium and metabolic imbalances, uric acid changes, 
elevations of ALT, AST, LDH and alkaline phosphatase. 
 
Dose-limiting toxicity (DLT) is defined as grade III or IV occurring during the first 30 days: 
Renal 
Hepatic 
Intestinal 
Neurologic 
Pulmonary 
Cardiac 
Graft failure 
Treatment related death 
 
Adverse events considered serious 
1. 
Prolonged hospitalization due to infections and/or organ failure requiring 
extensive supportive care (i.e. dialysis, mechanical ventilation). 
2. 
Readmissions from any cause resulting in a prolonged hospitalization (>10 
days). 
3. 
Graft Failure/ rejection. 
4. 
Any expected or unexpected event resulting in an irreversible condition 
and/or leading to death. 
 
Adverse events data collection 
From the start of preparative regimen up to D+100 only adverse events 
considered unexpected and related will be collected. The data will reflect the 
onset and resolution date and maximum grade. Intermittent events should be 
labeled as such and followed until resolution. If a patient is taken off study while 
an event still ongoing, this will be followed until resolution unless another therapy 
is initiated. Pre-existing medical conditions will be recorded only if an 
exacerbation occurs during the active treatment period. Medical events not 
considered adverse events will not be collected. Co-morbid events will not be 
scored separately. 
 
Adverse events will be documented based on progress notes, including the 
flowsheet, in the electronic (Clinic Station) patient medical record. 
 
 
 
 
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Concurrent medication 
As stated in the treatment plan, patients treated on this protocol will require 
supportive care treatment (concurrent medications). These medications are 
considered standard of care and have no scientific contributions to the protocol, 
therefore no data will be captured on the various medications needed or their 
side effects. 
 
Serious Adverse Events Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred in 
a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate 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. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
• 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported 
to the IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of the 
event to the Safety Project Manager in the IND Office. 
 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event has 
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stabilized, or there has been acceptable resolution of the event. 
 
• 
Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
Investigator Communication with Pfizer: 
 
For the purposes of SAE reporting on this protocol, SAE’s should also be reported to Pfizer only 
if the patient has received at least one dose of CMC-544 and up to 28 days after the last dose 
of study drug. SAE’s which occur prior to a patient receiving CMC-544 shall not be reported to 
Pfizer. 
11.0 References 
1. Chopra R, Goldstone AH, Pearce R, et. al. Autologous versus allogeneic 
bone marrow transplantation for non-Hodgkin’s lymphoma: a case-controlled 
analysis of the European Bone Marrow Transplant Group registry data. J Clin 
Oncol. 1992 10:1690-1695. 
 
2. Van Besien K, Sobocinski A, Rowlings PA, et. al. Allogeneic bone marrow 
transplantation for low-grade lymphoma. Blood. 1998;92:1832-1836. 
 
3. Demirer T, Weaver CH, Buckner CD, et. al. High-dose cyclophosphamide, 
carmustine, and etoposide followed by allogeneic bone marrow transplantation 
in patients with lymphoid malignancies who had received prior dose-limiting 
radiation therapy. J Clin Oncol. 1995;13:596-602. 
 
4. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-vs-leukemia effect of donor 
lymphocyte transfusions in marrow grafted patients. Blood. 1995; 
86:2041-2050. 
 
5. Van Besien KW, de Lima M, Giralt SA, et al. Management of lymphoma 
recurrence after allogeneic transplantation: the relevance of 
graft-versus-lymphoma effect. Bone Marrow Transplant. 1997;19:977-982. 
 
6. Champlin R, Khouri I, Shimoni A, et al. Harnessing graft-versus-malignancy: 
Non-myeloablative preparative regimens for allogeneic hematopoietic 
transplantation, an evolving strategy for adoptive immunotherapy. Br J 
Hematol. 2000;111:18-29. 
 
7. Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic 
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transplantation as adoptive immunotherapy for indolent lymphoma: low 
incdence of toxicity, acute graft-versus-host disease, and treatment-related 
mortality. Blood.2001; 98:3595-3599. 
 
8. Tam CS, Bassett R, Ledesma C, et al. Mature results of the MDAnderson 
Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. 
Blood. 2009;113:4144–4152. 
 
9. Morris E, Thomson K, Craddock C, et al.Outcomes after 
alemtuzumab-containing reduced-intensity allogeneic transplantation regimen 
for relapsed and refractory non-Hodgkin’s lymphoma. Blood. 
2001;104:3865-3871. 
 
10. Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is 
effective and has a favorable toxicity profile in the treatment of matle cell and 
low-grade non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:3383-3389. 
 
11. Rummell MJ, Chow KU, Hoelzer D, Mitrou PS, Weidmann E. In vitro studies 
with bendamustine: enhanced activity in combination with rituximab. Semin 
Oncol. 2002; 29(4 Suppl 13):12-14. 
 
12. DiJoseph JF, Amellino DC, Boghaert ER, et al. Antibody-targeted 
chemotherapy with CMC-544: a CD22-targeted immunoconjugate of 
calicheamicin for the treatment of b-cell malignancies. Blood 
.2004;103:1807-1814. 
 
13. Advani A, Coiffier B, Czuczman MS, et al. Safety, pharmacokinetics, and 
preliminary clinical activity of inotuzumab ozogamicin, a novel 
immunoconjugate for the treatment of b-cell non-Hodgkin’s lymphoma: results 
of a phase I study. J Clin Oncol. 2010;28:2085-2093. 
 
14. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an 
anti-CD22-calecheamicin conjugate, for refractory and relapsed acute 
lymphocytic leukemia: a phase 2 study. The Lancet Oncology. 2012 Feb 12. 
 
15. Ji Y, Li Y, and Bekele BN. Dose-finding in phase I clinical trials based on 
toxicity probability intervals. Clinical Trials. 2007;4:235-244. 
 
16. Kaplan EL and Meier P. Non-parametric estimation from incomplete 
observations. Journal of the American Statistical 
Association.1958;53:457- 481. 
 
17. Gooley TA, Leisenring W, Crowley J, and Storer BE. Estimation of failure 
probabilities in the presence of competing risks: new representations of old 
estimators. Statistics in Medicine. 1999; 18:695-706. 
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