Phase II Study of the Hyper-CVAD Regimen in Sequential Combination With Inotuzumab Ozogamicin as Frontline Therapy for Adults With B-Cell Lineage Acute Lymphocytic Leukemia
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia in Remission, B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative
Sponsor: M.D. Anderson Cancer Center

Protocol Page
Phase II Study of the Hyper-CVAD Regimen in Sequential Combination with 
Inotuzumab Ozogamicin as Frontline Therapy for Adults with B-Cell Lineage Acute 
Lymphocytic Leukemia
2015-0922
Core Protocol Information
Short Title 
Phase II Hyper-CVAD with INO in 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:
Chiamaka C. Nwachukwu
Full Title: 
Phase II Study of the Hyper-CVAD Regimen in Sequential 
Combination with Inotuzumab Ozogamicin as Frontline 
Therapy for Adults with B-Cell Lineage Acute Lymphocytic 
Leukemia
Public Description:
na
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 01/24/2019
Version:
05
Document Status:
Saved as "Final"
Submitted by:
Lori L. Smith--12/19/2018 11:54:31 AM
OPR Action:
Accepted by:  Elizabeth Orozco -- 1/2/2019 12:12:48 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

Protocol Body
 
  

 
 
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Phase II Study of the Hyper-CVAD Regimen in Sequential Combination with 
Inotuzumab Ozogamicin as Frontline Therapy for Adults with B-Cell 
Lineage Acute Lymphocytic Leukemia 
 
 
 
 
 
Principal Investigator:  Elias Jabbour, MD 
 
 
 
 
 

 
 
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Table of Contents 
1.0 
Objectives .................................................................................................. 3 
2.0 
Background ............................................................................................... 3 
3.0 
Background Drug Information ..................................................................... 9 
4.0 
Patient Eligibility ........................................................................................ 15 
Inclusion Criteria: ................................................................................................. 15 
Exclusion Criteria: ................................................................................................ 15 
5.0 
Treatment Plan ......................................................................................... 16 
6.0 
Pretreatment evaluation ............................................................................ 23 
7.0 
Evaluation During Study ............................................................................ 23 
8.0 
Criteria for Response ................................................................................ 25 
9.0 
Evaluation of Toxicity and Reporting Requirements ................................. 26 
10.0  Criteria for Removal from the Study .......................................................... 29 
11.0  Statistical Considerations .......................................................................... 29 
12.0  References ................................................................................................ 32 
 
 
 
 

 
 
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Phase II Study of the Hyper-CVAD Regimen in Sequential Combination with 
Inotuzumab Ozogamicin as Frontline Therapy for Adults with B-Cell Lineage 
Acute Lymphocytic Leukemia 
 
1.0 Objectives 
 
1.1 Primary Objectives: To evaluate the clinical efficacy of the sequential 
combination of hyper-CVAD + inotuzumab ozogamicin in patients with newly 
diagnosed B-cell acute lymphocytic leukemia (ALL) in terms of event-free 
survival (EFS) 
 
1.2 Secondary Objectives: To evaluate other efficacy endpoints such as overall 
survival, overall response rate, MRD negativity rate as well as the safety of this 
combination  
 
2.0 Background 
 
2.1 Acute lymphocytic leukemia (ALL) 
 
Adult ALL encompasses a heterogeneous group of lymphoid malignancies. 
Prognosis is related to age, karyotype, molecular profile, immunophenotype, and 
other disease features. Prognosis for pediatric ALL has improved significantly 
over the last several decades to current long-term survival rates of greater than 
80%.1 However, long-term survival in adults is currently only 35% to 45% .2,3 The 
predominant reason for failure is disease recurrence. 
 
Recent advances in treatment have been based on the pediatrics regimens. 
Murphy et al. designed an intensive, multi-agent chemotherapy program based 
on the concept of delivery of agents in rapid sequence in children with Burkitt's 
leukemias and lymphomas.4 Because it was recognized that these 
lymphomas/leukemias have high growth fractions and doubling times as short as 
25 hours, cyclosphosphamide was fractionated in the induction phase in an 
attempt to encompass the entire generation time of the tumor as well as to 
provide a smoother induction with fewer metabolic complications.5 The Total B 
regimen consists of cycles of fractionated high-dose cyclophosphamide 
(300mg/m2 q 12 hours for six doses), vincristine, and doxorubicin alternating with 
high dose methotrexate (1g/m2) and escalating doses of ara-C. Kantarjian et al 
modified this program, and developed the regimen of hyper-CVAD 
(hyperfractionated cyclophosphamide, vincristine, doxorubicin, and 
dexamethasone alternating with high dose methotrexate and ara-C).6,7 This 
regimen has significant activity in the treatment of Burkitt's disease, mantle cell 
lymphoma, multiple myeloma, lymphocytic lymphoma, and aggressive chronic 
lymphocytic leukemia with or without Richter's transformation. Of the 2004 
patients with de novo ALL who were treated with hyper-CVAD protocol, 91% 

 
 
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achieved a complete remission. The median time to achieve CR was 21 days 
with 81% of patients achieving CR after one course of chemotherapy. The 
estimated five-year survival was 39%, and the estimated median survival time 
was 35 months.  
 
2.2 Combination of hyper-CVAD and immunotherapy 
 
Expression of CD20 was associated with a higher incidence of relapse, lower 3-
year complete remission duration (CRD) and lower 3-year overall survival (OS) 
rate. The independent adverse influence of CD20 expression on event-free 
survival (EFS) was observed in a multivariate analysis, particularly among the 
youngest group of patients.8  
 
In order to improve the outcome of these patients, several modifications were 
incorporated, among them the addition of anti CD20 monoclonal antibody, 
rituximab and ofatumumab. The addition of rituximab to the hyper-CVAD 
program in patients with CD20 expression (≥20%) improved outcome compared 
to historical experience, with 3-year CRD rates (68% vs 28%, p<0.001) and OS 
rates (65% vs 35%, p=0.01) approaching those of the CD20 negative 
counterparts [8]. Similarly, the addition of ofatumumab to the hyper-CVAD 
regimen CVAD induced a CR rate of 94% with MRD negativity rate of 67% after 
induction. The 1-year CRD and overall survival rates were 100% and 95% 
respectively.9 
 
2.3 Inotuzumab ozogamicin 
 
2.3.1 Description 
 
Inotuzumab ozogamycin 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-ALL10.  
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 damage11. This is likely 
because IgG4 antibodies poorly fix complement, therefore cannot cause 
apoptosis via complement-mediated and antibody-dependent cytotoxicity12. 
Calicheamicin is natural product of Micromonospora echinospora species, and 
considered to be intolerantly toxic when not bound to the antibody13. 
Calicheamicin is linked to the antibody through 4-(4-acetylphenoxy) butanoic acid 
(acetyl butyrate) which provides stability in physiologic pH and successful 
calicheamicin release inside the acidic environment of the lysosomes14. 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 

 
 
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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. 
 
2.3.2 Pharmacodynamics 
 
Treatment with INO has been shown to provide greater therapeutic benefit, as 
single agent, compared to CVP or CHOP in B-cell NHL xenografts15. 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)16. However, drug resistance had negative impact on clinical outcome of 
patients treated with GO17. 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 drug18 [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 cells18. 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 cytotoxicity19. Anti-tumor efficacy of INO and rituximab 
combination has also been tested in B-cell NHL preclinical models, and 
demonstrated superior activity with the combination20. 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 benefit13. 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.  
 
2.3.3 Pharmacokinetics 
 
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 patients12. Most patients had follicular lymphoma (FL) (44%) and diffuse 
large B-cell lymphoma (DLBCL) (44%), and 61% of the patients had received ≥ 4 

 
 
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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 patients21. 
 
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 well22. 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 interaction23.  Anti-CD22 antibody and 
total calicheamicin followed similar elimination trend, and the free calicheamicin 
concentration remained less than 1ng/ml overtime, suggesting that the acetyl 
butyrate linker is noticeably stable in plasma12 
 
2.4 Inotuzumab ozogamicin in R/R ALL 
 
2.4.1 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.12 This led to a single institution phase II study in patients 
with relapsed-refractory ALL13. 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 1). 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. 
 
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 1).21    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 

 
 
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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 study24. 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 1.  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 
 
2.4.2 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.25 The 
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 

 
 
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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%, respectively.26 
 
2.5 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 veno occlusive 
disease, one of them post allogeneic stem cell transplantation. All but one patient 
had mild VOD that resolved subsequently. 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%) patients (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).   
 
2.6 Rationale for the combination of hyper-CVAD and inotuzumab ozogamicin 
 
Multi-agent combination chemotherapy regimens for the treatment of ALL are 
considered a cancer success story in the pediatric setting.27 For adults, the same 
magnitude of success has not been realized using similar strategies. These 
regimens produce high CR rates of 80-90% but the cure rates are 40-50% .28,29 
The incorporation of targeted agents (tyrosine kinase inhibitors in Philadelphia 
chromosome [Ph]-positive ALL; rituximab in Burkitt leukemia and CD20-positive 
preB-ALL) has improved survival and cure rates in adult ALL subsets.29-31  
 

 
 
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Persistence or reappearance of MRD after induction chemotherapy is the most 
important adverse prognostic factor in patients with B-lineage ALL and identifies 
chemorefractory disease.32-37 More than 90% of patients who fail to clear MRD 
after chemotherapy experience a clinical relapse despite continued 
chemotherapy. The median time to relapse of patients with MRD positive disease 
is 4-5 months.38 The only option to cure these patients is allogeneic 
hematopoietic stem cell transplantation (HSCT), but the outcome is 
suboptimal .39  
 
We have explored lower dose chemotherapy with inotuzumab ozogamicin in the 
frontline setting in elderly patients and in the relapse setting as well. The 
combination was found to be safe and extremely effective with an ORR of 97% in 
the frontline setting with all them becoming negative MRD (75% after one cycle) 
and 75% in the relapse setting with 2-year survival rate of 54% in Salvage 1 
setting. Therefore, sequential combination of hyper-CVAD with inotuzumab 
ozogamicin in adults All may optimize the rate of MRD negativity and 
subsequently improve the cure rates of adults patients with B-cell ALL. For this 
patient population, tolerance to chemotherapy is better than that for elderly with 
significantly less toxicities and less treatment related morbidities.  Inotuzumab 
dosing was reduced to 0.9mg/m2 in induction and 0.6mg/m2 in consolidation in 
the hyper-CVD + inotuzumab protocol to ameliorate risk of VOD. In this study we 
want to further reduce the toxicities and improved outcome by inducing higher 
rates of negative MRD and less relapses. Patients will receive 4 cycles of 
intensive chemotherapy instead of 8 (50% less). That will be followed by 4 cycles 
of inotuzumab and one year of maintenance therapy (instead of 3 years). We will 
assess this treatment regimen after 10 patient enrolled then after a total of 30 
patients then at the end of the 60 patient enrolled. 
 
3.0 Background Drug Information 
 
3.1 Drug information for the following agents is attached as an appendix to the 
back of this protocol (Appendices C, D, and E). 
 Cyclophosphamide 
 Doxorubicin 
 Vincristine 
 MESNA 
 Methotrexate 
 Cytarabine (Ara-C) 
 6-mercaptopurine 
 Filgrastim product (G-CSF) 
 Dexamethasone 
 Prednisone 
 Ofatumumab 
 Rituximab 
 

 
 
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3.4 Inotuzumab ozogamicin 
 
3.4.1 Formulation and packaging 
 
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. 
 
3.4.2 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. 
 
3.4.3 Administration  
 
All patients must be weighed within 72 hours 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 2 
weekly doses of inotuzumab ozogamicin over a 21- to 28-day cycle for a 
maximum of 4 cycles. 
 
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.  Premedication before inotuzumab ozogamicin may also include 
antiemetics. Antiemetics that do not predispose patients to Torsades de Pointes, 
such as granisetron (Kytril), are recommended. Subjects should be pretreated 
with either methylprednisolone (or other corticosteroid), or 
acetaminophen/paracetamol and diphenhydramine (or other antihistamine) 
approximately 0.5 to 2 hours before each inotuzumab ozogamicin administration. 

 
 
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Modifications to this premedication are also allowed. In cases of infusion 
reactions, discontinue infusion and institute appropriate medical treatment as 
needed (eg, glucocorticosteroids, 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. 
 
All patients will be given Ursodiol 300mg PO TID. Ursodiol should be started one 
week before the start of the first cycle of inotuzumab ozogamicin treatment and 
administered continuously through all 4 cycles of inotuzumab.  
 
Reconstituted inotuzumab ozogamicin will be administered over 1 hour ± 10 
minutes by intravenous infusion unless the subject requires temporary 
interruption of the administration. 
 
3.4.4 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: 
 Within a cycle: dose interruption until adequate recovery or omission of a 
dose during a given treatment cycle. 
 Between cycles: next cycle administration may be postponed due to 
toxicity in the previous cycle. 
 In the next cycle: dose reduction based on worst toxicity or to 0.6 
mg/m2/cycle if hematologic remission is achieved in the previous cycle. 
 
3.4.5 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. 
Recovery to grade 1 or baseline non-hematologic test article-related 
toxicity (including liver function test abnormalities, not including alopecia). 
2. 
Serum bilirubin ≤1.5 x ULN, and AST, ALT and alkaline phosphatase ≤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. 
3. 
Any serum creatinine level associated with a measured or calculated 
creatinine clearance ≥ 15 mL/min using the method standard for the 
institution. 
4. 
Prior to the start of each cycle, for subjects with pre-treatment ANC ≥1 x 
109/L: ANC ≥1 x 109/L. 

 
 
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5. 
Prior to the start of each cycle, for subjects with pre-treatment platelets 
≥50 x 109/L: platelets ≥50 x 109/L. 
6. 
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 or other logistical delays (such as 
travel, inclement weather, scheduling issues, etc.) 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) will result in permanent discontinuation of study treatment.  
All toxicity grades are according to National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4). 
 
3.4.6 Dose reductions 
 
Patients with inotuzumab ozogamycin associated complications (prolonged 
thrombocytopenia, grade 3-4 liver toxicity) will receive subsequent doses of 
inotuzumab ozogamycin at a 33% dose reduction.  Patients experiencing 
treatment interruption due drug toxicity ≥14 days may resume dosing with 33% 
dose reduction (-1 dose level is defined by inotuzumab dose at D1 of 0.4 mg/m2 
and 0.2 mg/m2 at D8) for the subsequent cycle once adequate recovery is 
achieved. Once a patient has a dose reduction for a drug-related toxicity, the 
dose will not be re-escalated.  Patient requiring more than one dose reduction 
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) 
0.6 
0.3 
0.9 
-1 
0.4 
0.2 
0.6 
-2 
0.3 
0.1 
0.4 
 
3.4.7 Drug storage and drug accountability 
 

 
 
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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 Pfizer. All unused 
investigational product must be returned in the original containers to Pfizer with 
the appropriate form, or transferred to another site as applicable for this study.  
The site and the site monitor are to contact Pfizer for detailed information before 
the transfer of investigational product to another site, or return to Pfizer is 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 
Pfizer’s permission. For this protocol, undispensed investigational product is 
destroyed at the site only with the Pfizer’s permission and after accountability has 
been performed by Pfizer. 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. 
 
3.4.8 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 2-3 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. 

 
 
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 
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.  
 
3.5 Antibiotic prophylaxis 
 
Prophylactic antibiotics, antifungals, and antiviral agents are recommended; 
however, the use of these or other drugs will be left to the treating physician’s 
discretion. Antifungal prophylaxis with azoles should be held 24 hours before 
inotuzumab infusion and not start until 24 hours after completion of the 
inotuzumab ozogamycin infusion. Antibacterial antibiotic may consist of 
ciprofloxacin, levofloxacin, cefpodoxime, or others. Antifungal prophylaxis will be 
fluconazole, voriconazole, or other antifungals. 
 
3.6 CNS leukemia 
 
Patients who develop CNS leukemia while on study will be receive CNS-directed 
therapy, and may continue on the protocol after discussion with the Principal 
Investigator. 
 
3.7 Concomitant medications 
 

 
 
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Necessary supportive measures for optimal medical care will be given throughout 
the study as determined by the treating physician and the patient’s medical need. 
No concomitant chemotherapy (with the exception of prophylactic or therapeutic 
intrathecal chemotherapy for active CNS disease or CNS disease in remission), 
will be allowed during the study. Investigational agents that are not used for the 
treatment of the leukemia per se (e.g. anti-infective prophylaxis or therapy) will 
be allowed. Use of any hematopoietic growth factor (e.g. G-CSF, GM-CSF, or 
erythropoietin) is at the discretion of the treating physician and is permitted if 
judged in the patient’s best medical interest.  Concomitant medication data will 
not be entered into the case report form (CRF); however, the subject’s 
medication record will contain a list of concomitant medications.  
 
4.0 Patient Eligibility 
 
Inclusion Criteria: 
1. 
Patients at least 16 years of age with newly diagnosed, previously 
untreated B-lineage ALL, or having achieved CR with one course of 
induction chemotherapy. 
2. 
Patients with extramedullary disease only are eligible 
3. 
Failure to one induction course of chemotherapy (these patients will be 
analyzed separately). 
4. 
Performance status of 0-3. 
5. 
Adequate organ function with creatinine less than or equal to 2.0 mg/dL 
(unless considered tumor related), bilirubin less than or equal to 2.0 mg/dL 
(unless considered tumor related). 
6. 
Adequate cardiac function as assessed by history and physical 
examination. 
7. 
No active or co-existing malignancy with life expectancy less than 12 
months. 
8. 
Women of childbearing potential (WOCBP) or male subjects with a partner 
who is WOCBP must agree to use contraception during the study, if 
sexually active. 
 
Exclusion Criteria: 
1. 
Pregnant or nursing women.  
2. 
Known to be HIV-positive 
3. 
Ph-positive ALL 
4. 
Active and uncontrolled disease/infection as judged by the treating 
physician 
5. 
Unable or unwilling to sign the consent form 
6. 
Subjects who have current active hepatic or biliary disease (with exception 
of patients with Gilbert's syndrome, asymptomatic gallstones, liver 
involvement or stable chronic liver disease per investigator assessment) 
7. 
Chronic or current infectious disease requiring systemic antibiotics, 
antifungal, or antiviral treatment such as, but not limited to, chronic renal 

 
 
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infection, chronic chest infection with bronchiectasis, tuberculosis and 
active Hepatitis C. 
 
5.0 Treatment Plan 
 
5.1 General 
 
All patients are registered through CORe. Sixty patients will be enrolled. 
No dose escalations beyond those specified in the protocol are allowed. Other 
variations to the treatment plan outlined are allowed if felt to be in the best clinical 
interest of the patient. Major deviations should be discussed with the Principal 
Investigator. 
 
Examples of these clinical scenarios include: 
 
1. 
Treatment delays (> 14 days from recovery) despite hematologic recovery 
for reasons of patients request or unavoidable social situations. Treatment 
delays to allow recovery from infections or other toxicities of therapy will 
not be considered deviations, as these are expected complications of the 
therapy.  Treatment delays due to unavoidable social or logistical 
situations such as travel, inclement weather, scheduling issues, etc. will 
not be considered deviations. 
2. 
Dose reductions or alterations in the chemotherapy administration beyond 
those specified in the protocol for reasons of patient request or 
unavoidable social situations. Dose reductions performed for clinical 
reasons will not be considered deviations, as patients may have unique 
toxicities or tolerance not accounted for by standard dose reductions. 
3. 
Other clinical scenarios after approval by the Principal Investigator. 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. All dose adjustments will be 
made according to the protocol unless otherwise specified. 
 
5.2 Doses and Schedule 
 
General: 
 
1. Hyper-CVAD (Cycles 1, and 3) will alternate with high-dose 
methotrexate/cytarabine (Cycles 2 and 4) administered approximately 
every 21 days or later to allow for recovery from myelosuppression or 
infection; or earlier if count recovery allows. 
2. Anti-emetic therapy with each course of intensive chemotherapy as 
indicated. 

 
 
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3. Filgrastim product (G-CSF) at 10 mcg/kg/day (rounded) or pegfilgrastim 6 
mg as a single dose within 72 +/- 48 hours after completion of 
chemotherapy until neutrophil recovery to at least 1 x 109/l or higher. 
GFilgrastim product may be stopped earlier for bone pain or other related 
toxicity. 
4. Next course may be started when granulocytes >= 1 x 109/L and platelets 
>= 50 x 109/L, following discontinuation of Filgrastim product (G-CSF). 
Courses may be started with dose reductions prior to full platelet recovery, 
if the treatment is delayed (e.g., 28 days or later from the start of last 
course). See section 3.4.4 “Recommended Dose Modifications”, 3.4.5 
“Dose Delays”, and 3.4.6 “Dose Reductions” for further clarification. 
5. Prophylactic antibiotics (e.g. levaquin, trimethprim-sulfamethoxazole, 
fluconazole, valacyclovir) may be given with each course as indicated until 
neutrophil recovery 500/L. Prophylactic antibiotics will vary based on the 
patients' tolerance and allergy status. 
6. Patients with newly diagnosed, active disease who are aged 60 years or 
older may receive the first induction course in the protective environment 
unless they refuse, are unable to be confined, and/or medical illness 
prohibits. Protective environment is optional. 
7. CNS prophylaxis: total number of prophylactic intrathecal treatments for 
previously untreated patients will be 8, two with each course, until total 
number reached. Intrathecal route preferred. 
8. Ofatumumab will be administered: Days 1, 2 and 11 of Cycle 1, Days 1 
and 11 of Cycle 3, and Days 1 and 8 of Cycles 2 and 4. Rituximab 375 
mg/m2 IV days 1 and 11 of Cycles 1 and 3 and days 1 and 8 of Cycles 2 
and 4 replaces ofatumumab if insurance does not approve ofatumumab.  
9. XRT to the chest for patients with bulky mediastinal disease when 
indicated. 
10. Inotuzumab ozogamicin will be IV over one hour at the dose of 0.6 mg/m2 
on Day 1 and 0.3 mg/m2 on Day 8 of every cycle for 4 additional cycles as 
a single agent after completion of 4 cycles in combination with Hyper-
CVAD alternating with methotrexate/cytarabine. 
11. Maintenance therapy with POMP (6-MP, vincristine, methotrexate, 
prednisone) for approximately 12 months after completing induction/ 
consolidation therapy.  
 
Patients who do not complete all therapy per protocol, but remain in remission, 
will not be considered off-protocol, but will be monitored for disease-free survival 
only. An end-of-treatment date will indicate completion of therapy. 
 
Variations in infusion times due to minor differences in IV bag overfill/underfill 
and institutional procedure on flushing chemotherapy lines will not result in 
protocol deviation.  All infusion times are considered approximate. 
 
Hyper-CVAD (Cycles 1 and 3): 
 

 
 
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1. Cyclophosphamide (CTX) 300 mg/m2 IV over 3 h every 12 hrs x 6 doses 
days 1, 2, 3 (total dose 1800 mg/m2). 
2. MESNA 600 mg/m2/d IV continuous infusion daily for 24 hrs, starting 
approximately 1 hour prior to CTX and completing by approximately 12 hrs 
after the last dose of CTX. 
3. Doxorubicin 50 mg/m2 IV over 24 hrs via central venous catheter on day 4 
after last dose of CTX given (infuse over 48 hrs in patients with reduced 
ejection fractions < 50%). May be given by shorter infusion if difficulty with 
central venous access. 
4. Vincristine 2 mg IV on day 4 (+/- 2 days) and day 11 (+/- 2 days). 
5. Dexamethasone 40 mg IV or p.o. daily on days 1-4 (+/- 2 days) and days 
11-14 (+/- 2 days). 
6. Ofatumumab 300 mg IV on Day 1, 2000 mg on Days 2 (+/- 2 days) and 11 
(+/- 2 days) of Cycle 1, and 2000 mg IV on Days 1 (+/- 2 days) and 11 (+/- 
2 days) of Cycle 3 .  
7. Rituximab 375 mg/m2 IV Days 1 (+/- 2 days) and 11 (+/- 2 days) of Cycles 
1 and 3 replaces ofatumumab if insurance does not approve ofatumumab. 
8. Pegfilgrastim 6 mg as a one time dose or filgrastim product (G-CSF) 10 
mcg /kg (rounded) subcutaneously daily (or 5 mcg /kg twice daily)  starting 
after completion of chemotherapy until post-nadir granulocytes > 1.0 x 
109/L. 
9. CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya 
reservoir) on day 2 (+/- 2 days). Cytarabine 100 mg intrathecally on day 7 
(+/- 2 days).   
10. Tumor lysis prophylaxis with allopurinol, intravenous alkalinization, oral 
bicarbonate for course 1 and if indicated. Urate oxidase (Rasburicase) 
may be substituted for allopurinol. 
 
Suggested Dose Modifications: 
 
1. Vincristine 
- 
50% reduction (1 mg): 
 Bilirubin > 2 mg/dL and </= 3 mg/dL 
 Grade 2 persistent neuropathy. 
- 
Eliminate vincristine: 
 Grade 3-4 neuropathy 
 Ileus suspected to be related to vincristine 
 Bilirubin > 3 mg/dL 
2. Doxorubicin 
- 
50% reduction: 
 Bilirubin 2 to </= 3 mg/dL 
- 
75% reduction: 
 
 Bilirubin 3.1 to 5 mg/dL 
- 
Eliminate doxorubicin: 
 Bilirubin > 5 mg/dL 

 
 
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 Consider elimination in the first course in patients with 
small/large bowel or gastric involvement to reduce the length 
of myelosuppression and risk of perforation. 
- 
Administer over 48 hrs: 
 LVEF (if known) < 50% 
 
High-Dose Methotrexate and Cytarabine (Cycles 2 and 4): 
 
1. Methotrexate (MTX) 200 mg/m2 IV over 2 hrs followed by 800 mg/m2 over 
22 hrs on Day 1. 
2. Cytarabine 3 g/m2 IV over 2 hrs every 12 hrs for 4 doses on Days 2, 3. 
Reduce to 1 g/m2 IV over 2 hrs every 12 hrs for 4 doses on Days 2 and 3 
for: 
 Neurotoxicity (Grade 2 reversible cerebellar toxicity or other ara-C 
related CNS toxicity) with previous cycles.  
 Age 60 years or greater. 
 Creatinine greater than or equal to 1.5 mg/dL. 
 MTX > 20 mcM at time "0" (see below), confirmed on repeat sample. 
3. Citrovorum rescue 50 mg IV followed by 15 mg IV every 6 hours for 8 
doses beginning 12 hrs +/- 2 hrs post MTX. Additional rescue allowed as 
indicated for elevated levels or delayed methotrexate clearance. 
4. Check MTX around time 0h, 24h, and 48h post completion of MTX unless 
cleared (e.g. 0.15 mcM or less). 
 if > 20 mcM at time "0", hold ara-C and repeat level; if continues to be 
> 20 mcM reduce ara-C to 1 g/m2 IV over 2 hrs every 12 hrs for 4 
doses on Days 2, 3. 
 if > 1 mcM at 24 hrs or > 0.1 mcM at 48 hrs, increase citrovorum 
rescue until serum MTX level is < 0.1 mcM.  
 Clearance to levels 0.15 mcM or less is acceptable in patients with 
normal renal function. 
5. Consider oral acetazolamide 250 mg PO twice daily to promote MTX 
excretion if the urine pH is <7.0. 
6. Ofatumumab 2000 mg IV on Days 1 (+/- 2 days) and 8 (+/- 2 days) for 
Cycles 2 and 4. 
7. Rituximab 375 mg/m2 IV on Days 1 (+/- 2 days) and 8 (+/- 2 days) of 
Cycles 2 and 4 replaces ofatumumab if insurance does not approve 
ofatumumab. 
8. Pegfilgrastim 6 mg as a one time dose or filgrastim product(G-CSF) 10 
mcg/kg (rounded) subcutaneously daily (or 5 mcg /kg twice daily) after 
completion of chemotherapy until post-nadir granulocytes greater than or 
equal to 1.0 x 109/L. 
9. CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya  
reservoir) Day 8 (+/- 2 days). Cytarabine 100 mg intrathecally Day 5 (+/- 2 
days). 
 

 
 
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Suggested Dose Modifications: 
 
1. Cytarabine: 
a. 1 g/m2 IV over 2 hrs every 12 hrs for 4 doses on Days 2, 3: 
 Creatinine >= 1.5 mg/dL. 
 Time "0" MTX level > 20 mcM (on repeat level). 
 Age >= 60 years. 
 Grade 2 reversible cerebellar toxicity related to high-dose 
Ara-C. 
b. 1 g/m2 IV continuous infusion Days 2, 3: 
 Grade 2 reversible cerebellar toxicity related to ara-C 1 g/m2 
or grade 3 reversible cerebellar toxicity related to any dose 
of ara-C. 
2. Methotrexate: 
a. 25% to 50% reduction: 
 Grade 3 or worse mucositis with previous methotrexate 
course. 
b. 25% to 75% reduction: 
 delayed excretion and/or nephrotoxicity with previous 
methotrexate course. 
c. 50% reduction: 
 pleural effusion or ascites (drain effusion if possible) 
 Calculated creatinine clearance: 
 10 to 50 ml/min: reduce by 50% 
 < 10 ml/min: hold MTX 
 
Dosing modifications based on age and performance status will be permitted on 
Cycles 1-4 and maintenance intensifications. Suggested dose adjustments as 
below: 
 
 
 
Age < 60 
Age 60 – 74 
PS 0–2 
Age >74 
Age > 60, PS 3–4 
Cyclophosphamide 
(mg/m2) 
300 
250 
200 
Doxorubicin 
(mg/m2) 
50 
37.5 
25 
Vincristine (mg) 
2 
2 
1 
Dexamethasone 
(mg) 
40 
20 
20 
Methotrexate 
(mg/m2) 
200 
800 
100 
400 
50 
100 
Cytarabine (g/m2) 
3 
1 
0.5 
 
Note:  Age 60 – 64 with PS 0-1 may be treated with full doses (except for reduction 
of cytarabine to 1 g/m2 as per design) at the discretion of the treating physician   

 
 
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Inotuzumab ozogamicin Consolidation (Cycles 5 – 8) 
 
1. Inotuzumab ozogamicin will be IV over one hour at the dose of 0.6 mg/m2 
on Day 1 and 0.3 mg/m2 on Day 8 (+/- 2 days) of every cycle 
(approximately 21 Days) for 4 additional cycles as a single agent 
2. See section 3.4 for information on administration, dose delays and 
suggested dose adjustments. 
3. Ursodiol 300 mg PO TID should be started one week before starting the 
first cycle of inotuzumab ozogamicin treatment and administered 
continuously through all 4 cycles of inotuzumab ozogamicin. 
 
Maintenance Therapy: 
 
1. Patients may be moved from the intensive chemotherapy to the 
maintenance phase prior to completion of 4 cycles of chemotherapy 
and/or 4 cycles of inotuzumab ozogamicin if significantly intolerant of the 
intensive chemotherapy or inotuzumab ozogamicin after discussion with 
the Principal Investigator. 
 
2. Maintenance chemotherapy with 6-mercaptopurine (6-MP), methotrexate 
(MTX), vincristine, and prednisone (POMP) for approximately 12 months: 
 6-MP 50 mg PO three times daily (TID) 
 MTX 20mg/m2 (rounded) PO weekly 
 Vincristine 2 mg IV approximately every 28 days 
 Prednisone 200 mg PO daily days 1 to 5 approximately every 28 
days, starting with vincristine (if given). 
 
Suggested maintenance chemotherapy dose adjustments as below: 
 
Level 
MTX (mg/m2) 
(rounded) 
6-MP (mg/d) 
Vincristine (mg) 
Prednisone (mg) 
0 
20 
150 
2 
200 
-1 
15 
100 
1 
100 
-2 
10 
50 
0 
50 
-3 
5 
50 
0 
0 
 
3. Dose adjustments for myelosuppression include MTX and 6-MP, but not 
vincristine or prednisone (the latter should remain 200 mg unless steroid 
myopathy or other uncontrolled significant toxicity occurs). Titrate to keep 
granulocytes >= 1 x 109/L and platelet count >= 50 x 109/L. 
4. Methotrexate 
 Decrease by one dose level for mucositis > grade 2. 
 Decrease by one dose level for bilirubin > 2.5 or elevation of 
transaminases >= 5 x upper limit of normal. 

 
 
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 Hold if granulocyte count nadir < 0.5 x 109/L or platelets < 10 x 
109/L, resume with decrease in one dose level or lower depending 
on duration of cytopenias. 
5. 6-mercaptopurine 
 Decrease by one dose level for bilirubin > 2.5 mg/dL or elevation of 
transaminases >= 5 x upper limit of normal. 
 Hold if granulocyte count nadir < 0.5 x 109/L or platelets < 10 x 
109/L, resume with decrease in one dose level or lower depending 
on duration of cytopenias. 
6. Vincristine 
 Decrease by one dose level for >= grade 2 peripheral neuropathy 
persisting for more than 2 weeks. 
 Discontinue for grade 3 or greater peripheral neuropathy. 
7. Note that the dose adjustments of POMP are guidelines, and the dosing 
needs to be individualized to the patient, as differential toxicities between 
6-MP and methotrexate may be difficult to discern. 
 
Continued antiviral prophylaxis to prevent herpes zoster is strongly 
encouraged. Consider antifungal prophylaxis during days of prednisone. 
Consider PCP prophylaxis. 
 
5.3 Central Nervous System (CNS) Management 
 
1. Standard CNS prophylaxis with intrathecal methotrexate and ara-C with 
each course if no evidence of CNS disease. 
2. Total number of prophylactic intrathecal treatments = 8, consisting of 2 
intrathecal treatments with methotrexate and ara-C with each course until 
total number reached. Missed intrathecals (e.g., related to failed 
procedure attempts, scheduling issues, patient social situations) can be 
"made up" with subsequent courses of chemotherapy. All patients will 
receive 8 intrathecal treatments. 
3. If the patient has been previously treated, and has had prior intrathecal 
therapy, or prior CNS disease, discuss management of CNS 
prophylaxis/therapy with the Principal Investigator. 
4. If active CNS disease: methotrexate alternating with ara-C twice weekly 
until CSF clear; then once weekly for 4 weeks, then back to prophylactic 
schedule. Consider XRT to the base of the skull, particularly with cranial 
nerve root involvement (cranial nerve palsies, except for instances where 
intrathecal therapy alone is expected to produce a response (e.g., mental 
neuropathy, isolated lateral rectus palsy). Alternative methods of treating 
CNS disease are allowed if appropriate for the patient (e.g., intrathecal 
liposomal ara-C, topotecan, ifosfamide, radionucleotides or others). 
 
5.4 Mediastinal disease 
 

 
 
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Patients with mediastinal lymphocytic lymphoma and bulky mediastinal disease 
(defined as >= 7 cm) or residual mediastinal lymphadenopathy at the end of the 
intensive chemotherapy portion of the treatment should be considered for 
consolidative mediastinal irradiation after recovery from the last course of 
consolidation therapy and prior to the inotuzumab ozogamicin phase of therapy. 
 
 
6.0 Pretreatment evaluation 
Procedure 
Comments 
Schedule 
Informed Consent 
Obtain standard informed consent approved by 
IRB 
Within 14 days of therapy 
Medical History 
History of present illness, known allergies, prior 
cancer history as far as traceable, 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), full physical exam and 
ECOG 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, alkaline phosphatase 
Within 14 days of therapy 
Bone marrow 
Aspirate and/or biopsy with flow cytometry for 
confirmation of diagnosis  
Within 21 days of therapy 
Lumbar puncture 
To assess for CNS disease 
Within 21 days of therapy 
Serology 
HIV titers and hepatitis B and C titers 
Within 21 days of therapy 
Pregnancy test 
Serum or urine, if female and of 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 
Liver Ultrasound/ 
Elastography 
 
Within 30 days of start of 
therapy 
 
 
7.0 Evaluation During Study 
Procedure 
Comments 
Schedule 
Hematology 
CBC with differential 
and platelet count 
Weekly during courses 1 to 4 of intensive chemotherapy and 
courses 1 to 4 of inotuzumab ozogamicin and at least 
monthly during maintenance  
Biochemistry 
at least creatinine, 
total bilirubin, SGPT 
or SGOT, alkaline 
phosphatase 
At least once every 2 weeks during course 1, then at least 
every 4 weeks during courses 2 - 4 of chemotherapy and 
courses 1-4 of inotuzumab ozogamicin, and at least every 4 
weeks during maintenance therapy 
Physical 
Examination 
Focused physical 
examination 
Prior to each treatment course 
Weight 
 
Within 72 hours prior to each cycle of inotuzumab 
ozogamicin (Cycle 5-8) 
Bone marrow 
Aspirate and/or 
biopsy (MRD  by flow 
multicolor cytometry. 
On day 14 +/- 3 days of the first course of chemotherapy for 
patients with involvement of marrow at diagnosis, then 
weekly +/- 3 days until remission or lack of response 
established. Once in CR, marrows will be repeated after 3 
additional courses of chemotherapy and/or before the start of 

 
 
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Page 24 
 
 
Procedure 
Comments 
Schedule 
inotuzumab ozogamicin, then on Day 21 +/- 7 days of the 
first course of inotuzumab ozogamicin, then after every cycle 
if MRD positive at the start of inotuzumab ozogamicin, and 
every 4 months (+/- 1 month), thereafter. In patients with 
negative MRD at the start of inotuzumab ozogamicin, bone 
marrow assessment will be performed every 4 months (+/- 1 
month) after finishing intensive chemotherapy administration. 
No marrow is necessary at anytime if non-response is 
obvious based on peripheral blood counts 
Imaging 
studies 
Chest X-ray and or 
PET/CT 
At the time of maximum response and/or when clinically 
determined to be necessary. 
 
7.1 Follow-up 
 
Thirty days after last dose of the inotuzumab ozogamicin concomitant medication 
and AE assessment will be performed.  This may be done over the phone with a 
member of the study staff. The phone call should last about 10 minutes.   
 
7.2 Long-term Follow-up 
 
Patients will be followed periodically every 6 months (+3 months) for survival via 
brief phone call, even after being taken off treatment.  
 
7.3 Outside Physician Participation During Treatment 
 
1. MDACC Physician communication with the outside physician is required 
prior to the patient returning to the local physician. This will be 
documented in the patient record. Standard laboratory examinations listed 
in Section 7.0 may be performed locally.    
2. A letter to the local physician outlining the patient's participation in a 
clinical trial will request local physician agreement to supervise the 
patient's care (Appendix H.).  
3. Protocol required evaluations outside MDACC will be documented by 
telephone, fax or e-mail. Fax and/or e-mail will be dated and signed by the 
MDACC physician, indicating that they have reviewed it.  
4. Changes in drug dose and/or schedule must be discussed with and 
approved by the MDACC physician investigator, or their representative 
prior to initiation, and will be documented in the patient record.  
5. A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician.  
6. Documentation to be provided by the local physician will include drug 
administration records, progress notes, reports of protocol required 
laboratory and diagnostic studies and documentation of any 
hospitalizations.  
7. The home physician will be requested to report to the MDACC physician 
investigator all life threatening events within 24 hours of documented 
occurrence.  

 
 
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8. Patients will return to MDACC after every 3 courses of chemotherapy, 
prior to the start of inotuzumab ozogamicin (if MRD positive), and then 
every 4 months after achieving Complete Remission for evaluation.  
 
 
8.0 Criteria for Response 
 
8.1 Acute lymphocytic leukemia: 
 
 Complete remission (CR): 
o Normalization of the peripheral blood and bone marrow with 5% or 
less blasts in a normocellular or hypercellular marrow with a 
granulocyte count of 1 x 109/L or above and a platelet count of 100 
x 109/L or above. Complete resolution of all sites of extramedullary 
disease is required for CR. 
 
 Partial response (PR): 
o As above, except for the presence of 6-25% marrow blasts. 
 
 MRD negativity: 
o 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 at least 10−4 and confirmed 
on a second bone marrow aspiration/biopsy performed after a 
subsequent cycle. In addition, patients should have normalization of 
the peripheral blood and bone marrow with 5% or less blasts in a 
normocellular or hypercellular marrow with a granulocyte count of 1 
x 109/L or above and a platelet count of 100 x 109/L or above. 
 
8.2 Lymphocytic lymphoma (with extramedullary disease): 
 
8.21 Objective response of bi-dimensionally measurable and uni-dimensionally 
measurable parameters: 
 
 Complete response (CR): 
o Complete disappearance of all known disease. 
 
 Partial response (PR): 
o 50% or more decrease in tumor size using the sum of the product 
(bi-perpendicular dimensions when available). This includes a 50% 
volume decrease in lesions measurable in three dimensions. 
 
 No response (NR): 
o No significant change (includes stable disease). Lesions decreased 
in size, but < 50% or lesions with slight enlargement but < 25% 
increase in size. 

 
 
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 Progressive disease (PD): 
o Appearance of new lesions. 25% or greater increase in size of 
existing lesions (increase 50% or greater if only one lesion is 
available and is 2 cm or less in size). 
 
8.2.2 Objective response for non-measurable parameters. 
 
 CR, NR, and PD same as above but estimated. 
 PR: definite improvement estimated to be at least 75% of lesion but not 
quantifiable by measurement. 
 
 
9.0 Evaluation of Toxicity and Reporting Requirements 
 
Adverse event (AE) reporting and recording in the CRF (Prometheus) will be as 
per the NCI criteria and the MDACC Leukemia Specific Adverse Event Recording 
and Reporting Guidelines (Appendix G). 
 
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).   
AEs will be recorded in the subject’s source documents from the first protocol-
specific intervention through 30 days after the last dose of study treatment.  
Serious Adverse Events (SAEs) will be captured and reported in accordance with 
Section 9.2 requirements.  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 to inotuzumab ozogamicin. 
 
9.1 Adverse events 
Information about all adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical examination, 
laboratory test or other means, will be collected and recorded and followed as 
appropriate. 
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, or require 
therapy. 

 
 
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The occurrence of adverse events should be sought by non-directive questioning 
of the patient at each visit during the study. Adverse events also may be detected 
when they are volunteered by the patient during or between visits or through 
physical examination, laboratory test, or other assessments. As far as possible, 
each adverse event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (grade 1-4) 
2. its relationship to the investigational agent(s) (unrelated, unlikely, possible, 
probably or definite) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or discontinuation, 
starting or stopping concomitant treatments, changes in the frequency or nature of 
assessments, hospitalization, or any other medically required intervention. Once 
an adverse event is detected, assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to 
the study drug, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational 
drug can be found in the Inotuzumab Ozogamicin Investigators’ Brochure – See 
Appendix F. This information should be included in the patient informed consent 
and should be discussed with the patient during the study as needed. 
 
9.2 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 

 
 
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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, 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 inotuzomab, 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. 
 
9.3 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. 

 
 
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9.4 Investigator Communications with Pfizer 
 
Reporting to the 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. 
 
 
10.0 Criteria for Removal from the Study 
 
Criteria for removal from study include, but are not restricted to, the following: 
 
 Progressive disease. 
 Non-compliance by the patient with protocol requirements. 
 Patient's request to be removed from the study. 
 If patient begins a new treatment for the disease, including stem 
cell transplant. 
 
11.0 Statistical Considerations 
 
This is a single-arm phase II study of the sequential combination of hyper-CVAD 
+ inotuzumab ozogamicin in patients with newly diagnosed B-cell ALL. The 
primary objective is to evaluate the clinical efficacy of this combination. The 
primary efficacy endpoint is event-free survival, which is defined as the time 
interval from date of treatment start until the date of death, disease progression 
or relapse. Patients who are alive and relapse-free at the last follow-up date will 
be censored at that time. In addition, patients who drop off the study due to 
receiving allogeneic stem cell transplantation will be censored at the time off 
study.  
 
The study will be continuously monitored for the primary endpoint, EFS, using the 
method of Thall, Wooten, and Tannir (2005).  Our goal is to improve the median 
EFS from 27 months (based on historical treatment) by at least 9 months using 
the combination of hyper-CVAD and inotuzumab ozogamicin. It is assumed that 
the EFS time is exponentially distributed with a median of E among patients who 
receive hyper-CVAD plus inotuzumab ozogamicin, and a median of H is 
assumed for the historical treatment.   Furthermore, we assume that H follows 

 
 
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an inverse gamma distribution, i.e., H ~ IG(74.9, 1995.3), which has a mean of  
27 months and variance of 10. To reflect the little prior knowledge of E we 
assume an inverse gamma prior distribution with the same mean of 27 months 
and a much larger variance of 100, i.e., E ~ IG(9.29, 223.83).  The trial will be 
stopped early if Pr(E  > H +δ|data) < pL, where δ = 9 months and pL=0.05 and 
this futility monitoring rule will be first applied when 10 patients have been 
enrolled. A maximum of 60 patients will be enrolled into this study at an expected 
accrual rate of 2 patients per month.  Patients will be followed up for an additional 
24 months after all patients have been enrolled. The trial will be conducted using 
the Clinical Trial Conduct (CTC) website maintained by the Department of 
Biostatistics at MDACC.  
 
The operating characteristics of the design, based on an overall assumed accrual 
rate of 2 patients per month with 1000 simulated trials per scenario, are given in 
the following table. OneArmTTE (version 2.2) was used for the design and 
simulation. 
 
Scenario 
True 
Median 
EFS  
(months) 
Pr(Stopped 
Early) 
Mean 
No. patients 
Average Trial 
Duration 
(months) 
1 
18 
0.906 
33.1 
40.6 
2 
21 
0.754 
39.4 
43.7 
3  
27 
0.373 
51.0 
49.6 
4 
36 
0.113 
56.8 
52.3 
5 
42 
0.045 
58.5 
53.2 
6 
48 
0.018 
59.4 
53.9 
 
In addition, we will continuously monitor treatment-related toxicities using the 
Bayesian approach of Thall, Simon, Estey (1995).  Specifically, the trial will be 
stopped if Prob(πT>0.30 | data)>0.93, where πT is the toxicity rate and we 
assume a beta (0.6, 1.4) prior for πT. That is, if at any given time, there is more 
than 93% probability that the toxicity rate of the maintenance therapy with 
inotuzumab ozogamicin is greater than 30%, the trial will be stopped. For the 
purpose of toxicity monitoring, toxicities are defined as any treatment –related 
grade 3 or 4 non-hematologic AEs occurred any time during the trial.  We will 
apply this stopping rule starting from the 5th patient and in cohort size of 5. An 
Efficacy/Toxicity Summary will be submitted to the IND Office Medical Affairs and 
Safety Group, after the first 5 evaluable subjects complete Cycle 5 f the study 
therapy, and every 5 evaluable patients thereafter.  The first summary is to 
include treatment related toxicity during Cycle 5.  On every upcoming summary 
submission, the Efficacy/Toxicity information from previous reported patients will 
be updated, until the end of their participation.  The stopping boundaries 
corresponding to this toxicity monitoring rule are described in the following table: 
 

 
 
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Stopping boundaries for treatment-related grade 3, 4 non-hematologic 
toxicities 
 
The number of patients evaluated for 
toxicities (in cohort size of 5) 
Stop the trial if this many of patients 
with toxicities 
5 
4-5 
10 
6-10 
15 
8-15 
20 
10-20 
25 
12-25 
30 
14-30 
35 
15-35 
40 
17-40 
45 
19-45 
50 
21-50 
55 
22-55 
60 
Always stop with this many of patients 
 
The operating characteristics for toxicity monitoring are described in the following 
table. MultcLean Desktop 2.1.0 was used for the design and simulations for 
toxicity monitoring.  
 
Operating characteristics for Toxicity Monitoring 
 
True Toxicity 
Rate 
Early Stopping 
Probability 
Sample Size 
25th 
percentile 
Median 75th 
percentile 
0.10 
0.0006 
 60 
 60 
 60 
0.20 
0.016 
 60 
 60 
 60 
0.30 
0.174 
 60 
 60 
 60 
0.40 
0.663 
 15 
 35 
 60 
0.50 
0.966 
 10 
 15 
 30 
 
Analysis Plan 
 
The probabilities of EFS and OS will be estimated using the method of Kaplan 
and Meier. For the primary analysis of the efficacy endpoint, we will compute the 
Bayesian posterior probability of Pr(E  > H +δ|data), where δ = 9 months. As a 
secondary analysis, we will perform a competing risk analysis treating stem cell 
transplant as a competing event for EFS.  The MRD negativity rate and overall 
response rate will be estimated along with the exact 95% confidence intervals. All 
treated patients will be included in the safety analysis set. The AEs will be 
summarized by organ type, grade and attribution to study treatment.  
 
 
 

 
 
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