Addition of Inotuzumab Ozogamicin Pre- and Post-Allogeneic Transplantation
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Lymphocytic Neoplasm, Lymphoma
Sponsor: M.D. Anderson Cancer Center

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Addition of Inotuzumab Ozogamicin 
Pre- and Post-Allogeneic Transplantation 
 
 
 
 
 
 
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, Pharmacy Clinical Programs 
3 The University of Texas MD Anderson Cancer Center, Leukemia Medicine Department 
4 The University of Texas MD Anderson Cancer Center, Pediatrics Department 
5 The University of Texas MD Anderson Cancer Center, Biostatistics Department  
 
 
 
 
 
Institution Study Number:  2018-0860 
Financial Support:   Pfizer Pharmaceuticals 
Sponsor:  The University of Texas MD Anderson Cancer Center  
 
IND Number:  142881 
Principal Investigator:  Issa F. Khouri, MD 
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: 713-794-4902 
ikhouri@mdanderson.org 
 
Co-Investigators:  Richard E. Champlin, MD1 
Alison M. Gulbis, PharmD2 
Jin Seon Im, MD, PhD1 
Elias J. Jabbour, MD3 
  Partow Kebriaei, MD1 
David Marin, MD1 
Amanda L. Olson, MD1 
Uday R. Popat, MD1 
Samer Srour, MD1 
Priti Tewari, MD4 
 
Statistician:  Roland L. Bassett, Jr., MS5 
 

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Table of Contents 
 
 
1.0  
OBJECTIVES ...................................................................................................................................................... 3 
2.0  
BACKGROUND .................................................................................................................................................. 3 
3.0 
PATIENT ELIGIBILITY ......................................................................................................................................... 5 
3.1 
INCLUSION CRITERIA .................................................................................................................................................... 5 
3.2 
EXCLUSION CRITERIA .................................................................................................................................................... 6 
4.0 
TREATMENT PLAN ............................................................................................................................................ 6 
4.1 
CHEMOTHERAPY AGENT DOSES AND ADMINISTRATION FOR ACUTE LYMPHOBLASTIC LEUKEMIA, AGGRESSIVE LYMPHOMA PATIENTS 
(BASED ON WHO CLASSIFICATION), ALSO INDOLENT LYMPHOMA IN TRANSFORMATION, OR THOSE WHO HAVE FAILED ≥ THREE SMALL 
MOLECULE INHIBITORS .............................................................................................................................................................. 6 
4.2 
CHEMOTHERAPY AGENT DOSES AND ADMINISTRATION FOR PATIENTS WITH INDOLENT LYMPHOMAS (BASED ON WHO 
CLASSIFICATION) ...................................................................................................................................................................... 8 
4.3 
CHEMOTHERAPY AGENT DOSES AND ADMINISTRATION FOR HAPLOIDENTICAL OR MISMATCHED STEM CELL TRANSPLANT RECIPIENTS9 
4.4  
SUPPORTIVE CARE ..................................................................................................................................................... 11 
4.5 
POST-TRANSPLANT .................................................................................................................................................... 13 
5.0 
EVALUATION DURING STUDY ......................................................................................................................... 14 
5.1 
PRE-TREATMENT EVALUATIONS ................................................................................................................................... 14 
5.2 
EVALUATIONS DURING STUDY ..................................................................................................................................... 15 
5.3 
OPTIONAL PROCEDURE .............................................................................................................................................. 16 
6.0 
STATISTICAL CONSIDERATIONS ....................................................................................................................... 16 
6.1 
OVERVIEW ............................................................................................................................................................... 16 
6.2 
FM COHORT SAFETY ................................................................................................................................................. 17 
6.3 
SAFETY MONITORING ................................................................................................................................................ 17 
6.4 
ANALYSIS PLAN ......................................................................................................................................................... 21 
6.5 
SAFETY MONITORING PLAN ........................................................................................................................................ 22 
7.0  
CRITERIA FOR REMOVAL FROM THE STUDY .................................................................................................... 23 
8.0 
ADVERSE EVENTS AND REPORTING REQUIREMENTS ....................................................................................... 23 
8.1 
ADVERSE EVENTS AND DATA COLLECTION ...................................................................................................................... 23 
8.2 
SERIOUS ADVERSE EVENT REPORTING (SAE) REPORTING .................................................................................................. 25 
9.0 
BACKGROUND DRUG INFORMATION .............................................................................................................. 27 
9.1 
BENDAMUSTINE ........................................................................................................................................................ 27 
9.2 
MELPHALAN ............................................................................................................................................................ 29 
9.3 
FLUDARABINE ........................................................................................................................................................... 29 
9.4 
INOTUZUMAB OZOGAMICIN ........................................................................................................................................ 30 
9.5 
RITUXIMAB .............................................................................................................................................................. 31 
9.6   
CYCLOPHOSPHAMIDE ................................................................................................................................................. 31 
9.7    MESNA ....................................................................................................................................................................... 32 
10.0  DATA SECURITY/CONFIDENTIALITY ..................................................................................................................... 32 
10.1   ACCESS TO STUDY RECORDS ............................................................................................................................................ 32 
10.2   METHODS OF STORAGE OF STUDY RECORDS....................................................................................................................... 33 
10.3  DURATION OF STUDY RECORD STORAGE ............................................................................................................................ 33 
10.4   SHARING OF STUDY RECORDS .......................................................................................................................................... 33 
10.5   CONSENT PROCESS AND DOCUMENTATION ........................................................................................................................ 33 
11.0  
REFERENCES ................................................................................................................................................... 35 

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Protocol Body 
 
1.0  
Objectives 
The primary objective of this study will be to assess the safety of the addition of 
Inotuzumab Ozogamicin pre- and post- allogeneic transplantation in patients 
with CD22-positive hematological malignancies. 
 
Secondary objectives include assessing: 
1. Overall survival, progression-free survival and relapse rates. 
2. Treatment-related mortality 
3. Cumulative incidence of acute and chronic graft-versus-host disease (GVHD). 
2.0  
Background 
The cell-surface glycoprotein CD22 is expressed in more than 90% of patients with 
b-cell lymphoid malignancies, and has emerged as an attractive therapeutic target for 
b-cell cancers.
1 Inotuzumab ozogamicin (IO) is a humanized anti-CD22 monoclonal 
antibody conjugated to calicheamicin, a cytotoxic antibiotic agent. After the conjugate 
binds to CD22, the CD22-conjugate complex is rapidly internalized, and calicheamicin is 
released. Calicheamicin binds to the minor groove of DNA and thus induces 
double-strand cleavage and subsequent apoptosis.
1
 
 
Recent studies have suggested that IO is associated with a high risk of veno-occlusive 
disease (VOD) in patients receiving allogeneic stem cell transplantation (alloSCT).
2 
Multivariate analysis using stepwise selection confirmed that conditioning regimens 
containing two alkylating agents (especially if busulfan and thiotepa are involved) and 
last available pre-alloSCT bilirubin concentration more than or equal to the ULN might 
increase the risk of sinusoidal obstruction syndrome.
2
 
 
Initial reports from MD Anderson Cancer Center using IO in relapsed/refractory B-ALL in 
both pediatric and adult patients showed promising results with overall response rate 
(ORR) of 57%.3The phase II Children’s Oncology Group study (AALL1621) using 
inotuzumab in treating younger patients with relapsed/refractory B-ALL (NCT02981628) 
showed an ORR of 58% among the 48 patients enrolled, an MRD negativity rate of 65% 
among responders.4 
 
A retrospective study using IO on a compassionate use program in pediatric patients 
reported on 51 heavily pretreated children with B-ALL who received the fractionated 
dosing schedule of IO: 67% achieved CR with most (71%) achieving MRD-negative 
status, and 41% undergoing alloSCT after IO. Notably VOD developed in 52% of patients 
who received alloSCT. Patients who developed VOD received dual alkylators, busulfan 
containing regimens, TBI based myeloablative regimens, or had history of one or more 
alloSCT prior to IO therapy. The 12 months EFS and OS for the entire group were 23.4% 

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and 36.3%, respectively.5  
 
We have prospectively studied the safety of IO when added to our standard 
nonmyeloablative conditioning regimen, bendamustine-fludarabine and rituximab.
6,74 IO 
was infused intravenously (IV) on day -13 outpatient, with a dose cohort of 0.6, 1.2 or 
1.8 mg/m
2, to determine the maximum tolerated dose. Bendamustine 130 mg/m2 IV 
daily on days -5 to -3 together with 30 mg/m2 IV of fludarabine on days -5 to -3 were 
given prior to transplantation. Rituximab was given at a dose of 375 mg/m2 IV on days 
-6, +1, and +8. Tacrolimus and mini-methotrexate were used for graft versus host 
disease (GvHD) prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days 
-2, and -1 in patients receiving an unrelated donor transplant. This study included 21 
patients (CLL=9; 3 with 17p- and 1 Richter’s), mantle cell=7, follicular=3, and diffuse 
large cell=2; including 1 double-expresser). Median age was 59 (range, 31-70) years. 
Median prior treatments was 3 (range, 1-6); Ten (48%) received their transplants from 
HLA-compatible siblings and 11 (52%) from unrelated donors. The number of patients 
who received the 0.6, 1.2 or 1.8 mg/m
2 of IO were 4, 2 and 15 patients, respectively. 
Fifteen patients (71%) never experienced an absolute neutrophil count < 0.5 x 10
9/L nor 
required platelet transfusions. All patients engrafted donor cells and no secondary graft 
failure occurred. By day 30, median donor myeloid and T-cells were 89% and 99%, 
respectively. Both increased to 100% by day 90. The cumulative incidence of acute 
grade 2-4 graft-versus-host disease (GvHD) and chronic extensive GvHD were 29% (5% 
of grade 3, and 0% of grade 4) and 35%, respectively. One patient with underlying 
cholelithiasis developed acute cholecystitis with IO and was able to proceed with alloSCT 
after recovery. No dose-limiting toxicities or VOD were observed. With a median follow-
up time of 23.5 (range, 3-54) months, the overall survival (OS) rate was 89% (90% 
CLL/follicular, 86% mantle cell and 100% in diffuse large cell; also 100% for siblings, 
81% for unrelated) and the progression-free survival (PFS) rate was 78%. 
 
A more intense chemotherapy conditioning is needed in acute lymphoblastic leukemia 
(ALL). In order to avoid the commonly used drugs of busulfan and thiotepa that are 
associated with VOD, we propose the use of fludarabine and mephalan (FM). The 
efficacy of reduced intensity conditioning (RIC) of FM in b-ALL has been studied in two 
retrospective studies.5,6 Indications for this conditioning at the City of Hope
8 were: (1) 
aged 50 years or older (42%), (2) compromised organ function (54%), or (3) recipient of 
a previous alloSCT (37.5%). Patients had a median age of 47.5 years and the median 
follow-up was 28.5 months for living patients. Both OS and disease-free survival rates at 
2 years were 61.5%.
8These results were recently confirmed by Kawamura and 
colleagues, in using the same conditioning in ALL9 
 
A study by the CIBMTR (Center for International Bone Marrow Transplant 
Research),
10analyzed the intertwining role of the intensity of the conditioning and 
minimal residual disease (MRD) status by flow-cytometry pre-alloSCT in 197 adults with 
Ph+ ALL in first complete remission. Sixty-seven patients receiving RIC were matched 
with 130 receiving myeloablative conditioning (MAC) for age, donor type and year of 
transplant. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) 

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was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 
49% in RIC and 28% in MAC (P=0.058). OS was similar (RIC 39% vs 35%; P=0.62). 
Patients MRD + pre-alloSCT had higher risk of relapse with RIC vs MAC [hazard ratio 
(HR) 1.97; P=0.026]. However, patients who were MRD (-) pre-RIC SCT had superior 
OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). This 
suggests that although RIC is associated with a lower TRM, additional non-toxic 
strategies are especially needed in b-ALL patients receiving RIC regimen. 
 
In this study, we propose to extend our experience with IO in the transplant setting and 
to treat more patients with lymphomas and to also include patients with ALL. In order to 
decrease the risk of toxicity and VOD, we propose to split the IO we have previously 
used into pre- and post-transplant components. This is justified by the more intense RIC 
regimens we are using. This strategy is also extrapolated from the conventional 
non-transplant hyper-CVAD+IO studies done at MD Anderson, where there has been a 
significant reduction of VOD with a split dose of IO.
11
 
 
3.0  Patient Eligibility 
 
3.1 
Inclusion Criteria 
 
3.1.1 Patient age 12 to 75. 
3.1.2 English and non-English speaking patients are eligible. 
3.1.3 CD22+ lymphoid malignancies including B-ALL 
3.1.4 Eligible to receive a reduced-intensity alloSCT 
3.1.5 Patients with:  
a. Indolent lymphoma patients who failed conventional treatment; or, 
b. Acute lymphoblastic leukemia (ALL), aggressive lymphoma, indolent 
lymphoma in transformation, or those who have failed ≥ three small 
molecule inhibitors 
3.1.6 Donor: HLA compatible (8/8 match) related or matched unrelated donor 
(HLA-A, B, C, DRB1) or mismatched MUD (7/8 match) or haploidentical16 
3.1.7 Performance status of 0 to 2, Lansky ≥ 80 for < 16 years and Karnofsky ≥ 
80 for ≥ 16 years of age. 
3.1.8 Adequate organ function at time of study entry 
a. Creatinine less than or equal to 1.6 mg/dL 
b. Bilirubin less than 1.6 mg/dL 
c. SGPT < 2 x UL 
d. Ejection fraction >/= 40% 
e. FEV1, FVC and cDLCO >/= 40% 
3.1.9 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 
 
3.2.1 HIV positive 
3.2.2 Prior autologous transplant less than 1 year prior to consent. 
3.2.3 Active and uncontrolled disease/infection 
3.2.4 Unable or unwilling to sign consent 
3.2.5 Current active hepatic or biliary disease (with exception of Gilbert’s 
syndrome) 
3.2.6 Active hepatitis B or C 
3.2.7 Recent systemic chemotherapy or radiation within 3 weeks of study 
entry (intrathecal therapy is allowed). Standard biological agents such 
as rituximab, TKIs such as ibrutinib, and venetoclax are allowed to be 
given within 3 days prior to receiving inotuzumab ozogamicin. 
Blinatumomab is allowed to be given until 1 week prior to Day -13 
inotuzumab ozogamicin on study. 
3.2.8 Prior Inotuzumab Ozogamicin within 3 weeks of study entry. 
3.2.9 Peripheral blast count of greater than 10 K/mL. 
3.2.10 QTcF interval > 470 ms. 
3.2.11 Patients with cognitive impairments and/or any serious unstable pre-
existing medical condition or psychiatric disorder that can interfere with 
safety or with obtaining informed consent or compliance with study 
procedures. 
 
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+).   
 
Obtain ECGs and electrolytes prior to the start of IO treatment and periodically 
monitor as clinically indicated during treatment. 
 
Within 3 weeks prior to start treatment, D-13, patients must be off any prior systemic 
biological therapy, chemotherapy, radiotherapy, or other investigational therapy 
(intrathecal therapy is allowed).  Blinatumomab is allowed to be given until 1 week 
prior to Day -13 inotuzumab ozogamicin on study. 
 
4.1 
Chemotherapy Agent Doses and Administration for Acute Lymphoblastic 
Leukemia, Aggressive Lymphoma Patients (based on WHO 
Classification), also indolent lymphoma in transformation, or those who 
have failed ≥ three small molecule inhibitors 
 
Day -13: Patients will receive IO on day -13 of conditioning at dose levels: 0.3 
mg/m
2 intravenously (IV). Dose is based on actual body weight/body surface area. 
Patients will receive premedication with diphenhydramine and hydrocortisone (or 
equivalent corticosteroid) as follows before IO infusion: 

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- 
Adults ≥ 18 years: diphenhydramine 25 mg orally or IV and 
hydrocortisone 50 mg IV  
- 
Pediatric patients 12 – 17 years old: diphenhydramine 0.5 mg/kg 
(max 25 mg) orally or IV and hydrocortisone 1 mg/kg (max 50 mg) 
IV 
- 
For pediatric patients, adjusted body weight will be calculated using 
pediatric standards. 
 
Day -5, -4, -3, -2: Fludarabine and Melphalan will be administered IV following 
SCTCT department standard practice.12,13 Fludarabine will be administered at a 
dose of 30 mg/m2 IV on days -5, -4, -3, and -2. Melphalan will be administered at 
a dose of 140 mg/m
2 on day -2. On day -2, fludarabine should be administered 
prior to melphalan. Fludarabine doses will be based on actual body weight/actual 
body surface area. Melphalan doses 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. 
Formula to calculate adjusted body weight for melphalan as follows: Adjusted 
BW (kg) = IBW + 0.5 (Actual body weight-IBW). 
 
Day 0 –Transplant 
 
Fresh or cryopreserved bone marrow or peripheral blood progenitor cells (bone 
marrow preferred) 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. 
 
 
 

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4.2 
Chemotherapy Agent Doses and Administration for patients with Indolent 
Lymphomas (based on WHO Classification) 
 
Day -13: Patients will receive IO on day -13 of conditioning at dose levels: 0.6 
mg/m
2 or 0.3 mg/m2 intravenously (IV) (if necessary. Please see statistical 
design). Dose is based on actual body weight/body surface area. Patients will 
receive premedication with diphenhydramine and hydrocortisone (or equivalent 
corticosteroid) as follows before IO infusion: 
- 
Adults ≥ 18 years: diphenhydramine 25 mg orally or IV and 
hydrocortisone 50 mg IV  
- 
Pediatric patients 12 – 17 years old: diphenhydramine 0.5 mg/kg 
(max 25 mg) orally or IV and hydrocortisone 1 mg/kg (max 50 mg) 
IV 
- 
For pediatric patients, adjusted body weight will be calculated using 
pediatric standards. 
 
D-5, -4 and -3: Fludarabine will be administrated at a dose of 30 mg/m2 IV 
followed by Bendamustine at a dose of 130 mg/m
2 IV. 
Fludarabine and Bendamustine will be administered IV following SCTCT 
department standard practice. Fludarabine will be based on actual body 
weight/actual body surface. Bendamustine will be dosed per adjusted body 

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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. Formula to calculate adjusted body weight for bendamustine is as 
follows: Adjusted BW (kg) = IBW + 0.5 (Actual body weight-IBW). 
 
Lymphoma patients will also receive rituximab IV at 1,000 mg/m
2 IV (based on 
actual body weight) on D-6, D+1 and D+8. Rituximab infusion will follow SCTCT 
department standard practice.  A rituximab biosimilar may be used based on 
institutional formulary and/or if required by insurance. 
 
Day 0 –Transplant 
 
Fresh or cryopreserved bone marrow or peripheral blood progenitor cells (bone 
marrow preferred) 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. 
 
 
 
 
4.3 
Chemotherapy Agent Doses and Administration for Haploidentical or 
Mismatched Stem Cell Transplant Recipients 
 
Day -13: Patients will receive IO on day -13 of conditioning at dose level 0.3 
mg/m
2 intravenously (IV). Dose is based on actual body weight/body surface 
area. Patients will receive premedication with diphenhydramine and 
hydrocortisone (or equivalent corticosteroid) as follows before IO infusion: 

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- 
Adults ≥ 18 years: diphenhydramine 25 mg orally or IV and 
hydrocortisone 50 mg IV  
- 
Pediatric patients 12 – 17 years old: diphenhydramine 0.5 mg/kg 
(max 25 mg) orally or IV and hydrocortisone 1 mg/kg (max 50 mg) 
IV 
- 
For pediatric patients, adjusted body weight will be calculated using 
pediatric standards. 
 
D-5, and -4: Fludarabine will be administrated at a dose of 40 mg/m2 IV. 
 
D-3, and -2: Fludarabine will be administrated at a dose of 40 mg/m2 IV 
followed by melphalan 50 mg/m2 IV. 
 
Fludarabine doses will be based on actual body weight/actual body surface 
area. Melphalan doses 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.  
Formula to calculate adjusted body weight for melphalan as follows: 
Adjusted BW (kg) = IBW + 0.5 (Actual body weight-IBW). 
 
 
      Day -1  
 
      Total body irradiation (TBI) 200 cGy will be administered. 
 
Day 0 –Transplant 
 
Fresh or cryopreserved bone marrow or peripheral blood progenitor cells 
(bone marrow preferred) 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. 
 

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4.4  
Supportive Care 
 
4.4.1 Prior to inotuzumab ozogamicin treatment, subjects should receive 
pretreatment medications to reduce the incidence and severity of an 
anticipated infusion syndrome characterized by fever and chills, and 
less commonly hypotension. Premedication before inotuzumab 
ozogamicin may also include antiemetics. Antiemetics that do not 
predispose patients to Torsade de Pointes, such as granisetron or 
palonosetron, are recommended. Subjects should be pretreated with 
hydrocortisone (or other corticosteroid) and antihistamine 
approximately 0.5 to 2 hours before each inotuzumab ozogamicin 
administration. In cases of infusion reactions, discontinue infusion 
and institute appropriate medical treatment as needed (e.g., 
corticosteroids, epinephrine, bronchodilators, or oxygen). Depending 
on the severity of the infusion reaction and interventions required, the 
investigator could consider restarting the infusion at a reduced rate. 
 
4.4.2 All patients will receive Graft Versus Host Disease (GvHD) prophylaxis, 
infectious disease prophylaxis, growth factors, blood and platelet transfusion and 
other supportive treatment as per departmental standard practice in patients 
receiving allogeneic transplant. In order to avoid liver toxicity related to 
antifungal agents, patients should receive an echinocandin 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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Post-transplant cyclophosphamide (PTCy) administration14 
 
PTCy will be administered on Days +3 and +4 as per dose level (50 mg/kg/dose) 
IV as per SOC guidelines unless otherwise indicated. PTCy dose is based on 
ideal body weight (IBW) unless patient’s actual weight is less than their IBW. If 
actual weight is less than IBW, then actual weight will be used.  Mesna may be 
used as per institutional guideline. 
 
Additional Standard GVHD Prophylaxis6,7,14 
 
Tacrolimus and Mycophenolate Mofetil (MMF) 
 
Tacrolimus will start at 0.015 mg/kg (then adjusted to a level 7-15 ng/mL) as a 
continuous IV infusion daily (or at an equivalent PO dose) starting Day +5, then 
continued PO for 6 months post-transplant followed by a taper, unless GVHD 
present. The dose may be modified as clinically indicated. MMF 15 mg/kg (max 
1000 mg per dose, based on actual body weight) PO or IV TID will be given from 
Day +5 until Day+35 (for 10/10 matched siblings or matched unrelated donors) or 
until Day +60 (for mismatched, unrelated, and haploidentical donors) unless 
otherwise indicated. MMF can be discontinued/tapered early if ANC<500 or 
dropping chimerism. Women of child-bearing potential will require a negative 
baseline serum/urine beta HCG test, education on the risks associated with 
MMF. 
 
Supportive Care 
 
− 
Mesna will be given per SOC guidelines on the days cyclophosphamide is 
administered. 
- 
Hydration for PTCy: 1.5 to 2 ml/kg/hr (max 150 ml/hr) starting 2 hours prior 
to each PTCy dose for a total of 10 hours each day of cyclophosphamide. 
− 
All patients will receive infectious disease prophylaxis, growth factors, 
blood and platelet transfusion and other supportive treatment as per SOC 
guidelines in patients receiving allogeneic transplant. 
− 
G-CSF (filgrastim-sndz, Zarxio) will be administered at a dose of 5 
mcg/kg/day (rounded to the nearest vial size) subcutaneously beginning 
on D+7 for all patients. G-CSF will continue until the absolute neutrophil 
count (ANC) is > 500 K/uL for 3 consecutive days. 
− 
All patients will receive ursodiol to prevent VOD at a dose of 12 mg/kg/day 
in divided doses and rounded to nearest tablet/capsule size. Max dose of 
1200 mg/day. Ursodiol should start on the first day of the conditioning 
regimen. 
 
The first 24 patients in the FM group may receive post-transplant maintenance 
intrathecal prophylaxis as per our SCT guidelines. If none develops VOD, we 
will move to the main study and add maintenance therapy in an additional 10 
patients. If any develops VOD, study enrollment into this group will terminate.  

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Patients with Ph+ ALL may receive standard of care maintenance with TKIs 
after Day 100.  
Patients with aggressive lymphoma would be treated on the same arm as ALL 
(i.e., with FM conditioning). 
 
The safety criteria of treating the first 24 patients with FM maintenance would 
include patients with ALL as well as those with aggressive lymphomas. 
 
4.5 
Post-transplant 
 
4.5.1 Criteria to receive cycle 1 of maintenance of IO Cycle 1 to be started 
anytime between day 45 and 100 after alloSCT 
 
1. 
Recovery to grade 1 or baseline non-hematologic related toxicity (including 
liver function test abnormalities, not including alopecia). 
2. 
Serum bilirubin <1.6, and AST, ALT and alkaline phosphatase <3 x ULN. IO 
dosing should be permanently discontinued for any patients with possible, 
probable or confirmed VOD or other severe liver toxicity. 
3. 
Serum creatinine <1.6 mg/dL and Creatinine clearance > 15 ml/min based 
on Cockcroft-Gault equation using IBW. 
4. 
Platelet count greater than 50,000/uL without transfusion for at least 2 days 
5. 
Absolute neutrophil count > 1,000/uL without growth factor for at least 2 
days 
6. 
QTcF </= 470 msec. 
7. 
No steroid refractory GvHD 
8. 
No active uncontrolled GvHD 
9. 
No evidence of life-threatening infection 
10. No evidence of overt relapse (MRD positive patients are still eligible) 
11. No active bleeding 
12. No autologous reconstitution (defined as absence of donor T cells on 
peripheral blood or donor chimerism) 
 
4.5.2 Criteria to receive cycle 2 of maintenance of IO Cycle 2 to be started 
28 to 100 days after start of first cycle. 
 
1.  Recovery to grade 1 or baseline non-hematologic related toxicity (including 
liver function test abnormalities, not including alopecia). 
2. Serum bilirubin <1.6, and AST, ALT and alkaline phosphatase <3 x ULN. IO 
dosing should be permanently discontinued for any patients with possible, 
probable or confirmed VOD or other severe liver toxicity. 
3. Serum creatinine <1.6 mg/dL and Creatinine clearance > 15 ml/min based on 
Cockcroft-Gault equation using IBW. 
4. Platelet count greater than 50,000/uL without transfusion for at least 2 days 
5. Absolute neutrophil count > 1,000/uL without growth factor for at least 2 days 

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6. QTcF </= 470 msec. 
7. No steroid refractory GvHD 
8. No active uncontrolled GvHD 
9. No evidence of life-threatening infection 
10. No evidence of overt relapse (MRD positive patients are still eligible) 
11. No active bleeding 
12. No autologous reconstitution (defined as absence of donor T cells 
on peripheral blood or donor chimerism) 
 
4.5.3   Dosing schema for Inotuzumab Ozogamicin 
 
Dose Level 
Day 1 Dose 
(mg/m2) 
Day 8 Dose 
(mg/m2) 
Total dose Per 
Cycle 
(mg/m2) 
0 
(Starting 
dose) 
0.3 
0.3 
0.6 
-1 
0.2 
0.2 
0.4 
 
Heme toxicity: stop current cycle and reduce total dose per cycle dose by 33% 
for next cycle if the following occurs: 
 
1. Platelet less than 15,000 for more than 4 days, not corrected by transfusion 
2. ANC less than 500 for more than 4 days, not responsive to growth factor 
 
5.0 Evaluation During Study 
Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other protocol requirements that do 
not affect the rights and safety of the patient will not be considered as deviations. Such 
variations may include laboratory assessments completed outside of schedule and 
occasional missed required research samples. 
 
5.1 
Pre-Treatment Evaluations 
 
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.  
 
Disease assessment 30 days prior to start of treatment (baseline): 
 
1. Unilateral bone marrow biopsy and aspiration. 
2. Disease specific PCR only if previously detected 
3. Cytogenetics and flow cytometry. 
4. Disease specific fluorescence in situ hybridization (FISH) only if previously 

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detected 
5. Immunophenotyping. 
6. PET for lymphoma patients, only if previously positive. 
7. Chest x-ray. 
8. Electrocardiogram and echocardiogram. 
9. CT neck, chest, abdomen and pelvis for lymphoma patients. 
10. 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. Serum pregnancy test for patients of 
child bearing potential. This is a female who has not been postmenopausal for at 
least 12 consecutive months or who has not undergone previous surgical 
sterilization. Patients of child bearing potential must agree to use birth control while 
on study. 
11. Patients with history of Gilbert's Disease: Right upper quadrant abdominal 
ultrasound. 
 
5.2 
Evaluations 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. 
Assessment and documentation of adverse events present at time of 
treatment initiation. 
 
2.  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 approximately every 3 months during 
the first year and then approximately every 6 months while the patient is on 
study. 
 
3.  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. 
 
4. 
EKG prior to each cycle of IO. When not feasible to discontinue 
concomitant drugs known to prolong QTc interval, obtain ECGs and 
electrolytes prior to the start of IO treatment and periodically as 
clinically indicated during treatment. 
 
 

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5. 
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. 
b) PCR (repeat these only if a positive history) 
c) Cytogenetics, flow cytometry. 
d) FISH (disease specific, if previously positive) 
e) CT scans of neck. chest, abdomen and pelvis for patients with 
lymphoma. 
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) Immunodeficiency panel (only repeat in pts with recurrent infections). 
 
 
5.3 
Optional Procedure 
 
Patients will have 10 cc blood sample in EDTA tube drawn 
pre-transplant and at approximately 3 months, 6 months, and 1 year after 
transplant to study minimal residual disease by next generation sequencing. 
De-identified samples from the patient's last bone marrow biopsy or archived 
lymph node biopsy will also be sent for next generation sequencing.  Patients will 
not be charged for these tests. No clinical data will be shared with Genomic 
Testing Cooperative or its representatives. De-identified samples will be sent for 
analyses to: 
 
Maher Albitar, MD 
CEO & CMO 
Genomic Testing Cooperative 
27 Technology Dr. # 100 
Irvine, CA 92618 
e-mail: malbitar@genomictestingcooperative.com 
Phone: (949) 540-9421, Mobile: (949) 275-7564 
 
Leftover samples will be discarded and will not be used for future research. 
 
6.0    Statistical Considerations 
6.1 
Overview 
 
This will be a Phase II trial of IO in patients with who are undergoing stem cell 
transplant for CD22+ hematologic disease. The primary objective is to assess 
the safety of this regimen. Secondary objectives include assessing TRM, 
relapse, OS, PFS, and acute and chronic GvHD. A maximum of 44 patients will 
be enrolled into two cohorts: 1) Lymphoma patients receiving Bendamustine, 

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Fludarabine, and Rituximab (BFR) in their conditioning regimen and 2) ALL 
patients receiving Fludarabine and Melphalan (FM) in their conditioning regimen. 
The first 24 patients in the FM cohort will be enrolled in a safety lead-in period, 
after which an additional 10 patients will be enrolled. We will enroll 10 patients in 
the Lymphoma/BFR cohort, yielding a total of 44 patients. 
 
6.2 
FM Cohort Safety 
 
The first 24 patients in the FM cohort may receive post-transplant maintenance 
intrathecal prophylaxis as per our SCT guidelines. If none develops VOD, we will 
move to the main study and add maintenance therapy in an additional 10 
patients. If any develops VOD, study enrollment into this cohort will terminate.  
 
Patients with Ph+ ALL may receive standard of care maintenance with TKIs after 
Day 100.  
 
6.3 
Safety Monitoring 
The PI will work with the study statistician to monitor safety. Safety will be 
monitored in three ways: first, by monitoring the rate of VOD separately by cohort 
(BFR or FM); second, by monitoring the rate of targeted toxicity separately by 
cohort, and third, by monitoring the rate of treatment-related mortality (TRM) 
separately by cohort. 
 
VOD 
VOD will be monitored in two ways in this trial, separately by cohorts defined by 
the conditioning regimen (BFR or FM). As noted above, in the FM cohort, if any 
of the first 24 patients develop VOD, enrollment into this cohort will stop. Second, 
if at least 3 of the first 10 patients develop VOD with IO as part of their 
conditioning regimen at a dose of 0.6 mg/m
2 for either BFR or FM, the 
conditioning dose for subsequent patients will drop to 0.3 mg/m
2. After the first 10 
patients in either cohort are treated with IO at the starting dose, accrual will stop 
temporarily until all patients have been evaluated at 45 days. If the true rate in a 
cohort of VOD is 15%, the chance that at least 3 patients out of 10 in the 
lymphoma cohort develop this condition is approximately 18%. 
 
Targeted Toxicity 
In addition, patients will be monitored separately by cohort defined by 
conditioning regimen (BFR or FM) for the development of grade 3 or higher renal, 
bladder cystitis, hepatic, cardiac, pulmonary, or neurologic toxicity through day 30 
after cycle 1 of maintenance using the Bayesian method of Thall, Simon, and 
Estey.
12 We will cease enrollment in either cohort if it is likely that this rate is 
higher than 30% and will monitor patients in groups of size 3. 
 
 
 

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Lymphoma/BFR Arm 
Enrollment into the lymphoma/BFR conditioning cohort will cease 
if: Pr [ prob(toxicity) > 0.30 | data] > 0.80 
That is, if we determine that there is a greater than 80% chance that the toxicity 
rate (as defined above) is greater than 30% in the BFR cohort, enrollment in 
that cohort will be stopped. We assume a beta (0.6, 1.4) prior distribution for the 
toxicity rate in this cohort, which has a mean of 0.3 corresponding to the 30% 
target toxicity rate. Stopping boundaries corresponding to this probability 
criterion are to terminate accrual if 
 
Stopping Boundaries for BFR Cohort 
 
Number of Patients 
Evaluated in Cohort 
Stop Enrollment in Cohort 
if this Many Patients have 
Toxicity 
3 
2-3 
6 
3-6 
9 
5-9 
10 
Always stop 
 
 
All patients who receive study treatment will be included in the monitoring rule. 
 
This stopping rule was chosen to satisfy concerns from the FDA about excess 
toxicity. The operating characteristics of this rule are shown below. 
 
Operating Characteristics for Toxicity Stopping Rule for BFR Cohort 
 
If the true 
toxicity 
rate is… 
Early Stopping 
Probability 
Achieved Sample Size 
25th, 50th, 75th percentiles 
0.1 
0.036 
10 
10 
10 
0.2 
0.150 
10 
10 
10 
0.3 
0.328 
6 
10 
10 
0.4 
0.534 
3 
6 
10 
0.5 
0.727 
3 
3 
10 
0.6 
0.873 
3 
3 
6 
 
FM Cohort 
Enrollment into the FM conditioning cohort will cease if: 
 
Pr [ prob(toxicity) > 0.30 | data] > 0.80 
 

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That is, if we determine that there is a greater than 80% chance that the toxicity 
rate (as defined above) is greater than 30% in the FM conditioning cohort, 
enrollment in that cohort will be stopped. Only the 10 patients in the treatment 
phase will be included in this monitoring rule. We assume a beta (0.6, 1.4) prior 
distribution for the toxicity rate in this cohort, which has a mean of 0.3 
corresponding to the 30% target toxicity rate.  Stopping boundaries 
corresponding to this probability criterion are to terminate accrual if: 
 
 
Number of Patients Evaluated 
in Cohort 
Stop enrollment in Cohort 
if this Many Patients have 
Toxicity 
3 
2-3 
6 
3-6 
9 
5-9 
10 
Always stop 
 
All patients who receive study treatment will be included in the monitoring rule. 
 
This stopping rule was chosen to satisfy concerns from the FDA about excess 
toxicity. The operating characteristics of this rule are shown below. 
 
Operating Characteristics for Toxicity Stopping Rule for FM Cohort 
 
If the true 
toxicity 
rate is… 
Early Stopping 
Probability 
Achieved Sample Size 
25th, 50th, 75th percentiles 
0.1 
0.036 
10 
10 
10 
0.2 
0.150 
10 
10 
10 
0.3 
0.328 
6 
10 
10 
0.4 
0.534 
3 
6 
10 
0.5 
0.727 
3 
6 
10 
0.6 
0.872 
3 
3 
6 
 
Treatment-Related Mortality 
 
Finally, patients will be monitored separately by cohort defined by conditioning 
regimen (BFR or FM) for treatment-related mortality at 1 year. Similar to the 
targeted toxicity rules above, the Bayesian method of Thall, Simon, and Estey15 
will be used in monitoring. We will cease enrollment in either cohort if it is likely 
that this rate is higher than 20%. We will monitor patients in groups of size 3. 
 
Indolent Lymphoma/BFR Cohort 
Enrollment into the lymphoma/BFR conditioning cohort will cease if: Pr [ 
prob(1-year TRM) > 0.20 | data] > 0.9 

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That is, if we determine that there is a greater than 90% chance that the 1-year 
TRM rate is greater than 20% in the BFR cohort, enrollment in that cohort will be 
stopped. We assume a beta (0.4, 1.6) prior distribution for the 1-year TRM rate in 
the BFR cohort, which has a mean of 0.20 corresponding to the 20% targeted 
maximum TRM Rate in this cohort. Stopping boundaries corresponding to this 
probability criterion are to terminate accrual if: 
 
Stopping Boundaries for TRM Rule for BFR Cohort 
 
Number of Patients Evaluated 
in Cohort 
Stop Enrollment in Cohort 
if this Many Patients 
Experience TRM 
3 
2-3 
6 
4-6 
9 
5-9 
10 
Always stop 
 
All patients who receive study treatment will be included in the TRM monitoring 
rule. 
 
This stopping rule was chosen to assure that if 15 patients are enrolled into this 
cohort, the probability of early stopping will be less than 20% if the true 1-year 
TRM rate is no more than 20%. The operating characteristics of this rule are 
shown below. 
 
Operating Characteristics for TRM Stopping Rule for BFR Cohort 
 
If the true 1-year TRM 
rate is... 
Early Stopping 
Probability 
Achieved Sample Size 
25th, 50th, 75th percentiles 
0.10 
0.038 
10 
10 
10 
0.20 
0.172 
10 
10 
10 
0.30 
0.385 
6 
10 
10 
0.40 
0.617 
3 
6 
10 
0.50 
0.809 
3 
3 
  9 
 
FM Cohort 
 
Enrollment into the FM conditioning cohort will cease if: 
 
Pr [ prob(1-year TRM) > 0.20 | data] > 0.95 
 
That is, if we determine that there is a greater than 95% chance that the 1-year 
TRM rate is greater than 20% in the FM conditioning cohort, enrollment in that 
cohort will be stopped. We assume a beta (0.4, 1.6) prior distribution for the 1-
year rate in this cohort, which has a mean of 0.20 corresponding to the 20% 

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maximum 1-year TRM rate. Stopping boundaries corresponding to this 
probability criterion are to terminate accrual if: 
 
 
Number of 
Patients 
Evaluated in 
Cohort 
Stop Enrollment in 
Cohort if this Many 
Patients Experience 
TRM 
3 
3 
6 
4-6 
9 
5-9 
12 
6-12 
15 
7-15 
18 
7-18 
21 
8-21 
24 
9-24 
27 
10-27 
30 
11-30 
33 
11-33 
34 
Always 
stop 
 
All patients who receive study treatment will be included in the monitoring rule. 
 
This stopping rule was chosen to assure that if 34 patients are enrolled into this 
cohort, the probability of early stopping will be approximately 10% if the true 1-
year TRM rate in the FM cohort is no more than 20%. The operating 
characteristics of this rule are shown below. 
 
Operating Characteristics for TRM Stopping Rule for FM Cohort 
 
If the true 1-year TRM 
rate is... 
Early Stopping 
Probability 
Achieved Sample Size 
25th, 50th, 75th percentiles 
0.1 
0.004 
34 
34 
34 
0.2 
0.103 
34 
34 
34 
0.3 
0.490 
18 
34 
34 
0.4 
0.868 
  9 
18 
24 
0.5 
0.987 
 6 
9 
15 
 
Each of the monitoring rules will be implemented by the clinic with assistance from 
the study statistician as necessary. 
 
6.4 
Analysis Plan 
 
All analyses will be performed separately by cohorts and by GvHD prophylaxis 

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groups. We understand that with small numbers of patients in some groups, 
conclusions will be limited. Analyses of the FM cohort will be performed separately 
by phase (24 lead-in phase/10 full treatment phase) and by GvHD prophylaxis 
group, but some analyses may be performed on the full cohort of 34. 
 
At the end of the trial, the rates of severe toxicity will be summarized separately 
for each cohort and group, and analyses will be performed to assess the 
relationship between each toxicity endpoint and covariates of interest using 
logistic regression. The cumulative incidence of TRM will be assessed in a 
competing risks framework with the competing risk of disease relapse. 
Regression models will be fit to assess the relationship between each and 
covariates of interest using the method of Fine and Gray.
16 The distribution of OS 
and PFS will be assessed using the Kaplan-Meier method, and distributions will 
be compared using the log-rank test. Cox proportional hazards regression models 
will be fit to assess the relationship between OS and PFS and covariates of 
interest. The cumulative incidence of acute GvHD and chronic GvHD will be 
assessed in a competing risks framework with competing risks of death without 
relapse and disease relapse. The method of Fine and Gray will be used to assess 
the association between GvHD and covariates of interest. 
 
6.5 
Safety Monitoring Plan 
 
The investigator will submit toxicity/TRM summaries to Clinical Trials Safety team. 
These will be submitted to INDSummariesReview@mdanderson.org as follows: 
 
Targeted Toxicity Monitoring 
• 
BFR cohort and FM with maintenance cohort: A toxicity summary must be 
submitted after every 3 subjects per cohort complete the first cycle (30 days) of 
maintenance therapy or discontinue maintenance therapy due to toxicity, 
whichever occurs first.  
 
Treatment Related Mortality (TRM) Monitoring: 
• 
BFR cohort and FM (with or without maintenance IO) cohort: A TRM summary 
should be submitted after every 3 subjects per cohort complete 1 year post-
transplant or experience treatment related mortality, whichever occurs first.  
 
VOD Monitoring:  
• 
FM cohort (with and without maintenance IO): If any of the first 24 patients 
develop VOD within 45 days of initial conditioning dose of IO on Day -13, 
enrollment to that cohort must be stopped and Clinical Trial Safety must be 
notified immediately via email at INDSummariesReview@mdanderson.org.  
• 
BFR cohort: If 3 patients develop VOD, enrollment to that cohort must be 
stopped and Clinical Trial Safety must be notified immediately via email at 
INDSummariesReview@mdanderson.org.  
 
 

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7.0  
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. Investigator judgment when the well being and best interest of the patient 
is compromised. 
5.    Three years after the last dose of inotuzumab ozogamicin. 
 
8.0  
 Adverse Events and Reporting Requirements 
 
       Adverse event definition: 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting 
study drug. Abnormal laboratory values or test results constitute adverse events only if 
they induce clinical signs or symptoms, are considered clinically significant, or require 
therapy. 
 
8.1 
Adverse Events and Data Collection 
 
8.1.1 For the purpose of this study, the investigational component of the treatment plan 
is the addition of Inotuzumab Ozogamicin pre- and post- allogeneic 
transplantation in patients with CD22-positive hematological malignancies. 
Therefore, serious and unexpected adverse events occurring up to 30 days of 
the intervention, as defined below, will be reported according to MDACC policy 
and procedures below. The end of active treatment is the completion of two 
cycles of maintenance therapy post-transplant. Serious adverse events must be 
followed until clinical recovery and laboratory test have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution 
of the event. 
 
8.1.2    Common Terminology Criteria Adverse Events (CTCAE) – a descriptive 
terminology developed by the National Cancer Institute (NCI) for use in reporting 
adverse events. The CTCAE includes a grading (severity) scale for each adverse 
event term. A copy of the current CTCAE guidelines (Version 5.0) is located at 
http://ctep.cancer.gov/reporting/. 
 
Grade – Severity of the adverse event. Grades were developed using the 
following guidelines: 
 
Grade 0 – No adverse event or within normal limits 
1 – Mild adverse event 

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2 – Moderate adverse event 
3 – Severe adverse event 
4 – Life-threatening or disabling adverse event 
5 – Fatal adverse event 
 
8.1.3 
Time for AE Collection 
 
Adverse events will be collected for 45 post first dose of IO infused, and for 30 
days post last cycle of IO maintenance post-transplant 
 
8.1.4 Adverse Event Reporting 
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events, and assigning attribution for each 
event on all subjects enrolled on this study. 
 
 
8.1.5 Data collection 
 
Collection of adverse events 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. 
 
Adverse events will be documented in the patient's electronic medical record. 
Events not to be considered adverse events in this study are those related to 
original disease or expected in the post-allogeneic transplant period. 
 
Isolated changes in laboratory parameters such as electrolyte, magnesium and 
metabolic imbalances, uric acid changes, elevations of GPT, GOT, LDH and 

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alkaline phosphatase will not be collected. 
 
Adverse events and protocol specific data will be entered into BMTWeb. 
BMTWeb will be used as the electronic case report form for this protocol. 
 
8.1.6 Concomitant medications 
 
Patients treated on this protocol will require supportive care treatment 
(concomitant medications). These medications are considered standard of care 
and have no scientific contribution to the protocol; therefore no data will be 
captured on various medications needed or their side effects. All antiviral 
therapy will be captured in the medical record. 
 
 
8.2 
Serious Adverse Event Reporting (SAE) Reporting 
 
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: 
 
ꞏDeath 
ꞏA 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. 
ꞏInpatient hospitalization or prolongation of existing hospitalization 
ꞏA persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
ꞏA 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 

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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 Serious 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. 
· 
MD Anderson’s Clinical Trial Management System, OnCore, 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 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. 
 
8.2.1   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. 
 
8.2.2 Reporting to Pfizer  
 
Reporting of Serious Adverse Events. Within twenty four 
(24) hours of first awareness of the event (immediately if the event is fatal or 
life-threatening), Principal Investigator will report to Pfizer by facsimile certain 
Serious Adverse Events (“SAEs,” as defined below) for which reporting is 
required under this provision (as described below). 
 
SAE Definition. An SAE is any adverse event at any time, without regard to 
causality, that is life-threatening (i.e., causes an immediate risk of death) or that 
results in any of the following outcomes: death; in-patient hospitalization or 
prolongation of existing hospitalization; persistent or significant disability or 
incapacity (i.e., substantial disruption of the ability to conduct normal life 

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functions); or a congenital anomaly or birth defect. Any other medical event 
that, in the medical judgment of the Principal Investigator, may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above is also considered an SAE. A planned medical or 
surgical procedure is not, in itself, an SAE. 
 
Subset of SAEs Reportable for this Study. Because the Pfizer Product used in 
this Study is a mature marketed product with a well-established safety profile, 
only SAEs that fit into any of the following categories need to be reported to 
Pfizer: (1) a death, regardless of whether it is considered related to treatment 
with the Pfizer Product, (2) a non-fatal SAE that occurs during the reporting 
period and that is assessed by the Principal Investigator as both related to 
treatment with the Pfizer Product and unexpected for that Product, (3) an SAE 
assessed by the Principal Investigator as related to the Pfizer Product that occurs 
after the SAE reporting period, or (4) an otherwise reportable event.  An event 
should be considered “related” to the Pfizer Product if a relationship is at least a 
reasonable possibility, and “unexpectedness” should be based upon a single 
safety reference document identified by the Principal Investigator and 
documented in association with the study. 
 
Exposure During Pregnancy, Exposure During Lactation, Occupational Exposure, 
and Lack Of Effect. Even though there may not be an associated SAE, exposure 
to the Pfizer Product during pregnancy, exposure to the Pfizer Product during 
lactation, and occupational exposure to the Pfizer Product are reportable, and 
lack of effect of the Pfizer Product may also be reportable. These requirements 
are further explained in the training material provided by Pfizer (see 
Pfizer-Provided Training, below). As used in this Agreement, the term SAE will 
be understood to include exposure during pregnancy, exposure during lactation, 
occupational exposure, and reportable instances of lack of effect. 
 
9.0    Background Drug Information 
9.1 
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
TM (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 

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T
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 
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. 
 
See package insert for additional information. 
 
 
 
 

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9.2 
Melphalan 
 
Description: Melphalan is an alkylating agent with cell cycle nonspecific cytotoxic 
effects on tumor cells. It inhibits DNA replication and transcription of RNA 
ultimately disrupting nucleic acid function. 
 
Dosing Information: The usual dose for conditioning in stem cell transplantation 
is 100-200 mg/m2/day intravenously. 
 
Administration: Administer according to institutional standards. 
Adverse Reactions: Hematologic: The most common adverse effect is bone 
marrow suppression. Leukopenia and thrombocytopenia are the major dose 
limiting side effects.  GI toxicity is frequent with higher doses and includes 
nausea and vomiting, stomatitis, abdominal cramping and diarrhea. Other 
adverse effects: Pulmonary fibrosis and infiltrates, amenorrhea, alopecia, sterility, 
and inappropriate ADH secretion. Hypersensitivity reactions: Acute 
hypersensitivity reactions have been reported including urticaria, pruritus, edema, 
tachycardia, bronchospasm and anaphylaxis (reported in 2.4% of patients 
receiving melphalan for myeloma). These patients respond to antihistamine and 
corticosteroid therapy. 
 
Special Precautions: None 
 
9.3 
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. 

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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. 
 
 
9.4 
Inotuzumab Ozogamicin 
 
Description: Inotuzumab Ozogamicin 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 0.9 mg. 
 
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 
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. 
 

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Fatigue and asthenia are common and sometimes severe. Chills, headache, 
pyrexia, and epistaxis have also been reported. 
 
Intracranial bleed resulting in death was reported in one patient with COVID-
19 as possibly related to inotuzumab ozogamicin in September, 2020. 
 
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 investigator’s brochure (Appendix G). 
 
 
9.5 
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.  A biosimilar of 
rituximab may be used. 
 
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 
from direct sunlight. Do not freeze or shake. 
 
See package insert for additional information. 
 
9.6   Cyclophosphamide 
 
Cyclophosphamide is an alkylating agent. 
 
Mechanism of Action: Cyclophosphamide prevents cell division by cross-
linking DNA strands and decreasing DNA synthesis. It is cell cycle phase 
non-specific. Cyclophosphamide also possesses potent 

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immunosuppressive properties. It is a pro-drug metabolized by the liver to 
active metabolites. 
 
Known Side Effects: Hematologic: Leukopenia, anemia, alopecia. GI: 
Nausea, vomiting, increased AST, ALT, mucositis, and diarrhea. Neurologic: 
Headache, dizziness. Cardiovascular: Cardiomyopathy, non-specific ST 
changes on EKG. Please refer to the package insert for a complete listing of 
all toxicities. 
 
9.7    MESNA  
 
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced 
by the oxazophosphorines (cyclophosphamide and ifosfamide). It has no 
intrinsic cytotoxicity and no antagonistic effects on chemotherapy. 
 
Mechanism of Action: Mesna binds with acrolein, the urotoxic metabolite produced 
by the oxazophosphorines, to produce a non-toxic thioether and slows the rate of 
acrolein formation by combining with 4-hydroxy metabolites of oxazophosphorines. 
 
Known Side Effects: At the doses used for uroprotection, mesna is virtually 
non-toxic. However, adverse effects which may be attributable to mesna 
include nausea and vomiting, diarrhea, abdominal pain, altered taste, rash, 
urticaria, headache, joint or limb pain, hypotension and fatigue. Please 
refer to the package insert for a complete listing of all toxicities. 
 
10.0  Data Security/Confidentiality 
 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigator, their staff, the safety and oversight monitor(s), and the sponsor(s) 
and funding agency. This confidentiality is extended to the data being collected as 
part of this study. Data that could be used to identify a specific study participant 
will be held in strict confidence within the research team. No personally identifiable 
information from the study will be released to any unauthorized third party without 
prior written approval of the sponsor/funding agency, as applicable. 
 
All research activities will be conducted in as private a setting as possible. 
 
10.1   Access to Study Records 
 
Study records may be accessed by IRB approved study personnel, or authorized 
inspectors. The study monitor, other authorized representatives of the sponsor or 
funding agency, representatives of the Institutional Review Board (IRB), regulatory 
agencies or representatives from companies or organizations supplying the 
product, may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will 

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permit access to such records. 
 
10.2   Methods of Storage of Study Records 
 
All data collected from MD Anderson Cancer Center (MDACC) sources will be 
maintained on a password protected server compliant with HIPAA. Study staff will 
have role based restricted access to directories and files on the server, according 
to project responsibilities. Only those with data entry permissions can add records. 
The PI or a delegate will review the conditions under which data will be released 
to recipient- investigators. Each application for use will need IRB approval and 
consents, if appropriate. The level of identifiability will determine the process for 
review and approval as well as the way information is shared. 
 
Any study data or records maintained in paper documents will be stored in the 
offices of the PI or other delegated study staff, in a locked cabinet or other 
comparable controlled environment, and will be accessible only to authorized 
study team members or authorized inspectors.   
 
10.3  Duration of Study Record Storage 
 
The study participant’s contact information will be securely stored at each clinical 
site for internal use during the study. At the end of the study, all records will 
continue to be kept in a secure location for as long a period as dictated by the 
reviewing IRB, Institutional policies, or sponsor/funding agency requirements. 
 
10.4   Sharing of Study Records 
 
There are no plans to share study data with entities external to MD Anderson 
Cancer Center, aside from authorized inspectors as applicable (i.e. authorized 
representatives of the sponsor or funding agency, representatives of the 
Institutional Review Board (IRB), regulatory agencies or representatives from 
companies or organizations supplying the product).  If data will be shared, IRB 
approval will be sought, and applicable inter-institutional agreements executed, 
prior to data sharing.   
 
10.5   Consent Process and Documentation 
 
Please select one of the following: 
 
☒   This protocol will follow the SOP 04_Informed Consent Process. SOP 04 has 
been read by the research staff and investigators. 
 
☐   This protocol will follow SOP 04_Informed Consent Process with the following 
changes:  SOP 04 has been read by the research staff and investigators. 
 
 

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Informed consent may be obtained using the following methods: (check all that 
apply): 
 
☒   Remote consent 
 
☒   In-person consent 
 
 
 
 
 

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11.0  
References 
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inotuzumab-ozogamicin in hematological malignancies. Mol Immunol. 2015; 67: 
107–16. 
 
2. Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse event profile of 
inotuzumab ozogamicin in adult patients with relapsed or refractory acute 
lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-
VATE study. Lancet Haematol 2017; 4: e387-398. 
 
3. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-
CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic 
leukaemia: a phase 2 study. Lancet Oncol 2012; 13(4): 403-411. 
 
4. O’Brien MM, Ji L, Shah NN, et al. A phase 2 trial of Inotuzumab Ozogamicin (InO) 
in children and young adults with relapsed or refractory (R/R) CD22+ B-acute 
lymphoblastic leukemia (B-ALL): Results from Children's Oncology Group Protocol 
AALL1621. Blood 2019; 134 (Suppl1): 741. 
 
5. Bhojwani D, Sposto R, Shah NN, et al. Inotuzumab ozogamicin in pediatric patients 
with relapsed/refractory acute lymphoblastic leukemia. Leukemia 2019;33(4):884-892. 
 
6. Khouri IF, Gulbis AM, Milton DR, et al. Safety of addition of inotuzumab ozogamicin 
(CMC 544) to bendamustine, fludarabine, and rituximab (BFR) allogeneic 
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7. Khouri IF, Wei W, Korbling M, et al. BFR (bendamustine, fludarabine, and rituximab) 
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myelosuppression and GVHD. Blood. 2014;124:2306-2312. 
 
8. Stein AS, Palmer JM, O’Donnell MR, et al. Reduced-intensity conditioning followed 
by peripheral blood stem cell transplantation for adult patients with high-risk acute 
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9. Kawamura K, Kako S, Mizuta S, et al. Comparison of conditioning with 
fludarabine/busulfan and fludarabine/melphalan in allogeneic transplantation 
recipients 50 years or older. Biol Blood Marrow Transplant. 2017;23:2079-2087. 
 
10. Bachanova V, Marks DI, Zhang M-J, et al. Ph+ ALL patients in first complete 
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11. Jabbour E, Pui C-H, Kantarjian H. Progress and innovations in the management of 
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13. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a 
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14. Brammer JE, Khouri K, and Ciurea SO. Outcomes of Haploidentical Stem 
Cell Transplantation for Lymphoma with Melphalan-Based Conditioning,  
Biology of Blood and Marrow Transplantation.  2016 Mar;22(3):493-8. 
 
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16. Bolanos-Meade J, Hamadani M, and Holton GD.  Post-Transplantation 
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