Clinical trial NCT00129740
Conditions: Leukemia, Myelogenous, Chronic
Keywords: Chronic phase CML Newly diagnosed chronic phase CML AMN107
Sponsor: M.D. Anderson Cancer Center
Start date: 2005-06-27; Completion date: 2018-07-11
Enrollment: 148 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if an experimental agent, AMN107 (nilotinib), can help to control CML in chronic phase. The safety of this experimental agent will also be studied.

Detailed description:
Nilotinib is a drug that is designed to block a protein that is responsible for the development of CML.

If you are found to be eligible to take part in this study, you will take 2-4 nilotinib capsules or tablets by mouth 2 times a day (4-8 capsules or tablets a day total) every day, at least 8 hours apart. Nilotinib should be taken each morning and evening with a large glass of water. The study medication will be given to you every 3 - 12 months. You will also be given a "pill diary" to write down when (day and time) you take the drug. You will also write in the diary any side effects you may experience. You should bring the diary, any unused capsules or tablets, and empty containers of nilotinib with you to every visit to the study doctor. Any unused supplies must be returned at the end of the study.

Every 1-4 weeks during the first 4 weeks of the study, you will have around 2 teaspoons of blood drawn for routine blood tests. The blood tests will then be repeated every 4-8 weeks (or more often if your doctor feels it is necessary) until you have been on study for 6 months, then every 3 to 6 months for another 18 months. After that, you may have the blood tests repeated as often as the doctor thinks it is needed. A bone marrow sample will also be taken every 3-4 months for the first year and then every 6-12 months in the 2nd year, then every 2-3 years for as long as you are on the study to check on the status of the disease. Additionally, blood (about ½ tablespoon) will be drawn or a bone marrow sample will be collected every 3-4 months for the first year and then every 6-12 months until 2 years, and then about one time a year for as long as you are on the study to check on the status of the disease. However, if you are in complete remission after Year 2, your doctor will decide when you will have a bone marrow aspiration. But you will still have blood drawn (about ½ tablespoon) every 1 - 3 years to check the status of your disease. An ECG will be repeated around Day 5, and then at about 6 weeks and about 3 months.

You will be asked to visit the doctor for a physical exam and to have vital signs measured periodically. These visits will be scheduled at least every 3 to 4 months the first year. After the first year, the study staff will recommend that you have physical exams once every year. The visits may be scheduled more often depending on the status of the disease.

Treatment may be continued for up to 8-10 years or as long as the doctor feels it is necessary to control the leukemia. If the disease gets worse or you experience any intolerable side effects, you will be taken off the study and your doctor will discuss other treatment options with you.

This is an investigational study. Nilotinib is FDA approved. A total of 150 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: 400 mg orally twice daily
Interventions: intervention 1: Nilotinib
Intervention descriptions: intervention 1: 400 mg orally twice daily

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2005-0048
November 13, 2013
Protocol Page
Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Oral 
Nilotinib
2005-0048
Core Protocol Information
Short Title 
Phase II nilotinib with newly diagnosed chronic phase CML
Study Chair: 
Jorge Cortes
Additional Contact:
David McCue
Rachel R. Abramowicz
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-794-5783
Unit:
428
Full Title: 
Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Oral Nilotinib
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 07/11/2018
Version:
34
Submitted by:
Rachel R. Abramowicz--3/13/2018 3:20:04 PM
OPR Action:
Accepted by:  Melinda E. Gordon -- 3/22/2018 9:54:24 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol 2005-0048
November 13, 2013
Protocol Body
 
Title:
Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) 
with Oral Nilotinib
Principal Investigator:
Jorge Cortes, M.D. 
Investigational Drug:
Nilotinib
Supplied by:
Novartis Pharmaceuticals
Contact:
Karen McDougall
Clinical Research Manager
Novartis Pharmaceuticals
One Health Plaza
Building 105, 2E79B
East Hanover, NJ 07936
phone: 862-778-3294
fax: 973-781-7453


 
2005-0048 
 
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Page 1 of 30 
 
 
 
 
 
 
 
 
TITLE: 
Therapy of Early Chronic Phase Chronic 
Myelogenous Leukemia (CML) with Oral 
Nilotinib 
 
 
PRINCIPAL INVESTIGATOR: Jorge Cortes, M.D. 
 
 
PROTOCOL NO.  
UT MD Anderson Cancer Center 
 
2005-0048 
 
 
INVESTIGATIONAL DRUG: 
Nilotinib 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Page 2 of 30 
TABLE OF CONTENTS 
1.0 
Objectives ............................................................................................. 3 
2.0 
Background .......................................................................................................... 3 
2.1 
Purpose ......................................................................................................... 3 
2.2 
Historical Experience ..................................................................................... 3 
2.3 
Interferon Therapy in CML ............................................................................. 4 
2.4 
Imatinib Mesylate (STI571; Gleevec) in CML ................................................ 4 
2.5 
Nilotinib .......................................................................................................... 5 
2.6 
Proposed Therapy with Nilotinib .................................................................... 5 
2.7 
Other Biologic Endpoints ............................................................................... 6 
3.0 
Background Drug Information .............................................................................. 6 
3.1 
Overview of Nilotinib ...................................................................................... 6 
3.2 
Preclinical Pharmacology .............................................................................. 7 
3.3 
Animal Pharmacokinetics and Drug Metabolism ........................................... 8 
3.4 
Animal Toxicology ......................................................................................... 9 
3.5 
Biomarkers .................................................................................................. 10 
3.6 
Phase I Study of Nilotinib ............................................................................ 10 
4.0 
Patient Eligibility ................................................................................................. 11 
5.0 
Treatment Plan................................................................................................... 13 
5.1 
General ........................................................................................................ 13 
5.2 
Treatment Plan ............................................................................................ 13 
5.3 
Dose modifications of Nilotinib .................................................................... 14 
5.4 
Duration of Therapy ..................................................................................... 15 
5.5 
Concomitant Medications ............................................................................ 16 
6.0 
Pretreatment Evaluation (See Appendix B) ........................................................ 17 
7.0 
Evaluation During Study (See Appendix B) ........................................................ 17 
8.0 
Criteria for Response ......................................................................................... 18 
9.0 
Criteria for Removal from the Study ................................................................... 19 
10.0 
Statistical Considerations ................................................................................... 19 
11.0 
Reporting Requirements .................................................................................... 23 
11.2 Serious Adverse Event Reporting (SAE) ............................................................ 23 
12.0 
References ......................................................................................................... 26 


 
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Protocol Body 
1.0 
Objectives 
Primary: 
To determine the percentage of patients who achieve low levels of PCR ratios of 
Bcr-Abl/Abl (molecular CR) after 12 months of therapy with nilotinib. 
Secondary: 
 To determine the proportion of patients with Ph-positive early chronic phase CML 
achieving a complete cytogenetic response after nilotinib therapy, and the time to 
achieve the response. 
 To evaluate the durations of PCR negativity, cytogenetic response, hematologic 
control, and survival. 
 To analyze differences in response rates and in prognosis within different risk 
groups and patient characteristics. 
 To evaluate symptom burden in patients with CML receiving nilotinib. 
 
2.0 
Background 
2.1 
Purpose 
The basic hypothesis underlying our therapeutic program in CML is to be able to 
achieve meaningful and long-lasting suppression of the Philadelphia 
chromosome and Bcr-Abl abnormalities.  Such complete cytogenetic responses 
and complete/major molecular responses have been associated with survival 
prolongation in CML.  
2.2 
Historical Experience 
The prognosis of patients with chronic myelogenous leukemia is improving (1).  
Historically, the median survival of untreated patients with CML was 19 months 
from diagnosis.  In our historical experience of 303 patients with a diagnosis of 
Philadelphia-positive early chronic-phase CML referred to our institution within 3 
months of diagnosis with minimal or no prior therapy, the overall median survival 
was 39 months (2).  Patients were divided into good, intermediate and poor risk 
groups with different hazard rates and median survivals (2).   
 
Symptoms are subjective phenomena reported by patients that indicate a change 
in normal functioning, sensation, or appearance due to disease (30). Symptom 
burden is the combined impact of disease- and therapy-related symptoms on the 
ability of persons to function as they did prior to onset of their disease and/or 
therapy (31). The MD Anderson Symptom Inventory (MDASI) is a valid and 
reliable measure of symptom burden (32). Recently a CML-specific version of the 
MDASI, the MDASI-CML, has been validated. Common symptoms of chronic 


 
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myeloid leukemia (CML) and its treatment can significantly impair the daily 
functioning of patients (33). Symptoms such as fatigue, nausea and vomiting, 
diarrhea, muscle cramps, skin changes, and headache add to the burden of 
CML. Patients with serious illnesses often report that they would like to “return to 
a normal life” (34). Decreasing the symptom burden of CML and its treatments 
will allow patients to function as normally as possible. Currently, there is little 
research on symptoms and their impact on daily functioning experienced by 
patients with CML to direct interventions that may assist patients in returning to 
normal.  
 
We have successfully developed IVR technology for the assessment of multiple 
symptoms using the MDASI in patients with cancer undergoing chemotherapy, 
radiation therapy, and surgery. We currently have one active study in a sample of 
patients with CML, many of whom are receiving kinase inhibitor therapies, using 
the MDASI-CML. Initial evaluation has shown this to be a feasible option for 
patient-reported symptom burden assessment in this group of patients and 
further evaluation is ongoing. The patient chooses the day and the time to 
receive the IVR system call; the system calls the patient three times if necessary 
to complete the assessment. 
2.3 
Interferon Therapy in CML 
At M.D. Anderson Cancer Center, 80% of patients with early chronic phase 
Philadelphia chromosome (Ph)-positive CML treated with interferon alpha (IFN-) 
alone or in combinations, achieved a complete hematologic response (CHR); 
55% had a cytogenetic response, which was major and durable in 25% (3-5).  
Achieving a complete cytogenetic response was associated with estimated 10-
year survival rates above 70% to 80%(5).  In randomized studies and by meta-
analysis, IFN- was associated with significant survival prolongation compared 
with conventional chemotherapy (6-11).  Similar associations of achieving 
minimal tumor burden and survival prolongation have been reported by these 
studies. 
The addition of low-dose cytarabine to interferon-alpha may have improved 
outcome (12-14). 
2.4 
Imatinib Mesylate (STI571; Gleevec) in CML 
Imatinib is an inhibitor of the protein-tyrosine kinases associated with Bcr-Abl, the 
platelet-derived growth factor (PDGF) receptor and c-Kit.  CML represents an 
ideal disease target for imatinib, given that the Bcr-Abl kinase plays a dominant 
role in the deregulated myeloid cell proliferation which is the hallmark of this 
disease.  
Imatinib shows selectivity for the Abl protein tyrosine kinase at the in vitro, 
cellular and in vivo level (15). The compound specifically inhibits proliferation of 
Bcr-Abl expressing cells. In colony forming assays using ex vivo peripheral blood 
and bone marrow samples, imatinib shows selective inhibition of Bcr-Abl positive 
colonies from CML patients (16-18). In animal models, the compound shows 


 
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potent anti-tumor activity against Bcr-Abl and v-Abl expressing cells at tolerated 
doses (16).  
In phase I studies, imatinib has demonstrated activity in all CML phases post 
IFN- failure and in Ph-positive ALL (19,20). 
Three large-scale pivotal trials of imatinib in CML chronic, accelerated and blastic 
phases have been completed (21-24). In chronic phase CML, 532 patients who 
had failed IFN- therapy were treated with imatinib 400 mg orally daily. The CHR 
rate was above 90%.  The major cytogenetic response rate (Ph-positive less than 
35%) was 60%.  Imatinib was well-tolerated. Side effects included nausea, 
vomiting, diarrhea, skin rashes, muscle cramps, bone and joint aches, and liver 
dysfunction.  Grade 3-4 toxicities requiring discontinuation of therapy occurred in 
2% or less of patients.  Periorbital and leg edema and fluid retention were 
frequent at imatinib doses of 600 to 1000 mg orally daily. 
An open-label, multicenter, randomized phase III study (International 
Randomized Interferon vs. STI571 [IRIS]) has been conducted in patients with 
newly diagnosed Ph+ CML.  This study compared treatment with either single-
agent Imatinib or a combination of IFN plus cytarabine (ara-C), and allowed for 
crossover for lack of response, loss of response, or toxicity. A total of 1106 
patients have been randomized from 177 centers in 16 countries, 553 to each 
arm. The major cytogenetic response rate for patients treated with Imatinib was 
83% (68% complete) compared to 20% with IFN and ara-C (7% complete). With 
the follow-up currently available, the 4-year estimated rate of free of progression 
to accelerated phase or blast crisis was above 90% with imatinib (25,26).  High-
dose imatinib 400 mg orally BID has improved the early incidences of complete 
cytogenetic and molecular remissions.  Its impact on long-term prognosis 
remains to be determined (27,28). 
 
2.5 
Nilotinib 
Nilotinib is a selective Bcr-Abl kinase inhibitor 10 to 100 times more potent than 
imatinib.  In a phase I study, nilotinib was given in a dose escalation schedule to 
patients with CML accelerated or blastic phase resistant to imatinib.  Doses of 
nilotinib were 50, 100, 200, 400, 600, 800 and 1200 mg orally daily, then 400 mg  
BID and 600 mg BID.  Ninety-five patients have so far been treated.  Sustained 
responses have been observed at nilotinib doses 200 mg daily or above.  The 
response rate was 50% in accelerated and blastic phases and the cytogenetic 
response rate 30+%.  Side-effects included skin rashes, and transient elevations 
of indirect bilirubin.  No MTD or DLT have yet been defined (29, and unpublished 
data 2005). 
2.6 
Proposed Therapy with Nilotinib 
In this study we propose to treat patients with nilotinib, a selective Bcr-Abl kinase 
inhibitor more potent than imatinib.  We hypothesize that nilotinib may be very 
effective in achieving molecular remissions in a larger proportion of patients with 


 
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early chronic phase CML.  
The endpoints of therapy in early chronic phase will be to achieve a PCR ratio of 
< 0.05%, as well as evaluate the cumulative overall incidences of complete and 
major cytogenetic responses.  In early chronic phase CML, PCR ratios < 0.05% 
are unusual (less than 10%) after 12 months of therapy.  We will treat 150 
patients, 125 chronic phase and 25 accelerated phase, in a phase II study.  
Based on the current accrual rate of 50 patients/year with a minimum follow up of 
1 year, the study will be completed in 3 years. 
2.7 
Other Biologic Endpoints 
We have recently shown the value of interphase FISH analysis in the evaluation 
of cytogenetic response and in monitoring patients on therapy.  In our long-term 
studies 50% of patients in complete cytogenetic response by regular 
cytogenetics were also PCR-negative for Bcr-Abl.  More recently, PCR 
quantification has proven useful in monitoring and predicting outcome of patients 
with CML.  Patients with CML on imatinib therapy who achieve a PCR value ratio 
of Bcr-Abl transcripts/Abl transcripts of 0.05% or less have an excellent long-term 
prognosis. These studies will help understand better the degree and quality of 
cytogenetic and molecular responses and their impact on prognosis. 
 
3.0 
Background Drug Information 
Nilotinib is an ATP-competitive inhibitor of the protein tyrosine kinase activity of Bcr-Abl, 
which prevents the activation of Bcr-Abl dependent mitogenic and anti-apoptotic 
pathways (e.g. PI-3 kinase and STAT5), leading to the death of the Bcr-Abl phenotype. 
Following oral administration to animals, nilotinib is well absorbed, shows a good 
pharmacokinetic profile and is well tolerated. Therefore, nilotinib is expected to be an 
effective treatment for Bcr-Abl driven diseases (Ph+ ALL and CML).  In proliferation 
assays nilotinib is more potent than imatinib against p210 Bcr-Abl expressing cell lines 
(IC50: 8-22 nM vs.61-577nM).  In a p190 Bcr-Abl-expressing cell line, the IC50 for 
autophosphorylation for nilotinib was 31 nM. In addition, nilotinib is effective against the 
following nilotinib-resistant mutants that have been identified in some relapsed patients: 
Glu255Val, Phe317Leu, and Met351Thr, inhibiting Bcr-Abl dependent cell proliferation 
with IC50 values: 313, 54, and 40 nM, respectively. It is believed that the increased 
potency and broader spectrum of activity of nilotinib against Bcr-Abl will result in clinical 
benefit for CML and Ph+ ALL patients. 
3.1 
Overview of Nilotinib 
Nilotinib is a novel aminopyrimidine, available as an oral formulation that is an 
ATP-competitive inhibitor of Bcr-Abl, which prevents the activation of Bcr-Abl 
dependent mitogenic and anti-apoptotic pathways (e.g. PI-3 kinase and STAT5), 
leading to the death of the BCR-ABL phenotype. Phase I trials of nilotinib in 
patients with accelerated-blastic phase CML post imatinib failure have shown 
hematologic response rates of 50% in accelerated and blastic phases of CML 
post-imatinib failure, and cytogenetic response rates of 30%.  In chronic phase 


 
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CML post imatinib failure, the results were better (Kantarjian.  Preliminary data 
2005). 
 
3.2 
Preclinical Pharmacology 
3.2.1 In-vitro Pharmacology 
The effects of nilotinib on Bcr-Abl autophosphorylation have been 
evaluated in K-562 and KU-812F human leukemia cell lines, which 
naturally express Bcr-Abl, as well as with p190 or p210-bcr-abl transfected 
murine hematopoietic 32D and p210-bcr-abl transfected Ba/F3 cells. In 
addition, 
the 
compound 
has 
been 
evaluated 
for 
effects 
on 
autophosphorylation in a panel of Ba/F3 cells, transfected murine 
hematopoietic cells, expressing different mutant forms of the Bcr-Abl 
kinase. Nilotinib potently inhibits the Bcr-Abl kinase in cell lines, derived 
from human leukemic CML cells and from transfected murine 
hematopoietic cells, with IC50 values in the range of 20 to 60 nM. In 
addition, nilotinib inhibits the tyrosine kinase activity of certain Bcr-Abl 
kinase domain mutants (Glu255Val, Phe317Leu, and Met351Thr), at 
relevant concentrations (IC50 values: 313 ± 75, 54 ± 8 and 40 ± 7 nM, 
respectively). Nilotinib also inhibits the tyrosine kinase activities of the 
PDGF-R (IC50 value in A31 cells 79 ± 11 nM) and the stem cell factor 
receptor, c-kit (IC50 value in GIST cells 190 ± 24 nM), determined by 
analogous cell-capture ELISA assays. 
Like the Bcr-Abl expressing human cell lines K-562 and KU-812F, murine 
Ba/F3 cells transfected to express Bcr-Abl exhibit growth factor 
independent cell viability and proliferation. Similarly, Ba/F3 cells 
transfected to express other protein kinases exhibit growth factor 
independent cell viability and proliferation. The effect of drugs on the 
viability and proliferation of cells may be determined as total growth 
inhibition of cell cultures, using a luminescent ATP-detection assay kit. In 
all of the above cell lines, the inhibition of the protein kinase activity is 
generally well correlated with the effect on cell viability and proliferation. 
Nilotinib potently inhibits the proliferation of K-562, KU-812F and murine 
Ba/F3 cells expressing p210 Bcr-Abl kinase, with IC50 values in the range 
of 8 to 22 nM. Consistent with the effects on mutant Bcr-Abl kinase 
activity, nilotinib inhibits Glu255Val, Phe317Leu, and Met351Thr Bcr-Abl 
dependent cell proliferation, with IC50 values of 528 ± 112, 74 ± 11 and 27 
± 5 nM respectively. Nilotinib also inhibits PDGF-Rα (IC50 values in FIP-
PDGF-Rα Ba/F3 cells in the range of 2.5 - 11 nM) and PDGF-Rβ (IC50 
value Tel-PDGF-Rβ Ba/F3 cells of 63 ± 15 nM), as well as c-kit (IC50 
value in GIST cells 153 ± 13 nM) dependent cell proliferation, determined 
by analogous assays. 
The selectivity of nilotinib as a protein kinase inhibitor has been 
demonstrated by its lack of appreciable activity (IC50 value for inhibition of 


 
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cell proliferation > 3000 nM) against a panel of Ba/F3 cells transfected to 
express a variety of different kinases. 
3.2.2 In-vivo Pharmacology 
Efficacy studies in murine models of Bcr-Abl dependent myeloproliferative 
disease models have been initiated. Preliminary data indicate nilotinib is 
capable of inhibiting disease progression, as measured either by the 
bioluminescence produced by luciferase-labeled bcr-abl.32D cells 
following 100 mg/kg/day, or by the effect on spleen weight following 75 
mg/kg/day. 
3.3 
Animal Pharmacokinetics and Drug Metabolism 
Absorption was moderate with a moderate bioavailability (34%) in rats following a 
single oral dose of 20 mg/kg. The plasma clearance was low in the rat. The 
volume of distribution was high for the rat, moderate for the dog and monkey. 
Elimination half-lives of the biphasic plasma profile were 1.5 h (83% of AUC) and 
116 h for the rat. 
The distribution of nilotinib between plasma and red blood cells was independent 
of concentration and blood-to-plasma concentration ratios were less than one in 
rats (0.79), dogs (0.83), and humans (0.71). The binding of nilotinib to plasma 
proteins was high and there were no species differences in binding among the rat 
(97.3-99.5%), dog (96.6-99.0%), and human (97.0-99.4%). Serum protein 
binding was similar to plasma protein binding. 
When radiolabeled nilotinib was administered intravenously to rats, drug-related 
radioactivity was widely distributed to most tissues, consistent with a large 
volume of distribution. The highest radioactivity levels were found in stomach 
glandular, adrenal, and liver and bile at 5 min post dose consistent with the in 
vivo finding where biliary excretion is a major elimination route. The radioactivity 
in bone marrow was similar to the blood (ratio = ~1). Drug-related radioactivity 
was highly bound to melanin. There was a minimal passage for drug-related 
radioactivity across the blood:brain and blood:testis barriers. 
The parent compound was the major circulating drug-related material in rats. The 
other main metabolites in rat plasma were glucuronic acid conjugates of nilotinib-
hydrolized metabolite, pyridine N-oxide-, and monohydroxy-nilotinib. Nilotinib was 
eliminated in the rats mainly via oxidative metabolism. All metabolites observed 
in the human liver slices incubate were also found in the animal species. The 
metabolism profiles of rat and monkey liver slices were most similar to that of 
human while the dog liver slice profile was most dissimilar to the other systems. 
Nilotinib was metabolized by oxidation of the methyl-imidazole ring, degradation 
of the oxidized imidazole, oxidation of the pyridinyl-pyrimidinyl-amino-methyl-
benzamide moiety, amide hydrolysis, glucuronic acid formation of the primary 
metabolites, and various combinations of the above pathways. 
Based on its inhibition (IC50  7.5 µM) for CYP enzymes, 2C8, 2C9, 2C19, 2D6, 
and 3A4/5, nilotinib may inhibit the metabolic clearance of comedications 


 
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metabolized by these CYP enzymes, if sufficiently high concentrations of nilotinib 
are achieved in vivo. 
3.4 
Animal Toxicology 
In 4-week toxicity studies with daily oral gavage dosing, the maximum tolerated 
dose (MTD) was 60 mg/kg in rats (AUC(0-24h) 120000 ng.h/mL in males and 
187000 ng.h/mL in females and 45 mg/kg in dogs (AUC(0-24h) 3880 ng.h/mL in 
males and 25700 ng.h/mL in females). 
The main target organ in both species was the liver and findings were consistent 
with hepatocholestatic disease. In dogs, drug effects were observed at 15 and 45 
mg/kg. These were more pronounced in females than males and included 
elevated liver enzymes (ALT and ALP), increased cholesterol, hyperbilirubinemia 
and bilirubinuria. Histopathologically this was associated with intrasinusoidal 
aggregates of hyperplastic and/or hypertrophic Kupffer cells, occasionally 
accompanied by bile duct proliferation, leading to a disturbance of the bile flow. 
Minor kidney findings were an increased number and severity of lipid containing 
vacuoles of tubular epithelium in female dogs at 45 mg/kg. These are not 
considered to be of toxicological significance, and the hyaline droplets seen at all 
dose levels in male rats are compatible with an exacerbation of hyaline droplet 
formation representing the initial phase of the inducible male rat α2 globulin 
nephropathy syndrome, a syndrome specific to male rats and of no relevance to 
other species including human. Clinically, female dogs showed emesis 
particularly during the last week of dosing. This finding correlates with the higher 
systemic exposure seen following multiple administration to female dogs at the 
high dose. 
In vitro electrophysiology data from the hERG channel assay revealed an IC50 
value of 0.13 µM. Nilotinib induced a decrease in the coronary perfusion rate at 
concentrations of 0.9 µM and higher and showed signs of prolonged action 
potential duration in the isolated rabbit heart at concentrations ≥ 3 µM. No effects 
were seen in ECG measurements included into the 4-week toxicity study in dogs 
up to 45 mg/kg and no effects on cardiac electrophysiological changes were 
observed in a special telemetry study in dogs at single doses up to 300 mg/kg. 
Based on the low IC50 value seen in the hERG channel assay it is concluded that 
nilotinib showed a preclinical signal for QT prolongation. 
Nilotinib did not show a genotoxic potential in the AMES test or Chromosome 
Aberration test in human peripheral lymphocytes. 
The NOAEL in rats was 20 mg/kg (AUC(0-24h) 20900 ng.h/mL in males and 46100 
ng.h/mL in females) and 5 mg/kg in dogs (AUC(0-24h) 1560 ng.h/mL in males and 
1780 ng.h/mL in females). 
Based on the findings observed in animals, kidney, liver and cardiac function 
should be monitored in humans. Emesis may also occur in patients. Following 
completion of a 4-week treatment, patients may continue treatment with nilotinib 
based upon the absence of unacceptable toxicity and/or disease progression. 


 
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3.5 
Biomarkers 
In Philadelphia-chromosome positive leukemias (CML-CP, CML-AP, CML-BC, 
Ph+ ALL), the following assays of Bcr-Abl activity will be performed to examine 
the ability of nilotinib to down-regulate Bcr-Abl and its downstream effectors: Bcr-
Abl phosphorylation, STAT 1, STAT 5 signaling, AKT phosphorylation and Q-RT-
PCR to detect the presence of Bcr-Abl transcripts. An attempt will be made to 
correlate the effects on the various biomarkers with plasma drug levels obtained 
at similar timepoints.  Mutational analysis of Bcr-Abl will be conducted at baseline 
and at the time of disease progression. 
3.6 
Phase I Study of Nilotinib 
The phase I study of nilotinib initially started as a single daily dose at 50 mg daily 
with dose escalation to 100, 200, 400, 600, 800 and 1200 mg orally daily.  
Patients with accelerated-blastic phase post imatinib failure were initially treated.  
Among the initial 65 patients, the CHR rate was 50% in accelerated and blastic 
phases, and the cytogenetic response rate 30+%.  The PK studies showed 
saturation of levels at 400 to 1200 mg daily.  The T ½ was 13 hours.  Because of 
possible GI-hepatic absorption/metabolism saturation, patients were then treated 
at 400 mg orally BID.  This showed a 50% increase of PK levels.  Side-effects so 
far have included mild-moderate nausea and skin rashes, and transient 
elevations of indirect bilirubin which normalized after 2 to 7 days with 
combination therapy.  The study is currently at a dose of 600 mg. P.O. BID, 
which maybe dose-limiting and PK saturating.  At 600 mg P.O. BID, grade 3 
thrombocytopenia was noted in 3 patients, grade 2 pancreatitis in 1 patient.  
Patients with chronic phase CML post imatinib failure are currently treated at 400 
mg orally BID, showing good tolerance and favorable responses.  A total of 17 
patients in chronic phase have so far been treated.  All had imatinib resistant 
disease.  With a median follow up time of 3 months on therapy, 12 (70%) 
achieved CHR, and 7 (41%) have already had a cytogenetic response.   
The onset of several cases of hyperbilirubinemia in the Phase I study prompted a 
pharmacogenetic analysis of UGT1A1 genotyping for all patients enrolled in this 
study who had signed an informed consent for pharmacogenetic testing and for 
whom a blood sample was available.  This analysis was performed while the 
study was ongoing; to date 51 patients have been genotyped.  A significant 
association between the susceptible genotype (7,7) and elevated bilirubin levels 
(> 1.5 x ULN) has been found.  Analysis of the remaining patients is ongoing.  
This result is consistent with previous reports linking UGT1A1*28 to Gilbert’s 
Syndrome and elevated bilirubin levels (Bosma et al., 1995; Monaghan et al., 
1996).  While the role of glucuronidation by UGT1A1 of nilotinib remains to be 
defined, the onset of hyperbilirubinemia during the study might suggest inhibition 
of overall AGT1A1 activity by nilotinib, through direct interaction, competition or 
some other mechanism. 
As part of the phase I study, we have performed over 3,000 EKGs so far on 
patients on nilotinib pretreatment and serially.  None have revealed any safety 
issues in relation to QT interval changes or other abnormalities. 


 
2005-0048 
 
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Page 11 of 30 
3.7 
Physical, chemical and pharmaceutical properties (per Investigator’s 
Brochure) 
3.7.1 Drug Substance 
The nilotinib-AA drug substance exists as the monohydrate form of the 
hydrochloride salt.   
Chemical name:  4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-
(trifluoromethyl)phenyl]-3-[[4-(3-pyridiny1)-2-pyrimidiny1]amino]-
benzamide, monohydrochloride, monohydrate. 
3.7.2 Drug product 
Clinical service form 
Novartis will supply nilotinib as 200 mg and 50 mg capsules or tablets.  
Dosage strengths correspond to the free base.  The inactive ingredients 
are lactose monohydrate, crospovidone, poloxamer, colloidal silicon 
dioxide and magnesium stearate. 
Shelf-life and storage conditions 
Based on currently available stability data, the drug product should be 
protected from light – do not store above 25C.  The re-evaluation period 
is 12 months. 
 
4.0 
Patient Eligibility 
4.1 
Diagnosis of Ph-positive or Bcr-positive CML in early chronic phase CML (i.e., 
time from diagnosis 12 months). Except for hydroxyurea, patients must have 
received no or minimal prior therapy, defined as <1 month (30 days) of prior 
interferon-alpha (with or without cytarabine) and/or an FDA-approved TKI. 
Patients with de novo accelerated phase will be treated but analyzed separately. 
4.2 
Age > 16 years (Age > 18 years to participate in optional symptom burden 
assessment) 
4.3 
ECOG performance of 0-2.  
4.4 
Adequate end organ function, defined as the following: total bilirubin < 1.5 x ULN, 
SGPT < 2.5 x ULN, creatinine < 1.5 x ULN.  
4.5 
Patients must sign an informed consent indicating they are aware of the 
investigational nature of this study, in keeping with the policies of the hospital. 
4.6 
Reliable telephone access to receive calls from an interactive voice response 
system (IVR) (only applicable to patients who will participate in optional symptom 
burden assessment). 
 
 
4.7 
Exclusions: 


 
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Page 12 of 30 
a. 
NYHA cardiac class 3-4 heart disease as well as impaired cardiac function 
defined as:   
 LVEF < 45% as determined by MUGA scan or electrocardiogram 
 Complete left bundle branch block 
 Use of cardiac pacemaker 
 ST depression of > 1 mm in 2 or more leads and/or T wave inversions 
in 2 or more continuous leads 
 Congenital long QT syndrome 
 History of, or presence of significant ventricular or atrial 
tachyarrhythmia’s 
 Clinically significant resting bradycardia (< 50 bpm) 
 QTc > 450 msec on screening ECG (using the QTcF formula) 
 Right bundle branch block plus left anterior hemiblock, bifascular block 
 Myocardial infarction within 12 months prior to starting nilotinib 
 Unstable angina diagnosed or treated within the past 12 months 
 Other clinically significant heart disease (e.g. congestive heart failure, 
uncontrolled hypertension, history of labile hypertension, or history of 
poor compliance with an antihypertensive regimen). 
b. 
Patients with active, uncontrolled psychiatric disorders including:  
psychosis, major depression, and bipolar disorders. 
c. 
Female patients of childbearing potential must have negative pregnancy 
test within 7 days before initiation of study drug dosing. Postmenopausal 
women must be amenorrheic for at least 12 months to be considered of 
non-childbearing potential.  Surgical sterilization is considered non-
childbearing potential.  Female patients of reproductive potential must 
agree to employ an effective method of birth control (hormonal or barrier) 
throughout the study and for up to 3 months following discontinuation of 
study drug. 
d. 
Patients with severe and/or uncontrolled medial disease (i.e., uncontrolled 
diabetes, chronic renal disease, or active uncontrolled infection [persistent 
fever and worsening clinical condition]). 
e. 
Patient with known chronic liver disease (i.e., chronic active hepatitis, and 
cirrhosis). 
f. 
Patient with known diagnosis of human immunodeficiency virus (HIV) 
infection. 
4.8 
Patients in late chronic phase (i.e., time from diagnosis to treatment >12 months) 
or blastic phase are excluded.   


 
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The definitions of CML phases are as follows:   
a. 
Early chronic phase: time from diagnosis to therapy < 12 months 
 
Late chronic phase: time from diagnosis to therapy > 12 months 
b.  
Blastic phase: presence of 30% blasts or more in the peripheral blood or 
bone marrow.   
c. 
Accelerated phase CML: presence of any of the following features:   
 Peripheral or marrow blasts 15% or more 
 Peripheral or marrow basophils 20% or more  
 Thrombocytopenia < 100 x 109/L unrelated to therapy 
 Documented extramedullary blastic disease outside liver or spleen due 
to past causes 
d. Clonal evolution defined as the presence of additional chromosomal 
abnormalities other than the Ph chromosome is part of accelerated phase 
CML. Ph chromosome variants or complex Ph chromosome translocations are 
not considered to indicate disease acceleration.  We have recently found 
clonal evolution to have a variable prognostic impact and may be suppressed 
with interferon-alpha therapy.  Hence these patients, like others with de novo 
accelerated phase, will be eligible, and analyzed separately. 
 
5.0 
Treatment Plan 
5.1 
General 
All patients should be registered with the Data Management Office PDMS 
system.  
5.2 
Treatment Plan 
Patients will receive nilotinib therapy according to the suggested guidelines 
below. Individual minor variations in the initiation of therapy, WBC count at start 
of therapy, are acceptable as indicated by patient condition and physician 
judgment.   
5.2.1 CML debulking: patients may receive hydroxyurea for debulking before 
and during the first 6 weeks of therapy. Patients who cannot take 
hydroxyurea may receive other agents such as 6-mercaptopurine and 6-
thioguanine.   
5.2.2 Therapy:  nilotinib 400 mg orally twice daily.   
Patients must not drink grapefruit juice or eat grapefruit while taking 
nilotinib. Patients should avoid drinking caffeine within an hour of taking 
nilotinib.  Patients should avoid alcohol while taking nilotinib. 
5.2.3 Dose adjustments: Dose adjustments will be done as described below 


 
2005-0048 
 
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Page 14 of 30 
using the following dose-levels: 
Dose Level 
Nilotinib 
0 
400 mg BID 
-1 
200 mg BID 
-2 
200 mg daily 
5.2.4 Ph studies including cytogenetics, interphase FISH, and PCR, to be done 
as follows, as a general guideline.  Some may be omitted if judged not 
necessary. 
a) 
Cytogenetic (or FISH) pretreatment 
b) 
Cytogenetic (or FISH), and PCR quantification every 3-4 months as 
indicated in year one then every 6-12 months as indicated (e.g., 
PCR not mandated when patient not with major cytogenetic 
response) 
5.3 
Dose modifications of Nilotinib 
General guidelines include the following: 
a) 
Non-Hematologic Toxicity 
 
Grade 2: Patients with persistent grade 2 toxicity that is considered 
clinically significant, unresponsive to appropriate therapy, may have 
treatment held until the toxicity has resolved to grade <1.  Nilotinib 
may then be resumed at the same dose the patient was receiving 
at the time treatment was interrupted. If the grade < 2 toxicity 
recurs, nilotinib may be held until the toxicity has resolved to grade 
1. Treatment may then be resumed at a reduced dose of 400 mg 
daily or the next –1 dose level. 
 
Grade 3-4: If a patient experiences Grade 3-4 toxicity, nilotinib 
must be withheld until the toxicity has resolved to Grade < 1. 
Nilotinib may then be resumed at a reduced dose of 400 mg daily, 
or the next –1 dose level. 
 
Do not reduce dose for indirect hyperbilirubinemia without 
hemolysis, unless indirect bilirubin exceeds 5 mg/dL and lasts for 
more than 5-7 days. 
b) 
Hematologic Toxicity 
If granulocytes are < 0.5 x 109/L or platelets are < 40 x 109/L, hold 
therapy until granulocytes are above 109/L and platelets are above 60 x 
109/l, then resume therapy. 
If recovery takes more than 2 weeks, resume nilotinib at 1 dose level 
reduction from the dose the patient was receiving at the time therapy was 
interrupted. 


 
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If recovery takes less than 2 weeks, resume nilotinib at the same dose the 
patient was receiving at the time treatment was interrupted. 
If myelosuppression recurs, resume nilotinib at one dose level reduction 
from the dose the patient was receiving at the time the treatment was 
interrupted. 
If a similar degree of toxicity returns, a further dose reduction by one 
dose level can be performed, using the above procedures.  
c) 
Modifications of dose schedules other than the above will be allowed 
within the following guidelines: 
 
Intermediate dose levels are acceptable when judged to be in the 
best interest of the patient. Acceptable dose levels are the 
following: 300mg BID, 150mg BID, and 150mg QD. 
 
Further dose reductions can be made to keep toxicity grade < 2. 
However, the lowest acceptable dose is 150 mg/daily.  
 
Dose adjustments by more than 1 dose level at a time can be 
considered when judged in the best interest of the patient (e.g., 
neutropenia with sepsis, bleeding requiring platelet transfusions) 
when toxicity has resolved. The reason for this reduction will be 
discussed with the PI or Co-PI and documented. 
 
A patient who has had a dose reduction because of any of the 
reasons mentioned above may have their dose escalated provided 
the patient has remained free of toxicity requiring dose adjustments 
as defined above for at least 1 month. Escalation will be made to 
the previous dose-level, and not more frequent than every month.  
5.3.1 Dose Escalations 
Patients who do not achieve a molecular remission at 12 months and who 
had a prior dose reduction of nilotinib, and who have no toxicity after 2 
months of therapy may increase the dose of nilotinib back to 800mg P.O. 
daily (400mg P.O. twice a day).   
5.4 
Duration of Therapy 
Total duration of therapy will be 8-10 years.  Subsequent changes of duration of 
treatment will depend on the earlier analyses of data with nilotinib to justify the 
safety of continued therapy versus treatment interruption. 
Novartis will supply nilotinib as 200 mg, 150 mg and 50 mg capsules or tablets 
for the core trial period of 6 years. Continuing treatment beyond this time will be 
at the discretion of the investigator and may become the financial responsibility of 
the patient if nilotinib becomes commercially available, if no alternative method of 
obtaining or paying for the drug can be identified at that time.  Medication labels 
will comply with the legal requirements of the US and will be printed in English.  
The storage conditions for nilotinib will be described on the mediation label.  The 
study medication must be stored in a safe, secure location. 


 
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5.5 
Concomitant Medications 
The use of hematopoietic growth factors (i.e., G-CSF, interleukin-11, 
erythropoietin) is allowed during the trial if clinically indicated for these patients. 
The use of anagrelide is allowed for severe thrombocytosis > 600 x 109/L. 
5.5.1 In general, concomitant medications and therapies deemed necessary for 
the supportive care and safety of the patient are allowed. Concomitant 
medications will be recorded in the patient records. The administration of 
any other anticancer agents including chemotherapy and biologic agents 
is NOT permitted except as mentioned above.  
5.5.2 Concomitant administration of agents that prolong the QT interval and 
CYP 3A4 inhibitors while patients are receiving nilotinib is contraindicated 
unless determined to be absolutely necessary. In addition to medications, 
patients must be counseled not to consume grapefruit, grapefruit juice, 
star fruit or star fruit juice. Please see http://www.torsades.org/medical-
pros/drug-lists/printable-drug-list.cfm for a comprehensive list of agents 
that prolong the QT interval as well as Appendix H. In cases where 
administration of a QT prolonging agent or a CYP 3A4 inhibitor cannot be 
avoided, it is strongly recommended that an ECG be obtained 24 to 48 
hours and one week after initiating the concomitant therapy. 
5.5.3 In in-vitro assays, nilotinib has been shown to interact with CYP 2C9, 
CYP 2C8, CYP 2 D6, and CYP 3A4. Because of the inherent risk of 
either reduced activity or enhanced toxicity of the concomitant medication 
and/or nilotinib, drugs known to interact with the same CYP450 
isoenzymes (2D6 and 3A4) as nilotinib should be used with caution 
(Appendix G). Patients using concomitant medications known to be 
metabolized by these cytochrome p450 enzymes will not be excluded 
from the study. However, the patients must be carefully monitored for 
potentiation of toxicity due to individual concomitant medication. 
Consideration should be given to using alternative agents with less 
potential for interaction with nilotinib. Special care has to be given to the 
concomitant use of acetaminophen (e.g. Tylenol or Percocet) with 
nilotinib.  Any use of concomitant medication will be captured in the 
patient's record.  
5.5.4 Since warfarin is metabolized through the CYP450 system, 
anticoagulation with warfarin (e.g. Coumadin® or Coumadine®) should 
be avoided whenever possible in patients participating in this study.  As 
an alternative, therapeutic anticoagulation may be accomplished using 
low-molecular weight heparin (e.g. Lovenox) or heparin.  In general, the 
use of Coumadin® is discouraged on this protocol. 
5.5.5 It is recommended that prophylactic anti-emetics be withheld until the 
patient has experienced grade 1 nausea or vomiting. Prophylactic use of 
loperamide  (e.g. Imodium®, with suggested dosing as start: 4mg po. x 1, 
than 2mg po after each loose stool, max 16mg/d) is recommended for 


 
2005-0048 
 
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patients experiencing grade 1 or 2 diarrhea, before dose interruption. 
 
6.0 
Pretreatment Evaluation (See Appendix B) 
6.1 
A complete history and physical examination including performance status. 
6.2 
CBC, platelet count and differential, total bilirubin, SGPT (or SGOT), and 
creatinine.  (Differential not required if WBC < 0.5 x 109/L). 
6.3 
Bone marrow aspirate for morphology; cytogenetics or FISH (if not done within 3 
months). 
6.4 
Pregnancy test for female patients of childbearing potential within 7 days before 
initiation of study drug dosing 
6.5 
Peripheral blood and bone marrow for Abl mutations. 
6.6 
Pretreatment EKG.  Patients with NYHA cardiac class I or II will have an 
echocardiogram or cardiac scan performed before start of therapy. 
6.7 
MDASI-CML and single item quality of life (QOL) rating completed by patient, 
and ECOG performance status (optional)  
6.8 
miRNA analysis (optional): one single blood sample (5cc) will be collected 
only by EDTA or citrate (Dr. Calin’s lab at MD Anderson Cancer Center). 
 
* Missed collection of any of the optional procedures will not be considered a protocol 
deviation or violation. 
 
7.0 
Evaluation During Study (See Appendix B) 
7.1 
Physical exam every 3-4 months.   After the first year, physical exams will be 
recommended once every year.  Toxicity will be assessed at every leukemia 
physician clinic visit. Patients will be instructed to notify the research nurse for 
any toxicities. 
7.2 
CBC, platelet, differential every 1-2 weeks for 4 weeks, every 4-8  weeks until 6 
months from the start of therapy, then every 3-6 months until 2 years on therapy 
then at the discretion of the treating physician. (Differential not required if WBC < 
0.5 x 10
9/L). 
7.3 
Bone marrow aspirate with cytogenetics or FISH every 3-4 months in year 1, 
then every 6-12 months in year 2, then every 2-3 years.   For patients in 
complete cytogenetic remission, bone marrow will be at the discretion of the 
treating physician after year 2.  Peripheral blood FISH for BCR/ABL may be 
substituted for bone marrow cytogenetic every 1-3 years. 
7.4 
Total bilirubin, SGPT or SGOT, and creatinine every 2-4 weeks for 1 month then 
every 4-8 weeks until 6 months from the start of therapy, then every 3-6 months 
until 2 years on therapy then at the discretion of the treating physician.  


 
2005-0048 
 
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7.5 
Diaries may be returned on every visit to MD Anderson Cancer Center  for bone 
marrow aspiration. Compliance to the treatment schedule may also be verified 
verbally with the patient at the clinic visit. 
7.6 
Peripheral blood or bone marrow for quantitative PCR (QPCR) every 3-4 months 
for 1 year then every 6-12 months in year 2 then once per year (+/- 3 months). 
7.7 
EKG on day 5 +/- 3 days of therapy, then at 6 weeks +/- 2 weeks, and 3 months 
7.8 
miRNA analysis (optional): one single blood sample (5cc – only by EDTA or 
citrate) will be collected at the time of any or all scheduled blood collections when 
PCR is scheduled (Dr. Calin’s lab at MD Anderson Cancer Center). 
7.9 
MDASI–CML weekly during the first three months of treatment, then every other 
week for the remainder of the study. MDASI-CML will be collected by paper, 
computer, or IVR system. Patients will be instructed during the first visit on the 
use of the Interactive Voice Response (IVR) system (optional*). 
7.10 Single item QOL at each clinic visit during study (optional*). 
 
* Every effort will be made to collect optional procedures at all time points for all 
patients; however, missing collection in one or more of these time points in occasional 
patients will not be considered a protocol deviation/violation. 
 
8.0 
Criteria for Response 
8.1 
Complete Hematologic Remission (CHR) - normalization for at least 4 weeks of 
the bone marrow (less than 5% blasts) and peripheral blood with WBC < 10 x 
109/L and no peripheral blasts, promyelocytes or myelocytes.  This is in addition 
to disappearance of all signs and symptoms of the disease.  
Partial Hematologic Response (PHR) = CHR except for persistence of immature 
cells (myelocytes, metamyelocytes), or splenomegaly < 50% of pretreatment, or 
thrombocytosis >450x109/L but <50% of pretreatment. 
8.2 
Complete hematologic remission will further be classified according to 
suppression of the Philadelphia chromosome (Ph) by cytogenetics or i FISH 
a) 
No cytogenetic response - Ph positive 100% of pretreatment value 
b) 
Minor cytogenetic response - Ph positive 35-90% of pretreatment value 
c) 
Partial cytogenetic response - Ph positive 1-34% of pretreatment value 
d) 
Complete cytogenetic response - Ph positive 0% 
* Major cytogenetic response = complete + partial (Ph positive <35%) 
8.3 
Molecular response = PCR ratio < 0.05%, or PCR negative  


 
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Page 19 of 30 
 
9.0 
Criteria for Removal from the Study 
9.1 
Ph-positive disease still > 35% after 6 months of nilotinib therapy.  Patients 
should be changed to imatinib 400 – 800 mg orally daily. 
9.2 
Patients who develop accelerated disease features (but not clonal evolution) or 
blastic phase with no response to optimization of therapy as defined under 5.2 
and 5.3.  
9.3 
Resistant hematologic disease on optimal therapy 
9.4 
Unacceptable severe (grade 3-4) toxicity despite dose optimization 
9.5 
Patient request 
 
10.0 Statistical Considerations 
 
10.1 This is a single-arm, phase II study of oral nilotinib to patients with Ph-positive or 
Bcr-positive CML in early chronic phase CML. The primary outcomes will be 
molecular response (MR) after 12 months of therapy (defined in protocol section 
8.3) and grade 3-4 therapy related toxicity. Major cytogenetic response at 6 
months is a secondary end point. A maximum of 125 patients, 100 chronic phase 
and 25 accelerated phase, will be recruited for the study. Patients are expected 
to be accrued to the trial at a rate of approximately 5 patients per month, 50 
patients are anticipated to be enrolled in each of the first two years. Due to the 
long time to assess molecular response (12 months) and major cytogenetic 
response (6 months), only the first 50 patients can be used for interim analysis 
for molecular response, and the first 75 patients will be used in interim analysis 
for cytogenetic response. The study will be completed in 3 years. 
 
Sample Size and End Point Monitoring 
Historical data on similar patients show molecular response rate of 19% at 12 
months, major cytogenetic response rate of 50% at 6 months, and toxicity rate of 
10%. The method of Thall, Simon, Estey (1995, 1996) as extended by Thall and 
Sung (1998) will be used for monitoring efficacy and safety simultaneously.  The 
stopping boundary tables are given below. Mathematical details are deferred to 
the end of this section. 
 
The trial will be monitored according to the following stopping boundaries for the 
primary end point, molecular response (MR) at 12 months. 
 
Recommend Stopping if  # of 
MR Observed 
Number of Patients 
Evaluated  
0 
7 
1 
19 


 
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Page 20 of 30 
2 
29 
3 
39 
4 
48 
5 
50 
 
The trial will be also be monitored according to the following stopping boundaries 
for major cytogenetic response (CyR) at 6 months. 
 
Recommend Stopping if  # of 
CyR Observed 
Number of Patients 
Evaluated  
0 
5 
1 
6-7 
2 
8-10 
3 
11-12 
4 
13-14 
5 
15-16 
6 
17-19 
7 
20-21 
8 
22-23 
9 
24-25 
10 
26-28 
11 
29-30 
12 
31-32 
13 
33-34 
14 
35-36 
15 
37-39 
16 
40-41 
17 
42-43 
18 
44-45 
19 
46-47 
20 
48-49 
21 
50-51 
22 
52-53 
23 
54-55 
24 
56-57 
25 
58-59 
26 
60-61 
27 
62-63 
28 
64-65 
29 
66-67 
30 
68-69 
31 
70-71 
32 
72-73 
33 
74-75 
 


 
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Page 21 of 30 
At the same time, the trial will be monitored according to the following stopping 
boundaries for toxicity. 
 
Recommend Stopping if  # of 
Toxicity Observed 
Among These Number of 
Patients 
2 
2-3 
3 
5-7 
4 
9-12 
5 
14-17 
6 
19-23 
7 
25-28 
8 
30-33 
9 
35-39 
10 
41-44 
11 
46-50 
 
The operating characteristics are summarized in the following table. 
 
True Toxicity 
Rate 
True MR 
Rate 
Probability of 
Stopping Early 
Achieved Sample 
Size Quartiles* 
25th  
50th  
75th  
0.05 
0.2 
0.26 
79 
100 
100 
 
0.3 
0.10 
100 
100 
100 
 
0.4 
0.04 
100 
100 
100 
 
0.5 
0.02 
100 
100 
100 
 
0.6 
0.01 
100 
100 
100 
0.1 
0.2 
0.31 
62 
100 
100 
 
0.3 
0.16 
100 
100 
100 
 
0.4 
0.11 
100 
100 
100 
 
0.5 
0.09 
100 
100 
100 
 
0.6 
0.08 
100 
100 
100 
0.15 
0.2 
0.46 
57 
100 
100 
 
0.3 
0.34 
70 
100 
100 
 
0.4 
0.30 
80 
100 
100 
 
0.5 
0.29 
85 
100 
100 
 
0.6 
0.28 
87 
100 
100 
0.2 
0.2 
0.69 
57 
70 
100 
 
0.3 
0.62 
57 
78 
100 
 
0.4 
0.59 
61 
83 
100 
 
0.5 
0.58 
62 
86 
100 
 
0.6 
0.58 
62 
87 
100 
0.25 
0.2 
0.87 
57 
61 
78 
 
0.3 
0.84 
57 
66 
85 


 
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Page 22 of 30 
True Toxicity 
Rate 
True MR 
Rate 
Probability of 
Stopping Early 
Achieved Sample 
Size Quartiles* 
25th  
50th  
75th  
 
0.4 
0.83 
57 
67 
87 
 
0.5 
0.83 
57 
67 
88 
 
0.6 
0.83 
57 
67 
88 
* Because MR can only be assessed after 12 months, all achieved quartiles are 
evaluable quartiles + 50. 
 
When toxicity is equal to the historical rate 0.10, the operating characteristics for 
the stopping rule for secondary end point (major cytogenetic response) are 
summarized in the following table. 
 
True Major 
Cytogenetic 
response 
Rate 
Probability of 
Stopping Early 
Achieved Sample Size 
Quartiles* 
25th  
50th  
75th  
0.4 
0.81 
58 
65 
87 
0.5 
0.41 
65 
100 
100 
0.6 
0.12 
100 
100 
100 
0.7 
0.04 
100 
100 
100 
0.8 
0.03 
100 
100 
100 
 
The stopping boundary tables are obtained using the following Bayesian rules. 
Let E correspond to the experimental regimen, H denote historical data, MR for 
molecular response, CyR for major cytogenetic response, and T for toxicity. The 
trial will be stopped if any of the following conditions is satisfied. 
 
1) Prob{p(MR,H)  + MR < p(MR,E) | data} < 0.05, where MR =0.20 
2)  Prob{p(CyR,H)  + CyR < p(CyR,E) | data} < 0.06, where CyR =0.10 
3)  Stop if Prob{p(T,H)  + T < p(T,E)| data}>0.95, where T =0.05 
 
10.2  Updated Statistical Design 
 
To date, 94 patients have been treated with 400 mg BID nilotinib, with an 
observed 12-month MMR rate of 84%.   Under the current design, which has 
target total sample size 100, 6 additional patients would be treated.  Under the 
proposed design with target total sample size 125, an  additional 31 patients 
would be treated . Assuming a non-informative  beta(0.5, 0.5) prior on 
Pr(MMR12) = probability of major molecular response at 12 months, the trial’s 
primary endpoint, and assuming  that the  currently observed rate of 84% for 
MMR12 persists,  under the current design if 84/100 (84%) MMR12’s were 
observed  then a posterior 95% credible for Pr(MMR12) would be [0.760 – 
0.902],   which has a width of 0.142.  Under the proposed design with 


 
2005-0048 
 
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Page 23 of 30 
125 patients, if 105/125 (84%) MMR12’s were observed then a posterior 95% 
credible for  Pr(MMR12) would be [0.768 – 0.896]  which has a width of 0.128.  
Consequently, in terms of reliability of estimation,25 additional patients would 
provide a 10% reduction in the width of a posterior 95% credible interval for  
Pr(MMR12).   Similarly, substantial improvements in statistical reliability would be 
obtained for estimates all other parameters of interest, including the probability of 
complete cytogenetic response,  distribution of response duration, Kaplan-Meier 
estimates of progression-free and overall survival time distributions, and toxicity 
rates. 
 
There will be no change in the planned accrual for accelerated phase. This will 
remain at 25 patients.  
 
 
10.3 Statistical Considerations for MDASI and QoL   
 
Continuous variables (e.g., age, hematology values) will be summarized using 
the mean (s.d.) or median (range).  Frequency tables will be used to summarize 
categorical variables.  Logistic regression will be used to assess the impact of 
patient characteristics on the molecular response rate and on symptom severity, 
interference, and QOL.  The distribution of time-to-event endpoints (e.g., 
molecular response, overall survival) will be estimated using the method of 
Kaplan and Meier.  Comparison of time-to-event endpoints by important 
subgroups of patients will be made using the log rank test.  Cox (proportional 
hazards) regression will be used to evaluate multivariable predictive models of 
time-to-event outcomes. Correlations of symptom severity and therapy 
adherence (from research nurse records) will be determined. 
11.0 Reporting Requirements 
11.1 Reporting requirements will be as per institutional guidelines. Exceptions will 
include: 
 
Grade 3-4 myelosuppression 
 
Grade 3 weight gain 
 
11.2 
Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include an 


 
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adverse experience that, had it occurred in a more severe form, might 
have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
 Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator or 
the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to 
the study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the Safety Project Manager in 
the IND Office.  
 Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  
 Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed 
until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event.  
 
 Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy.  


 
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Reporting to FDA: 
 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
11.3 ADVERSE EVENT REPORTING POLICY FOR LEUKEMIA LATER PHASE II 
AND PHASE III STUDIES 
Recognizing the need to protect patients and the unique characteristics of 
leukemia, viz  prolonged myelosuppression, consequent hospitalizations and 
potential for death, the following standards for reporting AEs in patients treated 
on later Phase II and Phase III Dept. of Leukemia protocols in which myelotoxic 
therapy is to be given will be followed. 
1. 
All deaths with possible, probable or definite attribution to the study drug 
must have a written report submitted to the Institutional Review Board 
(IRB) via OPR within 24 hours (next working day) of knowledge of the 
event.  All deaths not related to the study drug must have a written report 
submitted to the IRB within 5 working days. 
2. 
Unexpected life-threatening events will be reported within 5 working days 
of notification, regardless of attribution to study drug.  These events may 
include opportunistic infections e.g., CMV, pneumocystis, tuberculosis or 
other unusual organisms or their presentations. Other unexpected life-
threatening events, specifically events prompting initiation of life support 
and organ failure known not to be due to leukemia, will be reported.  
[Examples:  a) Simple febrile neutropenia with hospitalization is not an 
expedited reportable event to the IRB but will be included in the annual 
report to the IRB whereas febrile neutropenia complicated by Gram-
negative bacteremia with shock or its complications is to be  reported 
within 5 working days of notification. b) Thrombocytopenic epistaxis or 
bleeding from  mucosal surfaces easily managed with platelet support is 
not an expedited reportable event to the IRB but will be included in the 
annual report to the IRB whereas major gastrointestinal bleed will be 
reported within 5 working days of notification.] 
3a. 
Prolonged myelosuppression following induction therapy defined as viz 
marrow cellularity 5% without evidence of leukemia 42 or more days from 
start of therapy and not due to use of additional anti-leukemia agents 
before day 42 will be reported within 30 days of notification.   


 
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3b. 
Myelosuppression following post remission therapy will be reported if at 30 
days post-treatment marrow has not recovered to platelets >20,000 or 
granulocytes > 500. 
Myelosuppression and associated complications are expected events during leukemia 
therapy.  Myelosuppression and associated simple complications such as fever, 
infections, bleeding and related hospitalizations, will, except as noted above, not be 
reported as individual AEs, but will be summarized in annual report to the IRB.  
Expected Grade 4 events, as specified in the protocol, will not be reported in an 
expedited fashion, but will be reported in the annual report.  Leukemia-Specific 
Adverse Event Recording Guidelines 
 
11.4 Each serious adverse event (but not pregnancies) must be reported by the 
investigator to Novartis within 24 hours of learning of its occurrence, even if it is 
not felt to be treatment-related.  Follow-up information about a previously 
reported serious adverse event must also be reported to Novartis within 24 hours 
of receiving it.  If the serious adverse event has not been previously documented 
(new occurrence) and it is thought to be related to the study (or therapy), the 
Medical Safety Expert of the Clinical Safety & Epidemiology (CS&E) Department 
may contact the investigator to obtain further information.  If warranted, an 
investigator alert may be issued, to inform all investigators involved in any study 
with the same drug (or therapy) that this serious adverse event has been 
reported. 
 
Reporting Procedures 
The investigator must complete the Serious Adverse Event Report Form in 
English, assess the relationship to study treatment and send the completed form 
by fax 1.888.299.4565 within 24 hours to the local Novartis Clinical Safety & 
Epidemiology (CS&E) Department ensuring that the form is accurately and fully 
completed,.  The original and the duplicate copies of the Serious Adverse Event 
Form, and the fax confirmation sheet must be kept at the site. 
Follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, and whether the patient continued or 
discontinued study participation.  The form and fax confirmation sheet must be 
retained.  Pregnancy follow-up should describe the outcome of pregnancy, 
including any voluntary or spontaneous termination, details of the birth, and the 
presence or absence of any congenital abnormalities or birth defects. 
 
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