Clinical trial NCT02311998
Conditions: B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Blasts More Than 5 Percent of Bone Marrow Nucleated Cells CD22 Positive Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-04-16; Completion date: 2022-03-23
Enrollment: 22 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/II trial studies the side effects and best dose of bosutinib when given together with inotuzumab ozogamicin and to see how well it works in treating patients with acute lymphoblastic leukemia or chronic myeloid leukemia that has come back or does not respond to treatment. Bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotoxins, such as inotuzumab ozogamicin, are antibodies linked to a toxic substance and may help find cancer cells that express CD22 and kill them without harming normal cells. Giving bosutinib together with inotuzumab ozogamicin may be a better treatment for acute lymphoblastic leukemia or chronic myeloid leukemia.

Detailed description:
If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study and whether or not you have received earlier treatment for leukemia. Up to 36 participants will be enrolled in Part 1 of the study, and up to 44 participants will be enrolled in Part 2.

If you are enrolled in Part 2, you will receive bosutinib at the highest dose that was tolerated in Part 1. All participants in Parts 1 and 2 will receive the same dose of inotuzumab ozogamicin.

Study Drug Administration. You will take bosutinib tablets by mouth 1 time each day with food. If you miss or vomit a dose of bosutinib, do not take "make up" the dose. Wait and take your next dose as scheduled the next day.

You will also receive inotuzumab ozogamicin by vein over about 1 hour on Days 1, 8, and 15 of each 28-day cycle. If the doctor thinks it is needed, you may switch to a different dosing schedule and receive inotuzumab ozogamicin 1 time every 4 weeks.

You will be given standard drugs (such as acetaminophen/paracetamol, antihistamines, and/or steroids) to help decrease the risk of side effects. If your doctor thinks it is needed, you may also receive hydroxyurea to control your white blood cell count while you are on study. You may ask the study staff for information about how these drugs are given and their risks.

Follow-Up After your end-of-treatment visit or call, you will be called 1 time about every 12 weeks (for up to 1 year) and asked about any anti-cancer therapy you may have started. This call will last about 5 minutes.

After completion of study treatment, patients are followed up every 12 weeks for up to 1 year.

Arms: arm 1: Patients receive bosutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Patients with confirmed CR, CRi, CCyR and/or absence of MRD may receive inotuzumab ozogamicin IV on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive bosutinib at the Maximum Tolerated Dose from the Phase I dose part, PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Patients with confirmed CR, CRi, CCyR and/or absence of MRD may receive inotuzumab ozogamicin IV on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive bosutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Patients with confirmed CR, CRi, CCyR and/or absence of MRD may receive inotuzumab ozogamicin IV on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. arm 4: Patients receive bosutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Patients with confirmed CR, CRi, CCyR and/or absence of MRD may receive inotuzumab ozogamicin IV on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Bosutinib intervention 2: Inotuzumab Ozogamicin
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase I/II Study of Bosutinib in Combination with Inotuzumab Ozogamicin in CD22-
positive Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia and  
Chronic Myeloid Leukemia Lymphoid Blast Phase 
 
Principal Investigator: 
Name:  
 
Nitin Jain, MD 
 
 
 
 
Address: 
 
Department of Leukemia 
MD Anderson Cancer Center  
 
 
 
 
 
 
 
1515 Holcombe Blvd, Unit 428 
 
 
 
 
 
 
 
Houston, TX, 77030 
 
 
 
 
Telephone: 
 
713-745-6080 
 
 
 
 
Fax: 
 
 
713-794-4297 
 
 
 
 
e-mail address: 
njain@mdanderson.org 
 
Co-Principal Investigator: Name:   
 
Elias Jabbour, MD 
 
 
 
 
Address: 
 
Department of Leukemia 
MD Anderson Cancer Center  
 
 
 
 
 
 
 
1515 Holcombe Blvd, Unit 428 
 
 
 
 
 
 
 
Houston, TX, 77030 
 
 
 
 
Telephone: 
 
713-792-4764 
 
 
 
 
Fax: 
 
 
713-563-7746 
 
 
 
 
e-mail address: 
ejabbour@mdanderson.org 
 
Collaborator:  
 
Name:   
 
Raja Luthra, PhD 
 
 
 
 
Address: 
 
Department of Pathology 
MD Anderson Cancer Center  
 
 
 
 
 
 
 
1515 Holcombe Blvd, Unit 149 
 
 
 
 
 
 
 
Houston, TX, 77030 
 
 
 
 
Telephone: 
 
713-794-5443 
 
 
 
 
Fax: 
 
 
713-794-4297 
 
 
 
 
e-mail address: 
rluthra@mdanderson.org 
 
Statistician:  
 
 
 
 
Study Coordinator: 
Jing Ning, PhD 
 
 
 
 
 Evguenia Gachimova, RN 
MD Anderson Cancer Center  
 
 
MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 1411  
 
 
1515 Holcombe Blvd, Unit 428 
Houston, TX 77030                                               
Houston, TX 77030 
Telephone: 713-792-5310 
 
 
 
Telephone: 713- 563-8622 
Fax: 713-563-4243 
 
 
 
 
Fax: 713-745- 4138 
e-mail address: jning@mdanderson.org           
e-mail address  
eqachimova@mdanderson.org 


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1.0 
OBJECTIVES 
 
1.1  
Primary Objectives: 
Phase I: 
1. To determine the safety and MTD of bosutinib in combination with inotuzumab ozogamicin 
in patients with Ph+ ALL and CML in lymphoid blast phase that express CD22 
 
Phase II: 
1.  To determine the efficacy of bosutinib in combination with inotuzumab ozogamicin in 
patients with Ph+ ALL and CML in lymphoid blast phase that express CD22 
 
1.2  
Secondary Objectives: 
Phase I:  
1. To determine the efficacy of bosutinib in combination with inotuzumab ozogamicin in 
patients with Ph+ ALL and CML in lymphoid blast phase that express CD22 
2. To determine the duration of response of patients treated with this combination 
3. To determine the overall survival of patients treated with this combination 
4.  To determine the effect of the level of pre-treatment expression of CD22 with response to 
this combination 
5.  To determine the efficacy of this combination according to pre-treatment mutation status in 
the abl kinase domain 
6.  To determine the minimal residual disease after treatment with this combination and its 
impact in long-term outcome 
Phase II: 
1. To determine the safety bosutinib in combination with inotuzumab ozogamicin in patients 
with Ph+ ALL and CML in lymphoid blast phase that express CD22 
2. To determine the duration of response of patients treated with this combination 
3. To determine the overall survival of patients treated with this combination 
4.  To determine the effect of the level of pre-treatment expression of CD22 with response to 
this combination 
5.  To determine the efficacy of this combination according to pre-treatment mutation status in 
the abl kinase domain 
6.  To determine the minimal residual disease after treatment with this combination and its 
impact in long-term outcome 
 
2.0 
BACKGROUND AND RATIONALE 


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The Philadelphia chromosome [t(9;22)(q34;q11)] (Ph+), is the most common cytogenetic 
abnormality in acute lymphoblastic leukemia (ALL) in adults.1,2 Up to 40-50% of ALL patients 
older than 60 years will be Ph+. Before the introduction of molecularly targeted therapy, Ph+ 
ALL was associated with lower remission rates and a very poor prognosis with a median survival 
of less than one year.3  
With the introduction of therapy using ABL-tyrosine kinase inhibitors (TKIs) targeted to the 
aberrant BCR-ABL protein, the outcome of Ph-positive ALL has improved substantially and has 
been the major treatment advance for adults with ALL in the past two decades.4 Imatinib, the 
first TKI developed for use in Ph+ leukemias, has been combined with combination 
chemotherapy by various groups and this has substantially improved both complete remission 
(CR) and disease-free survival (DFS) rates.5,6 The MD Anderson group was the first to report on 
the combination of imatinib with chemotherapy.5,6 The 3 year CR duration and OS rates were 
significantly improved with hyper-CVAD-imatinib therapy compared to historical controls 
treated with hyper-CVAD alone (68% vs. 24% and 54% vs. 15%, respectively, p < 0.001). 
Second generation TKI dasatinib has also been combined with hyper-CVAD chemotherapy with 
improved outcomes.7 In a report of 35 patients treated with hyper-CVAD + dasatinib, the CR 
rate of 94% was achieved with estimated 2-year OS of 64%.7 Similar results have been reported 
by other groups and early TKI therapy is now established as the standard treatment of Ph+ 
ALL.1,2,4,8 Ponatinib is a novel TKI with single-agent activity in patients with T315I mutations.9 
Cortes and colleagues reported activity of ponatinib monotherapy in patients with Ph+ 
leukemias.9 The primary endpoint for the Ph+ ALL and CML in lymphoid blast phase disease 
phase was major hematologic response (MaHR), and was achieved in 31% of patients with CML 
in lymphoid blast crisis and 41% of patients with Ph+ ALL. 
Bosutinib is a second generation TKI and is a dual Abl and Src kinase inhibitor. Bosutinib was 
recently approved for the treatment of adult patients with chronic, accelerated, or blast phase 
CML with resistance/ intolerance to prior therapy.10-12 In a phase I/II study in advanced Ph+ 
leukemia with resistance/ intolerance to imatinib, patients received single-agent bosutinib (500 
mg daily).13 One hundred thirty four patients were enrolled (63 accelerated phase [AP], 48 blast 
phase [BP], 23 ALL). Non-hematologic treatment-related adverse events occurring in ≥10% of 
pts were diarrhea (67%), vomiting (40%), nausea (37%), rash (20%), and fatigue (10%). Grade 
3/4 adverse events of any causality occurring in ≥5% of pts were diarrhea (6%), pneumonia 
(6%), elevated ALT (6%), vomiting (5%), and dyspnea (5%). Grade 3/4 hematologic toxicity of 
any causality were anemia (37%), neutropenia (46%), and thrombocytopenia (65%). For the 
evaluable patients with BP and ALL, major cytogenetic response and major molecular response 
occurred in 57% and 34% patients, respectively. Thus, bosutinib is an active agent for treatment 
of patients with advanced Ph+ leukemia. 
CD22 expression occurs in >90% of patients with ALL. Inotuzumab ozogamicin (IO) is a CD22 
monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in 


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relapsed/refractory ALL.14 In a phase II study, patients were given IO at 1.8 mg/m2 
intravenously every 3-4 weeks. Forty-nine patients were treated. The median number of courses 
administered were 2 (range 1-5) and the median time between courses was 3 weeks (range 3-6). 
The overall response rate was 57% (CR 18%, marrow CR 39%).  There were 7 patients with Ph+ 
ALL of which 3 (43%) had a response. Twenty-four percent patients had grade 1–2 and 4% had 
grade 3 increases in bilirubin. Grade 1–2 elevations of serum aminotransferase were noted in 
55% patients and grade 3 elevations in 2% patients. Based on higher in vitro efficacy with more 
frequent exposure, a weekly schedule (0.8 mg/m2 day 1, 0.5 mg/m2 days 8 and 15, every 3-4 
weeks) has been developed.15 With the weekly schedule (n=34), overall response rate was 53% 
(similar to 57% noted with the every 3 weeks schedule). With the weekly schedule, reversible 
grade 1–2 and 3–4 bilirubin elevations were observed in 3% and 0% patients, respectively. 
Reversible grade 1–2 and 3–4 liver enzyme elevations were observed in 21% and 6%, 
respectively on the weekly dose. Thus, weekly schedule has similar efficacy as every 3 week 
schedule with improved toxicity profile.  
Despite these advances with the introduction of TKI therapy and of the monoclonal antibodies 
such as IO, relapses are still major challenges in patients with ALL and long-term survival 
remains poor. As both TKIs and IO have shown independent clinical activity in patients with 
Ph+ ALL (and CML lymphoid blast phase), we hypothesize that combination strategy (‘chemo-
free’ approach) would lead to improved clinical outcomes. We propose a phase I/II clinical trial 
with combination therapy with bosutinib and IO. If successful, this would represent a major 
advance in the management of patients with Ph+ ALL.  
The present study will include patients with either Ph+ ALL or CML in lymphoid blast phase 
(CML-LBC). Both these disorders are characterized by increased number of lymphoid blasts in 
the marrow and the presence of the Philadelphia chromosome.16,17 The disease biology, clinical 
outcomes and management of patients with CML-LBC and Ph+ ALL is identical [NCCN 
guidelines (version 4.2013)]. The presence of Philadelphia chromosome defines these disease 
subgroups which are many times impossible to differentiate from each other (e.g., de-novo blast 
phase versus Ph+ ALL) and therefore, it is not surprising that many pivotal clinical trials of TKI 
therapy have included both these groups of patients.9,18,19    
Frontline Ph+ ALL Cohort: Outcomes of older patients with ALL remain suboptimal with long-
term disease free control of <20% at 5 years.20 One of the major reasons for inferior outcomes in 
older patients is the risk of infection with standard chemotherapy. In analysis reported by O’Brien 
and colleagues, the risk of death in CR due to infections was 34%.21 Similar data have been 
reported by the UK ALL study group.22  
Low-intensity regimens have been reported to be effective and safe in patients with ALL. Use of 
antibody-drug conjugate inotuzumab and lower-intensity chemotherapy has been shown to be very 
effective in patients with Ph negative ALL (Jabbour et al. ASH 2015). Given suboptimal results 
with standard chemotherapy in older patients with ALL, and poor tolerability of chemotherapy in 


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older patients, there is a need to develop better therapy with non-chemotherapy approaches for this 
group of patients. We plan to include older patients with Ph+ ALL or CML-LBC for frontline 
treatment.   
 
3.0 
STUDY POPULATION 
To be eligible for this study, patients must meet all criteria outlined below in Section 3.1 and 
Section 3.2. 
 
3.1 
Inclusion Criteria 
1. 
Relapsed or refractory B-cell ALL or CML in lymphoid blast phase. Philadelphia 
chromosome must be present at screening (as determined by cytogenetic analysis, FISH, 
or PCR [i.e., BCR-ABL positive]). Note: patients with CML who have received treatment 
with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast 
phase are eligible for frontline treatment. 
 
 
Frontline Ph+ ALL or CML-LBC Cohort: Patients with newly-diagnosed Ph+ ALL or 
CML-LBC, who have received no or minimal treatment (minimal treatment is defined as 
treatment with steroids/hydroxyurea of ≤2 week duration; vincristine ≤ 2 doses; tyrosine 
kinase inhibitor of ≤4 week duration; ≤2 doses of cytarabine) and are ≥60 years or older 
are eligible. Patients must have bone marrow blasts >5% at the time of screening. 
 
2.  
Expression of CD-22 in ≥20% blasts  
 
3. 
Age 18 years or older (For Frontline Ph+ ALL or CML-LBC Cohort: Age 60 years or 
older) 
 
4. 
Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤2 
 
5. 
The following baseline laboratory data: 
● 
Serum bilirubin ≤2.0 mg/dl 
● 
Serum creatinine ≤2.0 mg/dl 
● 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x 
upper limit of normal (ULN) 
 
6. 
Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotrophin (β-hCG) pregnancy test result within 14 days prior to the first dose of 
study drugs and must agree to use one of the following effective contraception methods during 
the study and for 30 days following the last dose of study drug.  
Effective methods of birth control include: 


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• birth control pills, shots, implants (placed under the skin by a health care provider) or 
patches (placed on the skin) 
• Intrauterine devices (IUDs) 
• condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide 
Females of non- childbearing potential are those who are postmenopausal greater than 1 year or 
who have had a bilateral tubal ligation or hysterectomy. 
 
7. 
Males who have partners of childbearing potential must agree to use an effective 
contraceptive method during the study and for 30 days following the last dose of study drug 
 
8. 
Patients or their legally authorized representative must provide written informed consent 
 
3.2  
Exclusion Criteria 
1 
History of another primary invasive malignancy that has not been definitively treated or in 
remission for at least 2 years. Patients with non-melanoma skin cancers or with carcinomas 
in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses).  
 
2 
Patients with active unstable angina, concomitant clinically significant active arrhythmias, 
myocardial infarction within 6 months, or congestive heart failure New York Heart 
Association Class III-IV. Patients with a cardiac ejection fraction (as measured by either 
MUGA or echocardiogram) <40% are excluded. 
 
3 
Known evidence of active cerebral/meningeal disease. Patients may have history of CNS 
leukemic involvement if definitively treated with prior therapy and no evidence of active 
disease (defined as ≥2 consecutive spinal fluid assessments with no evidence of disease) 
at the time of consent.  
 
4 
Previous treatment with any anti-CD22 directed therapy 
 
5 
Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the 
following criteria: 
●  <100 days from allogeneic SCT 
●  Active acute or chronic graft-versus-host disease (GvHD), or  
● Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days 
 
6. 
Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible  
 
7. 
Active hepatitis B or C infection, or known seropositivity for HIV  
 


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8. 
 Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol 
abuse 
 
9.   History of autoimmune diseases (such as systemic lupus erythematosus (SLE), Wegener’s, 
Wegener’s granulomatosis, polyarteritis nodosa). Note: Prior autoimmune diseases are 
allowed as long as clinically stable.    
 
10. Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start 
of study drugs with the following exceptions: 
a. To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea. No 
washout necessary for these agents. 
b. For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, 
single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors. These agents 
should be discontinued at least 48 hours prior to start of study drugs. (Note: the interval 
of time from last dose of any approved TKI to start of protocol treatment is 48 hours 
regardless of the indication for treatment with the TKI.) 
 
11. Patients who have not recovered from acute non hematologic toxicity (to ≤ Grade 1) of 
all previous therapy prior to enrollment 
 
12. Females who are pregnant or lactating 
 
13. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that in the opinion of the investigator may increase the risk associated with study 
participation or investigational product administration or may interfere with the 
interpretation of study results and/or would make the patient inappropriate for enrollment 
into this study. 
14. Patients previously exposed to bosutinib are eligible unless they carry T315I 
15.    Patients with T315I mutations will be excluded (This criteria is not applicable for the 
frontline Ph+ ALL or CML-LBC cohort) 
 
3.3 
Discontinuation of Study Drug 
A patient’s treatment with study drug may be discontinued for any of the following reasons: 
 
● Clinically significant progressive disease 
● Adverse events that are not manageable with dose adjustments and/or optimal medical 
management, or that, in the opinion of the investigator, pose an unacceptable risk for the 
patient.  
● Investigator decision 


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● Patient decision (e.g., withdrawal of consent) 
● Study termination by Sponsor 
 
Patients who discontinue from the study for disease progression or initiation of new therapy 
are considered to have completed the study per protocol. Patients who discontinue study 
treatment will be contacted about every 12 weeks (for up to one year) and asked about any 
anti-cancer therapy they may be receiving. 
 
4.0 
TREATMENT PLAN 
 
4.1 
 Study Design 
The study will consist of two phases- 
4.1.1 Phase I dose-escalation Phase for relapsed or refractory B-cell ALL or CML in 
lymphoid blast phase patients will start therapy with bosutinib at 300 mg orally once 
daily (which is 40% lower than the FDA approved dose of 500 mg orally once daily). 
Bosutinib will be dose-escalated in subsequent cohorts in a standard 3+3 study design. 
Patients will receive inotuzumab ozogamicin as an intravenous infusion over 
approximately one hour on a weekly schedule (0.8 mg/m2 IV day 1, 0.5 mg/m2 day 8 (±3 
days), and 0.5 mg/m2 day 15 (±3 days). A minimum of 6 days should be maintained 
between subsequent doses. 
A cycle is defined as 28 days, however, start of cycle 2 may be delayed if the patient 
achieves a CR or CRi and/or to allow toxicity recovery.  
 
Dose Level 
Bosutinib (mg/day) 
orally once daily 
Inotuzumab ozogamicin IV (mg/m2), 
repeat cycles every 3-4 weeks 
-1 
200 
Day 1 - 0.8 mg/m2 
Day 8 - 0.5 mg/m2 
Day 15 - 0.5 mg/m2 
1 (starting dose) 
300 
Day 1 - 0.8 mg/m2 
Day 8 - 0.5 mg/m2 
Day 15 - 0.5 mg/m2 
2 
400 
Day 1 - 0.8 mg/m2 
Day 8 - 0.5 mg/m2 
Day 15 - 0.5 mg/m2 
3 
500 
Day 1 - 0.8 mg/m2 
Day 8 - 0.5 mg/m2 
Day 15 - 0.5 mg/m2 
 
4.1.1.1 For Cycles 2 to 6, if there are no peripheral blood blasts, the inotuzumab 
ozogamicin dose is reduced to 1.5 mg/m2 total but continues on a weekly 


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schedule (0.5 mg/m2 days 1, 8 (±3 days) and 15 (±3 days). The rationale for this 
is that, based on prior experience at our institution, the number of circulating 
blast cells is a significant covariant affecting inotuzumab clearance and 
therefore, once the peripheral blood blasts clear, the dose may be reduced 
maintaining efficacy.  This will also reduce the risk of toxicity for subsequent 
cycles.  
4.1.1.2  A minimum of 6 days should be maintained between the doses. 
4.1.1.3 For patients who have achieved CR/CRi – the next cycle (cycle 2 and onwards) 
will begin when ANC ≥1.0, and platelet count ≥75. These count recovery 
guidelines could be modified based on treating physician assessment if 
determined to be in the best interest of the patient after discussion with study PI 
(e.g., if there is evidence of minimal residual disease). 
4.1.1.4 Transition to the every 4-weekly schedule – In order to decrease the toxicity 
of the subsequent cycles, once a response is confirmed (CR, CRi, or whenever 
CCyR and/or absence of MRD by flow cytometry is documented), subsequent 
cycles will be administered at a dose of 1.0 mg/m2 once every 4 weeks.  Note: 
Patients who have been switched to every 4 weeks schedule may return to the 
weekly schedule if there is concern about recurrence of the disease. 
4.1.1.5 Patients who experience a clinical benefit (CR/CRi/PR) with acceptable toxicity 
can receive up to a total of 6 cycles of inotuzumab ozogamicin. Treatment with 
bosutinib should continue indefinitely as long as patient is tolerating it well and 
responding to it. 
4.1.1.6 Bosutinib will be dose-escalated in subsequent cohorts in a standard 3+3 study 
design (see Section 11.2).   
4.1.1.7 Dosing for the Frontline Ph+ ALL or CML-LBC Cohort 
 
Phase I dose-escalation Phase: in the phase I portion of the study, frontline Ph+ ALL or 
CML-LBC patients will start therapy with bosutinib at 300 mg orally once daily. This 
dose has already been shown to be safe in the relapsed cohort (we have treated 3 patients 
with R/R ALL, and no DLT was noted at the 300mg dose level). Bosutinib will be dose-
escalated in subsequent cohorts in a standard 3+3 study design.   
Patients will receive inotuzumab ozogamicin as an intravenous infusion over 
approximately one hour on a weekly schedule (0.8 mg/m2 IV day 1, 0.5 mg/m2 day 8 (±3 
days), and 0.5 mg/m2 day 15 (±3 days). A minimum of 6 days should be maintained 
between subsequent doses. 
A cycle is defined as 28 days, however, start of cycle 2 may be delayed if the patient 
achieves a CR or CRi and/or to allow toxicity recovery.  
 


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Dose Level 
Bosutinib (mg/day) 
orally once daily 
Inotuzumab ozogamicin IV (mg/m2), 
repeat cycles every 3-4 weeks 
-1 
200 
Day 1 - 0.8 mg/m2 
Day 8 - 0.5 mg/m2 
Day 15 - 0.5 mg/m2 
1 (starting dose) 
300 
Day 1 - 0.8 mg/m2 
Day 8 - 0.5 mg/m2 
Day 15 - 0.5 mg/m2 
2 
400 
Day 1 - 0.8 mg/m2 
Day 8 - 0.5 mg/m2 
Day 15 - 0.5 mg/m2 
3 
500 
Day 1 - 0.8 mg/m2 
Day 8 - 0.5 mg/m2 
Day 15 - 0.5 mg/m2 
 
For Cycles 2 to 6, if there are no peripheral blood blasts, the inotuzumab ozogamicin 
dose is reduced to 1.5 mg/m2 total but continues on a weekly schedule (0.5 mg/m2 days 1, 
8 (±3 days) and 15 (±3 days). A minimum of 6 days should be maintained between the 
doses. For patients who have achieved CR/CRi – the next cycle (cycle 2 and onwards) 
will begin when ANC ≥1.0, and platelet count ≥75. These count recovery guidelines 
could be modified based on treating physician assessment if determined to be in the best 
interest of the patient after discussion with study PI (e.g., if there is evidence of minimal 
residual disease). 
 
Transition to the every 4-weekly schedule – In order to decrease the toxicity of the 
subsequent cycles, once a response is confirmed (CR, CRi, or whenever CCyR and/or 
absence of MRD by flow cytometry is documented), subsequent cycles will be 
administered at a dose of 1.0 mg/m2 once every 4 weeks.  Note: Patients who have been 
switched to every 4 weeks schedule may return to the weekly schedule if there is concern 
about recurrence of the disease. 
 
Patients who experience a clinical benefit (CR/CRi/PR) with acceptable toxicity can 
receive up to a total of 6 cycles of inotuzumab ozogamicin. Treatment with bosutinib 
should continue indefinitely as long as patient is tolerating it well and responding to it. 
 
NOTE: For all patients included in this trial, inotuzumab doses may be omitted if deemed 
in the best interest of the patient (for e.g. patients with plans of undergoing stem cell 
transplant) by the treating physician (after discussion with the study PI). The reason for 
omission will be noted in the medical record.  


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Patients who achieve MRD negative remission may have further doses of inotuzumab 
omitted, if deemed in the best interest of the patient by the treating physician (in 
discussion with the study PI).   
 
4.1.2  Evaluation of dose limiting toxicity (DLT)  
4.1.2.1 Prior to advancing/changing cohorts a cohort summary will be completed and 
submitted to the Medical Monitor in the IND Office. 
4.1.2.2 DLT is defined as clinically significant non-hematologic adverse event or 
abnormal laboratory value assessed as unrelated to disease progression, 
intercurrent illness, or concomitant medications and occurring during the first 
cycle of therapy that meets any of the following criteria:  
• 
CTCAE Grade 3 or 4 AST (SGOT) or ALT (SGPT) for ≥ 14 days 
• 
All other clinically significant non-hematological adverse event possibly 
related to study drugs that is Grade 3 or 4 according to the NCI common 
terminology criteria version 4.0. with the following exceptions: 
• Grade 3 or 4 nausea, vomiting and diarrhea will be considered DLT 
only if not controlled by optimal therapy. 
• Grade 3 biochemical abnormalities (e.g., lipase or bilirubin elevation) 
will only be considered DLT if accompanied by clinical consequences.  
Grade 3 or 4 electrolyte abnormalities will only be considered DLT if 
possibly related to study drug and not corrected by optimal 
replacement therapy. 
• 
Hematologic DLT is defined as absolute neutrophil count (ANC) <0.5 
x109/L or platelet count <25 x109/L with a hypocellular bone marrow 
lasting for 6 weeks or more after the start of a course in the absence of 
residual leukemia (i.e., with less than 5% blasts).  (In case of a 
normocellular bone marrow with <5% blasts, 8 weeks with pancytopenia 
will be considered DLT). Anemia will not be considered for the definition 
of DLT. 
• 
The last patient enrolled in each cohort will be observed for toxicity for  
28 days (1 cycle) prior to advancing to the next dose level. 
4.1.2.3 Patients that are removed from study during cycle 1 for any reason other than 
toxicity and have not experienced DLT will be replaced.  
4.1.2.4 For the purpose of defining DLT, the first cycle will be considered; however 
information on observed toxicities during subsequent cycles will be collected 
from all patients. 
 


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4.1.3  Cycle 1 is a 4 week cycle. However, cycle 2 may be started up to 1 week early if the patient 
has not achieved a CR or CRi and/or has persistent disease or rapidly proliferating disease, 
provided all drug-related toxicity has recovered to grade 1 or less. All subsequent cycles 
are 4 week cycles. Note: Subsequent cycles may start early if there is recovery of all 
toxicity related to the study drugs to grade 1 or less, but not earlier than day 21.   
4.1.3.1 Subsequent cycles may be delayed for recovery of toxicity. Delays in start of 
subsequent cycles greater than 8 weeks should be discussed with the principal 
investigator. 
4.1.3.2 If the peripheral counts do not recover (ANC <1 x109/L and/or platelets <75 
x109/L) but there is evidence of residual leukemia in the bone marrow, subsequent 
cycles can be administered at the discretion of the treating physician. 
 
4.1.4 Phase II Phase: Once the MTD (or bosutinib 500 mg dose level, if MTD not exceeded at 
this level) is established in each cohort separately, a phase II portion will commence 
respectively for each cohort. For each cohort, the 6 patients at MTD from the phase I 
dose part will be enrolled in the phase II portion of the study.   
 
            Patients will receive bosutinib per the MTD established in the Phase I study. Patients will 
receive inotuzumab ozogamicin at the same dose and schedule as for the Phase I part of 
the study. For each cohort, a maximum of 28 patients (including the 6 patients at MTD 
from the phase I dose part) will be enrolled in the phase II portion of the study.   
 
5.0 
TREATMENTS ADMINISTERED 
 
5.1 
Inotuzumab ozogamicin, the investigational agent under study in this protocol, is an 
ADC comprised of a humanized IgG4 monoclonal antibody (G5/44) that recognizes CD22 
antigen and is covalently linked via an acetyl butyrate linker to N-acetyl--calecheamicin dimethyl 
hydrazide (CalichDMH), a semisynthetic derivative of calecheamicin.  
 
Detailed information describing the preparation, administration, and storage of inotuzumab 
ozogamicin is located in the Pharmacy Manual. 
 
5.1.1 Description 
Inotuzumab ozogamicin is a white to off-white powder or cake, lyophilized, 
unpreserved 4-mg protein equivalent powder for intravenous injection in an amber 
vial supplied by Pfizer.  
 
5.1.2 Dose and Administration 
Inotuzumab ozogamicin must not be administered as an IV push or bolus. Inotuzumab 
ozogamicin should not be mixed with other medications. Dosing is based on patient 


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weight according to the institutional standard; however, doses will be adjusted for 
patients who experience a ≥10% change in weight from baseline.  Please refer to the 
Dosage and Administration Instructions in the Pharmacy Manual for inotuzumab 
ozogamicin intravenous solution. Reconstituted inotuzumab ozogamicin will be 
administered over 1 hour ± 15 minutes by intravenous infusion unless the subject 
requires temporary interruption of the administration. A minimum of 6 days should be 
maintained between the doses. 
 
5.1.3 Required Premedication 
Recommended premedication before inotuzumab ozogamicin: acetaminophen 650 mg 
orally, diphenhydramine 10-25 mg IV, hydrocortisone 25 mg IV. Modifications to this 
premedication are also allowed. 
 
5.1.4 Drug Preparation, Storage and Handling 
Detailed drug preparation instructions are provided in the Investigator Brochure. 
Unused portions of the study drug will be discarded properly as per the institutional 
policies.   
 
5.2 
Bosutinib (BOSULIF®) is a kinase inhibitor FDA approved for the treatment of adult 
patients with chronic, accelerated, or blast phase Philadelphia chromosome positive CML with 
resistance or intolerance to prior therapy. The recommended dose is 500mg once daily with food. 
Bosutinib will be provided by Pfizer.  Bosutinib inhibits the abnormal Bcr-Abl kinase that 
promotes CML. Modeling studies indicate that bosutinib binds the kinase domain of Bcr-Abl. 
Bosutinib is also an inhibitor of Src family kinases including Src, Lyn and Hck. Bosutinib 
minimally inhibits PDGF receptor and c-Kit.  
5.2.1 Method of Administration 
Bosutinib tablets are available containing bosutinib monohydrate equivalent to either 100 
or 500 mg of bosutinib. The recommended dose of Bosutinib for the treatment of 
leukemia is 500 mg by mouth once daily with food. If a dose is missed, the patient should 
not take an additional dose, but take the usual prescribed dose on the following day. 
Unused portions of the study drug will be discarded properly as per the institutional 
policies.   
6.0 
DOSE MODIFICATIONS 
 
6.1 
Intrapatient dose reduction will be allowed depending on the type and severity of 
toxicity.  Dose interruption may occur within a cycle until adequate recovery or omission of 
a dose during a given treatment cycle. While doses given within a treatment cycle (i.e., Days 
8 and/or 15) need not be delayed due to neutropenia or thrombocytopenia, dose delays 


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within a cycle are required for drug-related non hematologic toxicity. The start of the next 
cycle may be delayed if additional time is required for the patient to recover from study 
treatment-related toxicity experienced during the current cycle. Delays in start of subsequent 
cycles greater than 8 weeks should be discussed with the principal investigator. Doses 
reduced for treatment-related toxicity should not be re-escalated without discussion with the 
principal investigator. 
 
6.2 
Recommended dose modifications for inotuzumab ozogamicin-related toxicity 
Dose reductions may be required based on the worst toxicity experienced in the previous cycle. 
Patients experiencing a treatment interruption due to inotuzumab ozogamicin-related toxicity 
(such as grade 3-4 thrombocytopenia, grade 3-4 transaminitis) ≥14 days will be dose reduced as 
per the Table below. Inotuzumab will be resumed once the toxicity recovers to grade 2 or less. 
Once a patient has a dose reduction for a drug-related toxicity, the dose will not be re-escalated.  
Patients who are unable to tolerate dose level -2 will be withdrawn from treatment unless the PI 
thinks it is in the best interest of the patient. In that situation, a further 25% dose reduction will 
be performed.  
Dose Modification table for inotuzumab ozogamicin  
Dose Level 
Cycles 1-6 
(in mg/m2) 
Cycles 2 to 6 # 
(in mg/m2) 
Cycles 2 to 6 * 
(in mg/m2) 
-2 
Day 1 – 0.6 
Day 8 – Skip 
Day 15 – 0.375 
Day 1 – 0.375 
Day 8 – Skip 
Day 15 – 0.375 
Day 1 – 0.5 
 
-1 
Day 1 – 0.6 
Day 8 – 0.375 
Day 15 – 0.375 
Day 1 – 0.375 
Day 8 – 0.375 
Day 15 – 0.375 
Day 1 – 0.75 
 
1  
(starting dose level) 
Day 1 – 0.8 
Day 8 – 0.5 
Day 15 – 0.5 
Day 1 – 0.5 
Day 8 – 0.5 
Day 15 – 0.5 
Day 1 – 1.0 
 
# if no peripheral blood blasts; * once a response is confirmed (CR, CRi, CCyR, and/or absence 
of MRD by flow cytometry) 
 
6.3 
Recommended dose modifications for bosutinib-related toxicity 
If the toxicities experienced by the patient are thought to be related to bosutinib, the following 
dose modification criteria will be used- 
Non-Hematologic Bosutinib-related toxicity   


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Adverse Event 
Action# 
Grade I 
Remain on current dose level 
Grade II  
For persistent, clinically relevant toxicity not responding to optimal 
management: Interrupt bosutinib, then reintroduce at the same dose or 
reduce dose by one level upon recovery to grade ≤ 1 
Grade III 
For persistent, clinically relevant toxicity not responding to optimal 
management: Interrupt bosutinib, then dose reduce by 1 level upon 
recovery to grade ≤ 1 
Grade IV 
Interrupt bosutinib. Discuss with PI about resuming bosutinib with 
appropriate dose reduction. Resumption should happen only upon 
recovery to grade ≤ 1 
# For subjects who have required a dose reduction due to toxicity, but then have been free of the 
specific toxicity (grade ≤ 1) for at least 1 month and are otherwise tolerating bosutinib well, the 
investigator may choose to re-escalate the dose by one dose level each month (i.e. increase the 
daily dose by 100 mg/month) until the subject is back to the starting or previous dose (whichever 
is higher). 
NOTE: Cytopenias are common in the patient population studied in this trial. Inotuzumab 
ozogamicin can cause low platelet count. Therefore, dose modification for bosutinib for 
hematologic toxicities would be considered only if the investigator and PI strongly feel that the 
cytopenias were related to bosutinib.    
Dose Modification table for bosutinib 
  
 
 
 
 
 
6.4 
For patients with adverse events that are due to one of the two agents, dose adjustments to 
only one of the study drugs may be adjusted as per the guidelines mentioned above.  
 
6.5 
Dose reductions different than dose described above are acceptable after discussion with 
the principal investigator and documentation of the rationale for such action. 
 
7.0 
CONCOMITANT THERAPY 
 
All concomitant medications will be noted in the medical record. All supportive measures 
consistent with optimal patient care should be provided throughout the study according to the 
institutional standards. 
Dose Level 
Bosutinib (mg/day) orally once daily 
-1 
200 
1  
300 
2 
400 
3 
500 


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7.1 
Allowed Concomitant Therapy 
Prophylactic intrathecal therapy is allowed. The use of hematopoietic growth factors or 
transfusions is allowed. The use of hydroxyurea and/or steroids is permitted for the first 2 
weeks of the study period for cytoreduction. Note: Patients with isolated CNS relapse while on 
the study can continue on the study if deemed in the best interest of the patient. These patients 
can receive intrathecal chemotherapy to clear the CNS leukemia.  
 
7.2 
Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, immunosuppressive medications 
(excluding therapy as described in Section 7.1), radiotherapy, or systemic anti-neoplastic 
therapy during the study.  Herbal supplements, including St. John’s Wort and grapefruit juice 
are prohibited. 
7.3        Concomitant Use With CYP3A Inhibitors 
Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with 
bosutinib as an increase in bosutinib plasma concentration is expected. Strong CYP3A 
inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, 
telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, 
nefazodone and conivaptan. Moderate CYP3A inhibitors include fluconazole, darunavir, 
erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, 
verapamil, grapefruit products and ciprofloxacin.  
7.4        Concomitant Use With CYP3A Inducers 
Avoid the concomitant use of strong or moderate CYP3A inducers with bosutinib as a 
reduction in exposure is expected. Strong CYP3A inducers include rifampin, phenytoin, 
carbamazepine, St. John's Wort, rifabutin and phenobarbital. Moderate CYP3A inducers 
include bosentan, nafcillin, efavirenz, modafinil and etravirine. 
7.5        Concomitant Use with Proton Pump Inhibitors 
Proton Pump Inhibitors decrease bosutinib plasma concentration. Consider using short-acting 
antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure. Separate 
antacid or H2 blocker dosing and bosutinib dosing by more than 2 hours. 
 
8.0 
STUDY CALENDAR 
 
 
 
Cycle 1 
At the start of 
each 
subsequent 
cycle, Day 1 of 
each cycle (3 
days), Cycle 2-6 
At the start of 
each 
subsequent 
cycle, Day 1 of 
each cycle (3 
 


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days), Cycle 7 
onwards 
Study Assessments1 
Screen2 
Day 12 
Day 
8 
(3 
days) 
 
Day 15 
(3 
days) 
Continuation3 
 
Continuation3 
 
End of 
Treatm
ent 
Visit10 
Informed Consent 
X 
 
 
 
 
 
 
Baseline 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
Continuous 
X 
Physical Exam 
X 
X 
 
X 
 
X  
X 
X 
ECOG Performance 
Status 
X 
X 
 
 
 
X 
X 
X 
Vital Signs 
X 
X 
X 
 
X 
 
X 
X 
X 
Weight 
X 
X 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Hematology, Clinical 
Chemistry4,5 
X 
X 
X 
 
X 
 
X 
X 
X 
Screening for 
Hepatitis B, Hepatitis 
C and HIV 
X7 
 
 
 
 
 
 
Pregnancy Test6 
X 
 
 
 
 
 
 
 
12-Lead ECG 
X7 
 
 
 
 
 
 
ECHO or MUGA 
X7 
 
 
 
 
 
 
Disease Assessment8 
X7 
 
 
 
X8 
X8 
X11 
CD22 
immunophenotyping 
X9 
 
 
 
X9 
X9 
X11 
Inotuzumab 
 
X 
X 
X 
X12 
 
 
Bosutinib 
 
Continuous daily 
Adverse Events 
 
Continuous 
 
 
 


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1. Assessments scheduled on days of dosing should be done prior to administration of study 
drug(s), unless otherwise specified. 
2. Within 14 days before first dose. Screening assessments can be used as day 1 
assessments if done within 72 hrs. 
3. If clinically indicated, assessments during Continuation period can occur more 
frequently. 
4. Hematology (WBC with differential, unless WBC <0.5 x109/L in which case differential 
not needed), Hemoglobin, Platelet count); Clinical Chemistry (Alanine aminotransferase 
(ALT), Bilirubin total, Creatinine, uric acid). 
5. Hematology and Clinical Chemistry will be performed 1 to 3 times weekly during the 
cycle 1 and at least weekly during the cycles 2-6. For patients who continue bosutinib as 
maintenance therapy, at least monthly labs are required. Outside labs will be permitted 
and the PI/treating physician will review the labs for clinical significance, and sign/date 
the results.   
6. Perform only in women of child-bearing potential. Pregnancy test can be done in either 
serum or urine. 
7. Within 30 days of start of treatment   
8. Disease assessment by bone marrow samples (aspirate and/or biopsy) should be done at 
screening, end of cycle 1 (before start of cycle 2), and then before of start cycles 3-6. 
Note: Once CR/CRi is achieved, bone marrow will repeated every 2 cycles, or as 
clinically indicated. For patients who continue bosutinib as monotherapy (after 
completing all 6 cycles of inotuzumab or if inotuzumab is discounted early), bone 
marrow will be repeated every 3 months. ABL-kinase domain mutation analysis will be 
performed at baseline (except in patients on the Frontline Ph+ ALL or CML-LBC 
cohort) and may be repeated after starting treatment, as clinically indicated. Peripheral 
blood (or bone marrow) PCR for BCR-ABL would be obtained at baseline and  prior to 
start of each cycle.    
9. CD22 immunophenotyping performed at screening on peripheral blood or bone marrow 
aspirate. CD22 immunophenotyping will be performed in follow-up bone marrow to 
assess for minimal residual disease. 
10. End of Treatment Visit should occur 28 days (10 days) after last dose of study drugs. 
For patients who cannot come for the clinic visit, a phone call to assess for any side-
effects will be done. Final study visit assessments will be performed before any other 
therapeutic intervention, if possible. 
11. These procedures will not be performed on patients who cannot come to MD Anderson 
for their final study visit. 
12.  The schedule of Inotuzumab could be days 1, 8, and 15 OR once every 4-weeks (please 
see Section 4.1 for details) 
 


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9.0 
CRITERIA FOR RESPONSE 
 
Major hematologic response (MaHR): The detailed definition of MaHR is listed below. 
 
Major hematologic response (MaHR) defined as either: 
 
Complete Hematologic 
Response (CHR) 
 
No Evidence of 
Leukemia (NEL) 
 
▪ White blood count (WBC) 
 institutional upper limit 
of normal (ULN) 
 
▪ Absolute neutrophil 
count (ANC) 
≥1000/mm³ 
 
▪ Platelets ≥100,000/ mm³ 
 
▪ No blasts or promyelocytes 
in peripheral blood 
 
▪ Bone marrow blasts ≤5% 
 
▪ <5% myelocytes plus 
metamyelocytes in 
peripheral blood 
 
▪ Basophils <5% in 
peripheral blood 
 
▪ No extramedullary 
involvement (including 
no hepatomegaly or 
splenomegaly) 
 
▪ WBC 
 institutional 
ULN 
 
▪ No blasts or 
promyelocytes 
in peripheral 
blood 
 
▪ Bone marrow blasts 
≤5% 
 
▪ <5 % myelocytes 
plus 
metamyelocytes in 
peripheral blood 
 
▪ Basophils <5% 
in peripheral 
blood 
 
▪ No extramedullary 
involvement 
(including no 
hepatomegaly or 
splenomegaly) 
 
▪ At least one of 
the following: 
 
(i) 20,000/mm³ ≤ 
platelets < 100,000/mm³ 
(ii) 500/mm³ ≤ ANC < 
1000/mm³ 
 
Complete Response (CR):  
Disappearance of all clinical and/or radiologic evidence of disease  
Neutrophil count ≥ 1.0 x 109/L 


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Platelet count ≥ 100 x 109/L 
Normal bone marrow differential (≤ 5% blasts) 
No extra-medullary leukemia 
 
Complete Remission without Incomplete Blood Count Recovery (CRi): 
CR except for ANC < 1.0 x 109/L and/or platelets < 100 x 109/L 
 
Partial Remission (PR): 
Blood count recovery as for CR, but with a decrease of at least 50% in the percentage of 
marrow blasts to >5% to 25% in the bone marrow.  
 
10.0   ADVERSE EVENT REPORTING 
 
10.1 
Leukemia-specific Adverse Event Recording and Reporting Guidelines 
These guidelines serve to bring the Department of Leukemia in compliance with the 
institutional policy on Reporting of Serious Adverse Events-definition of expected AE-"  
 
Adverse event is any untoward medical occurrence that may present during treatment with 
a pharmaceutical product but which does not necessarily have a causal relationship with 
this treatment.  
 
Adverse drug reaction is a response to a drug which is noxious and unintended and which 
occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or 
for the modification of physiologic function.  
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) the event 
would not have happened at all, 2) the event would have occurred later than it actually did, 
or 3) the event would have been less severe. 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial. 
10.1.1  PDMS/CORe will be used as the electronic case report form for this protocol.  Adverse 
events will be documented in the medical record and entered into PDMS/CORe. 


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10.1.2 Adverse Events (AEs) will be evaluated according to the CTCAE version 4.0 and 
documented in medical record.  All AE’s regardless of grade and attribution will be 
collected on toxicity logs; however, unexpected and related AE’s of all grades will be 
entered into CORe.  Only unexpected AEs, any grade, will be recorded in the Case Report 
Form (CRF).  Expected events during leukemia therapy are: 
10.1.2.1 Myelosuppression related events (due to disease or leukemia therapy) 
10.1.2.1.1 
Febrile or infection episodes not requiring management in the 
intensive care unit 
10.1.2.1.2 
Epistaxis or bleeding except for catastrophic CNS or pulmonary 
hemorrhage 
10.1.2.1.3 
Anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia 
10.1.2.2 Disease related events 
10.1.2.2.1  Symptoms associated with anemia (fatigue, weakness,          
shortness of breath) 
10.1.2.2.2 
Electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, 
magnesium) 
10.1.2.2.3 
Chemistry abnormalities (LDH, phosphorus, calcium, BUN, 
protein, albumin, uric acid, alkaline phosphatase, glucose) 
10.1.2.2.4 
Coagulation abnormalities 
10.1.2.2.5 
Disease specific therapy (induction, maintenance, salvage, or stem 
cell therapy) 
10.1.2.2.6 
Alopecia 
10.1.2.2.7 
Bone, joint, or muscle pain 
10.1.2.2.8 
Liver function test abnormalities associated with infection or disease 
progression 
10.1.2.2.9 
Disease progression 
10.1.2.2.10 Abnormal hematologic values  
10.1.2.3  General therapy related events 
10.1.2.3.1 
Catheter related events 
10.1.2.3.2 
Renal failure related to tumor lysis syndrome or antibiotic/ 
antifungal therapy 
10.1.2.3.3 
Rash related to antibiotic use 
10.1.2.4  Hospitalization for the management of any of the above expected events 
 
10.1.3 Abnormal hematologic values will not be recorded on the case report form.  For abnormal 
chemical values, the apogee or nadir (whichever is appropriate) will be reported per course 
on the case report form. 
 


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10.1.4 All events that are not listed as expected in section 10.1.2 will be collected for the 
purpose of grading, and determining attribution to study drug by the PI. 
10.1.5 Serious Adverse Event Reporting (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
• Important medical events as defined above, may also be considered serious 
adverse events.  Any important medical event can and should be reported as 
an SAE if deemed appropriate by the Principal Investigator or the IND 
Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition 
of a SAE must be reported to the IRB and IND Office in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. Anderson 
Cancer Center Institutional Review Board Policy for Investigators on Reporting 
Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise 
in the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of attribution (within 5 working days of knowledge of the 
event). 


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 "Serious Adverse Event Reporting (SAE) for M. D. Anderson-Sponsored IND 
Protocols": 
• All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, progression of the event 
has stabilized, or there has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
Investigator Communication with Supporting Companies: 
Any individual expedited SAE reports required by the FDA will be reported to 
Pfizer within 24 hours of first awareness of the event (immediately if the event is 
fatal or life-threatening), Principal Investigator will report to Pfizer by facsimile any 
Serious Adverse Event as soon as it is determined to meet the definition. Principal 
Investigator will report SAEs using one of the following forms: (1) an FDA 
MEDWATCH form, (2) a CIOMS form, (3) an Investigator-Initiated Research 
Serious Adverse Event (IIR SAE) form, or (4) any other form prospectively 
approved by Pfizer.  The Reportable Event Fax Cover Sheet provided by Pfizer must 
also be included with each SAE submitted.  
 
11.0 
STATISTICAL CONSIDERATIONS 
 


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11.1   Endpoints 
11.1.1  Primary Endpoints: 
Phase I: 
1. MTD of bosutinib in combination with inotuzumab ozogamicin in patients with Ph+ ALL 
and CML in lymphoid blast phase that express CD22 
 
Phase II: 
2.  Major hematologic response (MaHR) for relapsed ph+ALL and CR/CRi for newly diagnosed 
Ph+ ALL or CML-LBC with age≥60.  
 
11.1.2  Secondary Endpoints: 
Phase I:  
1. Overall MaHR 
2. Duration of response and overall survival 
 
Phase II: 
3. Incidence and severity of adverse events  
4. Duration of response and overall survival  
 
11.2  Sample size 
This will be a single arm, single center, open label study of bosutinib in combination with 
inotuzumab ozogamicin in patients with Ph+ ALL and CML in lymphoid blast phase that 
express CD22.  There are two parallel cohorts of patients: relapsed ph+ALL and newly 
diagnosed Ph+ ALL or CML-LBC with age≥60.  
 
Sample size – Up to 18 patients will be enrolled in phase I part of the study for each cohort. 
Therefore, there will be a maximum of 36 patients, 18 patients per cohort in phase I part.  A total 
of 56 patients will be enrolled in phase II with 28 patients for each patient cohort: relapsed ph+ALL 
and newly diagnosed Ph+ ALL or CML-LBC with age ≥60. The 6 patients treated at the MTD 
from the phase I dose cohort will be included in the phase 2 part for each cohort. Therefore, the 
maximum sample size is 36 in phase I + 44 in phase II = 80. 
Phase I 
Bosutinib will be dose-escalated in a standard 3+3 study design separately for two cohorts 
(relapsed ph+ALL and newly diagnosed Ph+ ALL or CML-LBC with age ≥60). Patients will be 
entered sequentially to each dose level.  Three combination dose levels are defined. The starting 
dose is dose 1.  If none of the first 3 patients at a dose level experience first cycle dose-limiting 
toxicity (DLT), new patients may be entered at the next higher dose level. If 1 of 3 patients 
experience first cycle DLT, up to 3 more patients are started at that same dose level. If 1of 6 
experience DLT, then new patients may be entered at the next higher dose level. If 2 or more 


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experience first cycle DLT, no further patients are started at that dose. The MTD is the highest 
dose level in which <2 patients of 6 develop first cycle DLT. Detailed dose escalation rules are 
described in the following section. A maximum of 18 patients will enroll in the phase I study. 
DLT definition is provided in Section 4.1.2. 
 
Table 11.1 Dose-Escalation Decision Rules for 3+3 Escalation Schema is provided below: 
Number of Patients with 
DLT at a Dose Level 
Decision 
0 of 3 
Escalate and evaluate in 3 subsequent patients. 
1 of 3 
Enroll 3 additional subjects at this dose level. 
>/=2 of 3 
The MTD has been exceeded. Dose escalation will stop and this 
level will be declared the maximum administered dose. Evaluate 
3 additional patients at the prior dose level if only three were 
treated at that dose previously.  
An interim dose may be explored if the increments between 
maximally administered dose and the next lower dose is >50%. 
1 of 6 
Escalate dose and evaluate in 3 subsequent patients. 
</=1 out of 6 at the Highest 
Dose Below the Maximum 
Administered Dose 
This is the MTD. 
>/=2 of 6 
The MTD has been exceeded. Dose escalation will stop and this 
level will be declared the maximum administered dose. Evaluate 
3 additional patients at the prior dose level if only three were 
treated at that dose previously.  
An interim dose may be explored if the increments between 
maximally administered dose and the next lower dose is >50%. 
 
Phase II 
Cohort 1: relapsed ph+ALL 
Once the MTD (bosutinib 500mg dose level or lower,) is established, a phase II portion will 
commence. Patients will receive bosutinib per the dose established in the Phase I study. Patients 
will receive inotuzumab ozogamicin at the same dose and schedule as for the Phase I part of the 
study.  
A total of 28 patients (including the 6 patients treated at the MTD from the phase I dose cohort) 
will be enrolled in the phase II portion of the study.  The primary efficacy endpoint is MaHR 
during the study period of 4 cycles. We will employ Simon MinMax two-stage design.23 The 
target response rate will be 50% and a response rate of 30% or lower will be considered as not 


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having desired efficacy. With alpha of 0.1 and beta of 0.2, the first stage will require 12 patients. 
If there are 3 or fewer patients responded, the trial will be stopped. If 4 or more out of the first 12 
patients respond, accrual will continue until a total of 28 patients have been enrolled. At the end 
of the study, if 12 or more patients out of 28 patients respond, the regimen will be considered 
active. With this design, the probability of early termination is 49% if the true response rate is 
only 30%. 
The method of Thall, Simon, and Estey will be used to perform interim safety monitoring.24  We 
will assume a Beta (0.6, 1.4) prior distribution for the toxicity rate which in particular has mean 
of 30%.  The toxicity is defined as any DLT at least possibly attributed to the study drug during 
the treatment period. 
The following decision criteria will be applied continuously up to the 28 patient. The trial will be 
stopped early according to the following monitoring rule. 
Pr{toxicity  rate > 30%| data} > 0.93 
That is, if at any time during the study we determine that there is more than a 93% chance that the 
toxicity rate is more than 30% we will stop the study. The design software Multc Lean Desktop 
(version 2.1) developed by the Department of Biostatistics at M. D. Anderson Cancer Center 
(MDACC) was used to generate the toxicity stopping boundaries and the OC table. The stopping 
rule boundary is shown in table 12.2. 
Table 11.2: Safety monitoring boundary 
#patient 
Stop the trial if there are this 
many toxicities total: 
6 
4-6 
7-8 
5-8 
9-11 
6-11 
12-13 
7-13 
14-16 
8-16 
17-19 
9-19 
20-21 
10-21 
22-24 
11-24 
25-27 
12-27 
28 
13-28 
 
Table 11.3: the operating characteristics for safety monitoring 
True toxicity 
Early Stopping Probability 
Average number of patients treated 


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0.2 
0.03 
27.4 
0.25 
0.09 
26.5 
0.3 
0.19 
25 
0.35 
0.34 
22.7 
0.4 
0.53 
19.8 
 
 
Cohort 2: newly diagnosed Ph+ ALL or CML-LBC with age ≥60 
Patients in this cohort will be given the dosage of bosutinib in combination with inotuzumab 
ozogamicin that has been found to be safe in the relapsed patients.  A total of 28 patients will be 
enrolled.  The primary efficacy endpoint is CR/CRi during the study period of 4 cycles. Similar 
to the relapse cohort, we will employ Simon MinMax two-stage design.23 The target response 
rate will be 50% and a response rate of 30% or lower will be considered as not having desired 
efficacy. With alpha of 0.1 and beta of 0.2, the first stage will require 12 patients. If there are 3 
or fewer patients responded, the trial will be stopped. If 4 or more out of the first 12 patients 
respond, accrual will continue until a total of 28 patients have been enrolled. At the end of the 
study, if 12 or more patients out of 28 patients respond, the regimen will be considered active. 
With this design, the probability of early termination is 49% if the true response rate is only 
30%. 
The method of Thall, Simon, and Estey will be used to perform interim safety monitoring.24  We 
will assume a Beta (0.6, 1.4) prior distribution for the toxicity rate which in particular has mean 
of 30%.  The toxicity is defined as any DLT at least possibly attributed to the study drug during 
the treatment period. 
The following decision criteria will be applied continuously up to the 28 patient. The trial will be 
stopped early according to the following monitoring rule. 
Pr{toxicity  rate > 30%| data} > 0.93 
That is, if at any time during the study we determine that there is more than a 93% chance that the 
toxicity rate is more than 30% we will stop the study. The design software Multc Lean Desktop 
(version 2.1) developed by the Department of Biostatistics at M. D. Anderson Cancer Center 
(MDACC) was used to generate the toxicity stopping boundaries and the OC table. The stopping 
rule boundary is shown in table 12.2. 
Table 11.2: Safety monitoring boundary 
#patient 
Stop the trial if there are this 
many toxicities total: 


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6 
4-6 
7-8 
5-8 
9-11 
6-11 
12-13 
7-13 
14-16 
8-16 
17-19 
9-19 
20-21 
10-21 
22-24 
11-24 
25-27 
12-27 
28 
13-28 
 
Table 11.3: the operating characteristics for safety monitoring 
True toxicity 
Early Stopping Probability 
Average number of patients treated 
0.2 
0.03 
27.4 
0.25 
0.09 
26.5 
0.3 
0.19 
25 
0.35 
0.34 
22.7 
0.4 
0.53 
19.8 
 
11.3 Statistical Analysis Plan 
The primary end-point is major hematologic response.  The response will be evaluated along 
with its 95% confidence interval.  Data from all subjects who receive any study drug will be 
included in the safety analyses. Subjects who entered the study and did not take any of the study 
drugs and had this confirmed will not be evaluated for safety. The severity of the toxicities will 
be graded according to the NCI CTCAE v4.0 whenever possible. We will follow standard 
reporting guidelines for adverse events. Safety data will be summarized by category, severity and 
frequency. 
Analysis of secondary endpoints will be predominantly descriptive statistics and will be 
interpreted as being exploratory and hypothesis generating. The duration of response and overall 
survival (OS) will be estimated using the method of Kaplan-Meier.   Cox regression models will 
be used to determine the relationship with the time-to-events (e.g. OS) and the potential 
prognostic factors.   
12.0 
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