Clinical trial NCT01806571
Conditions: Untreated Adult Acute Myeloid Leukemia
Sponsor: Mayo Clinic
Start date: 2015-03-12; Completion date: 2019-11-30
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well daunorubicin hydrochloride, cytarabine, and nilotinib work in treating patients newly diagnosed with acute myeloid leukemia. Drugs used in chemotherapy, such as daunorubicin hydrochloride and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving daunorubicin hydrochloride with cytarabine and nilotinib may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the complete response rates of combination nilotinib, cytarabine, and daunorubicin (daunorubicin hydrochloride) in patients newly diagnosed with acute myeloid leukemia (AML) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (Kit) overexpression.

SECONDARY OBJECTIVES:

I. Determine the 2-year overall survival (OS) and disease-free survival (DFS) rates.

II. Determine the complete response duration in patients treated with this regimen.

III. Assess the safety and toxicity of this regimen based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

TERTIARY OBJECTIVES:

I. Assess the prognostic and predictive factors (Kit mutation/expression level, fms-related tyrosine kinase 3 \[Flt3\] mutation) for patients treated with this regimen.

II. Assess the patterns of molecular response and relapse for Kit. III. Assess the effect on minimal residual disease (MRD) by polymerase chain reaction (PCR) or flow cytometry.

OUTLINE:

INDUCTION THERAPY: Patients receive daunorubicin hydrochloride intravenously (IV) over 10 minutes on days 1-3, cytarabine IV continuously on days 1-7, and nilotinib orally (PO) twice daily (BID) on days 4-14. Patients achieving complete remission (CR) or complete remission with incomplete blood count recovery (CRi) proceed to consolidation therapy. Patients not achieving a significant decrease in bone marrow recovery or CR/CRi upon bone marrow recovery receive another course of induction therapy.

CONSOLIDATION THERAPY: Patients receive cytarabine IV every 12 hours on days 1, 3, and 5, and nilotinib PO BID on days 4-14. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRi proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive nilotinib PO BID on days 1-84. Treatment repeats every 84 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3 years.

Arms: arm 1: INDUCTION THERAPY: Patients receive daunorubicin hydrochloride IV over 10 minutes on days 1-3, cytarabine IV continuously on days 1-7, and nilotinib PO BID on days 4-14. Patients achieving CR or CRi proceed to consolidation therapy. Patients not achieving a significant decrease in bone marrow recovery or CR/CRi upon bone marrow recovery receive another course of induction therapy.

CONSOLIDATION THERAPY: Patients receive cytarabine IV every 12 hours on days 1, 3, and 5, and nilotinib PO BID on days 4-14. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRi proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive nilotinib PO BID on days 1-84. Treatment repeats every 84 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cytarabine intervention 2: Daunorubicin Hydrochloride intervention 3: Laboratory Biomarker Analysis intervention 4: Nilotinib intervention 5: Pharmacological Study
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given PO intervention 5: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
MC1284 
Protocol Version Date:  February 7, 2019 
 
 
Mayo Clinic Cancer Center 
 
A Phase II Study of Combination Daunorubicin and Cytarabine (Ara-c) and Nilotinib (Tasigna) 
(DATA) in Patients Newly Diagnosed with Acute Myeloid Leukemia and KIT Overexpression  
 
 
 
 
Study Chairs: 
Aref Al-Kali, MD  
Mayo Clinic 
200 First Street, SW 
Rochester, MN 55905 
507/284-2511 
507/284-5280 (FAX) 
 
 
Study Co-chair: 
  
 
 
 
 
 
 
 
Statistician: 
 
 
  
 
 
Drug Availability  
Commercial Agents:  cytarabine, daunorubicin  
Drug Company Supplied:  nilotinib (AMN107, Tasigna®)  
 
√Study contributor(s) not responsible for patient care. 
 
 
Document History 
(Effective Date) 
Activation 
July 19, 2013 
Mayo Add 1 
July 19, 2013 
Mayo Add 2 
July 19, 2013 
Mayo Add 3 
October 2, 2013 
Mayo Add 4 
April 22, 2014 
Mayo Add 5 
August 13, 2015 
Mayo Add 6 
January 29, 2016 
Mayo Add 7 
October 20, 2016 
Mayo Add 8 
March 1, 2018 
Mayo Add 9 
July 17, 2018 
Mayo Add 10 
March 6, 2019 
 
 
 
 
 
 




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Protocol Version Date:  February 7, 2019 
Table of Contents 
A Phase II Study of Combination Daunorubicin and Cytarabine (Ara-c) and Nilotinib (Tasigna) (DATA) 
in Patients Newly Diagnosed with Acute Myeloid Leukemia and KIT Overexpression .............................. 1 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
List of Abbreviations .................................................................................................................................... 6 
1.0 
Background ............................................................................................... 7 
2.0 
Goals ....................................................................................................... 25 
3.0 
Patient Eligibility .................................................................................... 25 
4.0 
Test Schedule .......................................................................................... 30 
5.0 
Grouping Factors: None.......................................................................... 32 
6.0 
Registration Procedures .......................................................................... 32 
7.0 
Protocol Treatment ................................................................................. 33 
8.0 
Dosage Modification Based on Adverse Events ..................................... 36 
9.0 
Ancillary Treatment/Supportive Care ..................................................... 40 
10.0 
Adverse Event (AE) Reporting and Monitoring ..................................... 41 
11.0 
Treatment Evaluation .............................................................................. 48 
12.0 
Descriptive Factors ................................................................................. 49 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ........................ 49 
14.0 
Body Fluid Biospecimens ....................................................................... 51 
15.0 
Drug Information .................................................................................... 55 
16.0 
Statistical Considerations and Methodology .......................................... 67 
17.0 
Pathology Considerations/Tissue Biospecimens: None. ......................... 73 
18.0 
Records and Data Collection Procedures ................................................ 74 
19.0  
Budget ..................................................................................................... 75 
20.0 
References ............................................................................................... 75 
Appendix Ia:  Drugs with Risk of Torsades de Pointes .............................................................................. 80 
Appendix Ib:  Drugs with Possible or Conditional Risk of Torsades de Pointes ........................................ 82 
Appendix II: Protocol schema DATA ........................................................................................................ 84 
Appendix III: ECOG Performance Status ................................................................................................... 87 
Appendix IV: Patient Medication Diary ..................................................................................................... 88 
Appendix V:  Acute Myeloid Leukemia WHO 2008 Criteria .................................................................... 97 


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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length during Induction  = 14-28 days;  Cycle length during Consolidation = 28 days (see Section 
7.12);  Cycle length during Maintenance = 84 days.  The next cycle of treatment may be delayed up to 56 
days to achieve bone marrow recovery or meet CBC criteria for retreatment.  If the next cycle is delayed 
beyond 56 days, the patient will go to event monitoring per Section 18.0. 
2  If the patient has not achieved a complete response (CR or CRi) after the 2nd cycle of induction, the 
patient should go to event monitoring. 
3  The patient must have a sustained complete response (CR or CRi) after consolidation to initiate the 
maintenance phase; otherwise the patient should go to event monitoring. 
4  See Section 7.14 
 
 
 
Registration 
AML with Kit overexpression 
Treatment1,4 
Induction (up to 2 cycles) 
 Cytarabine Days 1-7  
Daunorubicin Days 1-3  
and Nilotinib Days 4-14 
 
Consolidation2 (4 cycles every 4 weeks) 
Cytarabine Days 1, 3, 5  
Nilotinib Days 4-14 
 
 Maintenance3 (8 cycles every 12 weeks) 
Nilotinib Days 1-84 
 
Event Monitoring 
Disease relapse at  
   any time 
Unacceptable adverse   
      Event 
    events   
 
 
      Monitoring 
Patient refusal  
 
 


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Protocol Version Date:  February 7, 2019 
Generic name:  Nilotinib 
Brand name:  Tasigna® 
Mayo abbreviation: AMN107 
Availability:  Novartis 
Generic name:  Cytarabine 
Brand name: 
Cytosar 
Mayo abbreviation:  ARAC 
 
Availability:  Commercial 
Generic name:  Daunorubicin 
 
Brand name:  Cerubidine® 
 
 
 
Mayo abbreviation:  DNM 
Availability:  Commercial 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
AE 
adverse event 
ALL 
Acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
bid 
bis in diem/twice a day 
CHR 
complete hematologic response 
CML 
chronic myelogenous leukemia 
CML-AP 
chronic myelogenous leukemia – accelerated phase 
CML-BC 
chronic myelogenous leukemia – blast crisis 
CML-CP 
chronic myelogenous leukemia – chronic phase 
CR 
complete response 
CRF 
case report/record form 
CS&E 
Clinical Safety and Epidemiology 
CT 
computerized tomography 
CTC 
common terminology criteria 
CyR 
cytogenetic response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GIST 
gastrointestinal stromal tumor 
HR 
hematologic response 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IULN 
Institutional Upper Limit of Normal 
iv 
intravenous(ly) 
LVEF 
left ventricular ejection fraction 
MCyR 
major cytogenetic response 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NEL 
no evidence of leukemia 
NIH 
National Institutes for Health 
PD 
progression of disease 
PFS 
progression free survival 
Ph + 
Philadelphia chromosome positive 
po 
per os/by mouth/orally 
PR 
partial response 
qd 
quaque die/every day 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
ULN 
upper limit of normal 
WBC 
White Blood Cell Count 
 
 


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1.0 
Background 
 
Thirteen thousand new cases of acute myeloid leukemia (AML) are diagnosed every year (Last 
accessed May 27, 2011 ). Prognosis and treatment of this blood cancer remain challenging in 
adult patients compared to pediatric patients. Remission rates are about 65% for front-line therapy 
and relapse rate is about 50-60% at 4 years (Robak and Wrzesien-Kus 2002; Burnett, Wetzler et 
al. 2011). Both cytogenetic and molecular features predict favorable versus adverse prognosis and 
govern our therapy options for these patients (Byrd, Mrozek et al. 2002; Marcucci, Haferlach et 
al. 2011). Hematopoietic stem cell transplant is recommended for adverse prognosis group at 
diagnosis but is deferred to the time of relapse in patients with favorable prognosis (Dohner, 
Estey et al. 2010). Cytarabine and anthracycline (7+3 regimen) is the most used regimen and all 
other regimens have failed to show any survival advantage (Dohner, Estey et al. 2010). 
 
Kit is a receptor tyrosine kinase and is vital in leukemic cells. It is expressed in more than 10% of 
the blasts in 95% of relapsed AML cases and mediates leukemic proliferation and has anti-
apoptotic effects (Domen and Weissman 2000; Hans, Finn et al. 2002). AML with high c-kit 
expression is associated with lower complete remission (CR) rates, shorter CR duration, and 
shorter overall survival (OS) (Del Poeta, Venditti et al. 2003). On multivariate analysis, c-kit 
mean fluorescent index >20.3 correlates with a decreased progression-free survival and overall 
survival, independent of known prognostic factors (Advani, Rodriguez et al. 2008). Patients with 
core-binding factor (CBF) AML carry a superior outcome compared to other AML subgroups, 
but patients positive for c-kit mutation (for example D816F) carry a worse prognosis evidenced 
by higher relapse rate and inferior survival to wild-type kit CBF AML (Bloomfield, Lawrence et 
al. 1998; Paschka, Marcucci et al. 2006). Schnittger et colleagues studied 1940 AML patients for 
kit D816 mutations and found it positive in 33 cases (1.7%) {Schnittger,2006 #40}. Eight out of 
33 patients were positive for t(8,21). Kit mutations were found to have an independent negative 
impact on event free and overall survival in patients with t(8,21). The D816V receptor expressed 
in Ba/F3 cells were fully sensitive to PKC412. On the expression level of kit, a semi-quantitative 
RT-PCR done on 60 acute leukemia cases correlated with complete remission rates {Han, 2006 
#41}. Further research showed down-regulation of miRNA-193b in AML cells where kit was 
mutated or overexpressed {Gao, 2011 #43}. Restoration of MiR-1933b expression in AML cells 
resulted in reduced c-Kit expression and inhibited cell growth. Finally, expression of c-kit has 
been linked to increased P-glycoprotein, a major mediator of multi-drug resistance (MDR) in de 
novo AML{Sincock, 1997 #39}.Therefore, targeting kit expression seems to be a of great impact 
in this group of patients. 
 
Tyrosine kinase inhibitors (TKI) (including imatinib, nilotinib, and dasatinib) are important drugs 
that are used for ABL inhibition in patients with chronic myeloid leukemia (CML) or 
Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL) (Kantarjian, Shah et al. 2010; 
Saglio, Kim et al. 2010). They are FDA approved agents for the management of CML in all its 
phases (including blast phase) (Sawyers, Hochhaus et al. 2002; Kantarjian, Giles et al. 2006; 
Cortes, Rousselot et al. 2007). Kit is also inhibited by these TKI, more so with a second 
generation agents like nilotinib (Kantarjian, Giles et al. 2006). They have also been recently tried 
in combination with chemotherapy with increased efficacy and synergy in patients with Ph+ 
ALL. 
 
Imatinib has been given to a patient with refractory AML and c-kit positive overexpression (no 
mutation) who achieved complete hematological remission followed by complete clearance of 
leukemic blasts in bone marrow lasting for more than 5 months (Kindler, Breitenbuecher et al. 
2003). Imatinib has been given in combination with chemotherapy achieving very encouraging 


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results (Walker, Komrokji et al. 2008; Brandwein, Hedley et al. 2011). Dasatinib is now under 
study with combination chemotherapy in CALGB phase II study in patients with core binding 
factor AML (NCT01238211). Nilotinib is currently given in addition to chemotherapy 
(mitoxantrone, etoposide, and high dose cytarabine, NOVE-HiDAC) in the setting of relapsed 
and refractory AML (NCT01222143). In addition, nilotinib is given to relapsed Ph+ALL patients 
and is well tolerated (including combination with high dose cytarabine). All of these active trials 
reflect the great interest of having those effective agents tested in patients diagnosed with AML. 
 
Chronic myelogenous leukemia (CML) is caused by the reciprocal translocation of the ABL 
kinase on chromosome 9 to the BCR region on chromosome 22. This results in a novel 
oncoprotein with constitutively activated ABL kinase activity leading to downstream pathway 
activation and uncontrolled myeloproliferation. The BCR-ABL fusion oncogene (the Philadelphia 
chromosome, Ph+) is the hallmark of Ph+ CML and is the driving characteristic molecular event 
in this diseases (Druker 2008) (Vardiman 2009). The other disease in which the BCR-ABL 
translocation plays an essential role in pathogenesis is Ph+ acute lymphoblastic leukemia 
(Ph+ALL), an aggressive form of blood cancers. Chemotherapy agents or single agent tyrosine 
kinase inhibitors (TKI) alone can induce high response rates but the response is often temporary. 
Therefore, combination of a targeted agent (TKI) with chemotherapy may provide a more durable 
response (Stock 2010). 
 
Imatinib, an adenosine tri-phosphate (ATP)-competitive specific inhibitor of the protein tyrosine 
kinase activity associated with Bcr-Abl, has revolutionized treatment of CML and significantly 
improved the prognosis of patients since its approval in 2001. It is effective in most patients with 
CML with minimal toxicity, and is now frontline drug therapy for CML. However, despite the 
remarkable success of imatinib, a percentage of patients are intolerant to the drug and resistance 
can develop. Some patients do not tolerate imatinib due to the development of SAEs, including 
grade 3 or 4 skin rash, fluid retention, cardiopulmonary events, thrombocytopenia, liver function 
abnormalities, and diarrhea, which persist in spite of optimal supportive care measures; other 
patients do not tolerate due to prolonged AEs of lower grade which do not meet criteria of a SAE 
(O’Hare 2006). Imatinib resistance is primarily due to mutation of the Bcr-Abl gene, impairing 
the ability of imatinib to bind to the tyrosine kinase domain of Bcr-Abl. Overexpression of the 
Bcr-Abl protein may also cause resistance. Rates of resistance increase with each stage of 
progression of CML (CP < AP < BC) (Apperley 2007).  
 
Nilotinib is a synthetic aminopyrimidine, which was developed as a second-generation inhibitor 
of Bcr-Abl tyrosine kinase. It is a more potent and selective inhibitor of Bcr-Abl than imatinib in 
vitro, and has shown efficacy in patients harboring a variety of Bcr-Abl mutations associated with 
imatinib resistance, except T315I. Nilotinib has an impressive anti-leukemia activity in mouse 
models of 190 BCR/ABL positive lymphoblastic leukemia (Kaur, Feldhahn et al. 2007). Its 
concentration in cell lines and primary CD34+ CML cells is not mediated by active uptake or 
efflux by major drug transporters (a known mechanism of resistance to imatinib (Davies, 
Jordanides et al. 2009). Nilotinib induces apoptosis in imatinib-resistant K562 CML cells via 
increase of caspase-3 enzyme and decrease in mitochondrial membrane potential (Ekiz, Can et al. 
2010). Most importantly, it poses synergistic activity with chemotherapeutic drugs in imatinib-
sensitive and –resistant BCR/ABL + cells ( Radujkovic, Fruehauf et al. 2010). Nilotinib is 
approved for use in the treatment of chronic phase and accelerated phase Philadelphia 
chromosome positive CML in adult patients resistant to or intolerant to prior therapy including 
imatinib and newly diagnosed adult patients with Philadelphia chromosome positive CML. 
 
Nilotinib also inhibits the platelet-derived growth factor receptor (PDGFR), stem cell factor (Kit), 
colony stimulating factor receptor (CSF-1R), discoidin domain receptor (DDR), and ephrin-A4 


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receptor (EphA4) kinases, and blocks the downstream cellular events mediated by these enzymes. 
Nilotinib was given to patients with metastatic melanoma harboring Kit gene mutation, where 
22% achieved partial response and 55.6% had stable disease {Cho, 2011 #45}. Nilotinib was 
tested as third-line therapy in patients with gastrointestinal stromal tumor (GIST), where disease 
control rate at week 24 was 29% and 66% patients had stable disease >6 weeks as best 
response{Sawaki, 2011 #46}. In mast cells, nilotinib, as well as imatinib, was potent against mast 
cell with wild type c-kit and D560G c-kit mutant but no significant activity against cells 
expressing c-kit D816V mutant tyrosine kinase {Verstovsek, 2006 #48}. However, Von Bubnoff 
showed that nilotinib did suppress the growth of Ba/F3c-kit D814V at concentrations of 1-2 µm {von 
Bubnoff, 2005 #53}. Similar results were found in cells expressing the human c-kit D816V. 
 
1.1 
Toxicology in animals 
 
Nilotinib was not considered genotoxic, but was embryolethal and produced fetotoxicity 
in embryo-fetal development studies in rats and rabbits at doses that also produced 
maternal toxicity. There were no signs of teratogenicity. In the pre- and postnatal study, 
administration of nilotinib to female rats was associated with decreased pup body weight 
and changes in some physical development parameters at a dose that also produced 
maternal effects. Carcinogenicity studies are currently ongoing. 
 
The fertility of male and female rats was not affected. Nilotinib is considered to be 
embryolethal, because of an increased post-implantation loss observed in both the fertility 
study, with treatment of both males and females, and in the embryotoxicity study with the 
treatment of females. It is recommended that women of childbearing potential should use 
effective contraceptive measures during the entire treatment period. Any women in early 
pregnancy when treatment starts should be informed about the potential risk to the fetus. 
Since nilotinib is transferred into the milk in lactating rats with a milk/plasma 
concentration ratio of approximately 2, women who are using the drug should not breast 
feed. 
 
1.2 
Pharmacokinetics and drug metabolism 
 
The extent of nilotinib absorption following oral administration was estimated to be 
approximately 30%. The bioavailability of nilotinib was increased when given with a 
meal. Compared to the fasted state, the systemic exposure [area under the plasma drug 
concentration time curve (AUC)] in the fed state increased by 15% (drug administered 2 
hours after a light meal), 29% (30 minutes after a light meal), or 82% (30 minutes after a 
high fat meal), and the maximum concentration (Cmax) increased by 33% (2 hours after a 
light meal), 55% (30 minutes after a light meal), or 112% (30 minutes after a high fat 
meal). 
 
With once daily (q.d.) dosing at steady-state, Cmax and AUC increased with increasing 
dose from 50 mg to 400 mg in a generally dose-proportional manner, but appeared to 
plateau at dose levels starting at 400 mg, remaining relatively constant over the dose 
range from 400 mg to 1200 mg. Dividing the daily dose in a twice daily schedule 
overcame the dose-limiting exposure to some extent with daily steady-state serum 
exposure to nilotinib with 400 mg twice daily dose being approximately 35% greater than 
with 800 mg q.d. dose. However, there was no further relevant increase in exposure to 
nilotinib when given 600 mg dose with the twice daily schedule (1200 mg/day). With 
multiple oral doses of nilotinib, steady-state conditions were achieved by day 8 after 
initiating nilotinib treatment.  There was a 2-fold or 3.8-fold accumulation with q.d. 


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dosing or twice daily dosing, respectively, in serum concentrations between the first-dose 
and steady-state. The median time to reach Cmax of nilotinib (tmax) was 3 hours. Drug 
elimination half-lives calculated during the dose interval averaged 17 hours for q.d. 
dosing, consistent with the observed accumulation in serum concentrations.  
 
Exposure to nilotinib in female patients was approximately 20% greater than in male 
patients. There was no difference in nilotinib apparent clearance between Caucasians and 
non-Caucasians. The population pharmacokinetic (PK) analysis showed that nilotinib PK 
is not affected by age. Hepatic impairment has a modest effect on nilotinib 
pharmacokinetics; however, impaired renal function is not expected to influence nilotinib 
PK. 
 
Results of a Phase I, open-label, multicenter, dose-escalation study in patients with 
GISTs who progressed on previous imatinib therapy suggest that nilotinib might have 
inhibitory effects on the metabolism of imatinib. The increases in serum concentration 
levels of imatinib on Day 8 were, in general, within the variability of fluctuation of serum 
imatinib concentrations in a dosing interval, suggesting that the inhibitory effects of 
nilotinib on the metabolism of imatinib might not be clinically significant. 
 
Coadministration of ketoconazole with nilotinib increased nilotinib Cmax by 84% and 
AUC by 3-fold on average. Single-dose nilotinib did not appear to affect ketoconazole 
concentrations. Single-dose administration of nilotinib (600 mg) with a single dose of 
midazolam resulted in mean increase in midazolam Cmax and AUC of 20% and 31%, 
respectively. 
 
Rifampin 600 mg, administered as a pretreatment for 8 days, had a pronounced impact on 
a single 400 mg dose of nilotinib. Apparent clearance of nilotinib was increased by 4.8-
fold on average. Induction with rifampin significantly reduced Cmax and AUC of 
nilotinib by 64% and 80%, respectively. 
 
Concurrent intake of grapefruit juice increased the nilotinib Cmax by 60% and AUC0-∞ by 
29%, but the median time to reach peak concentration (tmax) and the mean elimination 
half-life (t1/2) were not altered.  
 
Concurrent administration of nilotinib with a single oral dose of 25 mg warfarin in 
healthy subjects showed a lack of interaction between two drugs. Pharmacokinetic 
parameters of S- and R-warfarin as well as pharmacodynamic parameters of warfarin 
were all found to be similar between two treatments (warfarin+nilotinib versus warfarin 
alone), with the geometric mean ratios and 90% CIs all being within 80-125% range. 
 
Co administration of esomeprazole with nilotinib caused a modest reduction in the rate 
and extent of nilotinib absorption. The mean Cmax, AUC0-tlast and AUC0-∞ of nilotinib were 
decreased by about 27%, 34% and 33%. The mean T1/2 of nilotinib, however, was found 
to be similar between two treatments. 
 
1.3 
Efficacy  
 
1.31 
Efficacy in CML 
 
1.311 Imatinib resistant and imatinib intolerant CML-CP and CML-AP 
 


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A Phase II study [CAMN107A2101], was conducted to evaluate the 
efficacy and safety of nilotinib in CML-CP and CML-AP patients with 
imatinib-intolerant or imatinib-resistant (due to either a primary 
resistance to imatinib or due to acquired resistance primarily due to 
known Bcr-Abl mutations).  
 
A total of 321 CML-CP patients in the Phase II study were evaluated for 
efficacy. Of these, 71.4% were imatinib-resistant and 29.6% were 
imatinib-intolerant. Previous therapies, in addition to imatinib, which 
72.2% of patients had received at doses ≥ 600 mg, included prior 
interferon (64.4% of patients). Patients were treated with nilotinib 400 
mg b.i.d. for 6 months, and could be dose-escalated to 600 mg b.i.d. for 
lack of efficacy. Fifty-one of 321 patients (15.9%) were dose-escalated 
due to lack of efficacy. Dose reduction from either 400 or 600 mg b.i.d. 
occurred in 34.1% of all patients treated, primarily due to AEs.  
 
The median duration of exposure in CML-CP patients was 341 days 
(exposure range of 1 - 624 days). The median average daily dose of 
nilotinib for CML-CP patients was 792 mg which is indicative of 
relatively infrequent dose interruptions and reductions. At the time of 
data cutoff, 188 (58.8%) patients were ongoing and 132 (41.3%) had 
discontinued treatment. The reasons for discontinuation were mainly due 
to AEs (51 patients, 15.9%) and disease progression (51 patients, 
15.9%). 
 
The achievement of major cytogenetic response (MCyR) is associated 
with a survival benefit in CML patients treated with imatinib. For 
nilotinib-treated CML-CP patients, the percentage of patients who 
achieved MCyR by intent-to-treat (ITT) analysis was 56.3% (median 
exposure of 341 days; range 1 to 624 days). This is indicative of the 
durability of the response in CML-CP. A complete hematological 
response (CHR) was achieved in 76.2% of CML-CP patients. 
 


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Table 1-1 
Response rates in CML-CP patients 
 
The patients evaluated for efficacy consisted of 119 out of 127 enrolled 
CML-AP Phase II patients of which 80.7% were imatinib-resistant and 
19.3% were imatinib-intolerant. Previous therapies included interferon 
(58.0% of patients) and imatinib (82.9% of patients received doses ≥ 600 
mg). Patients were treated with nilotinib 400 mg b.i.d. for 4 months and 
could be dose-escalated to 600 mg b.i.d. for lack of efficacy.  
 
The median duration of exposure was 202 days for the overall enrollment 
population (N = 119; exposure range of 2 - 611 days). Notably, 67 (56%) 
and 29 (24%) CML-AP patients have been exposed for longer than 6 and 
12 months, respectively. Twenty-nine of 119 patients (24.4%) were dose-
escalated due to lack of efficacy. Dose reduction from either 400 or 600 
mg b.i.d. occurred in 42.0% of all patients treated, primarily due to AEs. 
Sixty-seven (56.3%) of CML-AP patients enrolled have received 
nilotinib for 6 months or more. The median average daily dose of 
nilotinib for CML-AP patients was 790.0 mg, and is indicative of 
relatively infrequent dose interruptions and reductions throughout the 
treatment period. At the time of data cutoff, 48 (40.3%) patients were 
still on treatment and 71 (59.7%) had discontinued treatment. The 
reasons for discontinuation included disease progression (35 patients, 
29.4%) and AEs (15 patients, 12.6%).  
 
The anticipated prognosis for imatinib-resistant or -intolerant CML-AP 
patients is poor since all will eventually progress to CML-BC, typically 
within 6 month’s time. Despite this, nilotinib-treated CML-AP patients 
achieved high rates of hematological response (HR) for the ITT 
population. The percentage of patients who achieved confirmed HR by 
ITT analysis was 47.1% (median exposure of 202 days; range 2 to 611 
days). The current estimate for median time to progression (TTP) has 
been reached at 16.4 months in CML-AP patients.  


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Table 1-2 
Response rates in CML-AP patients 
 
 
1.312 Newly diagnosed CML-CP 
 
Study [CAMN107A2303] is a Phase III, randomized, open-label, 
multicenter study comparing the efficacy of nilotinib 300 or 400 mg 
b.i.d. to imatinib 400 mg qd in adult patients with newly diagnosed Ph+ 
CML in CP. A total of 846 patients with newly diagnosed Ph+ CML-CP, 
diagnosed within 6 months, and stratified by Sokal risk score, were 
randomized 1:1:1 to nilotinib 300 mg bid (n=282), nilotinib 400 mg bid 
(n=281), and imatinib 400 mg qd (n=283) arms.  
 
The primary endpoint was rate of major molecular response (MMR) at 
12 months (mos). All patients had a minimum of 12 months of treatment 
or discontinued early; median follow-up was 14 mos. MMR was defined 
as a value of ≤ 0.1% of BCR-ABL/ABL ratio on the International Scale. 
Molecular response was assessed by RQ-PCR at baseline, monthly for 3 
months and every 3 months thereafter. Samples were analyzed at a 
central PCR laboratory. The major secondary endpoint was rate of 
complete cytogenetic response (CCyR) by 12 mos based on bone marrow 
cytogenetics.  
 
Baseline demographics, disease characteristics, and Sokal scores were 
well balanced among the 3 arms; patients with high-risk Sokal scores 
were 28% in all arms. Median dose intensities of nilotinib delivered were 
592 mg/day for 300 mg bid and 779 mg/day for 400 mg bid; imatinib 
dose intensity was 400 mg/day. Overall, 84%, 82%, and 79% of patients 
remained on the study for 300 mg bid nilotinib, 400 mg bid nilotinib, and 
400 mg qd imatinib, respectively. Rates of MMR at 12 mos were 
superior for nilotinib 300 mg bid compared with imatinib 400 mg qd 
(44% vs. 22%, P < .0001) and also for nilotinib 400 mg bid compared 
with imatinib 400 mg qd (43% vs. 22%, P < .0001). Median time to 
MMR among patients who achieved MMR was faster for nilotinib 300 
mg bid (5.7 mos) and nilotinib 400 mg bid (5.8 mos) compared with 
imatinib 400 mg qd (8.3 mos). Rates of CCyR by 12 months were 


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significantly higher for both nilotinib at either 300 mg bid compared with 
imatinib 400 mg qd (80% vs. 65%, P < .0001) and for nilotinib 400 mg 
bid compared with imatinib 400 mg qd (78% vs. 65%, P = .0005). 
Overall, progression to advanced disease was lower for nilotinib 300 mg 
bid (2 pts) and nilotinib 400 mg bid (1 pt) compared with imatinib 400 
mg qd (11 pts). Overall, both drugs were well-tolerated. Rates of 
discontinuation due to adverse events or laboratory abnormalities were 
7% for nilotinib 300 mg bid, 11% for nilotinib 400 mg bid, and 9% for 
imatinib 400 mg qd. Patients were monitored for QT prolongation and 
LVEF. No patients in any treatment arm showed a QTcF interval > 500 
msec. There was no decrease from baseline in mean LVEF anytime 
during treatment in any arm. The study is ongoing.  
 
Nilotinib at both 300 mg bid and 400 mg bid induced significantly higher 
and faster rates of MMR and CCyR compared with imatinib 400 mg qd, 
the current standard of care in patients with newly diagnosed CML. 
Nilotinib was effective across all Sokal scores. After only one year of 
treatment, both nilotinib arms resulted in a meaningful clinical benefit 
compared to imatinib, with reduction of transformation to AP/BC. 
Nilotinib exhibited a favorable safety and tolerability profile. The 
superior efficacy and favorable tolerability profile of nilotinib compared 
with imatinib suggests that nilotinib may become the standard of care in 
newly diagnosed CML (Saglio et al, 2009). It was approved in 2010 for 
the management of newly diagnosed CML CP patients. 
 
1.313 CML-BC and Ph+ ALL 
In a landmark study ( Kantarjian, Giles et al. 2006), 119 patients with 
imatinib-resistant CML or Ph+ ALL were enrolled in a phase I dose-
escalation study at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 
800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily. 
Of the 33 patients with blast phase, 13 had a hematological response and 
9 had a cytogenetic response. Of the 46 patients with accelerated phase, 
33 had a hematologic response and 22 had a cytogenetic response. A 
total of 51 ABL mutations were observed in 37 of 91 patients who had a 
baseline assessment for mutational status. Nilotinib was effective in both 
groups (regardless of mutation analysis) with no significant differences 
in response rates. T315I mutation was found in 2 patients and did not 
respond to nilotinib. Frequently noted side effects were mild-moderate 
rashes; transient, clinically insignificant elevations of indirect bilirubin 
levels and myelosuppression. The maximum tolerated dose was selected 
as 600 mg twice daily, though 400 mg twice daily showed similar 
response rates. 
 
A similar efficacy was reported in a small phase I/II of nilotinib in 
Japanese patients with imatinib-resistant or –intolerant Ph+ CML or 
relapsed/refractory Ph+ALL (Tojo, Usuki et al. 2009Tojo, Usuki et al. 
2009). Three out of seven patients with Ph+ALL had a complete 
hematologic response and 2 out of 4 patients with CML-BC had 
hematologic response (1 did achieve complete hematologic response). 
 
1.314 AML 


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Three current studies have been activated to study the clinical effect of 
adding nilotinib in patients with acute myeloid leukemia. 
 
Brandwein and colleagues are checking the safety and efficacy of 
nilotinib combined with mitoxantrone, etoposide, and high-dose 
cytarabine (NOVE-HiDAC) induction chemotherapy for high risk AML 
patients (NCT01222143); which include relapsed and refractory AML in 
addition to secondary AML from myeloproliferative neoplasm or chronic 
myelomonocytic leukemia. Patients need to be positive for c-kit (CD117) 
in at least 30% of the blasts measured by flow cytometry. This is a phase 
I/II study where nilotinib dose is escalated in the first phase to get the 
maximum tolerated dose, and then proceed with phase II to assess the 
clinical efficacy. No results have been reported yet. 
 
Duyster and colleagues are studying the combination of nilotinib and 
RAD001 in patients diagnosed with AML. Patients could be newly 
diagnosed but unfit for chemotherapy or have a relapsed/ refractory 
AML diagnosis. No results have been reported yet on this group of 
patients. 
 
Kim et al will be studying the combination of cytarabine and 
daunorubicin (7+3) in combination with nilotinib at a higher dose 
(400mg orally bid) in patients diagnosed with previously untreated CML 
myeloid BP or Ph+AML (NCT01690065). This is a phase II study using 
a higher dose of nilotinib than our proposed dose (300mg bid). The 
primary goal is to increase complete remission rates with secondary 
goals of safety and survival. 
 
In the clinical practice, we have given nilotinib in combination with 
chemotherapy (7+3) for newly diagnosed or relapsed refractory Ph+ 
AML with no excessive toxicity (personal experience). Due to rarity of 
Ph+AML cases, no protocol have yet published for these cases, 
therefore, we have been treating them as AML cases with adding 
tyrosine kinase inhibitor. 
 
1.4 
Nilotinib safety 
 
In Phase II study [CAMN107A2101], nilotinib given at the recommended dose of 400 
mg b.i.d. was well tolerated in imatinib-resistant and -intolerant CML-CP (study 
[CAMN107A2101E2], Group A) and CML-AP (study [CAMN107A2101E1], Group A) 
patients as evidenced by the high actual median dose intensities of 797 mg/day and 780 
mg/day for both populations.  In addition, the median cumulative duration of dose 
interruption was low relative to the median exposures in both CML-CP and CML-AP 
populations. Adverse events (AEs) were generally managed either with dose reduction, 
dose interruption, or supportive care. Discontinuation for drug related adverse reactions 
was observed in 16% of CML-CP and 10% of CML-AP patients.  
 
1.41 
Frequent adverse events 
 


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Table 1-3 lists the adverse events for the Phase II of study [CAMN107A2101]. 
The most frequently reported AEs overall included thrombocytopenia, rash, 
headache, nausea, pruritus, fatigue, anemia, diarrhea, constipation, neutropenia, 
vomiting and arthralgia.  These AEs were generally mild to moderate (CTC 
grade 1 or 2), were manageable with symptomatic treatment, and were reversible.   
 
 


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Table 1-3 
Frequent adverse events (>5%) in CML patients 
 
1.42 
Myelosuppression  


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Myelosuppression, as expected for this class of drug in a CML population, was 
seen with nilotinib, with CTC grade 3/4 thrombocytopenia, neutropenia, and 
anemia reported in 29.38%, 31%, and 10.7% in CML-CP and 41.9%, 42.1%, and 
27.4% in CML-AP patients (Table 1-4). Treatment emergent grade 3/4 
cytopenias were reported in higher proportion of CML-AP patients than CML-
CP. The majority of first episodes of grade 3 and 4 neutropenia and 
thrombocytopenia occurred within the first 2 months of therapy, and were 
generally manageable with dose adjustment or study drug interruption, only 
rarely requiring treatment discontinuation. Severe clinical consequences such as 
febrile neutropenia, sepsis, pneumonia and bleeding associated with 
thrombocytopenia, occurred infrequently in patients in both disease categories. 
 
Table 1-4 
Myelosuppression and abnormal blood chemistry 
 
 
1.43 
Blood chemistry 
 
Serum lipase and amylase 
Lipase and amylase were observed in clinical trials but not in preclinical 
toxicology studies. Increased lipase was reported in 13.1% and 12.8% of CML–
CP and CML-AP patients, respectively. Lipase (11.3%) is one of the most 
frequently reported grade 3 or 4 biochemical laboratory abnormalities. As for 
amylase it was reported in 2.6% and 2.3% of CML-CP and CML-AP patients, 
respectively.   
 
Hepatotoxicity 
Low grade increases in bilirubin and hepatic transaminases were frequently 
observed in CML-CP and CML-AP patients. However, grade 3/4 events occurred 
in 7.3% and 9% for bilirubin, 2.5% and 2.3% for AST, and 4.1% and 3.7% for 
ALT in CML-CP and CML-AP patients, respectively.  Elevations of bilirubin 
occurred early, were transient, and the more severe cases were managed with 
brief treatment interruptions or dose reductions, rarely requiring treatment 


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discontinuation. Patients with normal LFTs at baseline infrequently went on to 
develop grade 3 or 4 bilirubin or hepatic transaminase values on treatment. Of 
interest, a significant increase in relative risk of hyperbilirubinemia was seen in 
patients with the (TA) 7(TA) 7 genotype at the (A (TA) nTAA) element of the 
UGT1A1, suggesting that genetic susceptibility may contribute to the 
development of hyperbilirubinemia in some patients (Kantarjian 2006).  
Elevations of bilirubin and transaminases were observed in animal models, with 
histologic lesions in monkey showing bile duct hyperplasia, sinusoidal cell 
hyperplasia, and periportal fibrosis, partially reversible at 4 weeks. 
 
The incidence of grade 3 or 4 hyperglycemia was 12.2% and 6.1% in CML-CP 
and CML-AP patients. No CML-CP or CML-AP patients required dose 
adjustment and/or study drug interruption due to hyperglycemia. No CML-CP or 
CML-AP patients discontinued nilotinib due to hyperglycemia. Furthermore 
there was no evidence that insulin requirements increased in insulin-dependent 
diabetics receiving nilotinib. 
The incidence of Grade 3 or 4 hypophosphatemia was 15.1% in CML-CP and 
CML-AP patients each.  There were no reports of clinical symptoms related to 
hypophosphatemia.    
Table 1-5 
Abnormal blood chemistry
 
 
 


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1.44 
Clinically significant adverse events 
Rash and pruritus 
Rash and pruritus were frequently reported by patients in the pivotal phase II 
study (2101): rash (CML-CP: 30.8%, CML-AP: 21.2%) and pruritus (CML-CP: 
26.2%, CML-AP: 17.5%). Four CML-CP patients (1.3%) discontinued due to 
skin toxicity: two cases of rash or rash generalized, one case of dermatitis 
allergic, one case of pruritus, all suspected of study drug relationship. Two CML-
AP patients (1.7%) discontinued due to 4 AEs related to skin toxicity: 2 cases of 
rash, one case of urticaria and one case of skin burning sensation, all but the 
latter suspected of study drug relationship. 
 
Fluid retention 
The rates for all CTC grades of effusions (pleural, pericardial) and edema were 
low. Peripheral edema was seen in 5.1% and 6.2% for CML-AP and CML-CP, 
respectively. AE related to pleural effusion was 2.7% and pericardial effusion 
<1%. The incidence of fluid retention appeared to be slightly higher in elderly 
(>65 years old).   
 
Bleeding-related events 
Bleeding-related events are not uncommon in CML patients with compromised 
marrow function at baseline. GI and CNS hemorrhages were included as the 
indicators for significant bleeding. GI hemorrhage was common in both newly 
diagnosed CML-CP and imatinib-resistant/intolerant CML-AP and CML-CP 
patients treated with nilotinib. However, the incidence of SAEs indicative of GI 
hemorrhage was 1% in each of these CML patients’ populations. CNS 
hemorrhage was infrequent but medically significant. All reports of CNS 
hemorrhage were SAEs.   
 
QT prolongation 
In the phase III study in newly diagnosed Ph+ CML-CP patients the change from 
baseline in mean time-averaged QTcF interval at steady-state observed in the 
nilotinib 300 mg twice daily group was 6 msec. In the 300 mg twice daily 
treatment group, no patient had an absolute QTcF of >480 msec. No events of 
Torsade de Pointes were observed in any of the treatment groups.  
 
In the phase II study in imatinib-resistant and intolerant CML patients in chronic 
and accelerated phase, treated with nilotinib 400 mg twice daily, the change from 
baseline in mean time-averaged QTcF interval at steady state was 5 and 8 msec, 
respectively. QTcF of >500 msec was observed in 4 patients (<1% of these 
patients).  
 
Nilotinib should be used with caution in patients who have or who are at 
significant risk of developing prolongation of QTc, such as those:  
1- with long QT syndrome 
2- with uncontrolled or significant cardiac disease including recent myocardial 
infarction, CHF, unstable angina or clinically significant bradycardia   
 
Left ventricular function 
AEs related to cardiac failure or dysfunction occurred in 3 CML patients (1.0%) 
overall in Phase II of study 2101. Patients who presented with cardiac events 
within 12 months prior to nilotinib administration, such as myocardial infarction, 


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unstable angina, clinically significant atrial and ventricular arrhythmias and 
congestive heart failure (CHF) were excluded from nilotinib trials. It is therefore 
unknown whether patients with these concomitant conditions may be safely 
treated with nilotinib.    
 
1.45 
Serious adverse events 
 
In the CML-CP study (2101E2) 22.6% of patients experienced an SAE. The most 
frequent SAEs were thrombocytopenia (3.4%), neutropenia (2.2%), angina 
pectoris (2.8%), pyrexia (2.5%), and myocardial infarction (1.3%). In the CML-
AP study (2101E1) 30.8% of patients experienced an SAE. The most frequent 
SAEs were thrombocytopenia (8.0%), neutropenia (6.7%), pneumonia (5.8%), 
and pyrexia (4.4%). Other SAEs occurred in less than 1% of patients and are 
listed in detail in the Investigator’s Brochure. 
 
Deaths and Sudden Cardiac Deaths (SCD) 
Two deaths in CML-CP patients and 2 deaths in CML-AP have a cause of death 
suspected of study drug relationship by the investigator (multi-organ failure, 
sudden death, CNS hemorrhage and pneumonia.) These four cases are briefly 
described in the Investigator’s Brochure.  
10 deaths in CML-CP and CML-AP were related to progressive disease or 
underlying medical condition rather than the study drug (sepsis, multi-organ 
failure, cardiac disorders, CNS hemorrhage) and are briefly summarized 
described in the Investigator’s Brochure. 
 
A review of all cases received to date from all sources has identified a total of 12 
cases that meet the conservatively modified definition of sudden cardiac death 
(SCD).  These 12 cases have all been reported in the context of adverse event 
reporting for clinical trials including the Compassionate Use Program. No reports 
of sudden death have been received from post marketing sources. A total of 7170 
patients have received nilotinib in clinical trials through 31-Jan-2010 for an 
incidence of sudden death of 0.21%. 15 of these 16 cases have been reported as 
sudden death from a cardiac or presumed cardiac cause while 1 were reported as 
sudden death from unknown cause.  The sudden deaths are summarized in the 
Investigator’s Brochure. So far data indicated, the relative early occurrence of 
some of these deaths relative to the initiation of Nilotinib suggests the possibility 
that ventricular repolarization abnormalities may have contributed to their 
occurrence.  
 
Safety in Phase I Study 
In the Phase I CAMN107A2103 study [overall safety population (N=53)], AEs 
were reported in 100% of patients in each of the 5 dosing groups. Rash was the 
most common AE overall as well as the most common drug-related AE in the 
safety population. There were two deaths during the study (one in the nilotinib 
monotherapy group and one in the selected phase II dose group nilotinib 400 mg 
bid + imatinib 400 mg qd), both of which were assessed by the investigator to be 
due to disease progression and were not suspected to be related to study drug. 
SAEs occurred in 32.1% of patients; none of these were suspected by the 
investigator to be study drug related.  
 


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Overall, six patients (11.3%) experienced AEs associated with study treatment 
discontinuation. In addition to the two patients discontinuing due to death, two 
patients discontinued due to SAEs (abdominal pain and alteration of general 
status due to progressive disease) and two patients due to study drug-related AEs 
(hyperbilirubinemia and rash). The event of hyperbilirubinemia in the nilotinib 
monotherapy patient improved after discontinuation of study drug, but was 
reported as ongoing at the time of discontinuation from the study. The rash in the 
nilotinib 400 mg bid + imatinib 400 mg bid patient resolved after 34 days. Both 
events were considered as DLTs. 
 
Seventeen patients (32.1%) experienced a total of 52 SAEs, with gastrointestinal 
disorders the most frequently affected system organ class. Of these patients, two 
died. No SAEs were suspected by the investigator to be study drug related. 
 
Table 1.6 
Frequent adverse events occurring in at least 5% of GIST 
patients by preferred term (Study 2103 safety population) 
 
 
1.5 
Study rationale/ purpose  
 


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AML has been a challenging cancer for hematologists and adult patients. Combination 
chemotherapy using cytarabine and anthracycline (known as 7+3) induction success and 
relapse rates have been challenged by many concepts but yet remains the standard 
therapy. These strategies included using higher doses of anthracycline or cytarabine, 
addition of novel agents (like proteosome inhibitors or monoclonal antibodies (like 
gemtuzumab ozogamicin), or even using agents directed against drug-resistance targets. 
Fernandez H et colleagues randomized 657 patients diagnosed with AML between the 
ages of 17-60 to receive 7+3 but at different doses for daunorubicin (90 mg/m2 vs 45 
mg/m2). Patients who received high dose daunorubicin had higher complete remission 
rates (70% vs 57%, p<0.001) and better median overall survival (23.7 months vs 15.7 
months, p=0.003){Fernandez, 2009 #54}. In a similar study reported by Lowenberg et al, 
813 patients were randomized to the same treatment but in patients equal or older than 60 
years. The complete remission rate favored the higher dose daunorubicin (64% vs 54%, 
p=0.002), however the overall survival did not differ significantly {Lowenberg, 2009 
#55}. Dose intensification of cytarabine was studied compared to standard dose (2gm/m2 
IV q12 hours x 12 doses vs. 200 mg/m2/day continuos IV daily x 7 days) in addition to 
daunorubicin 45 mg/m2 daily x 3 days in AML patients less than 65 years old. A total of 
665 patients were treated where CR rates 55% vs 58% (high vs standard dose cytarabine) 
for patients aged less than 50 and there was no significant difference in 4-year overall 
survival (32% vs 22%, p=0.41){Weick, 1996 #56}. The British hematologists tested the 
role of adding gemtuzumab ozogamicin 3mg/m2 on day 1 of induction and course 3 of 
consolidation) to induction chemotherapy in their MRC AML 15 trial in 1113 patients 
diagnosed with AML and age less than 60{Burnett, 2011 #58}. Unfortunately, no overall 
survival benefit was found to adding this treatment in neither induction nor consolidation. 
On subsequent analysis, patients with favorable cytogenetics had a favorable effect from 
adding gemtuzuamb (p=0.001). Finally, in randomized study done by ECOG (3999), the 
addition of zosuquidar (a modulator of P-glycoprotein), did not improve the outcome of 
older patients newly diagnosed with AML (499 patients){Cripe, 2010 #59}. Remission 
rate was 52% vs 49% (p0.158) on placebo, while median overall survival was 7.2 vs 9.4 
months on placebo compared to patients who received zosuquidar. 
 
Over the last decade, molecular breakthroughs in understanding the genes role and 
pathways governing the cell cycles, proliferation, apoptosis and transcription have 
revolutionized our understanding and treatment of myeloid disease, especially chronic 
myeloid leukemia, myeloproliferative neoplasms and acute myeloid leukemias. Based on 
this molecular profiling we are able to identify high risk AML cases for low chance of 
remission and high risk of relapse. Consequently this affected our treatment 
recommendation, especially with regards to whether to proceed with allogeneic 
transplantation or not. For example patients harboring CEBPA mutation (single vs double 
mutations) had a favorable outcome compared with wild type AML cases {Taskesen, 
2011 #62}. In fact double mutation CEBPA was the only prognostic factor for overall 
survival on multivariate analysis (hazard ratio 0.36, p<0.0001). On the other hand, high 
EVI1 expression in young patients diagnosed with AML predicts worse outcome by 
having low CR rates (odd ratio 0.54, p=0.002) and adverse event-free survival (hazard 
ratio 1.46, p<0.001){Groschel, 2010 #63}. Patients who received allogeneic stem cell 
transplantation in CR1 had a better 5-year relapse free survival (33% vs 0%) compared to 
without transplantation. FLT3 is another potential gene, where mutations (internal 
tandem duplicate or tyrosine kinase domain mutation) predicts worse clinical outcome 
(especially in patients with normal cytogenetics){Kottaridis, 2001 #64}{Whitman, 2008 
#65}{Stirewalt, 2006 #67}. This became of utmost significance since many FLT3 
inhibitors have been tested in trials with encouraging results. This include both as a single 


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agent and in combination with chemotherapy {Fischer, 2010 #68}{Levis, 2011 
#69}{Borthakur, 2011 #71}{Al-Kali, 2011 #70}{Zarrinkar, 2009 #72}. 
 
Kit encodes for a transmembrane protein, which has tyrosine kinase activity. It is also 
thought to be a proto-oncogene with important role in hematopoiesis. Kit is activated by 
SCF (stem Cell factor) and results in proliferation of blast cells in many cases at 
diagnosis and at relapse. There has been a strong correlation between levels of Kit 
phosphorylation and AML cell lines proliferation {Kanakura, 1993 #76}. Many 
mutations in c-Kit are seen in core binding factor AML cases and predict worse clinical 
outcome. Paschka P et al assessed Kit mutations in exon 8 and 17 in 61 cases with AML 
harboring inv(16) and 49 AML cases with t(8;21) treated with standard chemotherapy 
and high dose cytarabine consolidation{Paschka, 2006 #78}. Kit mutations were detected 
in 30% of AML inv(16) and 22% with AML t(8;21). In inv(16), cumulative incidence of 
relapse for both Kit mutations compared to Kit wild-type (56% vs 29%, p=0.05); mutated 
Kit also predicted worse overall survival (after adjusting to sex). Additionally, Kit 
intensity (<20.3) assessed by fluorescence was found to be correlated with decreased 
progression-free and overall survival on multivariate analysis (independent of age, white 
blood count, and cytogenetics){Advani, 2008 #79}. Finally, a variant of t(8;21) called 
AML1-ETO9a was found to be correlated with c-kit overexpression/mutations and 
predicts poor prognosis{Jiao, 2009 #80}. 
 
Tyrosine kinase inhibitors (TKI) (including imatinib, nilotinib, and dasatinib) have 
changed the prognosis and therapy paradigms of patients diagnosed with CML, as well as 
Ph-positive acute lymphoblastic leukemia (ALL). Imatinib was first approved in patients 
diagnosed with chronic phase CML based on the landmark study IRIS, while both second 
generation TKIs (nilotinib and dasatinib) were approved for second line therapy in 
patients with imatinib-resistant or intolerant CML-CP ( O'Brien, Guilhot et al. 2003; 
Hochhaus, Kantarjian et al. 2007; Kantarjian, Giles et al. 2007). However, recently and 
based on randomized phase III studies, both nilotinib and dasatinib have been approved 
for frontline therapy of patients diagnosed with chronic phase CML (Kantarjian, Shah et 
al. 2010; Saglio, Kim et al. 2010). In more advanced stages of CML (accelerated and 
blast phases), second generation TKIs have been more effective in achieving 
hematological and cytogenetic remissions due to their improved potency (Cortes, 
Rousselot et al. 2007le Coutre, Ottmann et al. 2008). 
 
Nilotinib (Kantarjian, Giles et al. 2006), a second generation TKI, has been tested as 
single agent in imatinib-failure patients diagnosed with CML-BC with encouraging 
responses. Nilotinib has been approved for the treatment of CML as first line therapy and 
after imatinib failure as second line therapy in CML-CP. Therefore, a combination of 
chemotherapy regimen with nilotinib should be an effective strategy, better than 
chemotherapy alone, and may be superior to other combination (like imatinib and 
chemotherapy). Nilotinib is 20-50-fold more potent than imatinib in its ABL inhibition. It 
also is more effective than imatinib especially in the presence of tyrosine kinase 
mutations (except for T315I), frequently seen in Ph+ALL. In addition, nilotinib 
concentration in cell lines and primary CD34+ CML cells is not mediated by active 
uptake or efflux by major drug transporters (a known mechanism for imatinib resistance). 
Most importantly, it has a synergistic activity with established chemotherapeutic drugs in 
BCR-ABL positive cells. Additionally, nilotinib does not increase stem cell 
transplantation toxicity in patients with Ph+ acute lymphoblastic leukemia (Shimoni, 
Leiba et al. 2009). In a case report, nilotinib restored long-term full-donor chimerism in 
Ph+ ALL relapsed after allogeneic transplantation (Merante, Colombo et al. 2009).  


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We plan to study the clinical efficacy of nilotinib in combination with standard 
chemotherapy (7+3) in patients with Kit+AML as a frontline therapy. We will assess 
their CR rates, survival outcome (DFS and OS) in addition to predictive factors for 
superior outcome. Cytarabine and daunorubicin regimen (7+3) is one of the well-
established and widely used chemotherapy regimens for the treatment of adult AML. In 
addition, it has been successfully combined with other TKIs (imatinib, dasatinib) in the 
management of both newly diagnosed and relapsed AML. Cancer and Leukemia Group B 
(CALGB) is currently studying combination dasatinib and 7+3 in a phase II study 
(CALGB 110801) for core binding factor positive AML patients. Finally imatinib has 
been combined with mitoxantrone, etoposide and cytarabine (MEC) in patients with 
relapsed/refractory c-Kit+ AML. 
 
 
2.0 
Goals    
 
2.1 
Primary 
 
2.11 
To determine the complete response rates of combination Nilotinib, cytarabine, 
and daunorubicin in patients newly diagnosed with AML and Kit overexpression 
 
2.2 
Secondary 
 
2.21 
Determine the 2-year overall survival (OS) and disease-free survival (DFS) rates.  
 
2.22 
Determine the complete response duration in patients treated with this regimen. 
 
2.23 
Assess the safety and toxicity of this regimen based on NCI CTCAE version 4.0. 
 
2.3 
Correlative Research 
 
2.31 
Assess the prognostic and predictive factors (Kit mutation/expression level, Flt3 
mutation) for patients treated with this regimen. 
 
2.32 
Assess the patterns of molecular response and relapse for Kit 
 
2.33 
Assess the effect on minimal residual disease (MRD) by PCR or flow cytometry 
 
 
3.0 
Patient Eligibility   
3.1 
Inclusion Criteria 
3.11 
Age ≥ 18 years and < 70 years. 
3.12 
Untreated, histological confirmed acute myeloid leukemia (AML) based on 
WHO 2008 criteria (See Appendix V) with Kit expression (CD117) of 
myeloblasts ≥ 20% by flow cytometry from bone marrow aspirate at diagnosis. 
 
3.13 
ECOG Performance Status (PS) 0, 1, or 2 (Appendix3). 


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3.14 
The following laboratory values obtained ≤ 7 days prior to registration. 
• 
Magnesium/potassium/phosphorus WNL 
• 
Serum amylase and lipase ≤ 1.5 x ULN 
• 
Total Bilirubin ≤1.5 x ULN [Does not apply to patients with isolated 
hyperbilirubinemia (e.g., Gilbert’s disease), in that case direct bilirubin 
should be ≤ 2 x ULN] 
• 
Alkaline phosphatase ≤3 x ULN 
• 
SGOT (AST) ≤3 x ULN 
• 
Creatinine ≤1.5 x ULN  
 
3.15 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.16 
Provide informed written consent. 
 
3.17 
Willing to return to consenting Mayo Clinic (Mayo Clinic’s campus in 
Rochester, Mayo Clinic’s campus in Arizona, or Mayo Clinic’s campus in 
Florida) institution for follow-up during the Active Monitoring Phase of the 
study. 
 
3.18 
Willing to provide bone marrow aspirate and blood samples for correlative 
research purposes (see Sections 6.2 and 14.1).  
 
3.2 
Exclusion Criteria  
 
3.21 
Any of the following because this study involves investigational agent(s) whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown  
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception throughout the study and for 3 months after 
completion of study treatment  
 
3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.23 
Immunocompromised patients (other than that related to the use of 
corticosteroids) including patients known to be HIV positive. 
 
3.24 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.25 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 






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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
bypass surgery). 
 
3.29e 
Acute or chronic pancreatic disease.  
 
3.29f 
Known cytopathologically confirmed CNS infiltration.  
 
3.29g Acute or chronic liver disease or severe renal disease considered unrelated to the 
cancer. 
 
3.29h History of significant congenital or acquired bleeding disorder unrelated to 
cancer. 
 
3.29i 
Major surgery ≤4 weeks prior to registration of the study or who have not 
recovered from prior surgery. 
 
3.29j 
Treatment with other investigational agents ≤14 days of registration. 
 
3.29k    Diagnosis of AML-M3 (or acute promyelocytic leukemia). 
 


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4.0 
Test Schedule  
All routine assessments must be performed within ± 3 days of the day indicated on the Visit Schedule. 
 
Active Monitoring Phase 
Tests and procedures 
≤7 days 
prior to 
registration* 
Day 1 of 
induction/
re-
induction 
or SCT 
Cycle 
1,  
Day 4 
Cycle 1, 
days 8,14, 
and upon 
bone 
marrow 
recovery 
Cycle 2 if 
Re-
induction: 
day 14 and 
upon bone 
marrow 
recovery 
Day 1 of 
each 
consolidation 
cycle 
Every 3 
months 
during 
maintenance 
For patients 
who go to 
SCT:  End of 
stem cell 
transplant 
(prior to start 
of 
maintenance 
after SCT) 
Early Discontinuation or 
End of Study 
History and exam, weight, PS 
X 
X 
 
 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Adverse event assessment 
X 
X11 
 
 
 
X 
X 
X 
X 
BM testing2, 10 
X 
 
 
X9 
X9 
 
X2 
 
X 
Biomarkers CD117/ Flow cytometry,R 
X2 
 
 
X2 
X2 
 
X2 
 
X2 
Biomarkers Kit Mutation by PCR ,,R 
X 
 
 
 
 
 
X2,7 
 
X 
Hematology group 
HgB, WBC, PLT, WBC with diff. 
X 
X 
 
 
 
X 
X 
X 
X 
Serum Chemistry  
(magnesium R, potassium, phosphorus, total 
bilirubin, alkaline phosphatase, AST, ALT, 
creatinine) 
X 
X 
 
 
 
X 
X 
X 
X 
Serum Chemistry R 
(Serum Amylase & Lipase) 
X 
X 
 
 
 
X 
X 
X 
X 
MUGA/Echo 
X* 
 
 
 
 
 
 
 
 
Direct bilirubin 
X6 
 
 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
 
 
Hepatitis B surface Antigen, Anti-HBc 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test1 
X 
 
 
 
 
 
 
 
 
Urine analysis R (proteinuria, hematuria) 
X 
 
 
 
 
 
 
 
 
ECG (QTcF results preferred) R ,3 
X 
X 
 
X3 
X3 
X 
X 
X 
X 
Patient Medication Diary (Appendix IV)4  
 
X 
 
 
 
X 
X 
X 
X 
Research Correlatives ,8,R 
X 
 
X5 
X5 
 
 
 
 
 


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Mayo Addendum 9 
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1. For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
2. Bone marrow (BM) sampling will be done upon screening, bone marrow recovery of Cycle 1 (Standard of Care), upon bone marrow recovery 
of Cycle 2 if patient receives re-induction (Standard of Care), Day 1 Cycle 1 of maintenance (Standard of Care), and end of maintenance 
(Research Funded) and upon relapse (Standard of Care). Bone marrow MRD assessment for CD117 (Kit) by flow cytometry will be done at 
screening (Standard of care), upon recovery of Cycle 1 (Research funded), upon bone marrow recovery of Cycle 2 if patient receives re-
induction (Research funded). Bone marrow MRD assessment for CD117/Kit by flow cytometry will be done at day 1 Cycle 1 of maintenance 
(Standard of Care), end of maintenance (Standard of Care) and upon relapse (Standard of care) if deemed needed by the pathologist. Bone 
marrow MRD assessment for Kit mutation by PCR (if positive at diagnosis) will be done at screening (Research funded),  Day 1 of cycle 1 of 
maintenance (if positive at screening) (Research funded), and upon relapse (if positive at screening)  (Research funded). Bone marrow 
aspirate/biopsy done for cycle 1 day 1 of maintenance could be done up to 3 weeks prior. 
3. ECGs will be performed locally at screening, Day 1 (prior to dosing) of each cycle, Day 8 of induction/re-induction, and when there’s any 
dose change or re-initiation after a dose interruption. When a dose change occurs or upon re-starting nilotinib, an ECG must be obtained at 7 
days afterwards. QTcF results are preferred, however all reporting methods will be accepted. 
4. The diary must begin the day the patient starts taking nilotinib and must be completed per protocol and returned to the treating institution OR 
compliance must be documented in the medical record by any member of the care team.  Patients will be asked to return all unused medication 
at each visit. 
5. Serum nilotinib levels (research) will be checked only on cycle 1 days 4, 8, and 14 (30 minutes pre-dosing.)   See section 14.0  
6. Only if total bilirubin > upper normal limit. 
7.    Only if positive at diagnosis. 
8. See section 14.0 
9. Bone marrow aspirate and biopsy will be done on Day 14 of Cycle 1 Induction and Day 14 of Cycle 2 if patient receives Re-Induction to 
assess for cellularity and blasts assessment (Standard of Care).  
10. Additional bone marrow testing may be done as clinically indicated 
11. If the patient goes to stem cell transplant, the cycle length of the cycle proceeding transplant will be extended until the SCT (pre-transplant 
conditioning chemotherapy plus stem cell infusion). 
R Research funded (see Section 19.0). This will be charged to study and not to patient’s account. 
*  Labs done same day of consenting (prior to consenting) do not need to be repeated.  ≤14 days prior to registration for bone marrow biopsy 
(regardless of consent date).  MUGA/Echocardiogram done ≤ 28 days prior to screening is allowed. Correlative studies at screening could be 
done via a peripheral blood sample to avoid bone marrow resampling.  


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Protocol Version Date:  February 7, 2019 
5.0 
Grouping Factors: None.    
 
6.0 
Registration Procedures 
6.1 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page 
 and detail the process for 
completing and confirming patient registration.  Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent.  Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
.  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.2 
Correlative Research 
A mandatory correlative research component is part of this study. The patient will be 
automatically registered onto this component (See Sections 3.18 and 14.0). 
 
6.3 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 
  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
6.4 
Prior to accepting the registration, registration application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.5 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 


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Mayo Addendum 9 
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research of AML at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.6 
Treatment cannot begin prior to registration and must begin ≤ 7 days after registration. 
 
6.7 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.8 
All required baseline symptoms (see Section 10.5) must be documented and graded. 
 
6.9a 
Treatment on this protocol must commence at Mayo Clinic Rochester, Mayo Clinic 
Arizona, or Mayo Clinic Florida institution under the supervision of a hematologist. 
 
6.9b 
Study drug is available on site.  
 
 
7.0 
Protocol Treatment  
 
7.1 
Treatment Schedule 
 
7.11 
Induction (Cycle 1;  repeat for Cycle 2 for patients who require re-
induction): Patients eligible for the study based on screening tests will be 
enrolled on the study. During Cycle 1, patients will be assessed for 
hypocellularity on Day 14.  If the patient has a decrease in bone marrow blasts, 
they will be assessed for response upon marrow recovery (End of Cycle 1).   
Patients who achieve a CR/CRi will proceed to consolidation.  Patients who fail 
to achieve a significant decrease in bone marrow blasts on Day 14 of Cycle 1 or 
fail to achieve a CR/CRi upon bone marrow recovery at the end of Cycle 1will 
proceed to re-induction Cycle 2 (follow same treatment schedule as Cycle 1).  
Treating physician could repeat other bone marrow(s) on day 21 (and later) if felt 
best for patient interest and if felt that blast reduction might still happen then.  
These patients will get repeat bone marrow evaluation for hypocellularity on Day 
14 of Cycle 2 and will be assessed for response upon marrow recovery (End of 
Cycle 2). Patients who fail to achieve a decrease in bone marrow blasts on Day 
14 of Cycle 2 or fail to achieve a CR/CRi upon bone marrow recovery at the end 
of Cycle 2 will go to event monitoring.  Idarubicin (12mg/m2) instead of 
daunorubicin is allowed a substitute in cases of daunorubicin national shortages 
(Not a preferred first line anthracycline). 
 
Agent 
Dose 
Route 
Day 
Comments 
Daunorubic
in 
60 mg/m2 
IV  
1-3  
IV Push through the Y-site of a running IV 
over 10 minutes 
Cytarabine  
25 mg/m2/day 
IV 
1 
IV Push through the Y-injection site of a 
running IV prior to continuous infusion 


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
Cytarabine 
100 mg/m2/ 
day 
IV  
1-7  
Continuous infusion 
Nilotinib 
300 mg 
twice/day** 
Oral 
4-14 
Take on an empty stomach 1 hour before 
or 2 hours after food. 
** See Section 7.15 
 
7.12 
Consolidation (Cycles 2-5 or Cycles 3-6 for patients who received re-
induction): Patients who lose sustained CR/CRi will discontinue treatment and 
go to event monitoring. Cycles will be repeated every 28 days for a total of 4 
cycles.  . 
 
 
CBC criteria to receive subsequent cycles of consolidation: 
• 
ANC ≥ 1.0 x109/L  
• 
Platelets ≥80 x109/L 
 
 
NOTE:  If CBC criteria is not met, the next cycle of treatment may be delayed up 
to 56 days.  If CBC criteria is still not met, the patient will go to event 
monitoring.   
 
 
NOTE:  Patients > 60 years or  serum creatinine (Scr) > 2 mg/dL should get 
50% dose reduction of their cytarabine, for a total of 2-4 cycles, based on 
treating physician judgment 
 
Agent 
Dose 
Route 
Day 
Comments 
Cytarabine 
3000 mg/m2 q 
12 hours 
IV 
Day 1, 3, 5 
 
 
Nilotinib 
300 mg 
twice/day** 
Oral 
Day 4-14 
Take on an empty stomach 1 
hour before or 2 hours after 
food. 
** See Section 7.15 
 
7.13 
Maintenance (Cycles 6-13 or Cycles 7-14 for patients who received re-
induction): Prior to commencement of this phase, patients will get a repeat bone 
marrow evaluation. Patients who lose their sustained CR/CRi will discontinue 
treatment and go to event monitoring.  Cycles will be repeated every 84 days for 
a total of 8 cycles. 
 
NOTE:  If toxicity occurs, the next cycle of treatment may be delayed up to 56 days.  If 
toxicity is not resolved, the patient will go to event monitoring.   
 
Agent 
Dose 
Route 
Day 
Comments 
Nilotinib 
300 mg 
twice/day** 
Oral 
1-84 
Take on an empty stomach 1 hour 
before or 2 hours after food. 
** See Section 7.15 
 
 


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
7.14 
Stem Cell Transplantation (SCT): Allogeneic stem cell transplantation for 
intermediate and high risk patients (based on treating MD assessment) will be 
allowed at any time if a suitable donor is found and no chemotherapy will be 
given. In this case, the cycle length of the cycle proceeding transplant will be 
extended until the SCT (pre-transplant conditioning chemotherapy plus stem cell 
infusion).  Patients who undergo SCT will receive maintenance with nilotinib per 
Section 7.13 for 8 cycles starting day +100 (after achieving hematological 
recovery as defined by CR, or after day +100 as deemed appropriate per treating 
MD).  The SCT until the start of maintenance will be defined as a separate cycle, 
where the stem cell transplant form will be used instead of the 
evaluation/treatment form for that cycle. Post-transplant maintenance will be 
allowed between day100-200. 
 
7.15   Nilotinib dose will be increased to 400 orally twice daily in the following cases: 
1. 
Conversion of negative RT-PCR (CMR) for Kit mutation to positive on 2 
readings (if mutation was present at diagnosis). 
2. 
Failure to achieve negative RT-PCR (CMR) for Kit at the end of consolidation 
therapy. 
3. 
Failure to achieve negative flow cytometry for persistent AML (MRD) at the end 
of consolidation therapy. 
4. 
Failure to achieve CR at the end of cycle 1 of induction. 
 
NOTE: If nilotinib is dose escalated (e.g. from 300 mg b.i.d daily to 400 mg 
b.i.d.), an ECG should be repeated approximately 7 days after the dose 
adjustment. 
 
 
 


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
8.0 
Dosage Modification Based on Adverse Events  
 
Dose reduction for nilotinib is required in cases of grade 3 or 4 hematologic adverse events (AE) 
concerning white blood cells (WBC) and platelets (PLT) (not concerning hemoglobin level) 
during maintenance therapy, and in cases of grade 2, 3 or 4 non-hematologic AEs. The dose 
reduction schedule used in this study differs from the label recommendations, but has been 
successfully pioneered by the GIMEMA study group in a recently reported nilotinib trial (Rosti 
2008), which included similar patients treated with nilotinib for CML-CP.  
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
• 
Omit = The current dose(s) for the specified drug(s) during a cycle is skipped.  The patient does 
not make up the omitted dose(s) at a later time 
• 
Hold/Delay = The current dose(s) of all drugs during a cycle is delayed.  The patient does make 
up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
• 
Discontinue = The specified drug(s) are totally stopped.    
 
8.1  
Dose Levels (Based on Adverse Events in Tables below)  
Dose 
Level 
Dose 
Drug Name 
+1** 
 
400 mg orally bid  
Nilotinib 
 0* 
 
300 mg orally bid (also dose for 
maintenance) 
Nilotinib 
-1 
 
200 mg orally bid 
Nilotinib 
-2 
 
150 mg orally bid 
Nilotinib 
*Dose level 0 refers to the starting dose. 
** If nilotinib is dose escalated (e.g. from 300 mg b.i.d daily to 400 mg b.i.d.), an ECG should be 
repeated approximately 7 days after the dose adjustment. 
 


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
8.2 
Nilotinib dose adjustments for AE at least possibly related to treatment (WBC or PLT) 
during Maintenance Therapy.  
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
AT TIME OF NEXT DOSE (All treatment days of each cycle) 
Investigations 
Grade 3-4 White 
blood cell decreased 
(persisting >7days 
with optimal 
supportive care) 
Nilotinib 
 
1st and 2nd time: 
Hold nilotinib 
Check labs weekly until ≤ Grade 2.  
Resume nilotinib at 600 mg a day (300 
mg b.i.d.) if recovery to ≤ Grade 2 
occurs within 14 days 
If toxicity persists for 15-28 days, hold 
therapy and resume nilotinib at 400 mg 
a day (200 mg b.i.d.) after recovery to ≤ 
Grade 2 
Dose re-escalation to 600 mg a day (300 
mg b.i.d.) is permitted if tolerated and 
no recurrent Grade 3 or 4 hematological 
toxicities occur while on the reduced 
dose. 
3rd and 4th time: 
Hold nilotinib 
Check labs weekly until ≤ Grade 2.  
Resume nilotinib at 400 mg (200mg bid) 
a day.  
Dose re-escalation to 600 mg a day (300 
mg b.i.d.) is permitted if tolerated and 
no recurrent Grade 3 or 4 hematological 
toxicities occur while on the reduced 
dose. 
5th time: 
Stop nilotinib and proceed to event 
monitoring. 
Grade 3-4 Platelet 
count decreased 
(persisting >7days 
with optimal 
supportive care) 
 


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
8.3  
Nilotinib dose adjustments for AE at least possibly related to treatment (Other Non-
hematological) for All Cycles. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
AT TIME OF NEXT DOSE (All treatment days of each cycle) 
Other Non-
hematological  
 
Grade 2-3 Non- 
Hematologic 
(persisting >7days 
with optimal 
supportive care) 
Nilotinib 
 
1st and 2nd time: 
Hold nilotinib 
Check labs weekly (if applicable)until ≤ 
Grade 1 
Resume nilotinib at 600 mg (300 mg 
b.i.d.) if recovered to ≤Grade 1 
3rd time: 
Hold nilotinib 
Check labs weekly (if applicable)until ≤ 
Grade 1 
Resume nilotinib at 400 mg (200 mg 
b.i.d) a day if recovered to ≤Grade 1 
Resume nilotinib at 600 mg a day (300 
mg b.i.d.) if patient was able to tolerate 
2 weeks on 400 mg a day without the 
same Grade 2/3 non-hematologic AE 
recurring. 
4th time: 
Hold nilotinib 
Check labs weekly (if applicable) until ≤ 
Grade 1 
Resume nilotinib at 300 mg (150mg 
b.i.d) a day if recovered to less than or 
equal to grade 1. Resume nilotinib at 
400mg a day(200 b.i.d.) if  patient was 
able to tolerate 4 weeks on 300 mg a day 
without the same Grade 2/3 non-
hematologic AE recurring, re-escalation 
to 300 mg b.i.d. may be considered. 
 
Other Non-
hematological 
Grade 4 Non- 
Hematologic 
Nilotinib 
Discontinue nilotinib and proceed to 
event monitoring. 
If nilotinib is held and re-initiated, an ECG should be repeated prior to re-starting nilotinib and 
approximately 7 days after.  
8.4 
Nilotinib dose reduction for cardiac AE 
If QTc > 480 msec 
1. Stop nilotinib  
2. Perform an analysis of serum electrolytes (including potassium and magnesium) and 
correct with supplements to WNL if required. 
3. Review concomitant medications for drug interactions. 


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
4. Resume nilotinib within 2 weeks at prior dose if QTc returns to < 450 msec and to 
within 20msec of baseline. 
5. If QTc is between 450msec and 480msec after 2 weeks reduce the dose to 400mg  
daily 
6. If following a dose-reduction to 300mg  daily, the QTc returns to >480msec, nilotinib 
should be discontinued. 
7. An ECG should be repeated 7 days after any dose adjustment. 
 
8.5 
Dose modification on chemotherapeutic agents 
Chemotherapeutic agents will be given for Cycle 1 of induction (and also Cycle 2 if no 
CR is achieved after Cycle 1) regardless of the hematological panel results (i.e. CBC 
results) because it is related to the underlying disease (acute leukemia). If patient does not 
achieve CR by the end of Cycle 2 re-induction, the patient will discontinue treatment and 
go to event monitoring. Subsequent cycles of consolidation are to be given after 
peripheral blood recovery. Peripheral blood recovery is defined as ANC ≥1.0 x109/L, 
platelets ≥80 x109/L.  
Dose modification for chemotherapeutic agents will be mainly based on non-
hematological AEs as described below. Dose adjustments will be re-evaluated at the 
beginning of each cycle, For example, if a dose reduction was applied because of 
abnormal lab results on previous cycle and the lab results normalizes, then full dose will 
be given. Creatinine clearance will be calculated using Cockcroft formula with total body 
weight and race adjustment. 
 


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
AT TIME OF NEXT DOSE (All treatment days of each cycle) 
Investigations 
Grade 2 Blood 
Bilirubin Increased 
with total bilirubin 
>2 mg/dL 
Daunorubicin 
Decrease by 50% 
Grade 3 Blood 
Bilirubin Increased 
with total bilirubin 3-
5 mg/dL 
Decrease by 75% 
Grade 3 or 4 Blood 
Bilirubin Increased 
with total bilirubin>5 
mg/dL 
Omit for remainder of the cycle 
Investigations 
Creatinine > 2 mg/dL 
Cytarabine 1.5 
to 3 
grams/m2/dose 
Decrease by 50% 
Grade 3 or 4 
increased creatinine 
> 4 mg/dL 
Discontinue treatment and 
proceed to event monitoring 
Total bilirubin  > 2 
mg/dL 
Decrease by 50% 
AST/ALT > 2 X 
ULN 
Decrease by 50% 
Grade 3 or 4 
bilirubin >5 mg/dL,  
increased AST, ALT 
Discontinue treatment and 
proceed to event monitoring 
 
 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.   
 
9.3 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
9.4 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
hydration, octreotide, and antidiarrheals.   
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring  
10.1 
Adverse Event Characteristics 
Adverse events for this study will be collected while the patient is receiving protocol 
chemotherapy.   If the patient becomes eligible for Stem Cell Transplant, neither the 
hospitalization nor prolonged hospitalization for transplant will be reported as an adverse 
event.  Adverse events related to the Stem Cell Transplant will not be collected.  At the 
time the patient returns to treatment with nilotinib, recording of adverse events will 
resume. 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site:  
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.52 
and 18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).   
  
• 
NOTE:  A severe AE, as defined by the above grading scale, is NOT 
the same as serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 


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Mayo Addendum 9 
Protocol Version Date:  February 7, 2019 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assigning attribution category, the attribution refers to the relationship to Cytarabine, 
Daunorubicin or Nilotinib (not Stem Cell Transplant). Adverse events are not collected during 
Stem Cell Transplant. 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
 
NOTE: The combination of an investigational agent with a commercial agent is 
considered investigational. 
 
Routine Reporting 
 
• Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent 
is stated in the protocol.  See Section 10.52. 
 
NOTE:  When a commercial agent(s) is (are) used on the same 
treatment arm as the investigational agent/intervention (also, 
investigational drug, biologic, cellular product, or other 
investigational therapy under an IND), the entire combination (arm) is 
then considered an investigational intervention for reporting. 
 
Expedited Reporting 
 
• An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for CTEP investigational agents/interventions in Section 10.4, and 
where indicated, an expedited report must be submitted. 
 
• An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible 
attribution to the commercial agent require an expedited report.  Refer to 
Section 10.4 for specific AE reporting requirements or exceptions. 
 


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• Commercial agent expedited reports must be submitted by the Cooperative 
Group to the FDA via MedWatch. 
 
• An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent.  Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity, expedited reporting 
is required.  The clinical investigator must determine severity. 
 
10.32 Special Situations for Expedited Reporting and submission of 
Notification Forms 
Exceptions to Expedited Reporting and Submission of Notification Forms: 
EXPECTED Serious Adverse Events 1 
An expedited report or notification form may not be required for specific Serious 
Adverse Events where the AE is listed in Section 15.0 of the protocol as 
EXPECTED. Any protocol specific reporting procedures MUST BE 
SPECIFIED BELOW and will supercede the standard Expedited Adverse Event 
Reporting and Notification Form Requirements (see Footnote 1):   
CTCAE System Organ 
Class (SOC) 
Adverse event/ Symptoms 
CTCAE Grade at 
which the event will 
not be expeditedly 
reported 
Blood and lymphatic 
Anemia 
≤Grade 4 
system disorders 
Febrile neutropenia 
≤Grade 3 
Investigations 
Lymphocyte count decreased 
≤Grade 4 
Neutrophil count decreased 
≤Grade 4 
Platelet count decreased 
≤Grade 4 
White blood cell decreased 
≤Grade 4 
Metabolism and  
Hyperglycemia 
≤Grade 3 
nutrition disorders 
Hyperkalemia 
≤Grade 3 
 
Hyperuricemia 
≤Grade 3 
 
Hypocalcemia 
≤Grade 3 
 
Hypokalemia 
≤Grade 3 
 
Hypophosphatamia 
≤Grade 3 
Vascular disorders 
Hypertension 
≤Grade 3 
1  These exceptions only apply if the adverse event does not result in hospitalization.  If the adverse event 
results in hospitalization, then the standard expedited adverse events reporting requirements must be 
followed. 
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 
10.321 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to 
as disabilities), congenital abnormities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under 
an IND/IDE since they are considered to be a serious AE and must be reported 
to the sponsor as specified in 21 CFR 312.64(b). 
 


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10.322 Death 
 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by 
cessation of life during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported 
as Grade 5 “Neoplasms benigh, malignant and 
unspecified (incl cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death 
was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
10.323 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 


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o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.324 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
 




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1. Contact Novartis within 24 hours via email using the applicable SAE Cover Sheet (see Forms 
Packet) 
 
2. Use Mayo Clinic Cancer Center SAE Reporting Form:  
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-56/Processes/MC4158-56-
Process.MC4158-56. 
 
Provide documentation to the MCCC Regulatory Affairs Unit (RAU) Risk Information Specialist 
who will determine and complete IRB reporting. The RAU will submit to the MCCC SAE 
Coordinator and the MCCC IND Coordinator to determine if FDA submission is needed. 
 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading 
unless otherwise stated in the table below: 
 
 
System Organ Class 
(SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Investigations 
Electrocardiogram QT 
corrected interval prolonged 
X 
X 
Blood bilirubin increased 
X 
X 
Alanine aminotransferase 
increased 
X 
X 
Aspartate aminotransferase 
increased 
X 
X 
Lipase increased 
X 
X 
Skin and subcutaneous 
tissue disorders 
Rash maculo-papular 
X 
X 
 
10.52 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.5. When assigning attribution category, the attribution refers to the 
relationship to Cytarabine, Daunorubicin or Nilotinib (not Stem Cell Transplant).   
 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure (not Stem Cell Transplant). 
 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure (not Stem Cell Transplant). 
 
 


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10.523  Grade 5 AEs (Deaths) 
 
10.5231  
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.5232      Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.53    Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
11.0 
Treatment Evaluation 
11.1 
Complete hematologic response (CR) 
Less than 5% blasts in a non-hypocellular marrow with a granulocyte count ≥ 1.0, and a 
platelets count ≥ 100 of with complete resolution of any extramedullary disease and 
absence of peripheral blood blasts. The patient is in sustained CR if they have previously 
achieved a CR and continue to meet the CR criteria (at least 28 days). 
 
CR incomplete (CRi) is called if patient meets all CR criteria except for residual 
neutropenia (ANC<1 x109/L) or thrombocytopenia (platelets<100 x109/L) 
 
11.11 Complete cytogenetic remission (CCyR) 
The absence of chromosome abnormalities (if present at diagnosis) on 
conventional cytogenetic study using G-banding (at least 10 metaphases present). 
 
11.12 Complete molecular remission (CMR) 
The achievement of negative RT-PCR for Kit mutation (if present at diagnosis).  
11.13    MRD: Minimal Residual Disease  
 
Positive PCR for Kit mutation or flow cytometry for Kit overexpression from 
peripheral blood or bone marrow. 
 
11.2 
Morphologic leukemia-free state (MLFS): 
If bone marrow blasts <5%, absence of Auer rods blasts, absence of extramedullary 
disease without hematological recovery. 
 


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11.3 
Partial remission (PR) 
The presence of trilineage hematopoiesis in the bone marrow with recovery of ANC and 
platelet count to above levels, but with 5-25% bone marrow blasts and ≥50% decrease in 
bone marrow blast percentage from baseline. 
 
11.4   No response (NR) 
Failure to achieve a PR, MLFS, CRi, or CR.   
 
11.5 
Relapse: 
Disease recurrence after achieving CR. Disease recurrence is defined by blast ≥5% in the 
bone marrow, or recurrence of peripheral blood blasts or extramedullary involvement.  
 
11.6 
Treatment failure: 
             Resistant disease: Failure to achieve CR or CRi by the end of 2 cycles of induction . 
Note:  These patients will be recorded as an objective status of MLFS, PR, or NR 
to document depth of response but will be considered treatment failures at the 
time of analysis. 
   
Death in aplasia: Death occurring ≥ 7 days following completion of treatment with 
aplastic/hypoplastic bone marrow (obtained within 7 days of death) with no evidence of 
persistent leukemia 
   
 
Death from indeterminate cause: Death occurring during therapy or < 7 days following 
treatment completion, or ≥ 7 days following completion of treatment with no blast in the 
blood but no bone marrow examination available 
 
12.0 
Descriptive Factors  
 
12.1   Bone marrow Kit mutation by PCR at baseline:  positive vs. negative 
 
12.2    Bone marrow transplant candidate:  Yes vs. No. 
 
12.3  
Bone marrow FLT3 mutation:  positive vs. negative vs. not done 
    
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Criteria for Patient Initiation of Event Monitoring: 
 
 
•   Delay > 56 days for the next cycle 
 
•   Disease relapse 
•    Failure to achieve CR or CRi during induction/reinduction 
•   Patient withdraws consent to continue in the trial 
•   Patient develops an intercurrent illness that precludes further participation 
•   The Investigator withdraws the patient in the patient’s best interests 
•   Administrative reasons (e.g., the patient is transferred to hospice care) 
•   An adverse event, which in the opinion of the Investigator, precludes further trial 
participation  
 


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All attempts should be made to complete the End of Study procedures if a patient 
withdraws from the trial early.  The patient will go to the event-monitoring phase per 
Section 18.0. 
 
13.2 
Patients who achieve and sustain a CR or CRi will receive a maximum total of 13 cycles 
or 14 cycles for patients who received re-induction:  
 
If the patient has not achieved a complete response (CR or CRi) after 2 cycles of 
induction treatment, the patient should go to event monitoring 
 
The patient must have a sustained complete response (CR or CRi) after consolidation 
to initiate the maintenance phase; otherwise the patient should go to event monitoring 
 
Patients who complete all cycles of treatment will go to event monitoring 
 
 
13.3      Event monitoring:  Patients who are alive and recurrence-free will be followed in event 
monitoring every 6 months until disease recurrence.   After disease recurrence, the patient 
will be followed in event monitoring every 6 months until death or up to 3 years from 
registration.   
 
13.4 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
 
13.5 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
 
13.6 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 


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14.0 
Body Fluid Biospecimens   
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
 
 
Mandator
y (M) or 
Optional 
(O) 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Screening 
Cycle 1 
Day 4 
(pre-
nilotinib 
treatment, 
30 mins 
pre-
dosing) 
Cycle 1 
Day, 8, 14 
and upon 
bone 
marrow 
recovery(30 
mins pre-
dosing) 
Process at 
site? (Yes 
or No) 
Temperature 
 Conditions for 
Storage 
/Shipping  
Serum 
nilotinib level-
See sect. 14.31 
M 
Blood 
Serum 
Separator 
VacutainerTM 
tube (SST) 
3 ml 
 
yes 
yes1 
yes 
Stored frozen at 
or below -20 C 
until shipped. 
Correlative 
studies - See 
sect. 14.32 
M 
Blood 
BD 
Vacutainer 
EDTA 10ml 
366643 
30-40 ml 
in total 
yes 
yes 
yes 
no 
Ship right away 
away (ice bags 
+4C)  or pick up, 
room temperature 
Correlative 
studies - See 
sect. 14.32 
M 
Bone 
marrow 
aspirate 
BD 
Vacutainer 
EDTA 10ml 
366643 
20-30 ml 
in total 
yes 
 
yes2 
no 
Ship right away 
away (ice bags 
+4C)  or pick up, 
room temperature 
Biomarker-Kit 
mutation-- See 
sect. 14.33 
M 
Bone 
marrow 
aspirate 
BD 
Vacutainer 
EDTA 
3 ml 
minimum 
yes 
no 
no 
no 
Pick up, room 
temperature 
 
1. Days 4, 8 and 14 only, pre-nilotinib treatment. (30 mins pre-dosing)  
2. Day 14 and upon bone marrow recovery only 


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When possible, samples should be obtained prior to the nilotinib dose. The exact time since the last dose 
should be documented. For the correlative studies, blood samples should be collected at screening, pre-
treatment (day 4), day 8 day 14) and upon marrow recovery. For the correlative studies, bone marrow 
aspirate samples should be collected at screening, day 14, and day upon marrow recovery. 
 
 
 
14.2  
Collection and Processing  
 
14.21 Serum Nilotinib level (PK study) 
 
For the determination of nilotinib concentrations, 3 mL of whole blood will be 
drawn at each time point using a Serum Separator (SST) VacutainerTM tube. 
The tube will be placed vertically (avoiding prolonged contact with the rubber 
stopper) for about 30 minutes at room temperature and will then be centrifuged at 
about 5 ºC for 10 minutes at approximately 1100 x g. This should be done within 
60 minutes of drawing the sample. Immediately after centrifugation, the upper 
serum sample (about 1.5 mL) will be transferred into a 2-mL, tapered, 
polypropylene screw-cap tube and stored frozen at ≤ -20 ºC until shipped (on 
dry-ice) to the analytical site for sample analyses. 
Document the time since last nilotinib dose on the sample tube. 
 
14.22    Correlative studies: Compare the pre-treatment with post-treatment samples for 
the alteration of nilotinib’s direct and potential-indirect targets: 
             1) Manley et al (2010) demonstrated that nilotinib has inhibitory effect 
on c-Kit, the direct measurement of c-Kit kinase activities by Western 
blot, will be performed, including c-Kit phosphorylation, and its 
downstream effectors (e.g. AKT, ERK, STAT5); 
 
             2) Because the target patients are c-Kit overexpression that critically 
drives leukemogenesis (Liu et al, 2010), the expression of c-Kit mRNA 
and total protein will be examined by PCR and Western blot; 
 
             3) We demonstrated that c-Kit gene is regulated by Sp1 (Liu et al, 2010), 
therefore, Sp1 expression will be measured by PCR and Western blot; 
 
             4) Since Sp1 is also a positive regulator of DNA methyltransferases 
(DNMT1, DNMT3a and DNMT3b), the expression of DNMTs will be 
investigated;  
 
             5) If the results from “4)” are positive, the global DNA methylation will 
be studied, since DNA methylation is under control of DNMTs; 
 






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14.44 Characterization of Sp1/microRNA (miR) 29b network by PCR or western blot, 
because our previous report showed that Sp1/miR29b network regulates both 
DNMT and KIT (Liu et al, Blood, 2008; Garzon and Liu et al, Blood, 2009; Liu 
et al, Cancer Cell, 2010).  
 
15.0 
Drug Information 
 
15.1 
Nilotinib (Tasigna®, AMN107) 
 
 
Note: As per Nilotinib IB Edition 13 
 
15.11 Background: Nilotinib is a protein tyrosine kinase (TK) inhibitor, which 
selectively inhibits the kinase activity of ABL and BCR-ABL, the sterile alpha 
motif and leucine zipper containing kinase (ZAK), the platelet-derived growth 
factor receptor (PDGFR), the stem cell factor receptor (KIT), the colony 
stimulating factor receptor (CSF-1R), the discoidin domain receptors (DDR) and 
of several ephrin receptors (e.g. EPHB4), and blocks the downstream cellular 
events mediated by these enzymes. 
 
 
Nilotinib is currently approved for the treatment of adult patients with 
Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in 
chronic phase (CP) and accelerated phase (AP) resistant to or intolerant to at least 
one prior therapy including imatinib and for the treatment of adult patients with 
newly diagnosed Ph+ CML in CP. 
 
 
Age is not expected to have an effect on the PK in the age range of 15-85 years.  
In the pediatric population (age 1 to < 18 years), PK exposure in pediatric 
patients dosed at 230 mg/m2 twice daily was comparable to the reference data for 
nilotinib 400 mg BID in adult Ph+ CML patients.  No significant effect of 
ethnicity and gender on dose-adjusted exposure of nilotinib was observed.  
Following multiple oral doses of nilotinib, steady state concentrations were 
achieved as early as Cycle 1 Day 8 across the disease cohorts and age groups (2 
to 12 years, 12 to <18 years). The exposure of nilotinib after single dose/multiple 
doses was comparable across the disease cohorts, within the respective age 
groups.  In addition, a flat exposure-response relationship was observed for 
efficacy (BCRABL/ABL% ratio and MMR) and incidence of adverse events 
(adverse events of special interest and/or hepatic abnormalities). This would 
suggest that the PK fluctuations at the dose of 230 mg/m2 bid in the age range of 
1-18 years would be too small to affect response and, therefore, that dose and 
dosage regimen is appropriate. With regards to QT prolongation, QTcF and 
QTcB prolongation potential was observed with increasing exposure levels and at 
the median observed exposure for 230 mg/m2 bid. No significant exposure-
related changes were observed in the ECG parameters PR, QRS, and heart rate. 
This is consistent with the already well known safety profile of adult patients 
treated with nilotinib. 
 
15.12 Formulation: The drug product is formulated as an immediate release (IR) solid 
oral dosage form (hard capsule). The HGCs contain the active drug substance 
nilotinib as the hydrochloride monohydrate salt at dosage strengths of 50 mg, 150 
mg and 200 mg. The 150 mg and 200 mg capsules strengths are currently 


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approved and marketed. Dosage strengths correspond to the free base. The 
inactive ingredients are colloidal silicon dioxide (silica, colloidal anhydrous), 
crospovidone, lactose monohydrate, magnesium stearate, and poloxamer. 
 
15.13 Preparation and storage:  Do not store nilotinib capsules above 30°C (86°F).   
 
15.14 Administration:  Nilotinib should be taken twice daily approximately 12 hours 
apart and must not be taken with food. The capsules should be swallowed whole 
with water. For patients who are unable to swallow capsules, the content of each 
capsule may be dispersed in one teaspoon of applesauce (pureed apple) and 
should be taken immediately.  Not more than one teaspoon of applesauce and no 
food other than applesauce must be used. Food increases blood levels of 
nilotinib. No food should be consumed for 2 hours before the dose is taken and 
no food should be consumed for at least one hour after the dose is taken. Due to 
possible occurrence of tumor lysis syndrome (TLS), correction of clinically 
significant dehydration and treatment of high uric acid levels are recommended 
prior to initiating therapy with nilotinib. 
 
 
15.15 Pharmacokinetic information: 
 
a)  Absorption – The extent of nilotinib absorption following oral administration 
of drug was estimated to be approximately 30%.  The bioavailability of nilotinib 
was increased when given with a meal. Compared to the fasted state, the 
systemic exposure (AUC) increased by 82% when the dose was given 30 minutes 
after a high fat meal. 
 
b)  Distribution: The extent of nilotinib binding to human plasma was high 
(98% on average), and independent of concentration tested. 
 
c)  Metabolism: Nilotinib is metabolized in the liver via oxidation and 
hydroxylation pathways, mediated primarily by CYP3A4. Nilotinib was 
identified as the main circulating component in the serum, while none of the 
metabolites was found to contribute significantly to the pharmacological activity 
of nilotinib.  
Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib.  A 
lower starting dose is recommended for patients with mild to severe hepatic 
impairment (at baseline) and QT interval should be monitored closely. 
 
d)  Excretion – Primarily as metabolites: Feces (93%; 69% as unchanged drug).  
The average elimination half-life of nilotinib is 17 hours.  Steady state conditions 
were achieved by Day 8. 
 
 
15.16 Potential Drug Interactions:   
 
Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 
and UGT1A1 in vitro, potentially increasing the concentrations of drugs 
eliminated by these enzymes. In vitro studies also suggest that nilotinib may 
induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of 
drugs which are eliminated by these enzymes.  
 
Single-dose administration of nilotinib with midazolam (a CYP3A4 substrate) to 
healthy subjects increased midazolam exposure by 30%. Single-dose 
administration of nilotinib to healthy subjects did not change the 
pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The 
ability of nilotinib to induce metabolism has not been determined in vivo. 
Exercise caution when co-administering nilotinib with substrates for these 


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Mayo Addendum 9 
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enzymes that have a narrow therapeutic index. 
 
Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of 
strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib 
concentrations significantly. The administration of nilotinib with agents that are 
strong CYP3A4 inhibitors should be avoided. Concomitant use of nilotinib with 
medicinal products and herbal preparations that are potent inducers of CYP3A4 
is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, 
in patients receiving nilotinib, concomitant use of alternative therapeutic agents 
with less potential for CYP3A4 induction should be selected. 
 
Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. 
Drugs such as proton pump inhibitors that inhibit gastric acid secretion to elevate 
the gastric pH may decrease the solubility of nilotinib and reduce its 
bioavailability. Increasing the dose of nilotinib when co-administered with such 
agents is not likely to compensate for the loss of exposure. Since proton pump 
inhibitors affect pH of the upper GI tract for an extended period, separation of 
doses may not eliminate the interaction. The concomitant use of proton pump 
inhibitors with nilotinib is not recommended. When the concurrent use of a H2 
blocker is necessary, it may be administered approximately ten hours before and 
approximately two hours after the dose of nilotinib.  If necessary, an antacid 
(aluminum hydroxide/magnesium hydroxide/simethicone) may be administered 
approximately two hours before or approximately two hours after the dose of 
nilotinib. 
 
Nilotinib inhibits human P-glycoprotein (P-gp).  If nilotinib is administered with 
drugs that inhibit P-gp, increased concentrations of nilotinib are likely, and 
caution should be exercised. 
 
The administration of nilotinib with agents that may prolong the QT interval, 
such as anti-arrhythmic medicines or serotonin receptor antagonists, should be 
avoided. Data suggests nilotinib has the potential to prolong cardiac ventricular 
repolarization (QT interval). This clinically meaningful prolongation of the QT 
interval may also occur when nilotinib is inappropriately taken with food and/or 
strong CYP3A4 inhibitors.  The presence of hypokalemia and hypomagnesemia 
may place patients at risk of developing QT prolongation. 
 
The effects of nilotinib on the pharmacokinetics of valsartan were assessed in a 
healthy volunteer study [CAMN107A2132]. The results showed limited effects 
of nilotinib on valsartan PK which indicates that nilotinib does not inhibit 
OATP1B1 (organic anion transporting polypeptide 1B1) uptake transporter in a 
competitive and time-dependent manner. 
 
There is an ongoing study to evaluate the effects of nilotinib on the 
pharmacokinetics of valsartan in healthy volunteers [CAMN107A2132]. This 
study is intended to provide further clarification about possible nilotinib-
mediated OATP1B1 (organic anion transporting polypeptide 1B1) inhibition. 
 
 
Food Effect: The bioavailability of nilotinib is increased with food. Nilotinib 
must not be taken with food. No food should be taken at least 2 hours before and 
at least one hour after the dose is taken. Grapefruit products and other foods that 


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Mayo Addendum 9 
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are known to inhibit CYP3A4 should be avoided. 
 
 
15.17 Known potential toxicities:  Consult the Investigator’s Brochure for the most 
current and complete information.  
 
Important Safety Information including Boxed WARNING: QT 
PROLONGATION AND SUDDEN DEATHS. Nilotinib prolongs the QT 
interval. Prior to nilotinib administration and periodically, monitor for 
hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to 
monitor the QTc at baseline, seven days after initiation, and periodically 
thereafter, and follow any dose adjustments.  Sudden deaths have been 
reported in patients receiving nilotinib. Do not administer to patients with 
hypokalemia, hypomagnesemia, or long QT syndrome. Avoid use of 
concomitant drugs known to prolong the QT interval and strong CYP3A4 
inhibitors.  Patients should avoid food 2 hours before and 1 hour after 
taking dose.  
 
Patients should be tested for hepatitis B infection before initiating treatment with 
nilotinib, as reactivation of hepatitis B can occur in patients who are chronic 
carriers of this virus and are receiving a BCR-ABL tyrosine kinase inhibitor 
(TKI). Experts in liver should be consulted before treatment is initiated in 
patients with positive hepatitis B serology (including those with active disease) 
and for patients who test positive for hepatitis B infection during treatment. 
Carriers of hepatitis B virus who require treatment with nilotinib should be 
closely monitored for signs and symptoms of active hepatitis B infection such as 
liver injury or progression of liver injury throughout therapy and for several 
months following termination of therapy. 
 
Very Common known potential toxicities, > 10%:   
Central nervous system: Headache 
Dermatologic: Rash (Includes the following PTs: Rash pustular, Genital rash, 
Miliaria, Rash, Rash erythematous, Rash follicular, Rash generalized, Rash 
macular, Rash maculo-papular, Rash papular and Rash pruritic), pruritus, 
alopecia 
Gastrointestinal: Nausea, constipation, diarrhea, vomiting, upper abdominal pain 
General disorders: Fatigue 
Hematologic: Neutropenia, thrombocytopenia, anemia, myelosuppression 
Hepatobiliary: hyperbilirubinemia  
Investigations: ALT increased, AST increased, lipoprotein cholesterol  increased, 
total cholesterol increased, lipase increased, blood triglycerides increased 
Musculoskeletal and connective tissue disorders: Musculoskeletal pain upon 
discontinuation (Including myalgia, pain in extremity, arthralgia, bone pain, 
spinal pain) , myalgia 
Metabolism and nutrition disorders: hypophosphatemia 
Psychiatric disorders: Insomnia 
Respiratory: Cough, oropharyngeal pain, dyspnea 
Vascular disorders: Hypertension 
 
Common known potential toxicities, 1% - 10%:  
Cardiovascular: Angina pectoris, arrhythmia (including atrioventricular block, 
cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), 


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palpitations, electrocardiogram QT prolonged, cardiac murmur  
Dermatologic: Hyperhidrosis, eczema, urticaria, erythema, dermatitis, contusion, 
acne 
Ear and Labyrinth: Vertigo 
Eye disorders: eye hemorrhage, vision impairment, periorbital edema, eye 
pruritus, conjunctivitis, dry eye (including xerophthalmia) 
Gastrointestinal: Abdominal discomfort, abdominal pain, flatulence, abdominal 
distension, pancreatitis, dysgeusia, dyspepsia, gastroesophageal reflux, stomatitis 
General disorders and administrative site conditions: pyrexia, asthenia, peripheral 
edema, facial edema, chest pain or discomfort, pain, malaise, feeling body 
temperature changes (hot or cold) 
Hematologic: Febrile neutropenia, pancytopenia, lymphopenia, eosinophilia, 
leukopenia 
Hepatobiliary: hepatic function abnormal 
Infections and infestations: Folliculitis, upper respiratory infection, 
nasopharyngitis, pharyngitis, rhinitis, pneumonia 
Investigations: Hemoglobin decreased, blood amylase increased, gamma-
glutamyltransferase increased, weight decreased, weight increased, blood 
alkaline phosphatase increased, blood creatine increased, , globulins decreased 
Metabolism and Nutrition: Decreased appetite, electrolyte imbalance (including 
hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, 
hyperphosphatemia, hypomagnesemia), hyperglycemia, diabetes mellitus, 
hyperlipidemia, hypercholesterolemia 
Musculoskeletal: Musculoskeletal chest pain, musculoskeletal pain, neck pain, 
back pain, joint swelling, bone pain, pain in extremities, muscular weakness, 
arthralgia, muscle spasms   
Neoplasms: Skin papilloma 
Nervous system disorders:  dizziness, peripheral neuropathy, hypoesthenia, 
hyperesthesia, paraesthenia, tremor, intracranial hemorrhage 
Psychiatric disorders: depression, insomnia, anxiety 
Renal: Pollakuria, nocturia 
Reproductive system and breast disorders: Gynecomastia 
Respiratory: Epistaxis, oropharyngeal pain, pleural effusion dysphonia, dyspnea 
(and exertional), cough 
Skin and Subcutaneous Tissue Disorders: Dry skin, night sweats, eczema, 
urticaria, erythema, hyperhidrosis, confusion, acne, dermatitis (including allergic, 
exfoliative, and acneiform), skin pain 
Vascular: Flushing, hypertension, peripheral arterial occlusive disease, peripheral 
artery stenosis 
 
Uncommon, Rare, and Very Rare, less than 1% (limited to important or life-
threatening): 
Cardiovascular: Myocardial infarction, pericarditis, ventricular dysfunction, 
ejection fraction decrease, cardiac failure, pericardial effusion, coronary artery 
disease, cyanosis,  
Central nervous system: Confusional state, disorientation, amnesia, dysphoria, 
ischemic stroke, transient ischemic attack, cerebral infarction, cerebrovascular 
accident, migraine, loss of consciousness (including syncope), disturbance in 
attention, hyperesthesia, brain edema, optic neuritis, lethargy, dysesthesia, 
restless legs syndrome 
Dermatologic: Exfoliative rash, drug eruption, swelling face, ecchymosis, 


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psoriasis, erythema multiforme, erythema nodosum, skin ulcer, petechiae, 
photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin 
discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, 
hyperkeratosis, palmar-plantar erythrodysesthesia syndrome 
Endocrine: Hyperthyroidism, hypothyroidism, hyperparathyroidism secondary, 
thyroiditis 
Eye Disorders: vision blurred, visual acuity reduced, eyelid edema, photopsia, 
hyperemia, eye irritation, conjunctival hemorrhage, papilloedema, diplopia, 
photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis 
allergic, ocular surface disease 
Gastrointestinal: Gastrointestinal hemorrhage, melena, mouth ulceration, 
esophageal pain, dry mouth, gastric ulcer, gastrointestinal ulcer perforation, 
retroperitoneal hemorrhage, hematemesis, esophagitis ulcerative, gastritis, 
subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, sensitivity 
of teeth, non-infective gingivitis 
General: Gravitational edema, influenza-like illness, chills, localized edema, face 
edema, fluid retention 
Hematologic: Thrombocythemia, leukocytosis 
Hepatobiliary: Toxic hepatitis, jaundice, cholestasis, hepatotoxicity, 
hepatomegaly 
Immune System: Hypersensitivity 
Infections and infestations: Urinary tract infection, gastroenteritis, sepsis, 
bronchitis, candidiasis, subcutaneous abscess, anal abscess, furuncle, tinea pedis, 
herpes virus infection, hepatitis B reactivation 
Investigations: Blood lactate dehydrogenase increased, blood bilirubin 
unconjugated increased, blood urea increased,  troponin increased, blood insulin 
decreased, blood insulin increased, insulin C-peptide decreased, blood 
parathyroid increased 
Metabolism and Nutrition: Increased appetite, dehydration, hyperuricemia, gout, 
hypoglycemia, dyslipidemia, hypertriglyceridemia 
Musculoskeletal: Musculoskeletal stiffness, arthritis, flank pain 
Neoplasms: Oral papilloma, paraproteinemia 
Otic: Hearing impaired, ear pain, tinnitus 
Renal: Dysuria, micturition urgency, renal failure, hematuria, urinary 
incontinence, chromaturia 
Reproductive System and Breast: Breast pain, erectile dysfunction, breast 
induration, menorrhagia, nipple swelling 
Respiratory: Pharyngolaryngeal pain, interstitial lung disease, pleuritic pain, 
pleurisy, pulmonary edema, throat irritation, pulmonary hypertension, wheezing 
Vascular: Hypertensive crisis, hematoma, shock hemorrhagic, hypotension, 
thrombosis, arteriosclerosis, intermittent claudication, arterial stenosis limb, 
arterial occlusive disease, peripheral ischemia 
 
Other Potential Toxicities: 
 
Pregnancy:  There were reports of congenital anomalies in babies, reports of 
premature babies, and reports of neonatal deaths.  Nilotinib should not be used 
during pregnancy.  Women of childbearing potential should be informed of the 
potential risk to the fetus and must be advised to use highly effective 
contraception during treatment with nilotinib for up to 2 weeks after ending 
treatment.  Patients using an oral hormonal contraception method should 


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complete their monthly treatment course.Lactation:  Excretion of nilotinib in 
breast milk has not been studied in humans, but is excreted in animal breast milk. 
Women should not breast-feed while taking nilotinib, as a risk to the infant 
cannot be excluded. 
 
Ischemic vascular or ischemic cardiovascular events: Newly diagnosed or 
worsened Ischemic Vascular and Ischemic Cardiovascular Events such as 
Ischemic Heart Disease (IHD), Ischemic Cerebrovascular Event (ICVE) or 
Peripheral Artery Occlusive Disease (PAOD) have occurred in a relatively small 
number of CML chronic phase patients treated with nilotinib.  The majority of 
reported events were in patients with associated risks. 
 
15.18 Drug procurement 
Drug will be provided free of charge to study participants by Novartis 
Pharmaceuticals. 
 
15.19 Nursing Guidelines 
 
15.191 
Patients should take nilotinib twice daily approximately 12 hours apart 
on an empty stomach (no food 2 hours prior or 1 hour after a dose) 
with water.  Capsules may be dispersed in one teaspoon of applesauce 
(pureed apple) and should be taken immediately. Do not use more than 
one teaspoon of applesauce and no food other than applesauce must be 
used.  
 
15.192 
Nilotinib is known to prolong the QT interval. Patients with a history 
of long QT syndrome should not receive nilotinib. Sudden death has 
been reported in patients receiving nilotinib. Assess patient’s 
concomitant medications,   for other medications that may prolong the 
QT interval. These medications should be avoided. Patients should 
undergo a baseline and 7 days post initiation ECG to assess the QTc 
and periodically thereafter.  
 
15.193 
Nilotinib is known to have significant drug-drug interactions with 
strong CYP3A4 inducers and should be avoided.  Additionally, caution 
should be used when administered with drugs that inhibit P-
glycoprotien as this can increase the levels of nilotinib. Assess patients 
concomitant medications, over the counter, and herbal supplements, 
avoid those that may interact with nilotinib. 
 
15.194 
Patients should avoid the use of protein pump inhibitors, if absolutely 
necessary, use with caution. If necessary to administer with an H2 
blocker or antacid, doses should be separated from the nilotinib by at 
least 2 hours. 
 
15.195 
May cause headache. Treat symptomatically and monitor for 
effectiveness. 
 
15.196 
Rash and itching may occur. Instruct patients to report rash to study 
team. Treat symptomatically and assess for effectiveness. 
 


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15.197 
GI disturbances are common (nausea, constipation, diarrhea, 
vomiting).  Assess patients for need of premedication prior to nilotinib 
and/or treat symptomatically and monitor for effectiveness. 
 
15.198 
Monitor electrolytes (especially potassium and magnesium).  Do not 
administer nilotinib to patients with hypokalemia and/or 
hypomagnesemia. These electrolyte disturbances should be corrected 
prior to initiating therapy and monitored periodically. 
 
15.199a Monitor LFT’s. Patients with elevated LFT’s may need dose   
reductions.  
 
15.199b Monitor CBC. Cytopenias are common. Instruct patient to report any 
signs or symptoms of infection, unusual bruising or bleeding to the 
study team. 
 
15.199c Instruct patient to report any rash to the study team.  
 
15.199d Headache is commonly seen. Treat patient symptomatically and 
monitor for effectiveness. 
15.199e Monitor for eye disorders (hemorrhage, periorbital edema, itching, 
conjunctivitis and dryness). Instruct patients to report these symptoms 
to study team. Refer to Ophthalmology as necessary.  
15.199f Hypertension can be seen. 
15.199g Patients should undergo testing for Hepatitis B, as a reactivation of 
Hepatitis B can occur.  
15.999h Tumor lysis syndrome can occur, correction of clinically significant 
dehydration and treatment of high uric acid levels should occur prior to 
initiation of therapy. 
 
15.2 
Daunorubicin  
 
15.21 Background: Daunorubicin inhibits DNA and RNA synthesis by intercalation 
between DNA base pairs and by steric obstruction. Daunorubicin intercalates at 
points of local uncoiling of the double helix. Although the exact mechanism is 
unclear, it appears that direct binding to DNA (intercalation) and inhibition of 
DNA repair (topoisomerase II inhibition) result in blockade of DNA and RNA 
synthesis and fragmentation of DNA. 
 
15.22 Formulation: Commercially available for injection as:  
 
Injection, powder for reconstitution: 20 mg 
 
Injection, solution: 5 mg/mL (4 mL, 10 mL) 
 
15.23 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store intact vials of powder for injection 
at room temperature of 15°C to 30°C (59°F to 86°F); intact vials of solution for 
injection should be refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. 
Dilute vials of powder for injection with 4 mL SWFI for a final concentration of 
5  mg/mL. May further dilute in 100 mL D5W or NS. Reconstituted solution is 


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stable for 4 days at 15°C to 25°C. Further dilution in D5W, LR, or NS is stable at 
room temperature (25°C) for up to 4 weeks protected from light. 
 
15.24 Administration:  Refer to the treatment section for specific administration 
instructions. Daunorubicin is not for I.M. or SubQ administration. Administer as 
a slow I.V. push over 1-5 minutes into the tubing of a rapidly infusion I.V. 
solution of D5W or NS or dilute in 100 mL of D5W or NS and infuse over 15-30 
minutes. 
 
15.25 Pharmacokinetic information: 
Distribution: Vd: 40 L/kg; to many body tissues, particularly liver, spleen, 
kidney, lung, heart; does not distribute into the CNS; crosses placenta 
Protein binding, plasma: 70% to 76% 
Metabolism: Primarily hepatic to Daunorubicinol (active), then to inactive 
aglycones, conjugated sulfates, and glucuronides 
Half-life elimination:  
 
Distribution: 2 minutes 
 
Elimination: 14-20 hours 
 
Terminal: 18.5 hours 
 
Daunorubicinol plasma half-life: 24-48 hours 
Excretion: Feces (~40%); urine (~25% as unchanged drug and metabolites) 
 
 
15.26 Potential Drug Interactions: 
Avoid Concomitant Use of Daunorubicin with any of the following: BCG; 
Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vaccines (Live). 
Increased Effect: Daunorubicin may increase the levels/effects of: Leflunomide; 
Natalizumab; Vaccines (Live).  
 
The levels/effects of Daunorubicin may be increased by: Bevacizumab; 
Denosumab; P-Glycoprotein inhibitors; Pimecrolimus; Tacrolimus (Topical); 
Taxane Derivatives; Trastuzumab 
 
Decreased Effect: Daunorubicin may decrease the levels/effects of: BCG; 
Cardiac Glycosides; Sipuleucel-T; Vaccines (Inactivated); Vaccines (Live) 
 
The levels/effects of Daunorubicin may be decreased by: Cardiac Glycosides; 
Echinacea; P-Glycoprotein Inducers 
 
Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (Due to GI irritation). 
 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, > 10%:   
Cardiovascular: Transient ECG abnormalities (supraventricular tachycardia, S-T 
wave changes, atrial or ventricular extrasystoles); generally asymptomatic and 
self-limiting. CHF, dose related, may be delayed for 7-8 years after treatment. 
Dermatologic: Alopecia (reversible), radiation recall 
Gastrointestinal: Nausea, vomiting, stomatitis 
Genitourinary: Discoloration of urine (red) 
Hematologic: Leukopenia, thrombocytopenia, anemia 


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Less common known potential toxicities, 1% - 10%:  
Dermatologic: Skin “flare” at injection site; discoloration of saliva, sweat, or 
tears 
Endocrine & metabolic: Hyperuricemia  
Gastrointestinal: Abdominal pain, GI ulceration, diarrhea  
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Anaphylactoid reaction, bilirubin increased, hepatitis, infertility, cellulitis, pain at 
injection site, thrombophlebitis at injection site, MI, myocarditis, nail banding, 
onycholysis, pericarditis, pigmentation of nailbeds, secondary leukemia, skin 
rash, sterility, systemic hypersensitivity (including urticaria, pruritus,  
angioedema, dysphagia, dyspnea); transaminases increased. 
 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
15.29 Nursing Guidelines:  
 
15.291 
Drug is a potent vesicant. Establish patency of IV before    and 
frequently during administration as to avoid extravasation. If drug is 
being administered IV push administer through side port of rapidly 
running IV solution.  If suitable vein cannot be used, central venous 
access may become necessary. Discuss with treating MD. If 
extravasation occurs treat per your institution’s policy. 
 
15.292 
Drug is not compatible with heparin. Be sure to flush heparin locked 
IV’s or central lines before administering agent. 
 
15.293 
Moderate to severe nausea occurs in up to 50% of patient within first 
24 hours. Administer antiemetics as ordered and assess for their 
effectiveness. 
 
15.294 
Inform patient about alopecia 
 
15.295 
Potent myelosuppressive agent. Monitor CBC closely. Inform patient 
to report any signs or symptoms of infection, or unusual bruising or 
bleeding. 
 
15.296 
Drug is cardiotoxic.  Dose limit at 550mg/m2.  Monitor for signs of 
acute cardiac toxicity, which is possible within hours after 
administration. This is unrelated to cumulative dose and may manifest 
symptoms of pump or conduction dysfunction.  Watch for signs or 
symptoms of CHF, pericardial effusion, and transient ECG 
abnormalities.  
 
15.297 
Monitor liver function tests. Dose reduction is necessary in patients 
with impaired liver function. 
 
15.298 
Radiation recall is a possibility with this drug. Monitor patient’s skin at 


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site of previous irradiation for damage. 
 
15.299 
Inform patient that urine may be pink or red for up to 48 hours after 
administration. 
 
15.3 
Cytarabine (Cytosar, ARAC) 
 
15.31 Background: Cytarabine (cytosine arabinoside) inhibits DNA synthesis. 
Cytosine gains entry into cells by a carrier process, and then must be converted to 
its active compound, aracytidine triphosphate. Cytosine is a pyrimidine analog 
and is incorporated into DNA; however, the primary action is inhibition of DNA 
polymerase resulting in decreased DNA synthesis and repair. Cytarabine is 
specific for the S phase of the cell cycle (blocks progression from the G1 to the S 
phase). 
 
15.32 Formulation: Commercially available for injection, powder for reconstitution: 
100 mg, 500 mg, 1 gram, 2 gram 
 
15.33 Preparation, storage, and stability: Store intact vials of powder at room 
temperature 15ºC to 30ºC (59ºF to 86ºF). Reconstitute with bacteriostatic 
water for injection. Reconstituted solutions are stable for up to 8 days at 
room temperature, although the manufacturer recommends use within 48 
hours. Further dilution in 250-1000 mL of D5W or 0.9% NaCL is stable 
for 8 days at room temperature (25C). Note: Solutions containing 
bacteriostatic agents should not be used for the preparation of either high 
doses or intrathecal doses of cytarabine. 
 
15.34 Administration:  Refer to the drug treatment section of the protocol for specific 
administration directions and infusion rates.  
15.35   Pharmacokinetic information: 
Distribution: Vd: Total body water; widely and rapidly since it enters the 
cells readily; crosses blood-brain barrier with CSF levels of 40% to 50% of 
plasma level 
Metabolism: Primarily hepatic; metabolized by deoxycytidine kinase and 
other nucleotide kinases to aracytidine triphosphate (active); about 86% to 
96% of dose is metabolized to inactive uracil arabinoside. 
Half-life elimination: I.V.: Initial: 7-20 minutes; Terminal: 1-3 hours. 
Excretion: Urine (~80%) within 24 hours 
 
 
15.36 Potential Drug Interactions:   
Decreased Effect: Cytarabine may decrease the effect of Flucytosine; cytarabine 
may decrease digoxin absorption. 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Warnings/Precautions: Potent Myelosuppressive agent 
Common known potential toxicities, frequency not defined:   
Central nervous system: Fever 
Dermatologic: Rash 
Gastrointestinal: Anal inflammation, anal ulceration, anorexia, diarrhea, 
mucositis, nausea, vomiting 


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Hematologic: Myelosuppression, neutropenia, anemia, thrombocytopenia, 
bleeding, leukopenia, megaloblastosis, reticulocytes decreased 
Hepatic: Hepatic dysfunction, transaminases increased (acute) 
Local: Thrombophlebitis 
 
Less common known potential toxicities:  
Cardiovascular: Chest pain, pericarditis 
Central nervous system: Dizziness, headache, neural toxicity, neuritis 
Dermatologic: Alopecia, pruritus, skin freckling, skin ulceration, urticaria 
Gastrointestinal: Abdominal pain, bowel necrosis, esophageal ulceration, 
esophagitis, pancreatitis, sore throat 
Genitourinary: Urinary retention 
Hepatic: Jaundice 
Local: Injection site cellulitis 
Ocular: Conjunctivitis 
Renal: Renal dysfunction 
Respiratory: Dyspnea 
Miscellaneous: Allergic edema, anaphylaxis, sepsis 
 
Infrequent and/or case reports: 
Amylase increased, aseptic meningitis, cardiopulmonary arrest (acute), cerebral 
dysfunction, cytarabine syndrome (bone pain, chest pain, conjunctivitis, fever, 
maculopapular rash, malaise, myalgia); exanthematous pustulosis, 
hyperuricemia, injection site inflammation (SubQ injection), injection site pain 
(SubQ injection), interstitial pneumonitis, lipase increased, paralysis, 
rhabdomyolysis, veno-occlusive liver disease 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.39 Nursing Guidelines:  
 
15.391 Can be a potent myelosuppressive agent. Monitor CBC closely. Anemia, 
leukopenia, and thrombocytopenia are expected. Nadir within 5-7 days 
with recovery expected in 2-3 weeks. Hematological toxicity is more 
intense if ARA-C is given as a continuous IV infusion versus an IV 
bolus. 
 
15.392 Nausea and vomiting is dose-related, common, and often preventable 
with antiemetic drugs. Administer as ordered and assess for their 
effectiveness. 
 
15.393 Instruct patient of possibility of metallic taste.  The use of sugarless hard 
candies may lessen this effect. 
 
15.394 Stomatitis is possible.  Instruct patient not to swallow. 
 
15.395 May cause pancreatitis or peritonitis. Instruct patient to report any severe 
or worsening abdominal pain immediately. 
 
15.396 Monitor LFT’s-elevations of LFT’s may occur. 


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15.397 Cerebellar toxicity can occur in 16-40% of patients with more severe 
symptoms at higher doses. Monitor for these toxicities with each dose of 
ARA-C. Signs and symptoms of cerebellar toxicity can include: lethargy 
with progressive confusion, ataxia, nystagmus, slurred speech. Report 
any of these or other neurological changes to the MD immediately. 
 
15.398 Instruct patient to report any shortness of breath or difficulty breathing as 
this may be a sign of a rare but life threatening pulmonary complication. 
 
15.399a Monitor for signs of conjunctivitis and/or keratitis.  This is usually 
prevented with prophylactic glucocorticoid eye drops. 
 
15.399b Assess for skin rash. This may present itself as a erythema without 
exfoliation, or a generalized rash. Report to MD. 
 
15.399c Monitor for “ARA-C” syndrome. This is characterized by bone and 
muscle pain, chest pain, fever, general weakness, reddened eyes, and 
skin rash. Report these to the MD, as patient may need to be treated with 
corticosteroids. 
 
16.0 
Statistical Considerations and Methodology  
16.1 
Overview 
This is a phase II study of a combination of Nilotinib, cytarabine, and daunorubicin in 
patients with newly diagnosed AML with Kit overexpression.   This study will use a one-
stage design with an interim analysis to assess the efficacy of this combination.   
 
16.11 
Endpoint:   The primary endpoint in this trial is the proportion of complete 
responses during induction therapy.  A success is defined as a CR or CRi as the 
objective status during induction therapy.  Throughout Section 16.0, complete 
response will be considered synonymous with “success”, unless specified 
otherwise.  All patients meeting the eligibility criteria who have signed a consent 
form and have begun treatment will be evaluable for response. 
 
16.2  
Statistical Design: 
 
16.21 Decision Rule:   
 
In a previous phase 3 randomized study including 582 patients with previously 
untreated AML who were treated with induction therapy of daunorubin combined 
with cytarabine, 64% of patients received a complete response (Fernandez et al, 
2009).  More specifically, the complete response rate was 57% in 293 patients 
treated at the standard dose (45 mg/m2) of daunorubicin and 71% in 289 patients 
treated at a higher dose (90 mg/m2) of daunorubicin.  This study will include 
patients with previously untreated AML who will be treated with induction 
therapy of 60 mg/m2 daunorubicin combined with cytarabine and the addition of 
nilotinib.  It is expected that a dose of 60 mg/m2 daunorubicin combined with 
cytarabine will have a complete response rate similar to the higher dose group of 
the previous phase 3 study.  However, that study included only patients between 
17 and 60 years of age, while the median age at diagnosis of AML is 
approximately 57 years.  This study will include patients of all ages and thus a 


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lower rate of complete response is expected.  Therefore, a complete response rate 
of 60% is a reasonable estimate for 60 mg/m2 daunorubicin combined with 
cytarabine in the population that will be accrued to this study.  The addition of 
nilotinib to this combination is anticipated to increase the complete response rate.   
 
This study will include only patients with Kit overexpression.  Studies looking at 
the effect of Kit overexpression on complete response rate have not yet been 
conducted.  If there is any new evidence showing an effect of Kit overexpression 
on complete response rate for previously untreated AML patients treated with 
daunorubicin plus cytarabine, it will be taken into consideration when evaluating 
the efficacy of this regimen.    
 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 60%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 80%.  A one-stage design with an interim analysis based 
on a Simon optimum design uses 39 evaluable patients to test the null hypothesis 
that the true complete response rate is at most 60%.   
 
16.211     Interim Analysis:  Enter 18 evaluable patients into the study.  If 11 or 
fewer successes are observed in the first 18 evaluable patients, we will 
consider this regimen ineffective in this patient population and 
terminate this study.  Otherwise, if the number of successes is at least 
12, we will continue accrual. 
 
16.212     Final Decision Rule:  If 27 or fewer successes are observed in the first 
39 evaluable patients, we will consider this regimen ineffective in this 
patient population. If 28 or more successes are observed in the first 39 
evaluable patients, we may recommend further testing of this regimen 
in subsequent studies in this population. 
 
16.213     Over Accrual: If more than the target number of patients are accrued, 
the additional patients will not be used to evaluate the stopping rule or 
used in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.34. 
 
16.214     NOTE: We will not suspend accrual at the interim analysis to allow the 
first 18 patients to become evaluable, unless undue toxicity is 
observed. Given the limited overall sample size and the inclusion of an 
adverse events stopping rule, we feel it is ethical to not halt accrual for 
the interim analysis. However, if accrual is extremely rapid, we may 
temporarily suspend accrual in order to obtain safety data on these 
patients before re-opening accrual to further patients. 
 
16.22 
Sample Size:  This study is expected to require a minimum of 18 and a maximum 
of 39 evaluable patients. We anticipate accruing 4 additional patients to account 
for ineligibility, cancellation, major treatment violation, or other reasons.  
Therefore, the study is expected to accrue a maximum of 43 patients overall. 
 
16.23 
Accrual Rate and Study Duration:  The anticipated accrual rate is 1-2 evaluable 
patients per month.  Therefore, the accrual period is expected to be 2 years.  The 


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primary endpoint will be evaluated approximately 2.5 years after the trial opens, 
or after the last patient accrued has been observed for at least 2 months and data 
collection for the induction phase is complete.  The total study duration is 
expected to be approximately 4.5 years, or until all patients have completed all 
cycles of treatment.   
 
16.24 Power and Significance Level:  Assuming that the number of successes is 
binomially distributed, the significance level is .08, i.e. there is an 8% chance of 
finding the drug to be effective when it truly is not.  The probability of declaring 
that this regimen warrants further study (i.e. statistical power) under various 
success proportions and the probability of stopping accrual after the interim 
analysis can be tabulated as a function of the true success proportion as shown in 
the following table. 
 
If the true success proportion is... 
0.60 
0.65 
0.70 
0.75 
0.80 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.08 
0.22 
0.45 
0.71 
0.90 
and the probability of stopping after 
the interim analysis is … 
0.63 
0.45 
0.28 
0.14 
0.05 
 
16.25 Other considerations:  Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study 
 
16.3 
Analysis Plan 
 
16.31 Primary Outcome Analyses: 
 
16.311 Definition:  The primary endpoint of this trial is the proportion of 
complete responses to induction therapy.  A success is defined as a CR or 
CRi as the objective status during induction therapy. All patients meeting 
the eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for response.   
 
16.312 Estimation:  The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. 
Confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner (Duffy D 1987). 
 
16.32 Secondary Outcome Analyses:  These analyses will include all patients meeting 
the eligibility criteria who have signed a consent form and have begun treatment, 
including patients who fail to achieve a complete response after 2 cycles of 
treatment (unless noted otherwise). 
 
16.321 Overall survival time is defined as the time from registration to death 
due to any cause. The distribution of survival time will be estimated 
using the method of Kaplan-Meier(Kaplan E 1958).  In addition, the 
overall survival rate at 2 years after registration will be reported. 
 


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16.322   Disease free survival time is defined for all evaluable patients who have 
achieved a CR or CRi as the time from registration to relapse or death 
due to any cause.  The distribution of disease-free survival will be 
estimated using the method of Kaplan-Meier.  In addition, the disease-
free survival rate at 2 years after registration will be reported. 
 
16.323  Duration of complete response is defined for all evaluable patients who 
have achieved a CR or CRi as the date at which the patient’s objective 
status is first noted to be a CR or CRi to the earliest date relapse is 
documented. The distribution of duration of complete response will be 
estimated using the method of Kaplan-Meier 
 
16.324 Adverse Events:  All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s).  The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns.  
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
 
16.33  Correlative Analyses 
 
16.331  Prognostic and predictive factors including age, Kit mutation/expression, 
Flt3 mutation and whether the patient received a transplant will be 
assessed.  These factors will be summarized and used to help 
characterize the types of patients accrued to this trial. In addition, we will 
explore differences in the distributions of these risk factors by clinical 
outcome (disease-free survival status at 2 years and whether the patient 
remains in sustained CR). Nonparametric quantitative comparisons by 
group will be made as appropriate (Fisher’s exact or Wilcoxon rank 
sum).  Kaplan-Meier methods and log-rank statistics will be used to 
compare between groups for time-to-event measures.  Given the limited 
number of patients, the difference in risk factor distribution by outcome 
will be largely exploratory. 
 
16.332  In patients who are Kit mutation positive at diagnosis and achieve a 
complete molecular remission (i.e. negative RT-PCR for Kit mutation) to 
treatment, the Kit mutation status (positive vs. negative) will be 
reassessed at time of relapse.   Due to the small number of patients that 
are expected to be in this subgroup, this analysis will be primarily 
descriptive in nature. 
 
16.333  MRD will be assessed by PCR or flow cytometry at the end of each 
phase of treatment (induction, consolidation, and maintenance) and at 
time of relapse.  MRD status will be correlated with response using 
Fisher’s exact test.  In addition, the relationship between MRD status 
(positive vs. negative) and disease-free survival will be evaluated using 
landmark analyses. 
 
16.34 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 


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decision making processes; however, they will be included in final endpoint 
estimates and confidence intervals. 
 
16.4 
Data & Safety Monitoring: 
 
16.41 The principle investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
 
16.42 Adverse Event Stopping Rules:   The stopping rules specified below are based on 
the knowledge available at study development.  We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation.  The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as  “possible,” “probable,” or “definite”) that 
satisfy one of the following: 
 
• 
if 4 or more patients in the first 12 treated patients experience a grade 4 or 
higher non-hematologic adverse event at least possibly related to treatment 
excluding infections and hypophosphatamia, hypocalcemia, hypo- or 
hyperkalemia, hyperuricemia as these abnormal lab results tend to resolve 
quickly (≤7 days) without affecting or jeopardizing patient safety. 
 
• 
if after the first 12 patients have been treated, 30% of all patients experience 
a grade 4 or higher non-hematologic adverse event at least possibly related to 
treatment excluding infections and hypophosphatamia, hypocalcemia, hypo- 
or hyperkalemia, hyperuricemia as these abnormal lab results tend to resolve 
quickly (≤7 days) without affecting or jeopardizing patient safety.  
 
Grade 4 electrolyte abnormalities will be excluded only if the study PI has 
determined that they are not associated with any clinically significant events. 
 
Note:  Stem cell transplant will not be considered part of protocol treatment and 
attribution refers to the relationship to Cytarabine, Daunorubicin or Nilotinib (not 
Stem Cell Transplant). Adverse events are not recorded during Stem Cell 
Transplant (see section 10.0). 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 


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16.5   Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
along with other required information for this study will be reported on 
ClinicalTrials.gov. For purposes of timing of the Results Reporting, the initial estimated 
completion date for the Primary Endpoint of this study is 2.5 years after the study opens 
to accrual. The definition of “Primary Endpoint Completion Date” (PECD) for this study 
is at the time the last patient registered has been followed for at least 2 months. 
 
16.6 
Inclusion of Women and Minorities 
 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.62 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
 
16.63 The geographical region served by MCCC has a population which includes 
approximately 3% minorities.  Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 30% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 


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Accrual Estimates by Gender/Ethnicity/Race  
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
13 
29 
0 
42 
Ethnic Category: Total of all subjects* 
13 
30 
0 
43 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
12 
29 
0 
41 
Racial Category: Total of all subjects* 
13 
30 
0 
43 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial groups 
of Africa.  Terms such as “Haitian” or “Negro” can be used in addition to “Black or 
African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
17.0 
Pathology Considerations/Tissue Biospecimens: None.   
 
 


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18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
 
Initial Material(s) 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study Form 
 
 
≤2 weeks after registration 
Baseline Adverse Event Form 
Baseline Research Blood Submission Form 
Baseline Research Bone Marrow Submission 
Form 
Pretreatment Measurement and Bone 
Marrow  Biopsy Form 
Bone Marrow Biopsy and Aspirate Report 
including the Kit expression by flow 
cytometry, Kit mutation by PCR, and 
cytogenetics 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
 
At each evaluation 
during treatment 
At end of treatment 
 
Evaluation/Treatment Form 
X3 
X3 
Nadir/Adverse Event Form 
X4 
X 
Active Monitoring Measurement and Disease 
Response Form 
X 
X 
Bone Marrow Biopsy and Aspirate Report 
including the Kit expression by flow cytometry, 
Kit mutation by PCR, and cytogenetics 
X 
X 
Research Blood Submission Form 
X1  
 
Research Bone Marrow Submission Form 
X1 
 
Stem Cell Transplant Form 
X2 
 
End of Active Treatment/Cancel Notification 
Form 
 
X 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
1.  Only when required by the Test Schedule (see Section 4.0 and 14.0). 
 
 


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2. Submit only once if a patient receives a transplant.  The SCT (pre-transplant conditioning 
chemotherapy plus stem cell infusion) until the start of maintenance will be defined as a separate 
cycle, where the stem cell transplant form will be used instead of the evaluation/treatment form 
for that cycle. 
3. Only for cycles where the patient is receiving Nilotinib (NOT a Stem Cell Transplant). 
4. Not collected during Stem Cell Transplant 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
 
 
q. 6 
months 
until PD2 
 
 
 
At PD2 
 
After 
PD q. 6 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring Form 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the MCCC Operations Office, Attention: 
QAS for MC1284. 
 
 
19.0  
Budget 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
19.2 
Tests to be research funded: Study drug, Magnesium, Amylase, and Lipase test, 
Urinalysis, ECGs Bone marrow (BM) sampling at the end of maintenance . Bone marrow 
MRD assessment for CD117/Kit by flow cytometry at end of maintenance.  Bone marrow 
MRD assessment for Kit mutation by PCR (if positive at diagnosis) at screening , upon 
recovery of Cycle 1, upon bone marrow recovery of Cycle 2 if patient receives re-
induction,  Day 1 of cycle 1 of maintenance , end of maintenance, and upon relapse.  
 
19.3 
Other budget concerns: Protocol administration, data management and statistical analysis 
efforts will be by funded by Novartis. 
 
20.0 
References 
 
(Last accessed May 27, 2011. ). "Cancer Facts and Figures 2010. Atlanta, Ga: American Cancer Society, 
2010. ." American Cancer Society. 
 
Advani, A. S., C. Rodriguez, et al. (2008). "Increased C-kit intensity is a poor prognostic factor for 
progression-free and overall survival in patients with newly diagnosed AML." Leukemia research 
32(6): 913-918. 
 
Bloomfield, C. D., D. Lawrence, et al. (1998). "Frequency of prolonged remission duration after high-
dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype." Cancer 
research 58(18): 4173-4179. 
 
 


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Brandwein, J. M., D. W. Hedley, et al. (2011). "A phase I/II study of imatinib plus reinduction therapy for 
c-kit-positive relapsed/refractory acute myeloid leukemia: inhibition of Akt activation correlates 
with complete response." Leukemia : official journal of the Leukemia Society of America, 
Leukemia Research Fund, U.K. 
 
Buchdunger E, Matter A, Druker BJ (2001) Bcr-Abl inhibition as a modality of CML therapeutics. 
Biochim Biophys Acta; 1551:M11-M18. 
 
Burnett, A., M. Wetzler, et al. (2011). "Therapeutic advances in acute myeloid leukemia." Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 29(5): 487-494. 
 
Byrd, J. C., K. Mrozek, et al. (2002). "Pretreatment cytogenetic abnormalities are predictive of induction 
success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute 
myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)." Blood 100(13): 
4325-4336. 
 
Cortes, J., P. Rousselot, et al. (2007). "Dasatinib induces complete hematologic and cytogenetic responses 
in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis." Blood 
109(8): 3207-3213. 
 
Cowan-Jacob SW, Guez V, Fendrich G (2004) Imatinib (STI571) resistance in chronic myelogenous 
leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. 
Mini Rev Med Chem; 4(3):285-299. 
 
Davies, A., N. E. Jordanides, et al. (2009). "Nilotinib concentration in cell lines and primary CD34(+) 
chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug 
transporters." Leukemia 23(11): 1999-2006. 
 
Deininger MWN, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia. 
Blood; 96:3343-3356. 
 
Del Poeta, G., A. Venditti, et al. (2003). "Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio 
predicts outcome in acute myeloid leukemia (AML)." Blood 101(6): 2125-2131. 
 
Dohner, H., E. H. Estey, et al. (2010). "Diagnosis and management of acute myeloid leukemia in adults: 
recommendations from an international expert panel, on behalf of the European LeukemiaNet." 
Blood 115(3): 453-474. 
 
Domen, J. and I. L. Weissman (2000). "Hematopoietic stem cells need two signals to prevent apoptosis; 
BCL-2 can provide one of these, Kitl/c-Kit signaling the other." The Journal of experimental 
medicine 192(12): 1707-1718. 
 
Druker, B. J. (2008). "Translation of the Philadelphia chromosome into therapy for CML." Blood 
112(13): 4808-4817. 
 
Duffy D, S. T. (1987). "Confidence intervals for a binomial parameter based on multiusage tests." 
Biometrics 43: 81-93. 
 
 


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Ekiz, H. A., G. Can, et al. (2010). "Nilotinib significantly induces apoptosis in imatinib-resistant K562 
cells with wild-type BCR-ABL, as effectively as in parental sensitive counterparts." Hematology 
15(1): 33-38. 
 
Hans, C. P., W. G. Finn, et al. (2002). "Usefulness of anti-CD117 in the flow cytometric analysis of acute 
leukemia." American journal of clinical pathology 117(2): 301-305. 
 
Hochhaus, A., H. M. Kantarjian, et al. (2007). "Dasatinib induces notable hematologic and cytogenetic 
responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy." Blood 
109(6): 2303-2309. 
Kantarjian, H., F. Giles, et al. (2006). "Nilotinib in imatinib-resistant CML and Philadelphia 
chromosome-positive ALL." The New England journal of medicine 354(24): 2542-2551. 
 
Kantarjian, H., N. P. Shah, et al. (2010). "Dasatinib versus imatinib in newly diagnosed chronic-phase 
chronic myeloid leukemia." The New England journal of medicine 362(24): 2260-2270. 
 
Kantarjian, H., N. P. Shah, et al. (2010). "Dasatinib versus imatinib in newly diagnosed chronic-phase 
chronic myeloid leukemia." N Engl J Med 362(24): 2260-2270. 
 
Kantarjian, H. M., F. Giles, et al. (2007). "Nilotinib (formerly AMN107), a highly selective BCR-ABL 
tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic 
myelogenous leukemia in chronic phase following imatinib resistance and intolerance." Blood 
110(10): 3540-3546. 
 
Kantarjian HM, Talpaz M (1988) Definition of the accelerated phase of chronic myelogenous leukemia. J 
Clin Oncol; 6:180-182 
 
Kaplan E, M. P. (1958). "Nonparametric estimation for incomplete observations." Am Stat Assoc 53: 
457-481. 
 
Kaur, P., N. Feldhahn, et al. (2007). "Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic 
leukemia." Mol Cancer 6: 67. 
 
Kindler, T., F. Breitenbuecher, et al. (2003). "Sustained complete hematologic remission after 
administration of the tyrosine kinase inhibitor imatinib mesylate in a patient with refractory, 
secondary AML." Blood 101(8): 2960-2962. 
 
le Coutre, P., O. G. Ottmann, et al. (2008). "Nilotinib (formerly AMN107), a highly selective BCR-ABL 
tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-
phase chronic myelogenous leukemia." Blood 111(4): 1834-1839. 
 
Marcucci, G., T. Haferlach, et al. (2011). "Molecular genetics of adult acute myeloid leukemia: 
prognostic and therapeutic implications." Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 29(5): 475-486. 
 
Merante, S., A. A. Colombo, et al. (2009). "Nilotinib restores long-term full-donor chimerism in Ph-
positive acute lymphoblastic leukemia relapsed after allogeneic transplantation." Bone marrow 
transplantation 44(4): 263-264. 
 
Montemurro M et al (2009)] Nilotinib in the treatment of advanced gastrointestinal stromal tumours 
resistant to both imatinib and sunitinib. Eur J Can; doi:10.1016/j.ejca.2009.04.0303. 


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Nilotinib Current Investigational Brochure is used for drug information 
 
O'Brien, S. G., F. Guilhot, et al. (2003). "Imatinib compared with interferon and low-dose cytarabine for 
newly diagnosed chronic-phase chronic myeloid leukemia." N Engl J Med 348(11): 994-1004. 
 
O’Dwyer ME, Kurilik MJ, Mori M, et al (2002) The impact of clonal evolution on response to imatinib 
mesylate (STI571) in accelerated phase CML. Blood; 100:1628-1633. 
O'Hare T, Corbin AS, Druker BJ. (2006) Targeted CML therapy: controlling drug resistance, seeking 
cure. Curr Opin Genet Dev. 6(1):92-99. 
 
Paschka, P., G. Marcucci, et al. (2006). "Adverse prognostic significance of KIT mutations in adult acute 
myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study." Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 24(24): 3904-
3911. 
 
Pane F, Frigeri F, Sindona M, et al (1996) Neutrophilic-chronic myeloid leukemia: a distinct disease with 
a specific molecular marker (BCR/ABL with C3/A2 junction). Blood; 88:2410-2414 
 
Radujkovic, A., S. Fruehauf, et al. (2010). "Synergistic activity of nilotinib and established 
chemotherapeutic drugs in imatinib-sensitive and -resistant BCR-ABL-positive cells." Cancer 
Chemother Pharmacol 66(2): 255-264. 
 
Ravandi F, Cortes J, Albitar M, et al (1999) Chronic myelogenous leukaemia with p185BCR/ABL 
expression: characteristics and clinical significance. Br J Haematol; 107: 581-586. 
 
Robak, T. and A. Wrzesien-Kus (2002). "The search for optimal treatment in relapsed and refractory 
acute myeloid leukemia." Leukemia & lymphoma 43(2): 281-291. 
 
Saglio, G., D. W. Kim, et al. (2010). "Nilotinib versus imatinib for newly diagnosed chronic myeloid 
leukemia." The New England journal of medicine 362(24): 2251-2259. 
 
Sawyers CL (1999) Chronic Myeloid Leukemia. N Engl J Med; 340:1330-1340. 
 
Sawyers, C. L., A. Hochhaus, et al. (2002). "Imatinib induces hematologic and cytogenetic responses in 
patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study." 
Blood 99(10): 3530-3539. 
 
Shimoni, A., M. Leiba, et al. (2009). "Prior treatment with the tyrosine kinase inhibitors dasatinib and 
nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not 
increase SCT Toxicity in patients with chronic myelogenous leukemia and philadelphia positive 
acute lymphoblastic leukemia." Leukemia : official journal of the Leukemia Society of America, 
Leukemia Research Fund, U.K 23(1): 190-194. 
 
Schulte C and Beelen D (2005) Low pretransplant bone-mineral density and rapid bone loss do not 
increase risk of avascular osteonecrosis after allogeneic hematopoietic stem cell transplantation. 
Transplantation 79(12):1748-1755. 
 
Shah NP (2005) Loss of response to imatinib: mechanisms and management. Hematology 1:183-187 
 
Stock, W. (2010). "Current treatment options for adult patients with Philadelphia chromosome-positive 
acute lymphoblastic leukemia."  


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(2002) STI571™ (imatinib mesylate) induces durable hematologic and cytogenetic responses in patients 
with accelerated phase chronic myeloid leukemia: Results of phase 2 study. Blood; 99: 1928-
1937. 
Tojo, A., K. Usuki, et al. (2009). "A Phase I/II study of nilotinib in Japanese patients with imatinib-
resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL." International journal of 
hematology 89(5): 679-688. 
 
Vardiman, J. W. (2009). "Chronic myelogenous leukemia, BCR-ABL1+." American journal of clinical 
pathology 132(2): 250-260. 
 
Walker, A. R., R. S. Komrokji, et al. (2008). "Phase I study of cladribine, cytarabine (Ara-C), granulocyte 
colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of 
imatinib mesylate (Gleevec) in relapsed/refractory AML." Leukemia research 32(12): 1830-1836. 
 
 
 
 


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Appendix Ia:  Drugs with Risk of Torsades de Pointes 
 
This list contains medications that are generally accepted (and documented in published data) as having 
an increased risk of QT prolongation and/or torsades de pointes.  Concomitant administration of nilotinib 
and a medication on this list is prohibited.  
 
 
Generic Name 
Brand Name 
Comments 
Amiodarone 
Cordarone®, Pacerone® 
Low risk torsades de pointes 
Arsenic trioxide 
Trisenox® 
Torsades de pointes 
Bepridil 
Vasocor® 
 
Chloroquine 
Aralen® 
 
Chlorpromazine 
Thorazine® 
 
Cisapride 
Propulsid® 
Restricted availability in U.S. 
Clarithromycin 
Biaxin® 
 
Disopyramide 
Norpace® 
Torsades de pointes 
Dofetilide 
Tikosyn® 
Torsades de pointes 
Dolasetron 
Anzemet® 
 
Droperidol 
Inapsine® 
Torsades de pointes 
Erythromycin 
Erythrocin®, E.E.S. ® 
IV > PO 
Halofantrine 
Halfan® 
 
Haloperidol 
Haldol® 
IV > PO, high doses increase QT 
prolongation and torsades de pointes 
Ibutilide 
Corvert® 
Torsades de pointes, female > male, non-
Caucasian > Caucasian 
Levomethadyl 
Orlaam® 
 
Mesoridazine 
Serentil® 
 
Methadone 
Dolophine®, Methadose® 
 
Pentamidine 
Pentam®, Nebupent® 
 
Pimozide 
Orap® 
 
Procainamide 
Pronestyl®, Procan®, 
Procanbid® 
N-acetylprocainamide causes torsade de 
pointes, not parent compound 
Quinidine 
Cardioquin®, Quinaglute® 
Torsades de pointes 
Sotalol 
Betapace® 
Torsade de pointes female > male 
Sparfloxacin 
Zagam® 
 
Thioridazine 
Mellaril® 
 
Note:  the above list is not all-inclusive.   
 
References:   
 
Al-Khatib SM, Allen LaPointe NM, Kramer JM, Califf RM.  What Clinicians Should Know About the 
QT Interval.  Journal of the American Medical Association 2003;289:2120-2127. 
 
Crouch MA, Limon L, Cassano AT. Clinical Relevance and Management of Drug-Related QT Interval 
Prolongation.  Pharmacotherapy 2003;23:887-908. 
 
Kies SJ, Pabelick CM et al.  Anesthesia for Patients with Congenital Long QT Syndrome. Anesthesiology 
2005;102:204-210 
 


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Li EC, Esterly JS, Pohl S, Scott SC, McBride BF.  Drug-Incuded QT-Interval Prolongation:  
Considerations for Clinicans.  Pharmacotherapy 2010;30:684-701. 
 
Roden DM. Drug-Induced Prolongation of the QT Interval.  The New England Journal of Medicine 
2004;350:1013-1022. 
 
http://www.azcert.org/medical-pros/druginteractions.cfm   Accessed 5/13/11 
 
 


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Appendix Ib:  Drugs with Possible or Conditional Risk of Torsades de Pointes 
This list contains medications that, in some reports, have been associated or weakly associated with 
causing torsades de pointes and/or QT prolongation.  There is insufficient data that these medications 
alone may cause torsades de pointes and/or QT prolongation, however when nilotinib is given 
concomitantly with a medication on this list (or other risk factors are present such as bradycardia, 
electrolyte disturbances, congenital long QT syndrome, or concomitant drugs that inhibit metabolism), 
there may be possible or conditional risk of torsades de pointes and/or QT prolongation.  Extreme caution 
and careful monitoring should be instituted with concomitant administration of nilotinib and a medication 
on this list. 
 
Generic Name 
Brand Name 
Comments 
Alfuzosin 
Uroxatral® 
 
Amantadine 
Symmetrel® 
Low 
Amitriptyline 
Elavil® 
Nonspecific ECG changes reported. 
Atazanavir 
Reyataz® 
 
Azithromycin 
Zithromax® 
 
Chloral hydrate 
Noctec® 
 
Ciprofloxacin 
Cipro® 
 
Citalopram 
Celexa® 
 
Clomipramine 
Anafranil® 
 
Desipramine 
Pertofrane® 
QT prolongation, VF/sudden death 
reported 
Diphenhydramine 
Benadryl®, Nytol® 
 
Dolasetron 
Anzemet® 
Granisetron < Ondansetron < Dolasetron 
Doxepin 
Sinequan® 
 
Dronedarone 
Multaq® 
 
Escitalopram 
Lexapro®, Cipralex® 
 
Felbamate 
Felbatrol® 
 
Flecainide 
Tambocor® 
 
Foscarnet 
Foscavir® 
 
Fosphenytoin 
Cerebyx® 
 
Fluconazole 
Diflucan® 
IV > PO 
Fluoxetine 
Prozac®, Sarafem® 
1 in 10,000 ventricular arrhythmias 
reported 
Galantamine 
Reminyl® 
 
Gatifloxacin 
Tequin® 
 
Gemifloxacin 
Factive® 
 
Granisetron 
Kytril® 
Granisetron < Ondansetron < Dolasetron 
Imipramine 
Norfranil® 
Nonspecific arrhythmias reported 
Indapamide 
Lozol® 
 
Isradipine 
Dynacirc® 
 
Itraconazole 
Sporanox® 
 
Ketoconazole 
Nizoral® 
 
Lapatinib 
Tykerb® 
 
Levofloxacin 
Levaquin® 
Lower risk than that of similar agents 
Lithium 
Lithobid®, Eskalith® 
 
Moexipril/HCTZ 
Uniretic® 
 
Moxifloxacin 
Avelox® 
 
Nicardipine 
Cardene® 
 


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Nilotinib 
Tasigna® 
 
Nortriptyline 
Pamelor® 
Nonspecific arrhythmias reported  
Octreotide 
Sandostatin® 
 
Ofloxacin 
Floxin® 
 
Ondansetron 
Zofran® 
Granisetron < Ondansetron < Dolasetron 
Oxytocin 
Pitocin® 
 
Paliperidone 
Invega® 
 
Paroxetine 
Paxel® 
Lower risk than TCA’s 
Perflutren lipid 
microspheres 
Definity® 
 
Protriptyline 
Vivactil® 
 
Quetiapine 
Seroquel® 
QT prolongation 
Ranolazine 
Ranexa® 
 
Risperidone 
Risperdal® 
QT prolongation, sudden death reported 
Ritonavir 
Norvir® 
 
Sertraline 
Zoloft® 
Lower risk than TCA’s 
Solifenacin 
VESIcare® 
 
Sunitinib 
Sutent® 
 
Tacrolimus 
Prograf® 
 
Tamoxifen 
Nolvadex® 
 
Telithromycin 
Ketek® 
 
Tizanidine 
Zanaflex® 
 
Trazodone 
Desyrel® 
 
Trimethoprim-Sulfa 
Sulfa®, Bactrim®, Bactrim 
DS® 
Low 
Trimipramine 
Surmontil® 
 
Vardenafil 
Levitra® 
 
Venlafaxine 
Effexor® 
1 :1000 risk of arrhythmia reported 
Voriconazole 
VFend® 
 
Ziprasidone 
Geodon® 
QT prolongation, 1:1000 risk of 
arrhythmia 
Note:  the above list is not all-inclusive. 
 
References:   
Al-Khatib SM, Allen LaPointe NM, Kramer JM, Califf RM.  What Clinicians Should Know About the 
QT Interval.  Journal of the American Medical Association 2003;289:2120-2127. 
Crouch MA, Limon L, Cassano AT. Clinical Relevance and Management of Drug-Related QT Interval 
Prolongation.  Pharmacotherapy 2003;23:887-908. 
Kies SJ, Pabelick CM et al.  Anesthesia for Patients with Congenital Long QT Syndrome. Anesthesiology 
2005;102:204-210 
Li EC, Esterly JS, Pohl S, Scott SC, McBride BF.  Drug-Incuded QT-Interval Prolongation:  
Considerations for Clinicans.  Pharmacotherapy 2010;30:684-701. 
Roden DM. Drug-Induced Prolongation of the QT Interval.  The New England Journal of Medicine 
2004;350:1013-1022. 
http://www.azcert.org/medical-pros/druginteractions.cfm   Accessed 5/13/11 
 
 
 








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Appendix III: ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 
















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53 
 
a.m.  
 
p.m.  
 
54 
 
a.m.  
 
p.m.  
 
55 
 
a.m.  
 
p.m.  
 
56 
 
a.m.  
 
p.m.  
 
57 
 
a.m.  
 
p.m.  
 
58 
 
a.m.  
 
p.m.  
 
59 
 
a.m.  
 
p.m.  
 
60 
 
a.m.  
 
p.m.  
 
61 
 
a.m.  
 
p.m.  
 
62 
 
a.m.  
 
p.m.  
 
63 
 
a.m.  
 
p.m.  
 
64 
 
a.m.  
 
p.m.  
 
65 
 
a.m.  
 
p.m.  
 
66 
 
a.m.  
 
p.m.  
 
67 
 
a.m.  
 
p.m.  
 
68 
 
a.m.  
 
p.m.  
 
69 
 
a.m.  
 
p.m.  
 
70 
 
a.m.  
 
p.m.  
 
71 
 
a.m.  
 
p.m.  
 
 
 


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Date (mm/dd/yy) 
Nilotinib 
 
Time taken 
Dose in MG 
Number of 
tablets 
72 
 
a.m.  
 
p.m.  
 
73 
 
a.m.  
 
p.m.  
 
74 
 
a.m.  
 
p.m.  
 
75 
 
a.m.  
 
p.m.  
 
76 
 
a.m.  
 
p.m.  
 
77 
 
a.m.  
 
p.m.  
 
78 
 
a.m.  
 
p.m.  
 
79 
 
a.m.  
 
p.m.  
 
80 
 
a.m.  
 
p.m.  
 
81 
 
a.m.  
 
p.m.  
 
82 
 
a.m.  
 
p.m.  
 
83 
 
a.m.  
 
p.m.  
 
84 
 
a.m.  
 
p.m.  
 
 
 
 
Participant’s Signature:  __________________________________    Date:  ________________ 
 


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Appendix VAcute Myeloid Leukemia WHO 2008 Criteria 
 
 
Acute myeloid leukemia and related precursor neoplasms, 
and acute leukemias of ambiguous lineage (WHO 2008) 
----------------------------------------------------------------------------- 
Categories 
----------------------------------------------------------------------------- 
Acute myeloid leukemia with recurrent genetic abnormalities 
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
APL with t(15;17)(q22;q12); PML-RARA* 
AML with t(9;11)(p22;q23); MLLT3-MLL† 
AML with t(6;9)(p23;q34); DEK-NUP214 
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 
Provisional entity: AML with mutated NPM1 
Provisional entity: AML with mutated CEBPA 
Acute myeloid leukemia with myelodysplasia-related changes‡ 
Therapy-related myeloid neoplasms§ 
Acute myeloid leukemia, not otherwise specified (NOS) 
Acute myeloid leukemia with minimal differentiation 
Acute myeloid leukemia without maturation 
Acute myeloid leukemia with maturation 
Acute myelomonocytic leukemia 
Acute monoblastic/monocytic leukemia 
Acute erythroid leukemia 
Pure erythroid leukemia 
Erythroleukemia, erythroid/myeloid 
Acute megakaryoblastic leukemia 
Acute basophilic leukemia 
Acute panmyelosis with myelofibrosis (syn.: acute myelofibrosis; acute