An Open-Label Phase II Dose Optimization Study of Bosutinib at a Starting Dose of 300 Mg Daily for Adult Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase Post Frontline TKI Failure
Phase: PHASE2
Conditions: Blasts Under 15 Percent of Bone Marrow Nucleated Cells, Blasts Under 15 Percent of Peripheral Blood White Cells, Blasts Under 30 Percent of Bone Marrow Nucleated Cells, Blasts Under 30 Percent of Peripheral Blood White Cells, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Sponsor: M.D. Anderson Cancer Center

2016-0081
June 20, 2018
Page 1  
Protocol Page
An open-label phase II dose optimization study of bosutinib at a starting dose of 300 
mg daily for adult patients with chronic myeloid leukemia (CML) in chronic phase 
post frontline TKI failure 
2016-0081
Core Protocol Information
Short Title 
Bosutinib dose-optimization study in CML
Study Chair: 
Philip A. Thompson
Additional Contact:
Sabrina U. Harris
Vicky H. Zoeller
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-7430
Unit:
0428
Study Manager:
Debra L. Bull-Linderman
Full Title: 
An open-label phase II dose optimization study of bosutinib at a starting dose of 300 mg daily 
for adult patients with chronic myeloid leukemia (CML) in chronic phase post frontline TKI failure 
Public Description:
N/A
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 08/08/2019
Version:
08
Submitted by:
Sabrina U. Harris--7/19/2018 3:11:02 PM
OPR Action:
Accepted by:  Rosheta McCray -- 7/20/2018 11:03:42 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

2016-0081
June 20, 2018
Page 2  
Protocol Body
 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
1 
 
Protocol 2016-0081. An open-label phase II dose optimization study of 
bosutinib for adult patients with chronic myeloid leukemia (CML) in chronic 
phase post frontline TKI failure 
Contents 
 
1.0 
OBJECTIVES ............................................................................................................. 2 
2.0 
STUDY DESIGN ......................................................................................................... 3 
3.0 CHRONIC MYELOID LEUKEMIA ................................................................................... 3 
3.1 Disease Overview ....................................................................................................... 3 
3.2 Frontline management ................................................................................................ 4 
3.3 Management of TKI resistance ....................................................................................... 5 
3.4. Bosutinib ........................................................................................................................ 6 
3.5. Rationale for the starting dose of 300 mg per day of bosutinib ...................................... 7 
4.0 NUMBER OF PATIENTS ................................................................................................ 8 
5.1 Inclusion criteria: ......................................................................................................... 8 
5.2 Exclusion criteria: ...................................................................................................... 10 
6.0 TREATMENT PLAN ..................................................................................................... 10 
Table 2. Bosutinib dose levels ......................................................................................... 10 
6.2 Bosutinib dose reductions: ........................................................................................ 11 
6.3 Missed doses. ............................................................................................................... 12 
7.0 PRE-TREATMENT EVALUATION AND EVALUATION DURING TREATMENT ......... 12 
8.1 Hematologic response: .............................................................................................. 15 
8.2 Cytogenetic response: ............................................................................................... 15 
8.3 Molecular response: .................................................................................................. 15 
8.4 Survival:..................................................................................................................... 16 
9.0 EVALUATION OF TOXICITY ....................................................................................... 16 
10.0 CRITERIA FOR REMOVAL FROM THE STUDY ....................................................... 16 
11.0 STATISTICAL CONSIDERATIONS ............................................................................ 17 
12.0 REPORTING REQUIREMENTS ................................................................................ 20 
Reporting Requirements ................................................................................................. 20 
12.2    Adverse events related to study conditions ............................................................. 20 

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12.3   Serious Adverse Event Reporting (SAE) ............................................................... 20 
13.0 REFERENCES ........................................................................................................... 22 
14.0 ABBREVIATION LIST ................................................................................................. 24 
 
 
1.0 OBJECTIVES 
Primary:  
To assess the response rate within 24 weeks in patients in chronic phase receiving 
bosutinib with the starting dose of 300 mg per day, with potential escalation to 400mg, 500 
mg and 600mg per day.  
 
Response is defined as follows: 
1. For patients who do not currently have a partial cytogenetic response (PCyR), 
achievement of major cytogenetic response (MCyR) is considered a response. 
2. For patients who are currently in PCyR, achievement of complete cytogenetic response 
(CCyR), CCyR is considered a response. 
 
Secondary:      
 Safety of dosing schedule. 
 Frequency of treatment interruptions and dose reductions. 
 Determine the rate of BCR-ABL/ABL <10% at 3 months and <1% at 6 months, reported 
on the international scale, and the rate of complete cytogenetic response (CCyR) at 6 
months after the start of treatment.  
 Determine the cumulative rate of CCyR. 
 Determine the rate of major molecular response, MR4, MR4.5 and complete molecular 
response. 
 Determine long-term outcomes, including progression-free survival, event-free survival, 
and overall survival. 
 Investigate the correlation between ABL kinase domain mutations, if present at the time 
of enrollment, with outcome. 

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 Determine the rate of development and type of ABL kinase domain mutations during 
therapy with bosutinib. 
 
 
 
2.0 STUDY DESIGN 
The study is an open-label phase II trial in patients with CML in chronic phase who have 
experienced resistance or intolerance to frontline TKI therapy.  The starting dose of 
bosutinib is 300 mg per day. Patients will have the opportunity to dose escalate to 400mg, 
500mg and subsequently to 600mg if therapeutic targets are not met and toxicity does not 
preclude such dose escalation. 
 
Toxicity will be monitored continuously, throughout the duration of the study. 
 
3.0 CHRONIC MYELOID LEUKEMIA 
 
3.1 Disease Overview 
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 
cases per 100,000 adults, and accounts for approximately 15% of newly diagnosed cases of 
leukemia in adults.(1) Central to the pathogenesis of CML is the fusion of the Abelson murine 
leukemia (ABL) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on 
chromosome 22, which results in expression of an oncoprotein, termed BCR-ABL.2 BCR-
ABL is a constitutively active tyrosine kinase that promotes growth and replication through 
downstream pathways such as RAS, RAF, JUN kinase, MYC and STAT.(3-9) This influences 
leukemogenesis by creating a cytokine-independent cell cycle with aberrant apoptotic signals 
in response to cytokine withdrawal.  
 
Until approximately a decade ago, drug therapy for CML was limited to non-specific agents 
such as busulfan, hydroxyurea, and interferon-alfa (INF-a).(10) INF-a led to regression of the 
disease and improved survival but was hindered by a multitude of toxicities. Allogeneic stem 
cell transplantation (AlloSCT) was a curative intervention, but carried with it a high risk of 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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morbidity and mortality. Further, alloSCT is only an option for patients with excellent 
performance status and an appropriate stem cell donor.  
 
The landscape changed dramatically with the development of small molecule tyrosine kinase 
inhibitors (TKIs) that were shown to potently interfere with the interaction between the BCR-
ABL protein and adenosine triphosphate (ATP), blocking cellular proliferation of the 
malignant clone.(11) This “targeted” approach was found to dramatically alter the natural 
history of the disease, improving 10-year overall survival from approximately 20% to 80 – 
90%.(1,12) 
 
3.2 Frontline management 
Three TKIs have received regulatory approval for the frontline treatment of CML: imatinib, 
dasatinib, and nilotinib. Current guidelines endorse all three as excellent options for the initial 
management of CML in the chronic phase (CML-CP). Imatinib mesylate (Gleevec, Novartis 
Pharmaceutical Corporation, NJ, USA), was the first TKI to receive approval by the Food and 
Drug Administration (FDA) for the treatment of patients with CML-CP. It acts via competitive 
inhibition at the ATP-binding site of the Bcr-Abl oncoprotein, which results in the inhibition of 
phosphorylation of proteins involved in cell signal transduction. It efficiently inhibits the Bcr-
Abl kinase activity, but also blocks the platelet-derived growth factor receptor (PGDFR), and 
the C-KIT tyrosine kinase.(11-12) 
 
The International Randomized Study of IFN-a and STI571 (IRIS) study is considered a 
landmark clinical trial for TKIs and CML.(13) Investigators randomized 1,106 patients to 
receive imatinib 400 mg/day or IFN plus subcutaneous low-dose cytarabine. After a median 
follow-up of 19 months, relevant outcomes for patients receiving imatinib were significantly 
better than for those treated with IFN plus cytarabine, notably the rate of CCyR (74% vs. 9%, 
P < .001), and freedom from progression to accelerated phase (AP) or blast phase (BP)  at 
12 months (99% vs. 93%, P < 0.001). The responses to imatinib were also durable, as shown 
in an 8-year follow up of the IRIS study;(12) the estimated event-free survival rate was 81%; 
the overall survival (OS) rate was 93% when only CML-related deaths were considered.  
 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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While the results using imatinib were impressive, only 55% of patients enrolled remained on 
therapy at the 8-year follow up time. This underscores the need for additional options for 
patients who had failed or were intolerant to imatinib, and led to the rational development of 
second generation TKIs.  
 
Dasatinib (Sprycel, Bristol-Myers Squibb) is an oral, second generation TKI, which is 350 
times more potent than imatinib in vitro.(14-16) It also inhibits the Src family of kinases, which 
may also be important in blunting critical cell signaling pathways.(17) Following the positive 
results in the salvage setting post imatinib failure, dasatinib was evaluated as frontline CML 
therapy.  
 
The DASISION trial was a randomized, phase III, international study comparing imatinib 400 
mg daily versus dasatinib 100 mg daily in newly diagnosed patients with CML-CP.(18) The 
primary endpoint of the study was confirmed CCyR at 12 months, which was achieved in a 
higher percentage of patients randomized to dasatinib (77% vs. 66%, P = 0.007). Dasatinib 
was also able to induce higher rates of major molecular response (MMR) compared with 
imatinib.(19)  
 
Nilotinib (Tasigna, Novartis Pharmaceutical Corporation, NJ, USA) is a structural analog of 
imatinib, though Its affinity for the ATP binding site on Bcr-Abl is 50 times more potent in 
vitro.(20) Like dasatinib, nilotinib initially demonstrated the ability to induce hematologic and 
cytogenetic responses in patients with CML post imatinib failure, leading to nilotinib therapy 
in the frontline setting.  
 
ENESTnd was a randomized, phase III, international study comparing two doses of nilotinib 
(300 mg or 400 mg twice daily) to imatinib 400 mg once daily.(21) The primary study endpoint 
was the rate of MMR at 12 months, which was achieved at higher rates on the nilotinib arms 
compared with imatinib (44% and 43% vs. 22%, P <0.001). There were also fewer cases of 
progression to AP or BP noted with nilotinib.(22) 
 
3.3 Management of TKI resistance 

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A problem that may increase due to the widespread use of all of the commercially available 
TKIs for CML is increased drug resistance. One of the most common mechanisms of 
resistance involves point mutations in the kinase domain of BCR-ABL, which impair the 
activity of the available TKIs. Second generation TKIs are able to overcome most of the 
mutations that confer resistance to imatinib, though novel mutations rendering the leukemia 
resistant to dasatinib and/or nilotinib have emerged. One important mutation, the T315I, is 
known as the “gatekeeper” mutation, as it confers resistance to all currently available TKIs 
except ponatinib.  
 
Before their approval to treat first-line CML in chronic phase (CML-CP), both nilotinib and 
dasatinib were approved for use in second-line CML-CP following prior therapy, including 
imatinib.(23-24) Based on these clinical studies, several noteworthy ideas have emerged. 
First, second-line treatment can yield high rates of response in patients who have inadequate 
response to imatinib, including high rates of MMR. Second, dose escalation of imatinib can 
improve response rates in patients with inadequate response to standard-dose imatinib, but 
switching to second-line TKIs can be more effective.(25) In addition, earlier switch to second-
line TKI may be more effective than later switch.(26)  
 
3.4. Bosutinib 
Bosutinib was initially studied in patients that were resistant to or intolerant of imatinib.(27) 
After a dose escalation period, 500 mg once daily was selected to go forward as the phase 
II dose, with the potential for dose escalation to 600 mg once daily for patients not meeting 
pre-specified benchmarks. There were 288 patients enrolled in the pivotal phase II trial, with 
more than two thirds of the patients documented as having imatinib-resistant disease. The 
primary endpoint was MCyR at 6 months, and this was achieved in 31% of the patients 
treated. At any point during follow up, 41% achieved a CCyR.  Bosutinib appeared to retain 
activity across most known mutations that confer imatinib resistance, except for the T315I. 
Responses were independent of whether patients were resistant to or intolerant of imatinib. 
The most common toxicities noted were diarrhea, nausea, vomiting, and rash. Diarrhea 
occurred in 84% of the patients overall, with 9% experiencing an event classified as grade 3 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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(there were no grade 4 events documented). Other notable adverse events included 
myelosuppression and liver function test abnormalities.  
 
Bosutinib was assessed in the frontline therapy of patients with newly diagnosed CML.(28) 
In the phase 3 BELA study, which evaluated the effect of treatment in a first-line setting, 
bosutinib at 500 mg did not achieve the primary efficacy end point of a superior rate of CCyR 
at 12 months versus imatinib. However, bosutinib did demonstrate superiority across many 
other efficacy end points including MMR at 12 months, and importantly for patients, the 
percentage of patients with transformation to AP or BP was lower for bosutinib than 
imatinib.(28)  
 
In addition, the safety profile of bosutinib was distinct from that of imatinib in terms of 
increased gastrointestinal (GI) toxicity, especially diarrhea, and increased values for liver 
function tests (LFTs). Compared with imatinib, bosutinib was associated with higher 
incidences of Grade 3-4 GI toxicities, including diarrhea (12% vs. 1%), vomiting (3% vs. 0%) 
and abdominal pain (1% vs. <1%), although these AEs were usually transient and 
manageable. Notably, diarrhea occurred mostly in the first 1-2 months of therapy and 
improved or subsided spontaneously over time. Conversely, there were fewer patients with 
hematologic toxicity in the bosutinib arm compared to imatinib. 
 
Subsequently, the BFORE study was designed, which compared bosutinib at a lower dose 
of 400mg/d to imatinib 400mg/d. There remained a significant incidence of grade 3-4 AEs 
with bosutinib, especially elevated ALT (19%) and diarrhea (8%). Although somewhat lower 
in incidence than in the BELA study of 500mg/d, these were associated with a significant 
incidence of treatment interruptions and reductions (56%, overall). Median duration of dose 
interruption was 23 days. MMR rate at 12 months was 47% in BFORE, compared to 41% in 
BELA, indicating that the lower dose of bosutinib did not compromise efficacy.(1)  
 
3.5. Rationale for the starting dose of 300 mg per day of bosutinib 
The first studies in 2nd line and first line therapy used 500mg/d. In both studies, a substantial 
number of patients reported toxicities. The incidence of treatment emergent AEs (TEAEs) 

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overall as well as unique TEAEs were lower following dose reduction from 500 mg to 400 
mg, while the efficacy of bosutinib in patients who received dose reductions to 400 mg 
remained favorable. 
 
Therefore, it was concluded that a starting dose of 400 mg daily would be used in this phase 
II study in patients post frontline TKI failure, with potential escalation to 500 mg daily and 
subsequently to 600mg daily, if therapeutic targets at pre-specified timepoints are not met 
and toxicity is within acceptable limits. By starting at a lower dose and dose-escalating as 
tolerated/necessary, we will minimize dose interruptions, which may compromise efficacy. 
We hypothesize that such a dosing strategy will result in better tolerability and similar, if not 
superior, efficacy as a starting dose of 500 mg daily.  
 
Recently, results of the BFORE study were published, demonstrating favorable efficacy 
(higher rate of MMR at 12 months with a dose of 400mg bosutinib than when starting with 
500mg in the BELA study), confirming the above hypothesis. However, there was still a 
significant incidence of grade 3-4 toxicity and dose interruptions/reductions, which may have 
a greater impact on efficacy than receiving a lower, consistent dosing schedule. Additionally, 
in the first 8 patients treated on this study, we have had 3 patients with grade 3-4 toxicity 
(elevated LFTs in 2 patients and diarrhea in 1 patient). Therefore, we subsequently amended 
the study to commence dosing at 300mg per day, with the option to escalate doses if 
therapeutic targets are not met during treatment. 
 
4.0 NUMBER OF PATIENTS 
42 patients will be enrolled in this open-labeled phase II trial. 
 
5.0 STUDY ENTRY CRITERIA 
5.1 Inclusion criteria:  
1. 
Patients with CML in chronic phase who have resistance and/or intolerance to 
frontline TKI therapy. Resistance is defined as lack (lack defined as response not 
achieved or lost by the given dates mentioned hereafter) of CHR within 3 months, 
lack of MCyR within 6 months, and lack of CCyR within 12 months of therapy with 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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frontline TKIs. In addition, loss of MCyR or CCyR at any time during the course of 
therapy is also considered resistance to therapy. Intolerance is defined as persistent 
or severe toxicity that is unacceptable to the patient.  
2.       Chronic phase is defined as: 
a. 
<15% blasts in peripheral blood and bone marrow; 
b. 
<30% blasts plus promyelocytes in peripheral blood and bone marrow; 
c. 
<20% basophils in peripheral blood; 
d. 
> or =100 x 10^9/L platelets (> or =100,000/mm3); 
e. 
No evidence of extramedullary disease except hepatosplenomegaly; and 
f. 
No prior diagnosis of AP or BP-CML. Patients with clonal evolution but no 
other criteria for accelerated phase are eligible.  
3. 
ECOG performance status of 0, 1, or 2. 
4. 
Age 18 years or older. 
5. 
Adequate organ function with creatinine less than or equal to 2.0 mg/dl, bilirubin less 
than or equal to 3.5 mg/dl and ALT less than or equal to 2.5 times institutional upper 
limit of normal 
6.  
Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotrophin (beta-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: a. birth control pills, shots or 
implants (placed under the skin by a health care provider) or patches (placed on the 
skin); b. Intrauterine devices (IUDs); c. 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. 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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5.2 Exclusion criteria:  
1. 
Women that are pregnant or lactating 
2. 
Known to be HIV+ 
3. 
Active and uncontrolled disease/infection that in the opinion of the treating physician 
and principal investigator may affect the ability to participate in the trial or put the 
patient at unduly high risk 
4. 
Unable or unwilling to sign the informed consent document 
5. 
Received other investigational therapy within the past 14 days 
6. 
Presence of T315I mutation on ABL1 sequencing  
7. 
Patient is currently in complete cytogenetic remission (CCyR) 
 
6.0 TREATMENT PLAN 
Bosutinib will be commenced at 300mg/d. Subsequent dose changes may be made in the 
event of inadequate response or toxicity, according to the dose levels in table 2.  
 
Table 2. Bosutinib dose levels 
Dose level 
Bosutinib (mg) 
+3 
600 
+2 
500 
+1  
400 
Starting dose 
300 
-1 
200 
-2 
100 
 
6.1 Management of bosutinib dosing. 
Patients may have their dose increased by one dose level, at the 1, 3, 6 and 12 month 
assessments, if they do not achieve or subsequently lose the following therapeutic 
milestones:  
i)   month 1, complete hematologic response;  
ii)  month 3, BCR-ABL1 transcripts < or = 10% and/or Ph + metaphases < or = 35%; 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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iii)  month 6 BCR-ABL1 transcripts < or = 1% and/or Ph + metaphases 0%);  
iv) month 12, BCR-ABL1 transcripts <0.1%. All BCR-ABL targets refer to the 
international scale. 
AND 
They do not currently have grade >/= 3 hematologic or grade >/=2 non-hematologic 
toxicity.  
 
6.1.1 Patients who had their dose reduced for any reason may have the dose re-escalated 
after at least 28 days at the lower dose provided they do not currently have grade >/= 3 
hematologic or grade >/=2 non-hematologic toxicity.  
 
6.1.2 At least 28 days should have elapsed from a prior dose escalation before a new dose 
escalation can be implemented, and the patient should not currently have grade >/= 3 
hematologic or grade >/=2 non-hematologic toxicity. The highest dose level to be used in this 
study is 600 mg daily.   
 
6.1.3 Dose escalations outside the above timepoints may be initiated by the treating 
physician if deemed to be in the best interests of the patient, with the approval of the PI. 
 
6.2 Bosutinib dose reductions: 
General guidelines include the following: 
a) 
Non-Hematologic Toxicity 
 Grade 2: Patients with persistent grade 2 toxicity that is unresponsive to appropriate 
therapy, may have treatment held until the toxicity has resolved to grade < or =1. 
Bosutinib may then be resumed at the same dose the patient was receiving at the 
time treatment was interrupted. If the grade 2 toxicity recurs, bosutinib may be held 
until the toxicity has resolved to grade 1. Treatment may then be resumed with a 
one dose level reduction. 
 Grade 3-4: If a patient experiences Grade 3-4 toxicity that is related to bosutinib, 
therapy must be withheld until the toxicity has resolved to Grade < or = 1. Bosutinib 

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may then be resumed with a one dose level reduction. 
b) Hematologic Toxicity 
 If absolute neutrophil count is <1.0 x 109/L or platelets are <50 x 109/L, hold therapy 
until granulocytes are above 1 x 10
9/L and platelets are > or = 50 x 109/L, then 
resume therapy. 
 If recovery takes more than 2 weeks, resume bosutinib at 1 dose level reduction 
from the dose the patient was receiving at the time therapy was interrupted. 
 If recovery takes less than 2 weeks, resume bosutinib at the same dose the patient 
was receiving at the time treatment was interrupted. If myelosuppression recurs, 
resume bosutinib at one dose level reduction from the dose the patient was 
receiving at the time the treatment was interrupted. 
 If a similar degree of toxicity returns, a further dose reduction by one dose level can 
be performed, using the above procedures.  
c) Modifications of dose schedules other than the above will be allowed in the best interest 
of the patient, with the approval of the PI. 
 
6.3 Missed doses.  
Occasional missed doses will not be considered a deviation. Missed doses of > or = 2 
weeks will be considered a protocol deviation unless treatment interrupted for medical 
reasons. 
 
7.0 PRE-TREATMENT EVALUATION AND EVALUATION DURING TREATMENT 
Table 3. Pre-treatment evaluation and evaluation during treatment. 
Cycle 
Screening/ 
baseline(1) 
1 
1 
2 
3 
6 
9 
12 
18 
24 
At 
progression 
Day within cycle(2) 
-28 to 1 
15(a) 
28 
28 
28 
28 
28 
28 
28 
28 
 
Informed consent(3) 
X 
 
 
 
 
 
 
 
 
 
 
Medical history(4) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 

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Physical examination 
including vital signs(5) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Complete blood count 
with differential(6) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry(7) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow 
examination and 
conventional 
cytogenetics(8) 
X 
 
 
 
 
X 
 
 
 
 
X 
Cytogenetic analysis(9) 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
PCR testing for BCR-
ABL1(10) 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Kinase domain 
sequencing(11) 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test(12) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
(a) Evaluations on day 15 and 56 can either be performed in the context of a clinic visit at 
M.D. Anderson or patients can have labs drawn locally and the results provided to study 
staff. Additional evaluations may be ordered at the discretion of the treating physician, if 
deemed necessary. 
 
(1) Screening period testing. All the above must be completed within 28 days of study 
enrollment, with the exception of bone marrow examination, cytogenetics and kinase 
domain sequencing, which must be completed within 42 days prior to study enrollment and 
pregnancy test, which must be performed within 14 days prior to study enrollment. 
 
(2) Evaluations within the first month of therapy must take place within +/- 1 week of 
scheduled time. Evaluation at D56 must occur within +/-2 weeks. Subsequent evaluations 
must occur within 1 month of the scheduled time. 
 
(3) Informed consent. All patients must take part in the informed consent process.  
 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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(4) Medical history. A complete medical history will be obtained at screening, and at the 
end-of-treatment visit. At all other visits, the medical history taking can be focused to the 
needs of the patient. 
 
(5) Physical examination. Complete physical examination must be performed pre-
treatment. Thereafter, it can be directed to the specific needs of the patient. 
 
(6) Complete blood count with differential. CBC with differential is not required if WBC < or 
= 0.5 x 109/L  
 
(7) Biochemistry. Assessment will include, ALT, bilirubin and creatinine levels. Others will 
be performed at treating physician discretion according to the needs of the patient. 
 
(8) Bone marrow examination, with conventional cytogenetic analysis, will be performed at 
screening, at 6 months and at progression. Bone marrow obtained as part of standard of 
care prior to signing of informed consent form can be used at screening as long as it was 
collected within 42 days of commencing treatment.  
 
(9) Cytogenetic analysis. This will be performed every 3 months, either by conventional 
karyotype analysis in bone marrow, or using FISH in peripheral blood or bone marrow, until 
complete cytogenetic remission is achieved. After achieving complete cytogenetic 
remission, cytogenetic analysis need only be repeated if clinically indicated (eg. in the 
event of a significant rise in BCR-ABL levels). 
 
(10) RT-qPCR testing for BCR-ABL1 quantitation will be performed from peripheral blood or 
bone marrow at screening, then every 3 months (+/- 1 month) until achievement of MMR, 
then every 6 months or as clinically indicated.  
 
(11) Kinase domain sequencing; this will be performed during the screening period and 
then as clinically indicated In patients where the reason for changing therapy is intolerance, 

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rather than progression/lack of response, this test may be omitted and this will not be 
considered a deviation.  
 
(12) Pregnancy test. The pregnancy test must be a beta-human chorionic gonadotropin (β-
HCG) test, using either urine or serum. Women who are not of childbearing potential 
(status post-hysterectomy, status post-bilateral oophorectomy, or postmenopausal [defined 
as amenorrhea for at least 12 months]) do not need to have the test performed. If the test is 
deemed necessary, it must be performed within 14 days of commencement of study 
treatment and known to be negative prior to commencement of study treatment.  
 
8.0 CRITERIA FOR RESPONSE 
8.1 Hematologic response: 
Complete hematologic response is defined as a white blood cell count <10 × 10^9/l, a 
platelet count <450 × 10^9/l, no blasts in the peripheral blood and disappearance of all 
signs and symptoms related to leukemia, including palpable splenomegaly. 
 
8.2 Cytogenetic response: 
Cytogenetic assessments are based on at least 20 metaphases or fluorescence in situ 
hybridization with at least 200 cells on peripheral blood or bone marrow Cytogenetic 
response can be categorized as: 
 Complete: 0% Ph+ metaphases;  
 Partial cytogenetic response: 1%-35%;  
 Major cytogenetic response, 0%-35%;  
 Minor cytogenetic response, 36%-65%;  
 Minimal cytogenetic response, 66%-95%;  
 No cytogenetic response, > 95%.  
 
8.3 Molecular response: 
Molecular assessments are based on quantitative reverse transcriptase polymerase chain 
reaction for Bcr-Abl in peripheral blood. Molecular response is categorized as MMR (Bcr-

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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Abl/Abl ratio of < or =0.1% in the International Scale), MR4 (Bcr-Abl/Abl < or =0.01%), and 
MR4.5 (BCR-ABL/ABL < or =0.0032%). 
 
To convert M.D. Anderson BCR-ABL results to the international scale, multiply result by 0.35. 
 
8.4 Survival: 
 Overall survival: Overall survival is calculated from the start date of therapy to the date of 
death or last follow-up. 
 Failure-free survival: Failure-free survival is measured from the start of study drug to the 
earliest date of the following: an event as defined for event-free survival, transformation 
to AP or BP, intolerance, treatment discontinuation for any reason (as assessed by 
investigator), or death from any cause while on bosutinib therapy.  
 Event-free survival (EFS): EFS is defined as the time from treatment start until any of the 
following events that occur during study treatment: loss of complete hematologic 
response (CHR); loss of major cytogenetic response (MCyR); progression to AP/BP; 
death due to any cause. 
 Transformation-free survival: Transformation-free survival is defined as the time from 
treatment initiation until either progression to AP/BP or death from any cause. 
 
9.0 EVALUATION OF TOXICITY 
Toxicities will be graded in the research nurse/PI dictations in the medical record, according 
to the NCI Expanded Common Toxicity Criteria version 4.03 or later. 
 
10.0 CRITERIA FOR REMOVAL FROM THE STUDY 
Criteria for removal from study include, but are not restricted to, the following: 
1. Clinically significant progressive disease, defined as accelerated phase (except clonal 
evolution as the only criterion for accelerated phase) or blast phase, loss of complete   
2. Recurrent non-compliance by the patient with protocol requirements. 
3. Patient's request to be removed from the study. 
4. Unacceptable toxicity. 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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5. Failure to respond at 3, 6, 12 months according to European LeukemiaNet (ELN) 
criteria for response to second line therapy (i.e. "Failure" category in table 6, below), 
despite recommended optimization of therapy 
 
Table 4. ELN criteria for response in 2nd line therapy of CML. 
 
Optimal 
Warning 
Failure 
3 months 
BCR-ABL 
< 
or 
=10% and/or 
BCR-ABL >10% or 
Ph+ 65-95% 
Ph+ >95%. 
6 months 
BCR-ABL 
< 
or 
=10% and/or Ph+ 
<35% (i.e. MCyR) 
Ph+ 35-65% 
BCR-ABL 
>10% 
and/or Ph+ >65% 
and/or 
new 
mutations 
12 months 
BCR-ABL 
<1% 
and/or Ph+ 0 (i.e. 
CCyR) 
BCR-ABL 
1-10% 
and/or Ph+ 1-35%  
BCR-ABL 
>10% 
and/or Ph+ >35% 
and/or 
new 
mutations 
 
11.0 STATISTICAL CONSIDERATIONS 
This is a single-arm open-label phase II study to assess the response rate achieved with 
bosutinib therapy in patients with chronic phase CML who have experienced resistance or 
intolerance to frontline TKI therapy.  Patients will receive an escalating schedule of 
bosutinib with the starting dose of 400 mg per day. The primary endpoint is response rate, 
as defined in section 1.0, within the first 6 months therapy. The Simon’s optimal two-stage 
design will be used for interim futility monitoring. The null hypothesis is that the response 
rate is 20% and our target rate under the alternative hypothesis is 35%. Under the design, 
we will enroll 20 patients in the first stage. If 4 or fewer patients achieve the primary 
endpoint, enrollment of future patients will be halted. If 5 or more out of the first 20 patients 
have met the primary endpoint, accrual will continue until a total of 42 patients are enrolled. 
If 12 or more out of these 42 patients achieve the primary endpoint, the treatment will be 
considered efficacious and is worth further investigation. Under this Simon’s optimal two-
stage design, the type I error is 0.101, the power is 79.8%, the probability of early 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
18 
 
termination is 0.63 if the true hematologic remission rate is 20% and the expected sample 
size is 28.2 patients. After the first stage, if <5 responders are observed in the first 20 
patients, we will temporarily suspend the accrual until a sufficient number of responders 
(i.e., >/=5) is reached.  
 
We will also monitor treatment emergent toxicities using a Bayesian design by Thall, Simon 
and Estey, starting from the 6th patient and then in cohort size of 6. For monitoring 
purposes, toxicity is defined as the occurrence of grade 3-4 hematologic or non-
hematologic toxicity leading to treatment discontinuation and the associated toxicity 
stopping rule is to stop the trial if Prob{p(TOX) > 0.35| data} > 0.90, where p(TOX) is the 
toxicity rate and a beta(0.7, 1.3) distribution was assumed for the prior. That is, if at any 
time during the trial we determine that there is more than 90% chance that the toxicity rate 
is more than 35%, we will stop the trial due to safety concern. The corresponding stopping 
boundaries are shown in Table 1 below and the operating characteristics of the toxicity 
monitoring are illustrated in Table 2. Multc Lean Desktop (v2.1.0) 
(https://biostatistics.mdanderson.org/SoftwareDownload/) was used for generating the 
stopping boundaries and the OC table. Toxicities will be monitored continuously over the 
two year duration of the study. 
 
Table 5. Toxicity stopping boundaries in cohort size of 6.   
Number of patients  
Stop the trial if there are 
this many patients having 
toxicity 
6 
4-6 
12 
7-12 
18 
10-18 
24 
12-24 
30 
15-30 
36 
17-36 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
19 
 
42 
Always stop with this many 
patients 
 
Table 6: Operating characteristics for toxicity monitoring.  
True Toxicity 
Rate 
Early 
Stopping 
Probability 
Average 
number of 
patients 
treated 
25th, 75th 
percentile 
0.25 
0.050 
40.4 
42, 42 
0.30 
0.112 
38.6 
42, 42 
0.35 
0.227 
35.6 
42, 42 
0.40 
0.400 
31.2 
18, 42 
0.50 
0.789 
20.6 
6, 36 
0.60 
0.974 
12.4 
6, 18 
 
Analysis Plan: 
The response rate will be estimated along with the 95% credible interval. Data from all 
subjects who receive any study drug will be included in the safety analyses. 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 
AE category, severity and frequency. The Frequency of treatment interruptions and dose 
reductions will be summarized. The rates of major molecular response, MR4, MR4.5 and 
complete molecular response will be estimated along with the exact 95% confidence 
intervals. Similarly, the rates of BCR-ABL/ABL <10% at 3 months and BCR-ABL/ABL <1% 
at 6 months since treatment start, on the international scale, will be estimated along with 
the exact 95% confidence intervals. Kaplan-Meier method will be used to assess the overall 
survival (OS), failure-free survival (FFS), failure-free survival (FFS) and transformation-free 
survival (TFS). Cox proportional hazards regression models will be fit to assess the 
association between patient characteristics including ABL kinase domain mutation status 
and each survival outcome.  In addition, the change of ABL kinase domain mutation status 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
20 
 
over time will be summarized and its association with survival outcomes will be analyzed 
through landmark analyses. 
 
12.0 REPORTING REQUIREMENTS 
Reporting Requirements  
12.1 
Reporting requirements will be as per institutional guidelines.  
12.2    Adverse events related to study conditions 
The SAE reporting period will begin with the initiation of bosutinib 
 
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious.  This also applies to patients experiencing AEs that cause 
interruption or discontinuation of investigational product, or those experiencing AEs 
that are present at the end of their participation in the study.  Such patients should 
receive post-treatment follow-up as appropriate.   
 
12.3   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. 
 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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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. 
 All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”.  
 All SAEs will also be reported in parallel to Pfizer. No individual SAE reports will 
be sent to Pfizer but SAEs will be reported as a cumulative line listing to BMS 
approximately every 12 months. 
 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.  
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 

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13.0 REFERENCES 
1. Huang X, Cortes J, Kantarjian H. Estimations of the increasing prevalence and plateau 
prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. 
Cancer, 118 (12) 2012, 3123-31272. Rowley JD. Letter: A new consistent chromosomal 
abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and 
Giemsa staining. Nature, 243 (5405) 1973, 290-293 
3. Mandanas RA, Leibowitz DS, Gharehbaghi K, et al. Role of p21 RAS in p210 bcr-abl 
transformation of murine myeloid cells. Blood, 82 (6) 1993, 1838-1847 
4. Okuda K, Matulonis U, Salgia R. Factor independence of human myeloid leukemia cell 
lines is associated with increased phosphorylation of the proto-oncogene Raf-1. 
Experimental hematology, 22 (11) 1994, 1111-1117 
5. Raitano AB, Halpern JR, Hambuch TM. The Bcr-Abl leukemia oncogene activates Jun 
kinase and requires Jun for transformation. Proceedings of the National Academy of 
Sciences of the United States of America, 92 (25) 1995, 11746-11750. 
6. Sawyers CL, Callahan W, Witte ON. Dominant negative MYC blocks transformation by 
ABL oncogenes. Cell, 70 (6) 1992, 901-910 
7. Shuai K, Halpern J, ten Hoeve J. Constitutive activation of STAT5 by the BCR-ABL 
oncogene in chronic myelogenous leukemia. Oncogene, 13 (2) 1996, 247-254 
8. Carlesso N, Frank DA, Griffin JD. Tyrosyl phosphorylation and DNA binding activity of 
signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines 
transformed by Bcr/Abl. The Journal of experimental medicine, 183 (3) 1996, 811-820 
9. Ilaria RL, Jr., Van Etten RA. P210 and P190 (BCR/ABL) induce the tyrosine 
phosphorylation and DNA binding activity of multiple specific STAT family members. The 
Journal of biological chemistry, 271 (49) 1996, 31704-31710 
10. Silver RT, Woolf SH, Hehlmann R, et al. An evidence-based analysis of the effect of 
busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the 
chronic phase of chronic myeloid leukemia: developed for the American Society of 
Hematology. Blood, 94 (5) 1999, 1517-1536 
11. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl 
tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2:561-6. 

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12. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon 
vs. STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression of events 
in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) 
treated with imatinib. Blood, 114, 2009 
13. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose 
cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. The New England 
journal of medicine. 2003;348(11):994-1004. 
14. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-
(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-
354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. 
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15. O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 
and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. 
Cancer research. 2005;65(11):4500-5. 
16. Tokarski JS, Newitt JA, Chang CY, et al. The structure of Dasatinib (BMS-354825) bound 
to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL 
mutants. Cancer Research. 2006;66(11):5790-7. 
17. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase 
inhibitor. Science. 2004;305(5682):399-401. 
18. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed 
chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. 
19. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in 
chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). 
Blood 2013 [epub ahead of print]. 
20. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective 
inhibitor of native and mutant Bcr-Abl. Cancer cell. 2005;7(2):129-141. 
21. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed 
chronic myeloid leukemia. The New England journal of medicine. 2010;362(24):2251-2259. 
22. Larson RA, Hochhaus A, Clark RE, et al. Nilotinib vs imatinib in patients with newly 
diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: 
ENESTnd 3-year follow up. Leukemia 2012;26:2197-2203. 

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23. Bristol-Myers Squibb Company. Sprycel® (dasatinib) prescribing information. Princeton, 
NJ. , 2011. 
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Hanover, NJ. , 2011. 
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with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on 
standard-dose imatinib therapy. Blood. 2009;113(10):2154-2160. 
26. Quintas-Cardama A, Cortes JE, O'Brien S, et al. Dasatinib early intervention after 
cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia. 
Cancer. 2009;115: 2912-2921. 
27. Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of bosutinib (SKI-
606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients 
with resistance or intolerance to imatinib. Blood 2011;118:4567-4576. 
28. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed 
chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 
2012;30(28):3486-92. 
29. Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, et 
al. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results 
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American Society of Clinical Oncology. 2017:JCO2017747162. 
 
14.0 ABBREVIATION LIST 
ABL – Abelson tyrosine kinase. 
AE – adverse event 
alloSCT – allogeneic stem cell transplant. 
ALT – alanine transaminase. 
ANC – absolute neutrophil count 
AP – accelerated phase. 
AST – aspartate transaminase 
ATP – adenosine triphosphate. 
BCR – Breakpoint Cluster Region. 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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BELA – Bosutinib vs Imatinib in Newly Diagnosed Chronic Myeloid Leukemia. 
BP – blast phase 
BUN – blood urea nitrogen 
CBA – chromosome banding analysis 
CBC – complete blood count 
CCyR – Complete Cytogenetic Response. 
CHR – complete hematologic response. 
C-KIT – KIT protooncogene 
CML – Chronic Myeloid Leukemia. 
CP – chronic phase. 
CTCAE – Common Terminology Criteria for Adverse Events 
DASISION – Dasatinib or Imatinib in Newly Diagnosed Chronic Myeloid Leukemia 
EC – ethics committee 
ECG – electrocardiogram 
ECHO – echocardiogram 
ENESTnd – Evaluating Nilotinib Efficacy and Safety in Clinical Trials – newly diagnosed 
patients 
FDA – food and drug administration. 
FFS – failure free survival 
GI – gastrointestinal 
hCG – human chorionic gonadotropin. 
HIV – human immunodeficiency virus 
INF-a – interferon-alpha. 
IRB – institutional review board 
IRIS – International Randomized Study of INF-a and STI571 
IUD – intrauterine device. 
JUN – JUN protocooncogene 
LFTs – liver function tests 
MCyR – major cytogenetic response 
MDASI – M.D. Anderson Symptom Index 
MMR – major molecular response 

Protocol 2016-0081 Version 5 November 26, 2017. 
 
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MR4 – Molecular Response with 4 log reduction from baseline BCR-ABL transcript level. 
MR4.5 – Molecular Response with 4.5 log reduction from baseline BCR-ABL transcript 
level. 
MUGA – multigated acquisition scan 
MYC – MYC protooncogene 
NCI – national cancer institute 
NK – natural killer. 
OS – overall survival. 
PCR – Polymerase Chain Reaction 
PDGFR – platelet-derived growth factor receptor 
Ph – Philadelphia Chromosome 
PI – primary investigator 
RAF – Rapidly Activated Fibrosarcoma 
RAS – Rat Sarcoma 
RT-qPCR – real time quantitative polymerase chain reaction 
SRC – SRC protooncogene 
STAT – Signal Transducer and Activator of Transcription 
SUSAR – serious unexpected adverse event  
T315I – threonine-315-isoleucine mutation 
TEAE – treatment emergent adverse event 
TFS – transformation-free survival. 
TranscriptionTKIs – tyrosine kinase inhibitors. 
ULN – upper limit of normal 
WBC – white blood cell