Conditions: Acute Lymphoblastic Leukemia
Keywords: Relapsed Refractory Acute Lymphoblastic Leukemia ALL Burkitt's lymphoma Lymphoblastic lymphoma CMC-544 Inotuzumab Ozogamycin Rituxan Rituximab
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 90
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if CMC-544 given alone, and possibly given in combination with rituximab, can help to control the disease in patients with ALL. The safety of the study drug(s) will also be studied.

Detailed description:
Study Drugs:

CMC-544 is a monoclonal antibody (a substance that can locate and bind to cancer cells). It is designed to attach to C22, a molecule that is found on most cancer cells with ALL. This may cause the cancer cells to die.

Rituximab is a monoclonal antibody that is designed to attach to leukemia cells and activate a series of events that may cause the cancer cells to die.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive CMC-544 by vein over about 60 minutes on Day 1 of each study "cycle" or over 60 minutes at a lowered dose on Days 1, 8 and 15 of each cycle, depending on when you joined the study. No matter what dosing schedule you are on, you will receive the same total dosage of CMC-544. Each study cycle is about 3-4 weeks.

If the disease is not responding to the CMC-544 after 2 cycles, you will begin receiving rituximab. On Day 1 of Cycle 3, you will receive rituximab by vein over about 8 hours. On Day 2 of Cycle 3, you will receive CMC-544 alone by vein over about 60 minutes. Then, starting on Day 1 of Cycle 4, you will begin receiving rituximab by vein over about 8 hours and CMC-544 by vein over about 60 minutes at least 2-4 hours after you receive the rituximab. You will receive this combination 1 time every week.

Your dose of the study drug(s) may change depending on any side effects you may have.

Study Visits:

You will have study visits within 1 week before Day 1 of each study cycle. At each study visit, the following tests and procedures will be performed:

* You will have a physical exam.
* Your performance status will be recorded.
* You will be asked how you are feeling and about any drugs you may be taking.
* You will have an ECG before you receive treatment with CMC-544 (+ 2 days).
* Blood (about 1 tablespoon) may be drawn to test how the study drug(s) may affect cancer cells before you receive the CMC-544 infusion.
* If you are receiving rituximab and if you have a history of irregular heartbeat or chest pain (due to heart trouble), you will have ECGs performed before the start of the rituximab, once during the infusion, and within 2 hours after the infusion. Rituximab infusion will be stopped if you experience any serious episodes of irregular heartbeat.
* If you are receiving rituximab, you may be examined for any signs or symptoms of bowel obstruction (blockage) and/or perforation (hole in the intestines, which may cause the contents to leak). Appropriate radiologic tests and surgical consults will be performed as needed.

Blood (about 1 tablespoon each time) will be drawn 1-3 times each week during Cycles 1 and 2, and at least 1 time every week during all other cycles for routine tests. Your doctor may decide to have more than 3 blood draws during Cycles 1 and 2.

You will have a bone marrow aspirate and/or biopsy between Days 14-21 (+/- 3 days) of Cycle 1 then every 1-2 cycles to check the status of the disease. You may have additional bone marrow aspirates and/or biopsies if your doctor feels it is necessary.

Length of Study:

You may receive CMC 544 with or without rituximab for up to 12 months. You will be taken off study if the disease gets worse or if you have intolerable side effects

Follow-up Visits:

You will have a follow-up visit 30 days after your last dose of the study drug(s). At this visit, you will be asked about any side effects you may be having. If you cannot make it to the clinic for this visit, it can be done over the phone with a member of the study staff. The phone call should last about 10 minutes.

This is an investigational study. Rituximab is FDA approved and commercially available for the treatment of lymphoid cancer. Neither CMC-544 nor the CMC-544/rituximab combination are FDA approved or commercially available. Their use in this study is investigational.

Up to 90 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: First patients \> 16 years and \< 16 years receive CMC-544 (Inotuzumab Ozogamycin) at a dose of 1.3 mg/m\^2 by vein (IV) over 1 hour during Course 1, and 1.8 mg/m\^2 IV over 1 hour during Course 2 and subsequently. In all other patients beginning dose of 1.8 mg/m\^2 IV over 1 hour every 4 week cycle. With no improvement after 2 courses of CMC-544, addition of Rituximab dose 375 mg/m\^2 IV (by vein) over 2-6 hours every 3-4 weeks. arm 2: CMC-544 (Inotuzumab Ozogamycin) 0.8 mg/m\^2 IV over 1 hour (+ 15 minutes) on Day 1, 0.5 mg/m\^2 IV over 1 hour (+ 15 minutes) on Day 8, and 0.5 mg/m\^2 IV over 1 hour (+ 15 minutes) on Day 15. Weekly doses can be given at + 1 day. Course may be repeated every 3 weeks. Rituximab will be given on Day 1 and CMC-544 on Day 2 of the first dose; with subsequent weekly doses, both will be given weekly, rituximab preceding CMC-544. The weekly dose of rituximab will be 375 mg/m2. arm 3: First patients \> 16 years and \< 16 years receive CMC-544 (Inotuzumab Ozogamycin) at a dose of 1.3 mg/m\^2 by vein (IV) over 1 hour during Course 1, and 1.8 mg/m\^2 IV over 1 hour during Course 2 and subsequently. In all other patients beginning dose of 1.8 mg/m\^2 IV over 1 hour every 4 week cycle. With no improvement after 2 courses of CMC-544, addition of Rituximab dose 375 mg/m\^2 IV (by vein) over 2-6 hours every 3-4 weeks.

Interventions: intervention 1: CMC-544 (Inotuzumab Ozogamycin) intervention 2: Rituximab
Intervention descriptions: intervention 1: First patients \> 16 years and \< 16 years receive CMC-544 at a dose of 1.3 mg/m\^2 by vein (IV) over 1 hour during Course 1, and 1.8 mg/m\^2 IV over 1 hour during Course 2 and subsequently. In all other patients beginning dose of 1.8 mg/m\^2 IV over 1 hour every 4 week cycle.

Part 2 CMC-544 (Inotuzumab Ozogamycin) 0.8 mg/m\^2 IV over 1 hour (+ 15 minutes) on Day 1, 0.5 mg/m\^2 IV over 1 hour (+ 15 minutes) on Day 8, and 0.5 mg/m\^2 IV over 1 hour (+ 15 minutes) on Day 15. Weekly doses can be given at + 1 day. Course may be repeated every 3 weeks. Rituximab will be given on Day 1 and CMC-544 on Day 2 of the first dose; with subsequent weekly doses, both will be given weekly, rituximab preceding CMC-544. The weekly dose of rituximab will be 375 mg/m2. intervention 2: With no improvement after 2 courses of CMC-544, addition of Rituximab dose 375 mg/m\^2 IV (by vein) over 2-6 hours every 3-4 weeks.

Protocol document:
Prot_SAP_000.pdf: 
2009-0872
December 2, 2011
Page 1
Protocol Page
Treatment of Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) with 
CMC-544 (Inotuzumab Ozogamycin), with or without Later Addition of Rituximab
2009-0872
Core Protocol Information
Short Title 
CMC-544 in relapsed refractory ALL
Study Chair: 
Hagop Kantarjian
Additional Contact:
Jhinelle L. Graham
Vicky H. Zoeller
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-7026
Unit:
428
Full Title: 
Treatment of Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) with CMC-544 
(Inotuzumab Ozogamycin), with or without Later Addition of Rituximab
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 04/19/2018
Version:
15
Submitted by:
Vicky H. Zoeller--7/21/2017 11:39:36 AM
OPR Action:
Accepted by:  Julie Arevalo -- 7/31/2017 4:07:23 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2009-0872
December 2, 2011
Page 2
Protocol Body
 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 1 of 36 
 
 
 
 
Treatment of Relapsed or Refractory Acute Lymphoblastic Leukemia 
(ALL) with CMC-544 (Inotuzumab Ozogamycin), with or without Later 
Addition of Rituximab 
 
 
 
Short Title:  CMC-544 in relapsed refractory ALL 
 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 2 of 36 
Table of Contents 
 
1.0 
OBJECTIVES ....................................................................................................... 3 
2.0 
BACKGROUND ................................................................................................... 3 
3.0 
BACKGROUND DRUG INFORMATION ........................................................... 98 
4.0 
PATIENT ELIGIBILITY ...................................................................................... 16 
5.0 
TREATMENT PLAN ....................................................................................... 1817 
6.0 
PRETREATMENT EVALUATION ...................................................................... 22 
7.0 
EVALUATION DURING THERAPY ................................................................... 23 
8.0 
CRITERIA FOR RESPONSE ............................................................................. 25 
9.0 
CRITERIA FOR REMOVAL FROM THE STUDY .......................................... 2625 
10.0 
REPORTING REQUIREMENTS .................................................................... 2726 
11.0 
STATISTICAL CONSIDERATIONS ................................................................... 30 
12.0 
REFERENCES ................................................................................................... 33 
 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 3 of 36 
Treatment of Relapsed or Refractory Acute Lymphoblastic Leukemia 
(ALL) with CMC-544 (Inotuzumab Ozogamycin), with or without Later 
Addition of Rituximab 
 
1.0 
Objectives 
 
To evaluate the efficacy of treatment with CMC-544 with or without later 
rituximab in patients with relapsed or refractory ALL.  
 
To evaluate the side effects of the treatment.  
 
2.0 
Background  
2.1 
Acute Lymphoblastic 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. 
 
The hyper-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, 
doxorubicin, and dexamethasone alternating with high dose methotrexate and ara-C) 
(4,5), developed at M. D. Anderson, demonstrated significant activity, producing a 
complete remission (CR) rate of 90% and a cure rate of 40%-50%.  
 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 4 of 36 
Current outcomes of salvage chemotherapy for ALL are poor, with complete response 
rates of 20% to 30% depending on prior therapy and duration of first remission. Median 
disease-free survival ranges from 2 to 7.5 months. Long-term survival after ALL salvage 
therapy is rare.  Less than 10% of patients are eligible for allogeneic stem cell 
transplant.  Among them the cure rate is 20% or less.  No standard of care has been 
defined, so that salvage therapy options are generally limited to investigational agents 
once patients fail standard chemotherapy regimens(6,7). Not many treatments are 
available for ALL salvage.   
 
New agents or regimens are needed to improve outcome in ALL.  ALL blasts express 
several surface markers including CD19, CD20, and CD22.  CD22 is expressed on the 
surface of ALL blasts in more than 90% of patients.  Several new monoclonal antibodies 
have been developed that target these surface markers.  Monoclonal antibodies with 
proven efficacy against ALL could potentially, when used in combination with 
chemotherapy, significantly improve ALL prognosis.  For example, rituximab has 
minimal single agent activity in ALL but, when added to hyper-CVAD, has improved 
significantly the outcome in Burkitt’s ALL and in CD20-positive pre-B ALL. 
 
2.2 
The Treatment -- CMC-544 (Inotuzumab Ozogamycin) and Rituximab 
CMC-544 (inotuzumab ozogamicin) is a CD22-targeted cytotoxic agent composed of a 
humanized IgG4 anti-CD22 antibody covalently linked to N-acetyl-g-calicheamicin 
dimethyl hydrazide (CalichDMH) via the acid-labile 4-(4V-acetylphenoxy) butanoic acid 
linker (8-10). CD22 is a B-lymphoid lineage–specific differentiation antigen expressed 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 5 of 36 
on both normal and malignant B cells. CMC-544 binds CD22 with subnanomolar affinity, 
and, upon binding, is rapidly internalized delivering the conjugated CalichDMH inside 
the cells. This preferential intracellular delivery of CalichDMH causes DNA damage 
resulting in B-cellular apoptosis. CalichDMH is a derivative of g-calicheamicin, a natural 
product produced by Micromonospora echinospora and is significantly more potent than 
cytotoxic chemotherapeutic agents used in cancer therapy.  It binds in the minor groove 
of DNA and causes double strand DNA breaks in a relatively sequence-specific and 
thioldependent manner leading to apoptotic response in cells (11-13). CMC-544 exerts 
potent and CD22-selective growth inhibitory activity against CD22+ B-cell lymphoma 
(BCL) cell lines in vitro and causes regression of developing (minimal disease), small 
established (palpable disease), and large BCL xenografts, with a high therapeutic index 
(9). In addition, CMC-544 had in vitro high activity against CD22 positive ALL cell lines 
(14). In the absence of the conjugated CalichDMH, G5/44, the targeting monoclonal 
antibody (mAb) in CMC-544 is ineffective in vivo as an antitumor agent in various 
preclinical models (8).  Thus, CMC-544 is regarded as an antibody-targeted 
chemotherapy agent rather than an immunotherapeutic agent like rituximab. Largely 
due to its tumor-targeted, drug-delivery capability, CMC-544 is likely to have a better 
therapeutic index than that of conventional chemotherapeutic agents. Based on its 
potent antitumor activity in preclinical models, CMC-544 is currently being evaluated in 
patients with B-cell non-Hodgkin lymphoma (B-NHL).  Early results show encouraging 
activity with response rates of 40% to 75% in patients with refractory relapsed 
BNHL(15).  CD22 is expressed on leukemic blasts in more than 90% of adults with ALL.  
Thus, CMC-544 may be also an effective treatment for ALL. 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 6 of 36 
 
Rituximab is a chimeric human IgG1 antibody targeted to another B-lymphoid lineage–
specific molecule, CD20. It represents a major therapeutic advance in B-NHL therapy. 
Rituximab mediates its antitumor activity by multiple mechanisms that include 
complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity 
(ADCC), and direct induction of apoptosis in BCL (16-17). The activity of single agent 
rituximab is modest in BNHL, chronic lymphocytic leukemia, and ALL.  However when 
combined with chemotherapy it has improved outcome significantly in all 3 entities (18-
21).   
 
2.3 
Rationale for the Study Design 
Due to its clinical safety, rituximab is widely used in combination with various cytotoxic 
agents.  Treatments using combinations of rituximab with cytoreductive combination 
chemotherapy, like CHOP (a combination of cyclophosphamide, doxorubicin, vincristine, 
and prednisone), hyper-CVAD, or fludarabine-cyclophosphomide are highly active.  
However, such combinations of chemoimmunotherapy also suffer from various systemic 
toxicities associated with the non-targeted nature of chemotherapy.  Thus, studies of 
targeted therapy combinations like CMC-544 (target CD22) and rituximab (targets 
CD20) in pre-B ALL would be highly attractive, because of the potential of high efficacy 
and low toxicity.  This is the purpose of this study.  If successful, this combined targeted 
therapy may become a new standard of care for patients with refractory relapsed ALL.  
It may also be brought into frontline therapy of minimal residual disease to increase the 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 7 of 36 
cure of patients with newly diagnosed pre-B ALL.  Thus the study has major potential 
therapeutic implications for improving adult ALL prognosis.  
 
The phase I-II studies of CMC-544 determined the phase II dose to be 1.8 mg/m2 once 
every 3-4 weeks.  The DLT was myelosuppression.  Other side effects were 
gastrointestinal and hepatic.  Only 1 case of veno occlusive disease was noted among 
176 patients treated(14).  Phase II studies combining rituximab 375 mg/m2 on Day 1 
and CMC-544 1.8 mg/m2 on Day 2 were safe and effective in lymphomas(15). 
 
2.4 
Update of October 6, 2010 
At present, a total of 21 patients with refractory relapse ALL have been treated.  Fifteen 
of them were in second salvage or worse; eight of them have translocation 4;11 or 
Philadelphia positive ALL.  Overall, 12 of 21 patients have achieved either CR (n=5) or 
Cri (n=7), for an overall response rate of 57%.  This is even better than what is expected 
using standard combination intensive chemotherapy in first salvage, with which the CR 
rate would be expected to be about 30%.  Toxicity has been minimal.  There were two 
episodes of tumor lysis responding to standard measures.  Fever on Day 2 post therapy 
is common.  Transient grade 1-3 elevations of liver enzymes have been observed, 
which are expected and self-limited.  Two patients died within four weeks, one of them 
with progressive disease.  Overall the treatment appears to be extremely effective with 
minimal toxicity.  This has allowed so far at least 4 patients to undergo allogeneic stem 
cell transplant.  Based on the findings we propose to 1) allow treatment of patients in 
first salvage regardless of the duration of first CR, and 2) increase the total number of 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 8 of 36 
patients to 60 to allow more accurate assessment of the overall response rate and 
define more precisely predictive factors for response to therapy. 
 
2.5 
Update of January 7, 2011 
At the present update, 38 patients have been treated.  Of 32 evaluable patients, 8 
achieved CR and 10 achieved CRi or CRp for an overall response rate of 18/32 =56%.  
Toxicities were reasonable and included Grade 1-2 elevations of liver function tests 
which were transient.  Two patients had Grade 3 liver function abnormalities; the 
attribution to the drug was questionable. 
 
From preclinical studies, it is thought that lower dose more frequent exposure schedules 
to inotuzumab may offer better anti-ALL efficacy.  Following discussions in the 
Leukemia group and with Pfizer investigators, it was decided to study a different 
schedule of inotuzumab given weekly times 3.  The total dose per course is the same, 
1.8 mg/m2.  The treatment will be with inotuzumab 0.8 mg/m2 on Day 1, 0.5 mg/m2 on 
Day 8, and 0.5 mg/m2 on Day 15.  Courses are given every 3 weeks.  When rituximab 
is required, it will be given weekly with inotuzumab.  A total of 20 patients will be treated 
to gain experience with efficacy and toxicity.  Early stopping rules will be implemented 
for an overall response rate < 40%. 
 
2.6 
Update of December 2, 2011 
This study has completed accrual of 20 patients on the weekly schedule.  The early 
analysis shows encouraging results with trends for similar or better efficacy and less 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 9 of 36 
toxicity.  Among the first 15 evaluable patients, 2 achieved CR (12%), 5 achieved CRp 
(31%) and 1 achieved CRi (6%).  Thus, 8 of 15 evaluable patients (53%) achieved 
marrow CR.  Five of the 7 evaluable responders (71%) achieved MRD negativity.  Three 
patients underwent allogeneic SCT; no VODs were noted.  Transient liver enzyme 
elevations grade 1-2 were noted in 5 of 20 (25%), severe in 2.   
 
In discussions with Pfizer, we emphasized the importance of these findings but the 
limited number of patients makes definite conclusions difficult.  It was agreed to 
increase the number of treated patients on the weekly schedule by another 20, for a 
total of 40 patients, to assess more precisely the response and toxicity profile compared 
with the 49 patients treated with the single dose every 3-4 weeks. 
 
3.0 
Background Drug Information  
3.1 
Inotuzumab Ozogamicin Nonclinical Data 
Inotuzumab ozogamicin is an antibody-targeted intravenous (IV) chemotherapy agent 
composed of an antibody, targeting CD22 antigen, which is linked to calicheamicin, a 
potent cytotoxic antitumor antibiotic. The targeting agent in inotuzumab ozogamicin is a 
humanized IgG4 antibody, G544 that specifically recognizes human CD22. Being an 
IgG4 isotype antibody, G544 is not expected to mediate effector functions such as 
complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. CD22 is 
expressed on both normal and malignant cells of the mature B-lymphocyte lineage. 
Nonmalignant, mature lymphocytes express CD22; however, lymphocyte precursor 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 10 of 36 
cells and memory B cells do not express CD22. Thus, the impact of treatment with 
inotuzumab ozogamicin on long-term immune function is expected to be minimal. 
 
The concept of antibody-targeted chemotherapy has been successfully translated into a 
clinically validated therapeutic agent, gemtuzumab ozogamicin (Mylotarg). N-acetyl 
calicheamicin dimethyl hydrazide (N-acetyl calicheamicin DMH), the cytotoxic entity in 
both inotuzumab ozogamicin and gemtuzumab ozogamicin, is a derivative of 
calicheamicin methyl trisulfide. 
 
N-acetyl calicheamicin DMH is at least 100- to 1000-fold more potent than current 
cytotoxic therapeutics, such as doxorubicin. Its high potency makes N-acetyl 
calicheamicin DMH an ideal candidate for antibody-targeted chemotherapy. 
 
Inotuzumab ozogamicin is expected to have greater efficacy than unlabeled monoclonal 
antibodies and to have efficacy at least comparable to the leading chemotherapeutic or 
radio-immunoconjugate based therapies. Because of its targeted nature, it is expected 
to have a reduced incidence of side effects compared with conventional cytotoxic 
chemotherapy or radioimmunotherapy. This may confer important advantages in 
tolerability and reduced need for supportive care for subjects treated with inotuzumab 
ozogamicin as a single agent and offers the potential to intensify combination regimens 
without substantial additional toxicity. 
 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 11 of 36 
CD22 was chosen as a target for conjugate delivery for a number of reasons. CD22 is 
expressed on the malignant cells of the majority of B-lymphocyte malignancies. It is not 
expressed on hematopoietic stem cells or any other nonlymphoid hematopoietic or 
nonhematopoietic cells.  
 
Moreover, based on in vitro testing of human NHL cell lines, CD22 is one of the better 
internalizing molecules among several B- lymphoid lineage-specific surface antigens 
and is not shed into the extracellular environment. The normal function of CD22 is to 
regulate signal transduction of the surface immunoglobulin receptors on B cells. 
 
Inotuzumab ozogamicin exhibits a potent dose-dependent cytotoxicity in vitro and in 
vivo animal tumor models. Unconjugated G544 does not fix complement, does not 
mediate antibody-dependent-cellular cytotoxicity, and has no antitumor activity. In 
addition, inotuzumab ozogamicin was effective against human B-cell lymphomas in 
nonclinical murine models in which rituximab, a chimeric anti-CD20 monoclonal 
antibody, had failed as a therapeutic agent. 
 
This important nonclinical therapeutic advantage conferred by inotuzumab ozogamicin 
strongly supports its targeted clinical application in NHL. Nonclinical data also indicate a 
synergistic effect between inotuzumab ozogamicin and rituximab, as the combination of 
inotuzumab ozogamicin plus rituximab was: (a) more efficacious against established 
subcutaneous Ramos B lymphoma xenografts in nude mice, and (b) increased long 
term survival of severe immunodeficient mice with disseminated Ramos B lymphoma 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 12 of 36 
than either agent alone (22).  See the most recent version of the investigator’s brochure 
for all nonclinical data that potentially have a clinical significance and from clinical 
studies that are relevant to this study (23).  Also refer to the most recent version of the 
investigator’s brochure for a summary of the known and potential risks and benefits, if 
any, to human subjects. 
 
3.2 
Inotuzumab Ozogamicin Clinical Data 
The first in human trial (3129K1-100-WW [100-WW]) of inotuzumab ozogamicin was an 
open-label, dose-escalating, single-agent study in 79 subjects with CD22-positive B-cell 
NHL(23). 
 
The study defined the maximum-tolerated dose and showed a safety profile (and 
preliminary efficacy data) that supported advancement of inotuzumab ozogamicin’s 
clinical development(8,9,22). 
 
This continued clinical development included initiation of 4 additional trials (2 global and 
2 in Japan) involving the use of inotuzumab ozogamicin as either a single agent or in 
combination with rituximab for treatment of CD22-positive B-cell NHL. The combination 
strategy was evaluated since B-NHL cells consistently express both CD20 and CD22; 
thus, it is reasonable to combine rituximab and inotuzumab ozogamicin (anti-CD20 and 
CD22 targeting antibodies, respectively) in an attempt to enhance the therapeutic 
advantage of either agent. Nonclinical data supported this reasoning (see Inotuzumab 
Ozogamicin Nonclincal Data section). 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 13 of 36 
 
The following safety and efficacy discussions focus on 2 of the 5 studies currently 
comprising the clinical development of inotuzumab ozogamicin (studies 100-WW and 
3129K3-101-WW [101-WW]) since these are global trials that include patients with 
DLBCL. Furthermore, because response data are available by NHL class, efficacy 
discussions for studies 100-WW and 101-WW will focus on patients with diffuse large B-
cell lymphoma (DLBCL). 
 
3.2.1 Study 100-WW: Safety and Efficacy of Single-agent Inotuzumab 
Ozogamicin.  Study 100-WW was a phase 1, open-label, dose-escalation study of the 
safety, tolerability, and pharmacokinetics (PK) of inotuzumab ozogamicin administered 
as a single-agent to 79 subjects with CD22-positive B-cell NHL. Dose escalation was 
based on safety evaluations through days 21 to 28 after the first dose of inotuzumab 
ozogamicin. The maximum tolerated dose (MTD) was determined to be 1.8 mg/m2 
given every 28 days. Of the 49 subjects in the MTD cohort, 26 subjects had DLBCL. All 
79 subjects in the study had received prior chemotherapy, immunotherapy, or hormonal 
therapy per the inclusion criteria defined in the protocol, and most subjects (60.8%) had 
received at least 4 prior treatment regimens. Subjects ranged in age from 26 to 82 years 
(median, 60 years). 
 
The most common treatment emergent adverse events (TEAEs, incidence ≥ 20% of 
subjects) were hematologic (thrombocytopenia [84.8%], neutropenia [43.0%], anemia 
[22.8%], and leukopenia [21.5%]); gastrointestinal (nausea [51.9%], anorexia [31.6%], 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 14 of 36 
constipation [24.1%], and vomiting and diarrhea [21.5% each]); metabolic (aspartate 
aminotransferase [AST] increased [39.2%], alkaline phosphatase increased [26.6%], 
alanine aminotransferase [ALT] increased [21.5%], and bilirubinemia [20.3%]); 
respiratory (cough increased [21.5%]); asthenia (65.8%); fever (39.2%); abdominal pain 
(35.4%); and headache (21.5%). The most common grade 3/4 TEAEs (incidence ≥ 5% 
of subjects) were predominantly hematologic or metabolic: thrombocytopenia (59.5%), 
neutropenia (25.3%), leukopenia (13.9%), lymphopenia (11.4%), and anemia and 
hypokalemia (6.3% each). Others were: asthenia (10.1%) and gamma glutamyl 
transpeptidase (GGT) increased (6.3%) increased blood fibrinogen, blood lactate 
dehydrogenase, and venooclusive disease among adverse reactions or as adverse 
reactions leading to the discontinuation of the drug. Dose-limiting toxicities were all 
hematologic events: 3 cases of grade 4 thrombocytopenia, 1 event of bleeding (injury-
related) that required a platelet transfusion because of concurrent thrombocytopenia, 
and 1 event of grade 4 neutropenia. Fifteen (15) subjects with DLBCL in the expanded 
MTD cohort were evaluable for tumor response (24) (received ≥ 2 doses of inotuzumab 
ozogamicin and had tumor assessments at both baseline and postbaseline visits). 
These subjects had a best overall response rate (ORR) of 47.0% (2 CR and 5 PR), a 
median progression-free-survival (PFS) of 105 days (95% confidence interval [CI], 55 to 
343), and a median overall survival (OS) of 273 days (95% CI, 168 to 518). 
 
3.2.2 Study 101-WW: Safety and Efficacy of Inotuzumab Ozogamicin in 
Combination with Rituximab.  Study 101-WW is an ongoing phase 1/2, open-label, 
dose-escalation study of the safety, tolerability, and PK of inotuzumab ozogamicin in 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 15 of 36 
combination with rituximab in patients with relapsed DLBCL or follicular NHL. Subjects 
for whom curative therapies were available (ie, high-dose (HD) chemo and a stem cell 
transplant [SCT] for DLBCL) were not eligible for the study. Subjects who had relapsed 
after obtaining a response (progressed > 6 months after start of prior therapy) to first or 
second line rituximab-containing therapies were eligible for participation. For this 
ongoing study, the following results reflect data available as of September 23, 2008 (a 
third cohort recently opened to enroll 30 subjects with DLBCL that is refractory to 
treatment with rituximab in combination with chemotherapy [ie, progressed ≤ 6 months 
of start of prior therapy]; no safety or efficacy data is currently available for this new 
cohort). In total, 74 subjects have received study drug, including 66 subjects (27 with 
DLBCL) treated at the MTD (375 mg/m2 rituximab on day 1, and 1.8 mg/m2 inotuzumab 
ozogamicin on day 2). Subjects ranged in age from 29 to 85 years (median, 65.5 years) 
and most (54%) had received 2 prior lines of therapy.  
 
The observed TEAEs are those characteristic of rituximab and inotuzumab ozogamicin 
when administered as single agents. The most common TEAEs (incidence ≥ 20% of 
subjects) were hematologic (thrombocytopenia [40.5%], neutropenia [23.0%]); 
gastrointestinal (nausea [51.4%], constipation [21.6%], and vomiting [24.3%]); metabolic 
(AST increased [33.8%]); fatigue (43.2%); infections (40.5%); pyrexia (29.7%); 
headache (20.3%); and vascular disorders (20.3%). The most common grade 3/4 
TEAEs (incidence ≥ 5% of subjects) were predominantly hematologic 
(thrombocytopenia [21.6%], neutropenia [17.6%], and lymphopenia [5.4%]).  Others 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 16 of 36 
were: gastrointestinal (5.4%) or general (8.1%) disorders, infections (8.1%), and 
abnormal laboratory results (10.8%). 
 
A best overall response rate (ORR) of 79% (80% CI, 64.8% to 89.5%) has been 
achieved for 24 DLBCL subjects treated at the MTD. Informal analyses of current data 
indicate that the response rate is unaffected by both the number and duration of 
response to prior therapies, as well as IPI score and age: best ORRs were 80% (N =15) 
and 78% (N = 9) for subjects with 1 and 2 prior line of therapy, respectively; 75% (N = 8) 
and 81% (N = 16) for subjects with prior response durations of < 12 and ≥ 12 months, 
respectively; 72% (N = 18) and 100% (N = 6) for subjects with IPI scores > 1 and < 2, 
respectively; and 87.5% (N = 8) and 75% (N = 16) for subjects < 60 and > 60 years of 
age, respectively. At the time of evaluation (September 23, 2008), these 24 subjects 
have a 6-month PFS rate of 65% (80% CI, 48% to 78%).  
 
4.0 
Patient Eligibility  
 4.1 
Inclusion Criteria:  
1. Previously treated ALL (including Burkitt's lymphoma and lymphoblastic 
lymphoma) in relapse or primary refractory. Patients in first relapse will be 
eligible regardless of the first remission duration.  At least 10 patients in 
Salvage 1-2 will be treated to assess anti-ALL response more precisely. 
2. Age 16 years or older.  Pediatric patients (<16 years old) will be allowed into 
the study after safety is established, that is at least 10 adult patients having 
received 1 or more cycles each.  


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 17 of 36 
3. Zubrod performance status 0-3.  
4. Adequate liver function (bilirubin < 1.5 mg/dL and SGPT or SGOT < 3 x upper 
limit of normal [ULN], unless considered due to tumor), and renal function 
(creatinine < 2 mg/dL). Even if organ function abnormalities are considered 
due to tumor, the upper limit for bilirubin is < 2.0 mg/dL and creatinine < 3 
mg/dL.  
5. Male and female patients who are of childbearing potential agree to use an 
effective barrier method of birth control (e.g., latex condom, diaphragm, 
cervical cap, etc.) to avoid pregnancy. Female patients need a negative 
serum or urine pregnancy test within 14 days of study start (applies only if 
patient is of childbearing potential. Non-childbearing is defined as > 1 year 
postmenopausal or surgically sterilized).  
 
4.2 
Exclusion Criteria:   
1. Patient with active heart disease (NYHA class > 3 as assessed by history and 
physical examination). 
2. Patients with a cardiac ejection fraction (as measured by either MUGA or 
echocardiogram) < 45% are excluded. 
3. Patients who receive other chemotherapy. Patients must have been off 
previous therapy for > 2 weeks and must have recovered from acute toxicity 
(to grade 1 or less) of all previous therapy prior to enrollment (consent 
signing). (Concurrent therapy for central nervous system [CNS] prophylaxis or 
treatment for CNS relapse is permitted). Treatment may start earlier if 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 18 of 36 
necessitated by the patient's medical condition (e.g. rapidly progressive 
disease) following discussion with the Principal Investigator. 
4. Prior allogeneic stem cell transplant in previous 4 months. 
5. Peripheral lymphoblasts > 50 x 109/L. 
6. Pregnant and breast-feeding patients are excluded. 
7. Patients with known hepatitis B are excluded. 
 
5.0 
Treatment Plan  
5.1 General  
This is an open label, phase II study. The design will evaluate single agent efficacy of 
CMC-544 as initial treatment, first in patients > 16 years and then in patients less than 
16 years.  If stable disease or worse after 2 courses, CMC-544 will continue with the 
addition of rituximab, as detailed below.  
 
CMC-544 will be provided by Wyeth Corporation.  Any unused or expired drug will be 
destroyed per institutional policy. 
 
5.2 
Treatment Schema  
5.2.1 The first 3 patients > 16 years and the first 3 patients < 16 years will receive 
CMC-544 at a dose of 1.3 mg/m2 IV over 1 hour (+/- 15 minutes) during Course 1, and 
1.8 mg/m2 IV over 1 hour (+/- 15 minutes) during Course 2 and subsequently.  In all 
other patients, if there are no safety issues, CMC-544 will be given at a dose of 1.8 
mg/m2 IV over 1 hour (+/- 15 minutes) about every 4 weeks.  This will constitute a 
course of therapy. Courses will be repeated about every 4 weeks (range 3-6 weeks).  


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 19 of 36 
Courses can be started earlier, every 2 weeks if evidence of rapid progression after 
approval by the principal investigator. 
 
5.2.2 In a second phase (see 2.4), 20 patients will be treated with weekly CMC-544.  
CMC-544 will be given at 0.8 mg/m2 IV over 1 hour (+ 15 minutes) on Day 1, 0.5 mg/m2 
IV over 1 hour (+ 15 minutes) on Day 8, and 0.5 mg/m2 IV over 1 hour (+ 15 minutes) 
on Day 15.  Weekly doses can be given at + 1 day.  Course may be repeated every 3 
weeks. 
 
Recommended premedication before CMC-544:  acetaminophen 650 mg orally, 
diphenhydramine 10-25 mg IV, hydrocortisone 25 mg IV.  Modifications to this 
premedication are also allowed.   
 
Prophylaxis for tumor lysis syndrome may be administered at the discretion of the 
treating physician.   
 
5.2.3 If stable disease, no improvement or progression after 2 courses of CMC-544, 
patients may continue on CMC-544 at the same dose every 3-4 weeks, with the addition 
of rituximab 375 mg/m2 IV over 2-6 hours every 3-4 weeks.  The first dose of rituximab 
will be given as a slow infusion over 6-8 hours depending on reactions and side effects.  
It will be given on Day 1 and CMC-544 on Day 2.  Subsequent courses of CMC-544 and 
rituximab may be given on the same day; CMC-544 will be given at least 2-4 hours after 
completion of rituximab.  Courses can be started earlier, every 2 weeks if evidence of 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 20 of 36 
rapid progression after approval by the principal investigator.  In the second phase of 
weekly CMC-544, rituximab will be given on Day 1 and CMC-544 on Day 2 of the first 
dose; with subsequent weekly doses, both will be given weekly, rituximab preceding 
CMC-544.  The weekly dose of rituximab will be 375 mg/m2. 
 
Infusion 1 of rituximab will be over 6-8 hours following infusion rate increases as per 
hospital standards.  Infusions 2-6 of rituximab may be run at faster rates of 2-6 hours as 
indicated by side effects and per hospital standards. 
 
5.2.4 Patients achieving response, defined as CR or CRi, or partial remission (PR) 
may continue therapy for up to 8 cycles (about 8-12 months of therapy).  Patients with 
progression at any time or without objective response after 3 cycles will be taken off 
study. 
 
5.3 
Treatment Duration and Dose Adjustments 
Patients will receive 2 courses of CMC-544.  If CR, complete remission without platelet 
recovery (CRi), or PR is documented, whichever comes first, then continue CMC-544. If 
a patient does not achieve a CR, CRi, or PR then add rituximab as under 5.2.  
 
Patients who achieve a CR, CRi, or PR may receive up to a total of 8 cycles of therapy 
depending on leukemia response and resolution of toxicities. Subjects who demonstrate 
a CR or CRi after 1 or 2 cycles of therapy will receive a maximum of 4 cycles of therapy. 
Subjects who are in a CR or CRi after 3-4 cycles may receive a maximum of 2 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 21 of 36 
additional cycles of therapy after achieving a CR or CRi. After a total of 4 cycles, 
patients will be assessed for the need of the 4 additional cycles based on response and 
liver toxicities with the previous 4 cycles. Cycles are repeated about every 4 weeks 
(range 3-6 weeks) depending on leukemia response, resolution of toxicities, and 
recovery of hematopoiesis.  
 
Patients receiving subsequent cycles (cycles 2-8) will be treated at the same dose level 
if grade < 2 non-hematologic toxicity has occurred and if they have experienced a 
favorable response of their leukemia (decrease in peripheral blood or marrow blasts).  
Re-treatment will only occur upon recovery to < grade 2 non-hematologic or baseline 
toxicity. If they have non-hematologic toxicity of > grade 3 and a favorable response to 
therapy, additional cycles of therapy at 25% dose reduction of CMC-544 may be 
considered after this is discussed with and approved by the Principal Investigator.  No 
dose reductions for rituximab are needed. 
 
Patients who develop CNS leukemia while on study will be removed from the study and 
receive CNS-directed therapy, except where such patients have a positive response to 
therapy in which case they will continue on study after discussion with the Principal 
Investigator. 
 
5.4 
Concomitant Medications  
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 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 22 of 36 
concomitant chemotherapy (with the exception of prophylactic or therapeutic intrathecal 
chemotherapy for active CNS disease or CNS disease in remission), immunotherapy, or 
therapy with monoclonal antibodies 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.  
 
Prophylactic antibiotics, antifungals, and antiviral agents (e.g. levofloxacin, itraconazole, 
valacyclovir, etc.) are recommended; however, the use of these or other drugs will be 
left to the treating physician’s discretion.  
 
The use of hydroxyurea or steroids is permitted for temporary control of WBC elevations 
in patients with aggressive disease both prior and during treatment.  Hydroxyurea may 
be given at 1-5 g daily for up to 5 days in Course 1.  Dexamethasone may be given at 
40 mg daily x 4 with each of the first 2 courses.   
 
6.0 
Pretreatment evaluation  
Procedure  
Comments 
Schedule  
Informed Consent 
Obtain standard informed consent 
approved by IRB 
Within 14 days of study start  


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 23 of 36 
Procedure  
Comments 
Schedule  
Medical History 
Includes history of present illness, 
prior cancer history as far as 
traceable, and past medical/ 
surgical history as far as relevant. 
Within 14 days of study start  
Physical 
Examination 
Includes vital signs (temperature, 
heart rate, respiratory rate, blood 
pressure) and performance status 
Within 14 days of study start  
Concomitant 
Medications 
Document concomitant 
medications as far as traceable. 
Within 14 days of study start  
Hematology 
CBC with differential and platelet 
count 
Within 14 days of study start  
Biochemistry 
Creatinine, bilirubin, SGPT or 
SGOT, uric acid 
Within 14 days of study start  
Pregnancy test 
Serum or urine 
Within 14 days of study start  
Bone Marrow 
Aspirate and/or biopsy. Flow 
cytometry if required to establish 
diagnosis. 
Within 30 days of study start  
MUGA or 
Echocardiogram 
Assessment of QTc and cardiac 
ejection fraction 
Within 30 days of study start 
Immunophenotype 
Assess ALL markers including 
CD22 
Within 14 days of study start 
Flow cytometry 
CD22 expression 
Within 14 days of study start 
Optional:  In vitro 
CMC-544 sensitivity 
studies 
(Pharmacokinetics) 
CMC-544 saturation and survival 
studies 
Within 14 days of study start 
 
7.0 
Evaluation during therapy 
Procedure  
Comments  
Schedule  
Physical Examination  
Includes recording 
of vital signs, 
concomitant 
medications, 
adverse events, and 
performance status 
Prior to each subsequent course.  
Hematology  
CBC with differential 
(if granulocytes > 
1.0 x 109/L) and 
platelet count  
1 to 3 times weekly during induction (courses 1 
and/or 2) i.e. until achievement of response, 
then at least weekly during consolidation.  


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 24 of 36 
Procedure  
Comments  
Schedule  
Biochemistry  
Creatinine, bilirubin, 
SGPT or SGOT.  
Weekly during induction (courses 1 and/or 2), 
then at least once every 2 weeks during 
consolidation.  
Bone Marrow  
Aspirate and/or 
biopsy.  
 Bone marrow at Day 14-21(+/- 3 days), then as 
indicated in course 1 to confirm response, and 
then every 1-2 courses to confirm response. 
Other marrow examinations as indicated. No 
bone marrow is necessary if non-response or 
progressive disease can be diagnosed from 
peripheral blood evaluation, or, in patients with 
a WBC < 0.3, if the bone marrow test is 
considered non-contributory by the Investigator. 
Cytogenetic studies only if abnormal prior to 
study and/or the additional information is 
considered of consequence.  Cytogenetic 
studies may be assessed on any bone marrow 
at the discretion of the treating physician.  
Further bone marrow tests as indicated by 
development of peripheral blood counts.  
ECGs 
Assessment of QTc 
and cardiac ejection 
fraction 
Patients with history of arrhythmias or angina 
will have ECGs performed prior to the start of 
the rituximab, once during the infusion, and 
within 2 hours post infusion. Rituximab infusion 
will be discontinued for any clinically significant 
cardiac arrhythmia. In addition, all patients 
should have 12-lead ECG assessments to 
evaluate the potential for QTc prolongation 
regarding CMC-544 therapy. ECGs should be 
collected prior to course 1 CMC-544.  
Diagnostic evaluation 
 
Patients with complaints of abdominal pain will 
be examined for any signs or symptoms of 
bowel obstruction and/or perforation.  
Appropriate radiologic tests and surgical 
consults will be performed as needed. 
CD22 expression  
If peripheral blast 
count > 5000 
CD22 expression obtained pretreatment  
 
Pharmacokinetics  
(CMC-544) (optional) 
(see the laboratory 
manual or processing 
instruction) 
During Course 1 
PK during course 1:   
Day 1 pre-dose, end of infusion, 3 hrs post,  
Day 8 pre-dose, end of infusion, 3 hrs post, and  
Day 15 pre-dose, end of infusion, 3 hrs post.  


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 25 of 36 
Patients are allowed to have hematology tests performed in outside laboratory facilities.  
Laboratory results will be obtained by the research nurse assigned to this study. 
 
7.1 
Post Treatment Evaluation   
Patients will be evaluated 30 days post receiving the last treatment of CMC-544 to 
collect information regarding toxicity unless the patient receives further therapy.  This 
could be done during a regular clinic or inpatient visit or by phone call (research nurse 
or physician) if patient cannot be physically present at MD Anderson. 
 
8.0 
Criteria for Response 
8.1 
Complete remission (CR):  Disappearance of all clinical and/or radiologic 
evidence of disease. Neutrophil count > 1.0 x10
9
/L, platelet count >100x10
9
/L, and 
normal marrow differential (< 5% blasts).  
 
8.2 
Complete remission without recovery of counts (CRi): Peripheral blood and 
marrow results as for CR, but with incomplete recover of counts (platelets < 100 x 10
9
/L; 
neutrophils < 1 x 10
9
/L). 
 
8.3  
Partial remission (PR): Peripheral blood count recovery as for CR, but with 
decrease in marrow blasts of > 50% and not more than 25% abnormal cells in the 
marrow.  
 
8.4 
Other: All other responses will be considered as failures.  


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 26 of 36 
 
9.0 
Criteria for Removal from the Study  
The Investigator may remove patients from the study for any of the following reasons:  
 
9.1 
Progressive disease.  This is defined as a doubling of the peripheral blasts and 
an absolute increase of > 5 x 109/L. 
 
9.2 
Unacceptable adverse events/toxicities (any >/= grade 3 non-hematologic toxicity 
that does not at least resolve to < grade 2 or baseline).  
 
9.3 
Investigator thinks a change of therapy would be in the best interest of the 
patient.  
 
9.4 
If the patient has intercurrent, non-leukemia-related illness that would, in the 
judgment of the Investigator, affect assessments of clinical status to a significant degree 
and require discontinuation of protocol therapy.  
 
9.5 
Patient request.  
 
9.6 
Patient is non-compliant with protocol requirements.  
 
The Principal Investigator has the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to:  


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 27 of 36 
 
9.7 
If the incidence or severity of adverse events indicates a potential health hazard 
to patients.  
 
9.8 
If the patient enrollment is unsatisfactory.  
 
10.0 Reporting Requirements  
Adverse event reporting will be as per the NCI criteria and the MDACC Leukemia 
Specific Adverse Event Recording and Reporting Guidelines. 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 (Appendix A) will be utilized for 
adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html).   
 
Refer to Appendix E for Leukemia-Specific Adverse Event Recording and Reporting 
Guidelines.  Only unexpected AEs will be recorded in the Case Report Form 
(CRF).  The Principal Investigator will sign and date the PDMS Case Report Form 
toxicity pages per each patient at the completion of each course.  Following signature, 
the Case Report Form will be used as source documentation for the adverse events for 
attribution. 
 
Serious Adverse Event Reporting (SAE) 
A serious adverse event is – any adverse drug experience occurring at any dose that 
results in any of the following outcomes:  


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 28 of 36 
 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 disability/incapacity – a substantial disruption of a person’s 
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, Office of 
Research Education and Regulatory Management (ORERM). 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 29 of 36 
 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 “University of Texas M. D. Anderson Cancer Center Institutional Review 
Board Policy on Reporting Serious Adverse Events”.  Unless stated otherwise in the 
protocol, all SAEs, expected or unexpected, must be reported to ORERM, 
regardless of attribution (within 5 working days of knowledge of the event).  
Hospitalizations for the management of any expected adverse events (previously 
described) will not have an expedited report but it will be included in the annual 
report via the SAE log. 
 All life-threatening or fatal events, expected or unexpected, and regardless of 
attribution 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 
ORERM.   
 The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for 
reporting to ORERM.  
 Serious adverse events will be captured from the time the patient signs consent until 
30 days after the last dose of drug. Serious adverse events must be followed until 
clinical recovery is complete and laboratory test 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 ORERM. This may include the 
development of a secondary malignancy. 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 30 of 36 
 
(Please see Appendix E regarding data capturing of adverse events and adverse 
events source documentation.) 
 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager ORERM) 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. 
 
11.0 Statistical Considerations  
A total of up to 60 patients will be treated. The primary endpoint for efficacy is 
response which is defined as CR, CRi or PR. 
 
The method of Thall [1995] will be employed to perform interim futility monitoring.  
The trial will be stopped early if: Pr[ > 0.20 | data] < 0.10 . Where  denotes the 
response rate. That is, given the outcomes from the patients who have already 
been evaluated, if we determine that there is less than a 10% chance that the 
response rate is 20% or more, we will stop the trial for futility. We assume a prior 
distribution of  ~beta(1,1).  Stopping boundaries corresponding to this 
probability criterion are to terminate the trial if: 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 31 of 36 
(# patients with CR, CRi, or PR) / (# patients evaluated) 
                                    < 0/10, 1/17, 2/24, 3/31, 4/37 
 
The operating characteristics for the futility monitoring rule are shown in the 
following table.  
Operating Characteristics for Stopping Rule (PL=0.10) 
Clinical Scenario 
Early Stopping 
Probability 
Achieved Sample Size (25th, 
50th, 75th percentile) 
Response rate is 0.1 
0.79 
10, 17, 37 
Response rate is 0.2 
0.24 
40, 40, 40 
Response rate is 0.3 
0.044 
40, 40, 40 
Reference: 
Thall, Peter F., Simon, R. and Estey, E.H. "Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes," Statistics in Medicine 14:357-379, 
1995. 
11.1 In an update of the data on October 6, 2010, 12 of the first 21 patients treated 
(57%) had achieved CR or Cri.  This was achieved with minimal drug related side 
effects, and allowed several patients to proceed safely to allogeneic stem cell 
transplant.  These data are very encouraging and if consistent in a larger number of 
patients may show that single agent CMC-544 therapy is superior to standard 
combination intensive chemotherapy with regard to safety and efficacy.  We therefore 
propose to increase the total number of patients treated to 60 patients to allow a more 
accurate assessment of the response rate and to define more precisely predictive 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 32 of 36 
factors for response and outcome with CMC-544 therapy.  The analysis of predictive 
factors for response, durability of response, and survival will be conducted using 
standard statistical methods, and will be descriptive, for the purpose of guiding future 
large scale and pivotal trials with CMC-544 in ALL. 
 
11.2 Following the update of January 7, 2011, it is proposed to treat 20 patients with a 
weekly schedule of CMC-544, to gain experience with efficacy and toxicity.  This portion 
of the study should protect against an overall response rate < 40%.  Therefore the study 
will stop early if the number of responses over number evaluable is: 0/7, 1/10, 2/14, and 
3/17.  Otherwise a total of 20 patients will be treated.  The response and toxicity 
evaluations will be descriptive. 
 
11.3 Following an update on December 2, 2011, the weekly schedule was assessed 
to demonstrate equal or better efficacy and perhaps less toxicity than the single dose 
every 3-4 weeks.  In the first 15 evaluable patients, 8 (53%) achieved marrow CR.  An 
additional 20 patients will be treated for a total of 40 patients to assess more precisely 
the response and toxicity rates with the weekly schedule. 
 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 33 of 36 
12.0 References  
1.  
Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med 339: 605-615, 
1998.  
2.  
Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult acute 
lymphoblastic leukemia. Cancer 98: 1337-1354, 2003.  
3.  
Bassan R, Gatta G, Tondini C, Willemze R. Adult acute lymphoblastic leukemia. 
Crit Rev Oncol/Hematol 50: 223-261, 2004.  
4. 
Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, 
a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 18: 
547-561, 2000. 
5. 
Kantarjian H, Thomas D, O'Brien S, et al. Long-term follow-up results of 
hyperfractionated cyclophosphamide, vincristine, doxorubicin, and 
dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute 
lymphocytic leukemia. Cancer 101: 2788-2801, 2004. 
6. 
Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and relapsed adult 
acute lymphoblastic leukemia. Cancer 86: 1216-1230. 
7. 
Garcia-Manero G, Thomas DA. Salvage therapy for refractory or relapsed acute 
lymphocytic leukemia. Hematol Oncol Clin North Am 15: 163-205, 2001. 
8. 
DiJosephJF, Armellino DC, BoghaertER, 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.  
9. 
DiJoseph FJ, Dougher MM, Kalyandrug LB, Armellino DC, Boghaert ER, 
Hamann PR, Moran JK, and Damle NK.  Antitumor Efficacy of a Combination of 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 34 of 36 
CMC-544 (Inotuzumab Ozogamicin), a CD22-Targeted Cytotoxic 
Immunoconjugate of Calicheamicin, and Rituximab against Non-Hodgkin’s B-Cell 
Lymphoma.  Clin Cancer Res 12:242-249, 2006. 
10. 
Damle NK. Tumor-targeted chemotherapy using immunoconjugates of 
calicheamicin. Expert Opin Biol Ther 2004;4:1445-52. 
11. 
Lee M, DunneT, Chang C, eta l. Calicheamicins, a novel family of antibiotics. 4. 
Structural elucidations of calicheamicins. JAm Chem Soc1992;114:985-7. 
12. 
Zein N, Sinha A, McGahren W, Ellestad G. Calicheamicin  g1I: an antitumor 
antibiotic that cleaves doublestranded DNA site specifically. Science 1988;240: 
1198-201. 
13. 
Thorson J, Sievers E, AhlertJ, et al. Understanding and exploiting nature’s 
chemical arsenal: the past, presentand future of calicheamicin research. Curr 
Pharm Des 2000;6:1841-79. 
14. 
DiJoseph JF, Dougher MM, Armellino DC, Evans DY and Damle NK.  
Therapeutic potential of CD22-specific antibody-targeted chemotherapy using 
inotuzumab ozogamycin (CMC-544) for the treatment of acute lymphoblastic 
leukemia.  Leukemia 21:2240-45, 2007. 
15. 
Fayad L, Patel H, Verhoef G, et al.  Safety and clinical activity of the anti-CD22 
immunoconjugate inotuzumab ozogamycin (CMC-544) in combination with 
rituximab in follicular lymphoma or diffuse large b-cell lymphoma:  Preliminary 
report of a phase 1/2 study.  Blood, 112:Abst 266, 2008. 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 35 of 36 
16. 
Czuczman MS, Grillo-Lopez AJ,White CA, et al. Treatment of patients with low-
grade B-cell lymphoma with the combination of chimeric anti-CD20monoclonal 
antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268-76. 
17. 
Coiffier B, HerbrechtR , Tilly H, et al. GELA study comparing CHOP and R-
CHOP in elderly patients with DLCL: 3-year median follow-up with an analysis 
according to co-morbidity factors [abstract 2395]. Proc Am Soc Clin Oncol 2003; 
22:596. 
18. 
Wierda W, O’Brien S, Wang X et al.  Characteristics associated with important 
clinical end points in patients with chronic lymphocytic leukemia at initial 
treatment.  J Clin Oncol 27:1637-1643, 2009. 
19. 
Tam C, O’Brien S, Wierda W, et al.  Long-term results of the fludarabine, 
cyclophosphomide, and rituximab regimen as initial therapy of chronic 
lymphocytic leukemia.  Blood 112:975-980, 2008. 
20. 
Wierda W, O’Brien S, Wen S, et al.  Chemoimmunotherapy with fludarabine, 
cyclophosphomide, and rituximab for relapsed and refractory chronic lymphocytic 
leukemia.  J Clin Oncol 223:4070-4078, 2005. 
21. 
Thomas D, Faderl S, O’Brien S, et al.  Chemoimmunotherapy with hyper-CVAD 
plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or 
acute lymphoblastic leukemia.  Cancer 106:1569-80, 2006. 
22. 
DiJoseph J, Dougher M, Kalyandrug L, 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 Can Res. 2006;12:242-249. 


 
 
Protocol 2009-0872 
 
 
December 2, 2011 
Page 36 of 36 
23. 
Wyeth investigator’s brochure: inotuzumab ozogamicin [WAY-207294]. 
24. 
Cheson B, Horning S, Coiffie R, et al. Report of an international workshop to 
standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored 
International Working Group. J Clin Oncol. 1999;17:1244-1253.