Phase II Study of Low Dose Inotuzumab Ozogamicin in Patients With Relapsed and Refractory CD22 Positive Acute Lymphocytic Leukemia
Phase: PHASE2
Conditions: CD22 Positive, Recurrent Acute Lymphoblastic Leukemia, Refractory Acute Lymphoblastic Leukemia
Sponsor: M.D. Anderson Cancer Center

Protocol Page
Phase II Study of Low Dose Inotuzumab Ozogamicin in Patients with Relapsed and 
Refractory CD22 Positive Acute Lymphocytic Leukemia
2015-0870
Core Protocol Information
Short Title 
Low-Dose INO in R-R ALL
Study Chair: 
Elias Jabbour
Additional Contact:
Lori L. Smith
Vicky H. Zoeller
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-792-4764
Unit:
428
Study Manager:
Carissa G. Jurisprudencia
Full Title: 
Phase II Study of Low Dose Inotuzumab Ozogamicin in Patients 
with Relapsed and Refractory CD22 Positive Acute Lymphocytic 
Leukemia
Public Description:
NCT #:
NCT03094611
NCI CTRP Registration ID:Not Registered
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 01/24/2019
Version:
10
Document Status:
Saved as "Final"
Submitted by:
Lori L. Smith--11/12/2018 11:38:35 AM
OPR Action:
Accepted by:  Amber M. Cumpian -- 11/19/2018 6:28:54 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

Protocol Body
 
  
 

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Phase II Study of Low Dose Inotuzumab Ozogamicin in  
Patients with Relapsed and Refractory CD22 Positive Acute 
Lymphocytic Leukemia 
 
 
1.0 Objectives 
 
1.1 Primary Objectives: To evaluate the objective response rate of low dose of 
inotuzumab ozogamicin as measured by the hematologic remission rate (CR + 
CRp + CRi) in patients in first, second or later salvage setting.  
 
1.2 Secondary Objectives: To evaluate the overall safety profile and the efficacy; 
the efficacy is measured by the hematologic response rate (CR + CRi + PR), 
durations of response (DoR) and remission (DoR1), progression free survival 
(PFS), and overall survival (OS)  
 
2.0 Patient Eligibility 
 
Inclusion Criteria: 
1. Patients at least 12 years of age. 
2. Patients with a diagnosis of CD22-positive ALL based on local 
immunophenotying and histopathology) who have: 
a. Refractory disease, defined as disease progression or no response 
while receiving their most recent prior anti-cancer therapy. 
b. Relapsed disease, defined as response to their most recent prior 
anti-cancer therapy with subsequent relapse. 
3. Performance status of 0 to 3. 
4. Adequate renal function including serum creatinine ≤2 x upper limit of 
normal (ULN) or estimated creatinine clearance ≥15 mL/min as calculated 
using the method standard for the institution. 
5. Adequate liver function, including total serum bilirubin ≤1.5 x ULN unless 
the patient has documented Gilbert syndrome, and aspartate and alanine 
aminotransferase (AST or ALT) ≤2.5 x ULN.  If organ function 
abnormalities are considered due to tumor, total serum bilirubin must be 
≤2 x ULN 
6. No active or co-existing malignancy requiring chemotherapy or radiation 
within 6 months. 
7. Female subjects of childbearing potential should be willing to use effective 
methods birth control or be surgically sterile, or abstain from heterosexual 
activity for the course of the study.  Subjects of childbearing potential are 
those who have not been surgically sterilized or have not been free from 
menses for > 1 year. Effective methods of birth control include birth control 
pills or injections, intrauterine devices (IUDs), or double-barrier methods 
(for example, a condom in combination with spermicide). 

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8. Male subjects should agree to use an effective method of contraception 
starting with the first dose of study therapy through the duration of 
treatment.   
 
Exclusion criteria: 
1. Pregnant or nursing women  
2. Known to be HIV+ 
3. Ph+ ALL 
4. Active and uncontrolled disease/infection as judged by the treating 
physician 
5. Unable or unwilling to sign the consent form 
6. Prior allogeneic stem cell transplantation (ASCT) or other anti-CD22 
immunotherapy within ≤4 months before first dose of study treatment. 
7. Known CNS or extramedullary disease unless approved by the PI.  
8. Monoclonal antibodies therapy within 2 weeks before study entry 
9. Radiotherapy and cancer chemotherapy (except for intrathecal 
chemotherapy, hydroxyurea, and cytarabine. Cytarabine and hydroxyurea 
are allowed to be used emergently in case of leukocytosis) or any 
investigational drug within 2 weeks before study entry. 
10. Evidence or history of veno-occlusive disease (VOD) or sinusoidal 
obstruction syndrome (SOS) 
 
3.0 Treatment Plan 
 
3.1 This is an open-label, single-arm, phase II clinical study.  
 
3.2 All patients will be registered through CORe 
 
3.3 Patients will receive inotuzumab ozogamicin at the dose of 0.8 mg/m2 on Day 
1 (+/- 3 days), and 0.5 mg/m2 on Days 8 and 15 (+/- 3 days) of cycle 1. 
Subsequent cycles will consist of inotuzumab ozogamicin at the dose of 0.6 
mg/m2 on Day 1 (+/- 3 days) and 0.3 mg/m2 on Day 8 (+/- 3 days). Patients will 
have a bone marrow aspiration performed on Day 14 and Day 21 (+/- 3 days). If 
marrow aspiration shows no disease, Cycle 2 could resume on Day 28 (+/-7 
days) at the dose level recommended in section 8.1.6. If persistence disease 
(defined by bone marrow blasts >5%), Cycle 2 would resume as early as Day 22 
(+/- 7 days). Responding (CR, CRi, CRp) patients could receive up to 5 additional 
cycles. A maximum of 6 cycles will be administered.      
  
3.4 In patients with an allogeneic donor, an allogeneic stem cell transplantation 
will be offered at any time after the first cycle of treatment with inotuzumab 
ozogamicin. Cycles are to be repeated every 3 to 4 weeks. 
 
3.5 Responders will be permitted to receive up to five additional consolidation 
cycles of treatment with inotuzumab ozogamicin.  
 

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3.6 CSF prophylaxis consisting of an intrathecal regimen according to 
institutional guidelines during and after inotuzumab treatment will be left to the 
investigator’s discretion. 
 
3.7 Patients who relapse after achieving a response for at least 3 months can be 
retreatedfor up to 6 additional cycles.   
 
4.0 Pretreatment evaluation 
Procedure 
Comments 
Schedule 
Informed Consent 
Obtain standard informed 
consent approved by IRB 
Within 21 days before 
therapy 
Medical History 
History of present illness, known 
allergies, prior cancer history as 
far as traceable including ALL 
regimens and drugs uses, and 
past medical/ surgical history as 
far as relevant. 
Within 14 days of therapy 
Physical Examination 
Vital signs (temperature, heart 
rate, respiratory rate, blood 
pressure) and performance 
status. 
Within 14 days of therapy 
Concomitant Medications 
Document concomitant 
medications in the medical 
record 
Within 14 days of therapy 
Hematology 
CBC with differential and platelet 
count 
Within 14 days of therapy 
Biochemistry 
at least creatinine, total bilirubin, 
uric acid, LDH, SGPT or SGOT 
Within 14 days of therapy 
Bone marrow 
Aspirate and/or biopsy with flow 
cytometry for confirmation of 
diagnosis; a sample will be 
stored for PCR assessment 
Within 21 days of therapy 
Pregnancy test 
Serum or urine, if female and 
child-bearing potential only 
Within 14 days of therapy 
Imaging studies 
Chest X-ray and/or PET/CT as 
clinically indicated 
Within 14 days of therapy 
 
5.0 Evaluation During Study 
Procedure 
Comments 
Schedule 
Hematology 
CBC with differential and 
platelet count 
Weekly during cycles 1 to 6 
Biochemistry 
at least creatinine, total 
bilirubin, SGPT or SGOT 
 
Cycle 1, prior to study drug infusion  
Cycle 2-6, prior to each study drug infusion 
and/or at the discretion of the treating 
physician. 
Physical 
Examination 
Focused physical examination 
Prior to each treatment cycle 
Bone marrow 
Aspirate and/or biopsy (MRD)  
by flow multicolor cytometry 
and by polymerase chain 
reaction (PCR). 
On day 14, 21 +/- 3 days of the first cycle, 
then every 2-3 cycles. 

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5.1 
Follow-up 
 
Patients will be followed up to 30 days after completion of treatment.  
Afterward they may be enrolled and followed for survival under protocol 
DR09-0223. 
 
6.0 Criteria for Response 
 
Complete remission (CR): 
Normalization of the peripheral blood and bone marrow with 5% or less blasts 
with a granulocyte count of 1 x 109/L or above and a platelet count of 100 x 109/L 
or above and absence of extramedullary disease. 
 
Complete remission without platelet recovery (CRp): 
 As above except platelets < 100x109/L  
 
Complete remission with incomplete count recovery (CRi):  
CR without recovery of neutrophils or platelet counts  
 
Partial response (PR): 
As above, except for the presence of 6-25% marrow blasts. 
MRD negativity: 
 
MRD levels will be continuously assessed during induction and consolidation 
therapy by 6-color multiparameter flow. MRD negativity will be defined by a value 
of no more than 10−4 and confirmed on a second bone marrow aspiration/biopsy 
performed after a subsequent cycle.  
 
No response (NR): 
 
Patients will be considered non-responders if no response is achieved after 2 
cycles.  
 
7.0 Background 
 
7.1 Salvage therapy in acute lymphoblastic leukemia (ALL).  
 
Despite an exceptionally high rate of initial CR, many adults with ALL will relapse. 
Current strategies to induce a second remission translating into long-term 
survival are lacking. Cytotoxic chemotherapy results in modest CR rates of 30-
40% in first salvage and 10-20% in later salvages. Few patients can be bridged 
to allo-SCT, 5-10% in some studies but as high as 30-40% in the German 
trials1,2. This bridging to allo-SCT offers a chance of long term remissions and 
cures (<20-30%). One of the most exciting groups of compounds under 
investigation in relapsed refractory (R/R) ALL are monoclonal antibodies 

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targeting CD19 and CD22. Of these antibodies, blinatumomab and inotuzumab 
ozogamicin are in the most advanced investigational phases (Table 1). 
Blinatumomab was granted FDA approval for the treatment of R/R ALL in 
December 2014. Furthermore, inotuzumab was found to be superior to best 
available therapy in a randomized trial in patients with R/R ALL and was granted 
FDA approval for the treatment of R/R B-cell precursor ALL in August 2017.  
 
The randomized trial confirmed the findings of the initial phase II studies.  
Inotuzumab induces responses in 80% of the patients with a median survival of 
7.7 months.  The rate of VOD was 10%.  The aim of this study is to reduce the 
rate of VOD without minimizing efficacy. 
 
Table 1. Monoclonal antibodies in relapsed/refractory ALL 
 
N (%) 
 
Blinatumomab 
Inotuzumab 
 
Parameter 
Pivotal 
Study, 
n=36 
Confirmatory 
Study, 
n=189 
Single dose 
n=49 
Weekly 
n=40 
Overall Response 
25 (69) 
81 (43) 
28 (57) 
24 (60) 
Salvage Status 
 
 
 
 
Salvage 1 
11 (31) 
38 (20) 
13 (27) 
16 (40) 
Salvage 2+ 
10 (28) 
151 (80) 
36 (73) 
24 (60) 
Median survival 
(months) 
9.8 
6.1 
5.0 
9.5 
 
7.2 Inotuzumab ozogamycin 
 
7.2.1 Description 
 
Inotuzumab ozogamicin (INO) consists of a semisynthetic derivative of N-acetyl 
ɣ-calicheamicin 1, 2-dimethyl hydrazine dichloride (NAc ɣ-calicheamicin DMH), a 
potent DNA-binding cytotoxic antibiotic, attached to a humanized monoclonal 
IgG4 antibody, G544, directed against the CD22 antigen present on B cells in all 
patients with mature B-ALL and most patients (>90%) with precursor B-ALL3.  
Anti-CD22 monoclonal antibody without conjugated cytotoxic drug has shown to 
have no anti-tumor activity in preclinical models; instead conjugation with 
cytotoxic agent provides potent dose-depending cellular damage4. This is likely 
because IgG4 antibodies poorly fix complement, therefore cannot cause 
apoptosis via complement-mediated and antibody-dependent cytotoxicity5. 
Calicheamicin is natural product of Micromonospora echinospora species, and 
considered to be intolerantly toxic when not bound to the antibody6.  
 
Calicheamicin is linked to the antibody through 4-(4-acetylphenoxy) butanoic acid 
(acetyl butyrate) which provides stability in physiologic pH and successful 

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calicheamicin release inside the acidic environment of the lysosomes7. INO binds 
to CD22 receptor on the surface of B-cell, and the CD22 receptor-INO complex is 
internalized forming an endosome.  Subsequently, CD22 receptor-INO complex 
containing endosome fuses with lysosomes. This is followed by intracellular 
release of calicheamicin. Calicheamicin binds to the minor groove of DNA in a 
sequence specific manner, and breaks double-stranded DNA, resulting in cell 
death.   
 
7.2.2 Pharmacodynamics 
 
Treatment with INO has been shown to provide greater therapeutic benefit, as 
single agent, compared to CVP or CHOP in B-cell NHL xenografts8. INO also 
showed anti-tumor activity in CVP- and CHOP-refractory tumors; however 
duration of the INO effect was not as sustained as it was in treatment naïve B-
cell NHL xenografts.  This observation shows that INO treatment may regress 
tumor growth in chemotherapy refractory cases, but eventually, some malignant 
B-cells can escape the anti-tumor activity and re-grow. Gemtuzumab Ozogamicin 
(GO), another antibody-drug conjugate of NAc ɣ-calicheamicin DMH, is directed 
against CD33 antigen, and has been used in treatment acute myeloid leukemia 
(AML)9. However, drug resistance had negative impact on clinical outcome of 
patients treated with GO10. It is proposed that the drug resistance was associated 
with P-glycoprotein (P-gp) expression. P-gp is a membrane glycoprotein that 
actively pumps cytotoxic agents out of the cells and decreases intracellular 
concentration the drug11 [Takeshita et al., 2005]. As with GO, INO was also found 
to be effected with the same resistance mechanism. In a study, INO had no 
effect on CD22-positive malignant cell lines with P-gp expression compared to 
parental cells11. In clinical samples, the toxic effect of the INO was inversely 
related to the amount of P-gp (p=0.003). In contrast, the cytotoxicity of INO 
positively correlated with the amount of CD22 (p=0.010). 
 
INO is a CD22-targated cytotoxic chemotherapy agent without any effector 
capabilities; in contrast rituximab is a CD20-targated immunotherapeutic agent 
with the capability of complement-mediated and antibody-dependent cellular 
toxicity. Combination of INO and rituximab has been tested in vitro setting, and 
showed increased cytotoxicity12. Anti-tumor efficacy of INO and rituximab 
combination has also been tested in B-cell NHL preclinical models, and 
demonstrated superior activity with the combination13. In a phase 2 clinical trial 
evaluating the efficacy of INO in relapsed and refractory ALL patients, rituximab 
was added to the patients with stable or progressive disease after two courses of 
INO. Addition of rituximab in nine patients with CD20 positive ALL did not provide 
any additional benefit6. Nevertheless, it was a single-arm study with a small 
number of patients. Efficacy of this combination in ALL patients needs to be 
evaluated in larger clinical trials.  
 
7.2.3 Pharmacokinetics 
 

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Maximum tolerated dose (MTD) was determined as 1.8 mg/m2 by a first-in-
human clinical trial evaluating the safety of INO in 79 relapsed and refractory 
NHL patients5. Most patients had follicular lymphoma (FL) (44%) and diffuse 
large B-cell lymphoma (DLBCL) (44%), and 61% of the patients had received ≥ 4 
prior chemotherapies. Following dose escalation schedules were evaluated: 0.4, 
0.8, 1.34, 1.8 and 2.4 mg/m2 intravenously (as a 1-hour infusion) once every 3 
weeks in MTD lead-in cohort (36 patients). Escalation stop criteria were met as 2 
of 6 cohort patients had dose limiting toxicities (one grade 4 neutropenia, one 
grade 4 thrombocytopenia) at 2.4 mg/m2. Thus, 1.8 mg/m2 was established as 
MTD. Reversible thrombocytopenia is one of the main (90%) side effects of INO, 
and it led to a number of treatment delays. Therefore, declared MTD was 
evaluated in once every 4 weeks schedule to allow platelet recovery. Dose 
limiting toxicity was not observed in the six-patient cohort of 1.8 mg/m2 once 
every 4 weeks. As a result, this regimen was used in extended MTD cohort (43 
patients). At the end of treatment, objective response rate was 39% among 79 
enrolled patients. Administration of INO with a weekly dosing schedule (same 
total dose of 1.8 mg/m2 per cycle) compared to single-dose schedule allowed 
similar response rates and less toxicity in multiply relapsed B-ALL patients14. 
The data showed that inotuzumab ozogamycin disposition was non-linear with 
number of dose or increasing dose. Non-linearity is seen commonly with other 
antibodies as well15. Non-linear pharmacokinetics of monoclonal antibodies is 
due to target-mediated drug disposition, in which elimination and distribution are 
affected by the antibody and target cell interaction16.  Anti-CD22 antibody and 
total calicheamicin followed similar elimination trend, and the free calicheamicin 
concentration remained less than 50 pg/mL overtime, suggesting that the acetyl 
butyrate linker is noticeably stable in plasma5. 
 
7.3 Inotuzumab in R/R ALL 
 
7.3.1 Single agent inotuzumab ozogamicin 
 
Initial studies in patients with lymphoma established an MTD of 1.8 mg/m2 IV 
given every 3 to 4 weeks, with reversible thrombocytopenia emerging as a 
frequent adverse effect.5 This led to a single institution phase II study in patients 
with relapsed-refractory ALL6. The starting dose was 1.3 mg/m2 IV every 3 to 4 
weeks for the first three patients; later patients received 1.8 mg/m2.  
 
Acetaminophen, diphenhydramine, and hydrocortisone were administered to 
prevent infusion reactions. Forty-nine patients were treated, 73% of whom 
received inotuzumab for Salvage 2 or later. The ORR was 57%, and the median 
survival was 5.1 months (Table 2). Nearly half of the patients treated with 
inotuzumab were able to proceed to ASCT (n = 22), including four patients who 
were receiving their second ASCT. Survival was similar whether patients 
underwent subsequent ASCT or not. 
 

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To optimize the benefit:risk of inotuzumab, a weekly dosing regimen was 
evaluated based on preclinical studies indicating that toxicity might be minimized 
while maintaining efficacy (Table 2).14    Inotuzumab was given at 0.8 mg/m2 on 
Day 1, and 0.5 mg/m2 on Days 8 and 15, every 3-4 weeks. This is the same 
cumulative dose per course compared with single infusion inotuzumab every 
three to four weeks. With the weekly regimen, ORR was similar to the single-
dose schedule (59% versus 57%). The median survival was 9.5 months. The 
weekly regimen was less toxic. Additionally, 37 patients with relapsed/refractory 
ALL received weekly inotuzumab in a multicenter phase I/II study17. Seventeen 
(46%) patients were in Salvage 1, 9 (24%) in Salvage 2, and 11 (30%) in 
Salvage 3 or later. The CR and CR without count recovery rates were 79% 
(19/24) and 46% (6/13) in the dose expansion and dose escalation cohorts, 
respectively. Eighteen of the nineteen patients in the dose escalation cohort and 
four of the six in the dose expansion cohort achieved MRD negativity. These 
encouraging results led to an international study comparing weekly inotuzumab 
to standard ALL chemotherapy (FLAG at MD Anderson) in ALL salvage 1-2. The 
objective response rates were 81% and 33%, respectively. Among responders, 
the MRD-negativity rates were 78% and 28%, respectively. The median 
response duration was 4.6 versus 3.1 months (p=0.017), respectively.  
 
Table 2.  Activity of inotuzumab ozogamicin in patients with relapsed/refractory ALL 
 
N (%) 
 
Parameter 
Single-Dose, 
n=49 
Weekly, 
n=40 
Overall, 
n=89 
Response 
 
 
 
  CR 
9 (18) 
8 (20) 
17 (19) 
  CRp 
16 (33) 
13 (33) 
29 (33) 
  CRi, bone marrow CR 
3 (6) 
3 (8) 
6 (7) 
  PR 
0 
0 
0 
  Resistant 
18 (37) 
14 (35) 
32 (36) 
Death < 4 weeks 
3 (6) 
2 (5) 
5 (6) 
Salvage 
 
 
 
  Salvage 1 
13 (27) 
16 (40) 
29 (33) 
  Salvage 2+ 
36 (73) 
24 (60) 
60 (67) 
Median survival (months) 
5.0 
9.5 
6.2 
 
7.3.2 Combination of inotuzumab ozogamicin with chemotherapy  
 
Given the promising results in the salvage studies, inotuzumab was evaluated in 
combination with chemotherapy. A group of patients with ALL who may 
particularly benefit from a more targeted regimen is elderly patients (age greater 
than 60 years). This group is predisposed to severe toxicity from conventional 
chemotherapy, which is associated with high mortality rate (30-35%) during 
consolidation-maintenance in CR. Thirty-four older patients (median age of 69 
years; range, 60 to 79) with newly diagnosed ALL were treated in a phase II 
study combining inotuzumab and low-intensity hyperCVAD therapy.18 The 

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regimen eliminated doxorubicin in induction, used cyclophosphamide and 
steroids at 50% of the dose of previous regimens, and reduced methotrexate to 
250 mg/m2 on Day 1 and cytarabine to 0.5 mg/m2 x4 (Days 2 and 3) of even 
courses. Inotuzumab 1.3-1.8 mg/m2 was given once with each of the first 4 
courses. The ORR was 97% (CR 83%). All patients with cytogenetic 
abnormalities achieved complete cytogenetic response. All patients achieving 
response also had a negative MRD status, 75% of them after one cycle. The 2-
year progression-free and overall survival rates were 87% and 70%, respectively. 
The 2-year survival rate was superior to previous results obtained with HCVAD 
+/- rituximab in similar patient populations (2-year survival rates 70% and 38%, 
respectively).  
 
This combination was also assessed as a salvage therapy in 48 patients. The 
ORR was 74% (CR 52%) The 12-month progression-free and overall survival 
rates were 88% and 81%, respectively19.  
 
7.4 Inotuzumab ozogamicin toxicity profile 
 
Transient fever and hypotension were the 2 most frequent non-hematologic 
adverse events, and typically occurred shortly after the inotuzumab infusion. 
Liver function abnormalities were also observed, but tended to be reversible.  
Serious toxicity in the transplant group included the development of veno-
occlusive disease (VOD) in five patients (23%). Four of the 5 patients had 
received multiple alkylating agents in the transplant preparative regimen, 
including clofarabine which may have predisposed them to VOD. Two of the 4 
patients undergoing second ASCT developed VOD, suggesting this group of 
patients to be also at higher risk for VOD. In elderly ALL and in combination with 
low intensity chemotherapy, 4 patients (11%) developed a VOD, one of them 
post allogeneic stem cell transplantation. All but one patient had mild VOD that 
resolved subsequently. Only one patient developed a Grade 5 VOD after 2 
cycles, was switched to miniHCVD and ofatumumab, received 2 more additional 
courses, developed anasarca and multiple organ failure and expired thereafter. 
The safety profile of inotuzumab ozogamicin vs standard of care (SOC) was 
consistent with the initial studies. For inotuzumab vs SOC, Gr≥3 hepatobiliary 
AEs occurred in 9% vs 3% patients; any grade VOD occurred in 15 (14%) vs 1 
(0.9%) patient (Gr≥3, 13 vs 1 patients). More patients proceeded to ASCT with 
inotuzumab (n=48) vs SOC (n=20); in the inotuzumab arm, 5 VOD cases (2 in 
patients with prior ASCT) occurred during treatment and 10 after subsequent 
SCT (2 fatal).   
  
8.0 Background Drug Information 
 
8.1 Inotuzumab 
 
8.1.1 Formulation and packaging 

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Inotuzumab ozogamicin is a white to off-white powder or cake, lyophilized, 
unpreserved 1- mg or 4-mg protein equivalent powder for intravenous injection in 
an amber vial. 
 
8.1.2 Preparation and dispensing 
Specific preparation and dispensing instructions for inotuzumab ozogamicin are 
provided in the Dosage and Administration Instructions. Once inotuzumab 
ozogamicin has been prepared following the Dosage and Administration 
Instructions, the site pharmacist will label the study medication in accordance 
with local requirements. Only qualified personnel who are familiar with 
procedures that minimize undue exposure to them and to the environment should 
undertake the preparation, handling, and safe disposal of chemotherapeutic 
agents. 
 
8.1.3 Administration  
All patients must be weighed within 7 days prior to every cycle day 1 dosing to 
ensure they did not experience either a weight loss or gain >10% from the prior 
weight used to calculate the amount of inotuzumab ozogamicin required for dose 
preparation.  Decision to recalculate the dose of inotuzumab ozogamicin based 
on the weight obtained at each cycle can be in accordance with institutional 
practice; however, if the patient experienced either a weight loss or gain >10%, 
the required amount of inotuzumab ozogamicin needed for study drug 
preparation and administration must be recalculated using this most recent 
weight/BSA obtained.  If the dose administered is 10% greater or lower than the 
one prescribed, it will be reported as a dosing medication error. 
 
Inotuzumab ozogamicin is administered intravenously. Subjects will receive a 
dose of 1.8 mg/m2 over the first cycle (0.8 mg/m2 on D1, 0.5 mg/m2 on D8 and 
D15 [+/- 3 days]) of 21 to 28 days cycle. The remaining 5 cycles (total of 6 
overall) will consist of 0.9 mg/m2 administered in 2 divided weekly doses of 
inotuzumab ozogamicin (0.6 mg/m2 on Day 1 [+/- 3 days], 0.3 mg/m2 on day 8 
[+/- 3 days]) over a 21- to 28-day cycle. 
 
Pretreatment: 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. Pretreatment prior to inotuzumab ozogamicin includes 
corticosteroid, antipyretic, and antihistamine. Premedication before inotuzumab 
ozogamicin may also include antiemetics. Antiemetics with the least potential of 
side effects are recommended. Subjects should be pretreated with 
methylprednisolone (or other corticosteroid), acetaminophen/paracetamol and 
diphenhydramine (or other 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 (eg, 
glucocorticosteroids, epinephrine, bronchodilators, or oxygen). Depending on the 

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severity of the infusion reaction and interventions required, the investigator could 
consider restarting the infusion at a reduced rate. 
 
Reconstituted inotuzumab ozogamicin will be administered over approximately 1 
hour by intravenous infusion unless the subject requires temporary interruption of 
the administration. 
 
Vital Signs during inotuzumab administration: 
 Cycle 1 Day 1 (first inotuzumab infusion): Prior to inotuzumab, 
approximately 30 minutes into infusion, just prior to end of infusion, 
approximately 1 hour and approximately 2 hours after end of infusion. 
All Subsequent infusions: Prior to inotuzumab and at end of infusion (+/- 
15 min). 
 
8.1.4 Recommended dose modifications 
 
In the event of significant toxicity, dosing may be delayed as described below.  In 
the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed. Patients are to be instructed to notify Investigators at the first 
occurrence of any adverse symptom. 
 
Dose modifications may occur as follows: 
 
1. Within a cycle: dose interruption until adequate recovery (Grade ≤1) or 
omission of a dose during a given treatment cycle. 
2. Between cycles: next cycle administration may be postponed due to 
toxicity in the previous cycle. 
3. In the next cycle (Cycle 3 and beyond): dose reduction based on worst 
toxicity or to 0.6 mg/m2/cycle if hematologic remission is achieved in the 
previous cycle. 
 
8.1.5 Dose delays 
 
If patients do not meet the criteria below on the day of the scheduled treatment, 
the administration of the dose will be delayed. 
 
1. No evidence of progressive disease or relapse prior to the start of each 
cycle; however, treatment may continue, at the judgment of the 
investigator, in patients with only extramedullary CNS and/or testis 
relapse. 
2. Prior to the start of each cycle, decrease in blast percentage or stable 
disease (ie, not more than a 50% increase in blast percentage) based on 
the most recent bone marrow evaluation. 
3. Recovery to grade 1 or baseline non-hematologic clinically significant test 
article-related toxicity (including liver function test abnormalities, not 
including alopecia). 

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4. Serum bilirubin ≤1.5 x ULN, and AST or ALT ≤2.5 x ULN (or if elevated 
due to tumor, bilirubin ≤2 x ULN).  Isolated AST or alkaline phosphatase 
elevations need not result in dose delays if not related to hepatobiliary 
organs (eg, alkaline phosphatase elevations due to bone involvement).  
Inotuzumab ozogamicin dosing should be permanently discontinued for 
any patients with possible, probable or confirmed VOD or other severe 
liver toxicity. 
5. Any serum creatinine level associated with a measured or calculated 
creatinine clearance ≥ 15 mL/min using the method standard for the 
institution. 
6. Prior to the start of each cycle, for subjects with pre-treatment ANC ≥1 x 
109/L: ANC ≥1 x 109/L. 
7. Prior to the start of each cycle, for subjects with pre-treatment platelets 
≥50 x 109/L: platelets ≥50 x 109/L. 
8. Subjects with pre-treatment ANC <1 x 109/L and/or platelets <50 x 109/L: 
ANC and platelets must recover to baseline values obtained for the prior 
cycle, or ANC ≥1 x 109/L and platelets ≥ 50 x 109/L, or the most recent 
bone marrow must demonstrate stable or improved disease, and the ANC 
and platelets are believed to be low due to disease. 
 
There are no ANC or platelet count requirements for Cycle 1 day 1, as dosing 
criteria are relative to pre-treatment values. While doses given within a treatment 
cycle (ie, day 8) need not be delayed due to neutropenia or thrombocytopenia, 
dose delays within a cycle are recommended for non-hematologic toxicity. 
 
Dose delays due to drug toxicity ≤7 days during a treatment cycle are permitted. 
Dose delays of >7 days within a cycle will result in omission of the subsequent 
dose; the subject remains eligible to receive the subsequent planned doses. If a 
treatment interruption continues beyond day 14 of the current cycle, then the day 
when treatment is restarted will be considered day 1 of the next cycle.  Dose 
delays due drug toxicity >28 days at the end of a treatment cycle (ie, delay of day 
1 dosing of subsequent cycle) will result in permanent discontinuation of study 
treatment.  All toxicity grades are according to National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v 4.03). 
 
8.1.6 Dose reductions 
 
Dose reductions may also be required based on the worst toxicity experienced in 
the previous cycle.  Patients experiencing a treatment interruption due drug 
toxicity ≥14 days may resume dosing at the next lower dose level (if a lower dose 
level is available) for the subsequent cycle once adequate recovery is achieved. 
Dose reductions to the next lower dose level (if a lower dose level is available) 
should also be considered for patients with CRi, whose platelet counts have not 
recovered to values obtained prior to the start of the previous cycle. Once a 
patient has a dose reduction for a drug-related toxicity, the dose will not be re-

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escalated.  Patient requiring more than two dose reductions will be withdrawn 
from treatment study. 
 
 
Dose Level 
Day 1 Dose 
(mg/m2) 
Day 8 Dose 
(mg/m2) 
Total dose Per Cycle 
(mg/m2) 
0  
(Starting dose 
beyond C1) 
0.6 
0.3 
0.9 
-1 
0.4 
0.2 
0.6 
-2 
0.3 
0.1 
0.4 
 
8.2 Drug storage and drug accountability 
 
The amber vials of inotuzumab ozogamicin are to be stored at 2°C to 8°C (36°F 
to 46°F). Inotuzumab ozogamicin is light sensitive and should be protected from 
direct and indirect sunlight and unshielded fluorescent light during the 
preparation and administration of the infusion.  Preparation of inotuzumab 
ozogamicin should occur in full compliance with institutional or local regulations 
for reconstitution of IV medications under aseptic conditions.  Refer to the 
Dosage and Administration Instructions in the Study Manual for more information 
on stability, time frame of administration once reconstituted, and administration.  
Inotuzumab ozogamicin must be stored as indicated.  Deviations from the 
storage requirements for any products supplied (shipped) by Pfizer, including any 
actions taken, must be documented and reported to Pfizer.  Once a deviation is 
identified, the product must be quarantined and not used until Pfizer provides 
documentation of permission to use the investigational product.  Inotuzumab 
ozogamicin will be labeled according to regulations.  Storage conditions stated in 
the Investigator’s Brochure may be superseded by the label storage. 
 
The investigator must maintain a complete and current accountability record.  
Investigational product accountability applies to such products when they are 
required by the protocol and supplied (shipped) by the supporter. All unopened 
investigational product must be returned in the original containers to the 
supporter/contract distribution center with the appropriate form, or transferred to 
another site as applicable for this study.  The site and the site monitor are to 
contact the supporterfor detailed information before the transfer of investigational 
product to another site, or return to the supporteris to take place. Investigational 
product return must be documented on the accountability record. The site may 
destroy unused investigational product in an open container (ie, investigational 
product left after the vial was opened and/or reconstituted) and empty 
investigational product containers after accountability has been performed.  
Investigational product destruction must be documented on the accountability 
record.  Investigational product is destroyed at the site only with the supporters 
permission. For this protocol, investigational product is destroyed at the site only 

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with the supporter’s permission and after accountability has been performed by 
the supporter's monitor. The process of return, destruction, and accountability 
and reconciliation for controlled (eg, narcotics), hazardous (eg, investigational 
product used in oncology) and/or isotopically labeled substances, is performed in 
accordance with local laws and regulations.  Shipment of an investigational 
product that is a hazardous substance or whose shipment may expose humans 
to risk will be done according to local laws and regulations. 
 
8.3 Recommendations to reduce the risk of VOD for patients proceeding to 
ASCT 
 
 For patients planning to receive an allogeneic ASCT, it is recommended 
that treatment with inotuzumab ozogamicin be limited to 2 cycles of 
induction or the fewest number of cycles required to achieve a 
CR/CRi/CRp (if CR/CRi/CRp not achieved after 2 cycles). 
 The risk of relapse must be balanced against the potential risk of toxicity 
associated with beginning ASCT soon after the last dose of inotuzumab 
ozogamicin; however, approximately 5-6 weeks between inotuzumab and 
ASCT may be reasonable for most patients. 
 Healthcare providers should use their clinical judgment to determine the 
most appropriate course of therapy for prophylactic treatment before the 
start of conditioning therapy according to standard of care (eg, 
prophylactic ursodeoxycholic acid at 12-15 mg/kg/day, beginning 2 weeks 
before the start of conditioning therapy. 
 Use the least hepatotoxic conditioning regimen and, specifically, avoid 
using regimens that contain 2 alkylating agents and or that combine an 
alkylating agent with higher dose TBI (defined as >12 Gy). 
 If using a busulfan-containing conditioning regimen, please consider using 
pharmacokinetically-dosed busulfan. 
 When possible, avoid the concomitant use of hepatotoxic drugs peri-
transplant. 
 If significant liver toxicity occurs, consult a gastroenterology and/or 
hepatology service. 
 When evaluating liver toxicity, inform the radiologist of the potential for 
hepatic vascular disease. When VOD is in the differential diagnosis, a 
right upper quadrant ultrasound with colorflow doppler (including resistive 
indices to hepatic artery flow and evaluation of hepatic venous outflow) 
should be performed. In addition, the radiology report should describe the 
degree of gall bladder wall thickening in millimeters and the volume of 
ascites should be estimated as closely as possible (i.e., small and 
localized, moderate and generalized, or large and generalized). 
 Defibrotide may be used in the setting of severe VOD 
 If a patient will proceed to ASCT under the care of different physicians, 
these recommendation should be reviewed with the new treating 
physicians.  

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9.0 Evaluation of Toxicity 
 
Toxicities will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 
 
10.0 Criteria for Removal from the Study 
 
Criteria for removal from study include, but are not restricted to, the following: 
 
10.1 No response after 2 cycles or progressive disease, unless considered by 
the treating physician and after discussion with the PI to be in the best interest of 
the patient. In this situation, if the treatment is well tolerated, patient can receive 
up to a maximum of 4 cycles.   
 
10.2 Non-compliance by the patient with protocol requirements 
 
10.3 Patient's request to be removed from the study 
 
10.4 Occurrence of CTCAE grade 4 adverse event at least possibly related to 
inotuzumab. For CTCAE grade 4 adverse events that are numerically defined 
laboratory parameters, independent investigator assessment should be used to 
determine the risk:benefit for each individual patient to continue or discontinue 
inotuzumab treatment 
 
10.5 Occurrence of an adverse event which makes discontinuation from 
treatment necessary due to protocol specified safety criteria or desirable in the 
investigator’s and/or the subject´s opinion 
 
10.8 Investigator’s decision that a subject does not benefit from treatment 
anymore, e.g., non-response or development of progressive disease 
 
11.0 STATISTICAL CONSIDERATIONS  
This is a single-arm phase II study of a single agent of low dose inotuzumab 
ozogamicin in adult patients with relapsed or refractory CD22-positive ALL. 
Patients will receive inotuzumab ozogamicin for up to 6 cycles. The primary 
endpoint of this study is hematologic remission, defined as CR + CRp + CRi 
occurred any time during the treatment. The Simon’s optimal two-stage design 
will be used for interim futility monitoring. The null hypothesis is that the 
hematologic remission rate is 35% and our target rate under the alternative 
hypothesis is 50%. Under the design, we will enroll 18 patients in the first stage. 
If 6 or fewer patients achieve the primary endpoint, enrollment of future patients 
will be halted. If 7 or more out of the first 18 patients have met the primary 
endpoint, accrual will continue until a total of 48 patients are enrolled. If 21 or 
more out of these 48 patients achieve the primary endpoint, the treatment will be 

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considered efficacious and is worth further investigation. Under this Simon’s 
optimal two-stage design, the type I error is 0.113, the power is 78.3%, the 
probability of early termination is 0.549 if the true hematologic remission rate is 
35% and the expected sample size is 31.5 patients. After the first stage, if not at 
least 7 responders are observed in the first 18 patients, we will temporarily 
suspend the accrual until enough number of responders (i.e., >/=7) is reached.  
 
We will also monitor treatment emergent toxicities using a Bayesian design by 
Thall, Simon and Estey [Thall PF, Simon RM, Estey EH. Bayesian sequential 
monitoring designs for single-arm clinical trials with multiple outcomes. Statistics 
in medicine.1995;14(4):357-379], in cohort size of 8. For monitoring purpose, 
toxicities are defined as [any grade VOD that is deemed as related to 
inotuzumab] and the associated toxicity stopping rule is to stop the trial if 
Prob{p(TOX) > 0.20| data} > 0.92, where p(TOX) is the toxicity rate and a 
beta(0.4, 1.6) distribution was assumed for the prior. That is, if at any time during 
the trial we determine that there is more than 92% chance that the toxicity rate is 
more than 20%, we will stop the trial due to safety concern. The corresponding 
stopping boundaries are shown in Table 3 below and the operating 
characteristics of the toxicity monitoring are illustrated in Table 4. Multc Lean 
Desktop (v2.1.0) (https://biostatistics.mdanderson.org/SoftwareDownload/) was 
used for generating the stopping boundaries and the OC table.  
 
An Efficacy/Toxicity Summary will be submitted to the IND Office Medical 
Monitor, after the first 8 evaluable, and every 8 evaluable patients thereafter, in 
an accumulating method. 
 
Table 3. Toxicity stopping boundaries in cohort size of 8.  
  
Number of patients  
Stop the trial if there are 
this many patients having 
toxicity 
8 
4-8 
16 
6-16 
24 
8-24 
32 
11-32 
40 
12-40 
48 
Always stop with this many 
patients 
 
Table 4: Operating characteristics for toxicity monitoring.  

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True Toxicity 
Rate 
Early 
Stopping 
Probability 
Average 
number of 
patients 
treated 
25th, 75th 
percentile 
0.10 
0.008 
47.7 
48, 48 
0.15 
0.05 
46.4 
48, 48 
0.20 
0.17 
43.0 
48, 48 
0.25 
0.40 
37.1 
24, 48 
0.30 
0.65 
29.8 
16, 48 
0.35 
0.85 
23.0 
8, 40 
0.40 
0.95 
17.8 
8, 24 
0.45 
0.99 
14.3 
8, 16 
 
Analysis Plan: 
 
The hematologic remission rate will be estimated along with the 95% credible 
interval. Data from all subjects who receive any study drug will be included in the 
safety analyses. Subjects who entered the study but did not take any of the study 
drug and had this confirmed will not be evaluated for safety. The severity of the 
toxicities will be graded according to the NCI CTCAE v4.03 whenever possible. 
We will follow standard reporting guidelines for adverse events. Safety data will 
be summarized by AE category, severity and frequency. The proportion of 
patients with AEs will be estimated, along with the Bayesian 95% credible 
interval. Kaplan-Meier method will be used to assess the overall survival (OS), 
progression-free survival (PFS), duration of response (DoR) and durations of 
remission (DoR1). The rate of hematologic response (CR + CRi + PR) will also 
be estimated.  
 
12.0 Reporting Requirements 
 
Adverse event reporting and recording will be as per the NCI criteria and the 
MDACC Leukemia Specific Adverse Event Recording and Reporting Guidelines.  
All subjects will be monitored for AEs during the study. AEs will be recorded from 
the first dose through 30 days after the last dose. Serious Adverse Events 
(SAEs) will be captured starting from the date of consent. Any serious adverse 
events that occur after the 30 day time period that are related to the study 
treatment will also be reported. 
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for 
adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html).   

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The Principal Investigator will sign and date the Adverse Event Record (AE log) 
for each patient at the completion of each course.  Following signature, the AE 
logs will be used as source documentation for the adverse events for attribution. 
 
12.1 Serious Adverse Events 
 
Serious Adverse Event Reporting (SAE) Language for MD Anderson-
sponsored IND Protocols 
 
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 Serious Unanticipated Adverse Events for 
Drugs and Devices”.  Unless stated otherwise in the protocol, all SAEs, 

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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 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. 
 
12.2 Investigator Communications with Pfizer 
 
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), from after the first dose of inotuzumab ozogamicin until 
twenty-eight (28) calendar days after the last dose of inotuzumab 
ozogamicin.  Principal Investigator will report to Pfizer by facsimile any 
Serious Adverse Event (SAE) for which reporting is required.  Principal 
Investigator should report SAEs as soon as they are determined to meet 
the definition, even if complete information is not yet available using a 
reporting form approved by the local regulatory authority (eSAE).  Forms 
should be faxed to Pfizer at 1-866-997-8322. 
 
 
 
 

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13.0 References 
 
1. 
Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and relapsed adult 
acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with 
salvage therapy. Cancer 1999;86:1216-30. 
2. 
Tavernier E, Boiron JM, Huguet F, et al. Outcome of treatment after first relapse 
in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. 
Leukemia 2007;21:1907-14. 
3. 
Piccaluga PP, Arpinati M, Candoni A, et al. Surface antigens analysis reveals 
significant expression of candidate targets for immunotherapy in adult acute lymphoid 
leukemia. Leuk Lymphoma 2011;52:325-7. 
4. 
DiJoseph JF, Goad ME, Dougher MM, et al. Potent and specific antitumor 
efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against 
systemically disseminated B-cell lymphoma. Clin Cancer Res 2004;10:8620-9. 
5. 
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;28:2085-93. 
6. 
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;13:403-11. 
7. 
Hamann PR, Hinman LM, Beyer CF, et al. An anti-CD33 antibody-calicheamicin 
conjugate for treatment of acute myeloid leukemia. Choice of linker. Bioconjug Chem 
2002;13:40-6. 
8. 
DiJoseph JF, Dougher MM, Evans DY, Zhou BB, Damle NK. Preclinical anti-
tumor activity of antibody-targeted chemotherapy with CMC-544 (inotuzumab 
ozogamicin), a CD22-specific immunoconjugate of calicheamicin, compared with non-
targeted combination chemotherapy with CVP or CHOP. Cancer Chemother Pharmacol 
2011;67:741-9. 
9. 
Larson RA, Sievers EL, Stadtmauer EA, et al. Final report of the efficacy and 
safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute 
myeloid leukemia in first recurrence. Cancer 2005;104:1442-52. 
10. 
Matsui H, Takeshita A, Naito K, et al. Reduced effect of gemtuzumab ozogamicin 
(CMA-676) on P-glycoprotein and/or CD34-positive leukemia cells and its restoration by 
multidrug resistance modifiers. Leukemia 2002;16:813-9. 
11. 
Takeshita A, Shinjo K, Yamakage N, et al. CMC-544 (inotuzumab ozogamicin) 
shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients 
with B-cell chronic lymphocytic leukaemia and lymphoma. Br J Haematol 2009;146:34-
43. 
12. 
DiJoseph JF, Dougher MM, Kalyandrug LB, et al. Antitumor efficacy of a 
combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic 
immunoconjugate of calicheamicin, and rituximab against non-Hodgkin's B-cell 
lymphoma. Clin Cancer Res 2006;12:242-9. 
13. 
DiJoseph JF, Armellino DC, Boghaert ER, et al. Antibody-targeted chemotherapy 
with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of 
B-lymphoid malignancies. Blood 2004;103:1807-14. 

2015-0870 
September 12, 2018 
21  
 
 
14. 
Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a 
CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. 
Cancer 2013;119:2728-36. 
15. 
Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and 
pharmacodynamics. J Pharm Sci 2004;93:2645-68. 
16. 
Cao Y, Jusko WJ. Incorporating target-mediated drug disposition in a minimal 
physiologically-based pharmacokinetic model for monoclonal antibodies. J 
Pharmacokinet Pharmacodyn 2014;41:375-87. 
17. 
Deangelo Aea. Weekly Inotuzumab ozogamicin (InO) in adult patients with 
relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). Abst 3906. 
Blood 2013;122. 
18. 
Jabbour E. Abstract S114 EHA 2015. Haematologica 2015;100. 
19. 
Jabbour E. Abstract 7019 ASCO 2014. Journal of Clinical Oncology 2014;32.