Phase II Study of Dual Targeting of BCR-ABL1 by Adding the Allosteric Inhibitor ABL001 in Patients With Chronic Myeloid Leukemia (CML) and Minimal Residual Disease (MRD) While on Therapy With Tyrosine Kinase Inhibitors
Phase: PHASE2
Conditions: Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia
Sponsor: M.D. Anderson Cancer Center

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Phase II Study of Dual Targeting of BCR-ABL1 by adding the Allosteric Inhibitor ABL001 
in Patients with Chronic Myeloid Leukemia (CML) and Minimal Residual Disease (MRD) 
While on Therapy with Tyrosine Kinase Inhibitors 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2019-0618 
Protocol Title 
Phase II Study of Dual Targeting of BCR-ABL1 by adding the Allosteric 
Inhibitor ABL001 in Patients with Chronic Myeloid Leukemia (CML) and 
Minimal Residual Disease (MRD) While on Therapy with Tyrosine Kinase 
Inhibitors 
Protocol Phase 
II 
Protocol Version 
6 
Version Date 
November 21, 2022  
 
Protocol PI 
Ghayas Issa, M.D. 
Department 
Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
146981 
 
Principal Investigator:  
Ghayas Issa, MD 
 
 
 
 
Department of Leukemia  
 
 
 
 
The University of Texas MD Anderson Cancer Center  
 
 
 
 
1515 Holcombe Blvd., Unit 428  
 
 
 
 
(713) 745-6798 
 
Collaborators:  
 
Hagop Kantarjian, MD 
 
 
 
 
Micheal Andreeff, MD, PhD 
 
 
 
 
Andrew Futreal, PhD 
 
 
 
 
Jing Ning, PhD 
 
 
 
 
 
Study Product:  
 
Asciminib – ABL001 
Protocol Number: 
 
2019-0618 
Coordinating Center:  
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
 
 

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TABLE OF CONTENTS  
 
1. 
Objectives                      
 
 
 
 
 
 
 
1 
  
 
 
 
 
 
 
  
2. 
Background     
 
 
 
 
 
 
 
 
1 
 
3. 
Subject Eligibility 
 
 
 
 
 
 
 
 
10   
 
4. 
Treatment Plan  
 
 
 
 
 
 
 
 
13 
 
5. 
Study Procedures  
 
 
 
 
 
 
 
 
16 
 
6. 
Response Definitions  
 
 
 
 
 
 
 
23 
 
7. 
Investigational Agent Packaging and Labeling 
 
 
 
 
23 
 
8. 
Regulatory and Reporting Requirements   
 
 
 
 
24 
 
9. 
Statistical Considerations  
 
 
 
 
 
 
 
28 
 
10. 
References  
 
 
 
 
 
 
 
 
 
30 
 
11. 
Appendix   
 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 

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1. OBJECTIVES 
 
1.1. Primary Objective: To determine the clinical activity of the combination of asciminib 
(ABL001) and a tyrosine kinase inhibitor (TKI) in patients with CML in complete cytogenetic 
response (CCyR) but detectable BCR-ABL1 transcript 
 
1.2. Secondary Objectives:  
 
1.2.1. To determine the effect of the combination of ABL001 and TKI on the rate of MR4, 
MR4.5, and sustained MR4.5 (MR4 and MR4.5 rates will include only patients with a 
molecular response inferior to MR4 or MR4.5 respectively upon enrollment)  
1.2.2. To investigate treatment-free remission after at least 2 years of sustained deep 
molecular remission 
1.2.3. To determine the safety of the combination of asciminib and tyrosine kinase inhibitors 
1.2.4. To determine the event-free survival (EFS), survival free from transformation to 
accelerated and blast phase (TFS), and overall survival (OS) 
 
1.3. Exploratory Objectives:  
 
1.3.1. To determine the rate of MRD clearance using droplet digital polymerase chain reaction 
(ddPCR) detecting the BCR-ABL1 fusion transcript 
1.3.2. To determine the effect of therapy on quiescent leukemic Ph+ stem cells 
(CFSEmax/CD34+) 
1.3.3. To determine the effect of this combination on mutations in ABL1 and mutations in clonal 
hematopoiesis of indeterminate potential (CHIP)-associated genes using molecular 
barcode sequencing 
1.3.4. To determine the effect of therapy on bone marrow progenitors in clonogenic assays 
1.3.5. To describe immune effects of the combination of TKI and ABL001 
1.3.6. To describe patient reported outcomes (PRO) using the MDASI-CML instrument 
See Table 2 for summary of objectives and related endpoints.  
2. BACKGROUND AND SCIENTIFIC RATIONALE  
In order to achieve cure in CML, and eradicate MRD, a therapeutic combination of agents with 
non-overlapping mechanisms of resistance is needed. The successful use of TKIs targeting BCR-
ABL1, the fusion oncoprotein causing this disease, has markedly improved prognosis.1-3 
However, despite this success, resistance occurs. Circumventing resistance constitutes an 
important goal. In addition, the goal of therapy has shifted towards attaining deeper responses. 
Furthermore, treatment-free remission (TFR) has become an endpoint of increasing interest and 
relevance. In patients with chronic phase CML, who achieve and maintain undetectable BCR-
ABL1 transcript levels (termed complete molecular response or CMR) for at least 2 years, on 
imatinib, approximately 40% remain free of recurrence after stopping their treatment.4 Thus, 
developing novel strategies aimed at achieving deeper responses in CML for a larger number of 
patients would be a step closer towards treatment discontinuation, and cure. 
2.1. Chronic Myeloid Leukemia  

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Chronic myeloid leukemia (CML) is a pluripotent stem cell disorder characterized by the presence 
of the Philadelphia (Ph) chromosome in the leukemic cells. The Ph chromosome results from a 
(9;22) translocation in which the c-ABL oncogene has moved from chromosome 9 into the BCR 
(breakpoint cluster region) gene on chromosome 22, resulting in a chimeric BCR-ABL gene. This 
is the causative abnormality in CML.5-7 The fused gene encodes an 8.5 kb chimeric mRNA, which 
is translated into a 210-kDa protein.8-10 This p210 BCR-ABL protein functions as a constitutively 
activated tyrosine kinase and is uniquely present in the leukemic cells of CML patients.11 The 
breakpoint in the BCR gene occurs either between BCR exon b2 and b3 or between BCR exons 
b3 and b4. Therefore, in the mature BCR-ABL mRNA, either b2 or b3 is spliced to ABL exon a2, 
which results in two alternative chimeric p210 BCR-ABL proteins, with either a B2A2 or B3A2 
junction.12 
 
2.2. Therapy with Tyrosine Kinase Inhibitors  
 
Imatinib is a low molecular weight phenylaminopyrimidine designed to selectively inhibit BCR-
ABL tyrosine kinase activity,13 and is now the standard therapy for newly diagnosed patients with 
CML who do not undergo allogeneic stem cell transplant. For patients who develop resistance or 
intolerance to imatinib, effective therapy with 2nd generation TKIs has been developed. 
Approximately 50% of patients treated with these agents after imatinib failure achieve a CCyR, 
and these responses are also durable in most patients. 
 
Among patients who achieve a CCyR, those who achieve a MMR (ie, at 18 months from the start 
of therapy) have an improved EFS and survival free from transformation to accelerated or blast 
phase compared to those with CCyR but no MMR (7-year EFS 95% vs 86%, respectively).14 In 
this same analysis, none of the patients who had achieved a MMR transformed to accelerated or 
blast phase. Achieving CMR further improves the long-term outcome of patients after treatment 
with imatinib.4 Thus, improving the molecular response of patients who have already achieved a 
CCyR with TKI has become an important goal of therapy. It has been suggested that patients who 
achieve CMR may discontinue therapy with imatinib, an important goal for patients. However, 
discontinuation of imatinib among patient who achieve CMR results in relapse in over 50% of 
patients.4 Additional measures are needed to make treatment discontinuation a safer proposition. 
 
2.3. Resistance and Persistence with Single-agent TKI  
 
The most common mechanism of resistance to TKIs in CML is development of mutations in their 
binding site.15-18 Use of targeted therapy in this disease is by far the most successful application 
of precision medicine, however resistance still occurs. Lessons can be applied from human 
immunodeficiency virus treatment where simultaneous administration of highly active combination 
therapies has dramatically decreased the rate of resistance.19 In fact, use of sequential rather 
than simultaneous TKIs selects for drug-resistant ABL1 mutations with increased oncogenic 
potency.20 Even though second-generation TKIs such as dasatinib and nilotinib are mostly able 
to overcome imatinib-resistant mutations, combination therapies thus far have not been 
conceivable given the similar binding sites of these agents. A combination of agents with distinct 
targeting mechanisms and non-overlapping resistance profiles is essential for preventing 
emergence of mutations and further improving outcomes in this disease. 
 

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Despite the success of second generation TKIs, a significant number of patients do not achieve 
deep molecular responses. After 5 years of therapy, in the ENESTnd trial approximately 55% of 
patients achieve MR4.5 with nilotinib and only approximately 30% with imatinib.21 Similarly, in 
DASISION, only approximately 40% of patients treated with dasatinib and approximately 30% of 
those treated with imatinib achieve such response.22 The rates of sustained MR4.5 are 40-45% 
with nilotinib and 26% with imatinib23; no information is available with dasatinib. Pre-clinical 
studies have shown that neither TKI is able to eradicate the earliest CML progenitors. Thus, with 
current monotherapy approaches, most patients are either ineligible to attempt treatment 
discontinuation or experience relapse after discontinuation because of the persistence of residual 
disease.   
 
2.4. Treatment-free Remission as a New Therapy Goal 
 
The successful use of TKIs has markedly improved the prognosis for patients with CML. The last 
report on the pivotal IRIS study demonstrated an overall survival rate of 80% at 10 years in the 
arm investigating imatinib as initial therapy.1 Thus, it is estimated that the number of patients living 
with CML will increase overtime eventually reaching a near plateau of 181,000 of the United 
States population, nearly 35 times the annual incidence.24 The current standard is continuous, 
lifetime treatment with TKIs. This is associated with long-term side effects for some patients 
including the risk of arterio-thrombotic events, pleural effusions, pulmonary hypertension, second 
malignancies and others, and an increasing financial burden on individuals and healthcare 
systems.25,26  
 
That is why TFR has become an endpoint of increasing interest and relevance. In the STIM trial, 
approximately 40% of patients with chronic phase CML receiving imatinib, who achieve and 
maintain undetectable BCR-ABL1 transcript levels for at least 2 years, remain free of recurrence 
without the need to resume therapy.4 All other patients relapsed and required resumption of 
therapy. Therefore novel strategies are needed in order to achieve deep responses in more 
patients, and make treatment discontinuation a safe and effective strategy for those who 
discontinue therapy. 
 
2.5. Minimal Residual Disease 
 
Minimal or measurable residual disease (MRD) denotes the cancer cell reservoir remaining post-
treatment. All CML cells harbor the translocation t(9;22) leading to the oncoprotein BCR-ABL1. 
This provides a unique genetic fingerprint enabling detection and monitoring of CML. In clinical 
practice, RT-PCR of the BCR-ABL1 messenger ribonucleic acid (mRNA) is the most sensitive 
assay. However, as indicated previously in the STIM trial example, 60% of patients with 
undetectable transcript levels using this assay relapsed upon discontinuation of therapy, 
indicating presence of the disease below the clinical assay’s level of detection. Therefore, 
development of highly sensitive assays for detection of low transcript levels is essential for 
therapeutic strategies aimed at curing this disease. It has been suggested that ddPCR could be 
one alternative sensitive method to detect and quantify low BCR-ABL1 transcript levels.27 This 
method is based on isolation of the PCR reaction into single droplets, tested independently for 
the presence of the target.  
 

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Moreover, despite that BCR-ABL1 is present in quiescent leukemia initiating cells or stem cells 
(LSCs), these cells have a decreased dependence on this oncogene.28,29 In order to eradicate 
minimal 
residual 
disease 
in 
CML, 
a 
therapeutic 
combination 
targeting 
both 
proliferative and quiescent LSCs is needed. 
 
2.6. Allosteric Inhibition of ABL1 
 
Structural studies of ABL1 have shown an 
interaction between the N-terminal myristoyl 
group and a hydrophobic cleft located near 
the C terminus. This interaction is thought to 
provide a mechanism of auto-inhibition 
disrupted in the BCR-ABL1 fusion protein.30 
Small molecules binding the BCR-ABL1 
myristoyl pocket were shown to inhibit kinase 
activity 
via 
an 
allosteric 
mechanism.31 
ABL001 is a potent and selective allosteric 
BCR-ABL1 inhibitor. In contrast to catalytic-site ABL1 kinase inhibitors, it binds to the myristoyl 
pocket and induces formation of an inactive kinase conformation (Figure 1).32 Besides having in-
vitro potency similar to second-generation TKIs, ABL001 is more selective given that myristoyl-
binding sites analogous to that of ABL1 are only found in a limited number of kinases. In addition, 
ABL001 has a distinct pattern of resistance mutations and no shared resistance with the catalytic 
inhibitor nilotinib. Importantly, despite detection of pre-treatment clonal populations, the non-
overlapping resistance profiles of ABL001 and nilotinib allowed for durable tumor eradication in 
CML xenografts when used in combination (Figure 2).17  
 
2.7. Overview of Current Clinical Data with ABL001 
 
2.7.1. Safety Pharmacology and Toxicology  
 
An extensive toxicology safety 
evaluation 
program 
(subchronic, 
chronic, 
reproductive 
toxicology, 
phototoxicity and genotoxicity 
studies) was conducted.  
 
Safety pharmacology studies 
indicate that ABL001 is not 
expected to cause effects on the 
vital functions of the CNS, and 
the respiratory systems. No 
cardiovascular 
effects 
were 
observed in a single dose 
jacketed telemetry study in dogs 
at doses up to 200 mg/kg or the 
Figure 1: X-ray crystal structure of BCR-ABL1 with ABL001 
and nilotinib bound to distinct sites.  
 
Figure 2: Durable tumor eradication with ABL001 and nilotinib
combination. Each line represents an individual KCL-22 mouse xenograft.

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invasive telemetry cardiovascular safety study up to 60 mg/kg. Furthermore, no ECG related 
findings were noted in the 4 week GLP dog toxicology study at the end of treatment or recovery. 
As determined by the results of the phototoxicity assessment (in vitro and in vivo), phototoxic 
potential was identified in the mouse UV-LLNA assay. Given these data, patients should be 
advised to avoid prolonged exposure to sunlight (sunbathing) and to use sunscreen. 
 
In the embryo-fetal development study in rats, results indicate a risk of fetal malformations 
and/or visceral and skeletal variants. In the fertility study, administration of ABL001 by daily oral 
gavage at doses of 10, 50 and 200 mg/kg/day to males and females there was no evidence of 
effects on reproductive function (mean day to mating, mating and fertility indices) at any dose. 
There was evidence of a slight effect on male sperm motility and/or sperm count in individual 
animals and an embryo-lethal effect at 200 mg/kg/day. Based on these results, the no-
observed-adverse-effect level (NOAEL) for paternal and maternal toxicity was considered to be 
200 mg/kg/day and the no-observed-effect level (NOEL) for reproductive function and early 
embryo-fetal development was considered to be 50 mg/kg/day. 
 
Repeat dose toxicity studies have been performed in rats, dogs and monkeys up to 26, 4 and 
13 weeks duration, respectively. Rat and dog toxicology studies identified pancreas, liver, 
adrenal and harderian gland as potential target tissues. The cynomolgus monkey did not 
recapitulate in short or long-term studies the pancreatic changes observed in the dog or the rat 
hepatic changes. All findings thus far have demonstrated a partial to complete reversibility 
during a 4-week recovery phase, and can be readily monitored in preclinical and clinical settings. 
The maximal doses evaluated in the 13/26-week general toxicity studies was 200 mg/kg in rats 
and 100 mg/kg in monkey and provide substantive safety margins over the 40 mg BID clinical 
dose exposures. 
 
Please refer to the latest [ABL001 Investigator’s Brochure] for more details. 
 
2.7.2. 
Non-clinical Pharmacokinetics and Metabolism 
The preclinical pharmacokinetic profile of ABL001 has been investigated in three species: 
mouse, rat and dog. In these species, ABL001 exhibited low to moderate clearance, a moderate 
volume of distribution and a short apparent terminal half-life. Bioavailability was found to be low 
in rodents and moderate to high in dog. 
ABL001 displayed high plasma protein binding across all tested species (2-6% free fraction). 
The metabolite profile of ABL001 has been examined in vitro using rat, dog, monkey and human 
hepatocytes. Interspecies differences were observed. Direct glucuronidation occurred more 
readily in human and dog than in monkey and was noticeably absent in rat. However, no unique, 
major metabolites were identified in human hepatocytes. The overall metabolic turnover was 
low. 
The metabolite profile of ABL001 has also been examined in vivo in rats. Following intravenous 
and oral administration of [14C-ABL001] to intact rats, ABL001 was found to be the predominant 
component of plasma, accounting for ~86 - 91% of radioactivity from 0 - 8 h. ABL001 was 
excreted primarily in the feces, with ~90% of radioactivity detected in the feces from 0 - 48 h. 
Renal elimination represented a minor route, with ~2.4% of radioactivity detected in the urine 
from 0 - 72 h. In the feces, ~58% (intravenous) and ~71% (oral) of the dose was associated 

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with unchanged ABL001, with several oxidative metabolites accounting for the remaining 
radioactivity. The metabolites formed in vivo were consistent with those observed in vitro. 
Similar observations were noted in bile-duct cannulated rats. 
To assess for potential drug-drug interactions (DDI), studies have been conducted with 
cytochrome P450 (CYP) enzymes and several transporters in vitro.  
In human liver microsomes, the major metabolic route of ABL001 was found to be 
glucuronidation, followed by oxidative metabolism, consistent with findings from human 
hepatocytes. Several UGT enzymes were found to be capable of ABL001 glucuronidation 
(UGT1A3, UGT1A4, UGT2B7, and UGT2B17). The oxidative metabolism of ABL001 was also 
catalyzed by several CYP enzymes. CYP3A4/5 appears to contribute the most, followed by 
CYP2C8, CYP4F12, and potentially CYP2D6. Though the DDI risk with inhibitors of these 
enzymes is likely to be minimal, inhibitors of CYP3A4/5 still have the potential to increase 
ABL001 concentration. Therefore, strong inhibitors of CYP3A4/5 should be avoided. Strong 
inducers of CYP3A4/5 have the potential to reduce ABL001 concentrations. Therefore, the use 
of strong inducers of CYP3A4/5 or UGT1A/2B should be avoided on this trial. 
Transporter phenotyping studies have identified ABL001 to be a substrate of Breast Cancer 
Resistant Protein (BCRP) and Permeability glycoprotein (P-gp). While inhibition of BCRP is not 
expected to result in any clinical relevant changes, inhibitors of P-gp may increase ABL001 
concentrations significantly and should be avoided in this study.  
There is a potential for DDIs with co-medications metabolized by CYP3A4/5, CYP2C8 and 
CYP2C9 at the anticipated human efficacious dose. Therefore, narrow therapeutic index 
substrates of CYP3A4/5, CYP2C8 and CYP2C9 should be avoided. All other substrates of 
CYP3A4/5, CYP2C8 and CYP2C9 should be used with caution. 
Please refer to the latest [ABL001 Investigator Brochure] version for more detail.  
2.7.3. 
Clinical Experience 
In  a  phase  I,  multicenter,  first  in  human  study,  preliminary  results  show  that ABL001 is 
well tolerated in heavily pretreated patients with CML with resistance or  intolerance  to  prior  
TKIs.33 Among these patients, 65% had previously received ≥3 TKIs. In this study, 101 patients 
have been enrolled as of May 2, 2016, and recruitment is still ongoing. The  maximum  tolerated  
dose  (MTD)  was  not reached  and  40  mg  BID  has  been  recommended  for  CML-CP  
patients  without T315I mutation based on based on preliminary MMR and CCyR results from 
the study as well as overall ABL001 safety and pharmacokinetic information. Dose -escalation 
for patients with T315I mutation is currently ongoing.  
The combination of ABL001 with TKIs has been examined in a phase 1 study (NCT02081378). 
Patients with CML in chronic phase or accelerated phase (AP) and resistance or intolerance to 
≥2 prior TKIs were eligible. They were assigned (based on prior intolerance) to a combination 
with nilotinib or dasatinib. The following combinations were investigated: nilotinib 300 mg BID 
and ABL001 20 mg BID, nilotinib 300 mg BID and ABL001 40 mg BID, dasatinib 100 mg QD 
and ABL001 80 mg QD or 40mg BID. The combinations of ABL001 with nilotinib or dasatinib 
were generally safe and well tolerated. One dose-limiting toxicity was reported with ABL001 at 
20 mg BID + nilotinib (rash maculo-popular) and one with ABL001 at 40 mg BID + dasatinib 

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(increased lipase); both events resolved with dose reduction (reduction of nilotinib to 150 mg 
BID in the first case and reduction of ABL001 to 20 mg BID in the second) 34.  
2.7.3.1. 
Efficacy 
ABL001 resulted in molecular and cytogenetic responses at doses ≥10 mg BID. With a 
median duration of exposure of 8 months, 9/12 (75%) had a CCyR, and 10/50 (20%) had 
a MMR within 6 months of treatment. Clinical activity was seen in patients with non-mutant 
BCR-ABL1 as well as across multiple TKI-resistant mutations. In subsequent cohorts, 
ABL001 was also found to be safe in combination with other TKIs. These findings support 
further evaluation in combination with other TKIs. 
2.7.3.2. 
Safety 
ABL001 was generally well tolerated in heavily pre-treated CML patients resistant to or 
intolerant of prior TKIs. By data cutoff of May 2, 2016, 67 CML patients, including those 
with a T315I mutation (n=9), have been treated at any dose of the ABL001 BID regimen. 
There were no study drug related deaths reported. One death was reported due to general 
physical health deterioration unrelated to the study drug. Overall, 43 serious adverse 
events (SAEs) were reported in 20 patients of the 67 patients. Six patients (9%) 
discontinued ABL001 due to adverse events. Dose limiting toxicities in the study included 
acute cardiac syndrome, lipase increase, arthralgia/myalgia, and bronchospasm in 1 
patient each.  
Overall of 67 CML patients, almost all (94%) patients reported at least one AE, including 
45% reported grade 3/4 AEs. The most common AEs (>10%), regardless of study drug-
relationship, were headache, increased lipase (23.9%), rash (20.9), arthralgia, vomiting 
(both 19.4%), diarrhea, fatigue (both 17.9%), abdominal pain, pruritus (both 16.4%), 
constipation, myalgia, 
nausea, 
upper respiratory tract 
infection 
(all 
14.9%), 
thrombocytopenia (13.4%), peripheral edema (11.9%), increased amylase, dizziness, 
musculoskeletal pain (all 10.4%). 
At 40 mg BID dose (n=26), the most common adverse events (>10%), regardless of study 
drug-relationship, were: increased lipase (30.8%), rash (26.9%), abdominal pain, fatigue, 
vomiting (all 23.1%), arthralgia, diarrhea (both 19.2%), increased amylase, upper 
respiratory tract infection (both 15.4%), cough, bone pain, pruritus, increased weight, 
abdominal discomfort, anemia, constipation, dyspnea, ear pain, non-cardiac chest pain, 
and thrombocytopenia (all 11.5%). 
Please refer to the latest [ABL001 Investigator’s Brochure] for more details. 
2.7.3.3. 
Pharmacokinetics 
PK data from 61 patients (1 in 10 mg BID; 14 in 20 mg BID; 20 in 40 mg BID; 12 in 80 mg 
BID; 9 in 150 mg BID; 5 in 200 mg BID) were available from the phase I study, as of May 
2, 2016. 
Based on the available PK data, ABL001, administered orally is rapidly absorbed with a 
median time to maximum plasma concentration (Tmax) of 2 to 3 hours, independent of 
dose. Systemic exposure of ABL001, following oral administration of single and multiple 
doses, as measured by Cmax and AUC, increased in an approximately dose proportional 

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manner. The variability of exposure is low to moderate with inter-patient variability 
(geometric mean CV %) of 34 to 50% for Cycle 1 Day 1 AUC last and 36 to 60% for Cycle 
1 Day 1 Cmax. With the twice daily dosing regimen, median plasma ABL001 accumulation 
ratios ranged from 1.4 to 2.4. The median accumulation half-life was estimated to be 7 to 
15 hours. 
The emerging data show that the relative contribution of the glucuronidation pathway to 
the total clearance of ABL001 via metabolism is estimated to range from 30% to 61%, 
whereas the relative contribution of the oxidative pathway is estimated to range from 35% 
to 63%. CYP3A4 was the main contributor for the clearance of ABL001 via the oxidative 
pathway while UGT2B7 and UGT2B17 were responsible for the clearance of ABL001 via 
the glucuronidation pathway. There was no metabolite detected with mean contribution to 
plasma radioactivity AUC0-24hours ≥ 10%. ABL001 was the predominant drug-related 
component in plasma at all time points analyzed, ranging from 91.9 to 94.2% of the total 
radioactivity AUC0-24 hours AUC, with an average value of 92.7%. 
Please refer to the latest [ABL001 Investigator’s Brochure] for more details. 
2.7.3.4. 
Exposure-response Relationship 
A preliminary population PKPD model has been developed using data from the study (cut-
off 02May-2016). The time course of molecular response (change in BCR-ABL ratio % IS 
levels from baseline) was described using a semi-physiological model accounting for cell 
maturation, disease progression and existing resistance. 
Simulations performed using an ABL001 population PK model revealed that a dose of 40 
mg BID maintains Ctroughss above the clinical (0.07 to 61 ng/ml) threshold in >=95% of 
chronic phase CML patients without T315I mutation having failed ≥ 2 TKI or intolerant to 
TKIs. The estimates from this clinical study were found to be similar to the threshold trough 
concentration required for 90% inhibition of pSTAT5 derived from a preclinical PK-PD 
KCL-22 mouse xenograft model (free IC90: 30 to 121 ng/mL, after correction for protein 
binding) and in vitro gIC50 assessed in the KCL-22 cell line (1 ng/mL = 2.1 nM after 
correction for protein binding). 
Simulations performed using ABL001 population PKPD model revealed that chronic 
phase CML patients having failed ≥ 2 TKI or intolerant to TKIs are likely to exhibit a 1 log10 
reduction of (%) BCR-ABL mRNA transcript levels from baseline of ~33% (CI95%: 24-
42%) at 6 months, and ~42% (CI95%: 32-52%) at 12 months at a dose of 20 mg BID and 
~41% (CI95%: 31-51%) at 6 months, and ~53% (CI95%: 43-63%) at 12 months at a dose 
of 40 mg BID. 
Additional preliminary exposure response analyses (i.e. exploring the relationship 
between PK and both safety and efficacy) support the selected dose. 
The effect of food on ABL001 PK was characterized in a Phase I study in healthy 
volunteers. Food was found to influence the pharmacokinetics of ABL001. When 
administered with a low-fat meal, the exposure (AUC) decreased by approximately 30%. 
The overall exposure decreased by approximately 65% when administered with a high -
fat meal. 
Therefore, ABL001 will be administered in a fasted state. 

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3. SUBJECT ELIGIBILITY  
 
3.1. Inclusion Criteria: 
 
1. Patients 18 years or older with a diagnosis of Philadelphia chromosome (Ph)- or BCR-
ABL1-positive CML (as determined by cytogenetics, FISH, or PCR). 
2. Patients should be receiving therapy with nilotinib or dasatinib, whether as initial 
therapy or after prior TKI, at a dose equal or lower than the standard dose.  
3. Patients must have received TKI therapy for at least 24 months and not have required 
dose reductions, escalations, discontinuation or re-initiation after discontinuation of 
TKI in the last 6 months. 
4. Patients must be in CCyR (by conventional karyotype or FISH, or BCR-ABL/ABL ≤1% 
IS if no cytogenetic analysis available within 3 months).  
5. Patients must have detectable BCR-ABL1 transcript levels meeting at least one of the 
following criteria: 
a. Patient has never achieved a MMR after 18 months of therapy with their 
current TKI, or 
b. Patient has not achieved MR4.5 after 36 months of therapy with their current 
TKI, or 
c. Patient has lost MMR or MR4.5 confirmed in at least two consecutive analyses 
separated by at least 1 month, or  
d. BCR-ABL1 transcript levels have reached a plateau defined as a ratio that is 
stable in a molecular response category (i.e., MMR or MR4 ) in the last at least 
12 months, with at least 3 values obtained during this period and has not 
achieved MR4 prior to 24 months of therapy for those receiving it for < 36 
months.  
6. Patients must not have had a known continuous interruption of TKI therapy of greater 
than 14 days or for a total of 6 weeks in the 6 months prior to enrollment, unless the 
interruption was for an accident, unrelated hospitalization or surgical procedure. 
7. ECOG performance status ≤2. 
8. Participants must have normal organ function defined as:  
a. Creatinine ≤ 1.5x institutional upper limit of normal.  
b. Amylase and lipase values ≤ 3.0x institutional upper limit of normal.  
c. Alkaline phosphatase ≤ 2.5x institutional upper limit of normal unless 
considered to be not of hepatic origin.  
d. AST(SGOT)/ALT(SGPT) ≤ 3x institutional upper limit of normal.  
e. Total bilirubin ≤ 1.5x institutional upper limit of normal (≤ 3x upper limit of 
normal in patients with known Gilbert's syndrome). 
9. The effects of ABL001 on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for 
the duration of study participation. Women of child-bearing potential must agree to 
use highly effective methods of contraception during dosing and for 30 days after 
study treatment. Should a woman become pregnant or suspect she is pregnant while 

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she or her partner is participating in this study, she should inform her treating 
physician immediately. 
 
Allowable methods of birth control: 
 
- 
Total abstinence (when this is in line with the preferred and usual lifestyle of 
the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
- 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before 
the start of study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone 
level assessment. 
- 
Male sterilization (at least 6 months prior to screening). The vasectomized 
male partner should be the sole partner for that subject. 
- 
Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS), or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
- 
Sexually active males must use a condom during intercourse while taking the 
drug and for 30 days after stopping treatment and should not father a child in 
this period. A condom is required to be used also by vasectomized men in 
order to prevent delivery of the drug via seminal fluid. 
 
 
3.2. Exclusion Criteria: 
 
1. 
Patients with New York Heart Association (NYHA) Class III or IV congestive heart failure 
or LVEF < 40% by echocardiogram or multi‐gated acquisition (MUGA) scan. 
2. 
Patients with a history of myocardial infarction within the last 6 months or 
unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular 
arrhythmias. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), 
complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz 
type II and third degree AV block). 
3. 
Corrected QT interval (QTc) of > 480 milliseconds (ms) on baseline electrocardiogram 
(ECG or EKG) (using the Fridericia Formula) 
4. 
Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following: 
a. 
Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or 
hypomagnesemia, 
history 
of 
cardiac 
failure, 
or 
history 
of 
clinically 
significant/symptomatic bradycardia. 
b. 
Concomitant medication(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointes that cannot be discontinued or replaced 7 
days prior to starting study drug by safe alternative medication. 

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5. 
Patients with known infection with human immunodeficiency virus (HIV) or active 
Hepatitis B or C. 
6. 
Patients with known conditions that would significantly affect the ingestion or 
gastrointestinal absorption of drugs administered orally. 
7. 
Nursing women, women of childbearing potential (WOCBP) with positive blood or urine 
pregnancy test, or women of childbearing potential who are not willing to maintain 
adequate contraception (see inclusion criteria 9) 
8. 
History of acute pancreatitis within 1 year of study entry or past medical history of chronic 
pancreatitis. 
9. 
ANC < 500/mm3, platelet count < 50,000 mm3. 
10. History of other active malignancy within 2 years prior to study entry with the exception 
of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated 
curatively. 
11. Treatment with medications that meet one of the following criteria and that cannot be 
discontinued at least one week prior to the start of treatment with study treatment (see 
APPENDIX for list of medications)  
- 
Moderate or strong inducers of CYP3A. 
- 
Moderate or strong inhibitors of CYP3A and/or P-gp. 
- 
Substrates of CYP3A4/5, CYP2C8, or CYP2C9 with narrow therapeutic index. 
12. Previous treatment with or known/ suspected hypersensitivity to ABL001 or any of its 
excipients 
13. Subject has any other significant medical or psychiatric history that in the opinion of the 
investigator would adversely affect participation in this study. 
 
4. TREATMENT PLAN  
 
4.1. All patients should be registered in CORe. 
 
4.2. TKIs 
 
Patients will continue receiving the TKI (nilotinib, dasatinib) they had been receiving at the time 
of screening at the dose they had been receiving during the last 6 months. 
 
 
Figure 3: Overview of the treatment plan.  

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4.3. ABL001 
 
ABL001 will be administered orally daily on a continuous basis at 40 mg PO BID. Treatment with 
ABL001 will continue uninterrupted unless there are indications for dose delays/modifications.  
 
ABL001 tablets should be ingested as follows: 
 
- 
ABL001 should be administered in the fasted state at least 1 h before or 2 h after a meal. 
Water is permitted during this period. 
- 
ABL001 should be taken with approximately 8 ounces (240 mL) of water. 
- 
ABL001 should be swallowed whole and not chewed or crushed. 
- 
If vomiting occurs within the first hour after taking the drug, re-dosing is allowed before the 
next scheduled dose. 
- 
If the patient does not take ABL001 within 6 hours after the approximate time of the usual 
dosing time, that dose should be skipped and treatment should continue with the next daily 
dose at the prescribed level. 
 
4.4. Dosing Delays/Dose Modifications  
 
Dose escalation beyond the standard doses of 40 mg BID for ABL001 is not permitted. Patients 
experiencing unacceptable toxicity directly attributable to the study drug should temporarily stop 
treatment according to the guidelines in the dose adjustment schema. Toxicity grading will be 
according to the NCI CTCAE, v5.  
 
If toxicity is attributed to the baseline TKI (nilotinib, dasatinib), standard dose adjustment of the 
TKI is indicated while maintaining the same dose for ABL001. If it is not clear which of the 
medications is causing the toxicity (either the TKI or ABL001), both medication doses should be 
adjusted.  
 
The following guidelines for dose adjustment for drug-related toxicities are recommended: 
 
4.4.1. 
TKI 
 
Dose modifications and treatment interruptions will be performed according to institutional 
guidelines and standard clinical practice. The following guidelines may be followed: 
 
4.4.1.1. 
Non-Hematologic Toxicity: 
a. Persistent Grade 2: Patients with persistent grade 2 toxicity that is considered 
clinically significant and unresponsive to appropriate therapy may have treatment 
held until the toxicity has resolved to grade ≤1. Therapy may then be resumed at 
the same dose the patient was receiving at the time treatment was interrupted. If 
the grade 2 toxicity recurs, therapy may be held until the toxicity has resolved to 
grade 1. Treatment may then be resumed with a one dose level reduction. 
b. Grade 3-4: If a patient experiences Grade 3-4 toxicity that is considered clinically 
significant and possibly related to the TKI, therapy will be withheld until the toxicity 
has resolved to Grade ≤1. Treatment may then be resumed at a lower dose. If 

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toxicity recurs, additional dose reductions may be implemented following the same 
general guidelines.  
 
4.4.1.2. Hematologic Toxicity: 
 
If neutrophils are <0.5 x 109/L and/or platelets are <50 x109/L, hold therapy until 
granulocytes are above 0.5 x109/L and platelets are above 50 x109/L, then resume 
therapy at 1 dose level reduction from the dose the patient was receiving at the time 
therapy was interrupted. If a similar degree of toxicity returns, a further dose 
reduction by one dose level can be performed, using the above procedures. 
 
There will be no making up for missed doses. 
 
4.4.2. 
ABL001 
 
Dose modifications and treatment interruptions will be performed according to 
institutional guidelines and standard clinical practice. Briefly, dose adjustments will 
be as follows: 
 
4.4.2.1. 
Non-Hematologic Toxicity: 
 
a. Persistent Grade 2: Patients with persistent grade 2 toxicity that is considered 
clinically significant and unresponsive to appropriate therapy, may have treatment 
held until the toxicity has resolved to grade ≤1. Therapy may then be resumed at 
the same dose the patient was receiving at the time treatment was interrupted. If 
the grade 2 toxicity recurs, therapy may be held until the toxicity has resolved to 
grade 1. Treatment may then be resumed with a one dose level reduction. 
b. Grade 3-4: If a patient experiences Grade 3-4 toxicity that is considered clinically 
significant and possibly related to ABL001, therapy must be withheld until the 
toxicity has resolved to Grade ≤1. Treatment may then be resumed with a one 
dose level reduction. If toxicity recurs, additional dose reductions may be 
implemented following the same general guidelines.  
 
4.4.2.2. 
Hematologic Toxicity: 
 
If neutrophils are <0.5 x 109/L and/or platelets are <50 x109/L, hold therapy until 
granulocytes are above 0.5 x109/L and platelets are above 50 x109/L, then resume 
therapy at 1 dose level reduction from the dose the patient was receiving at the time 
therapy was interrupted. If a similar degree of toxicity returns, a further dose 
reduction by one dose level can be performed, using the above procedures. 
 
4.4.2.3. 
There will be no making up for missed doses. 
 
4.4.2.4. 
Alternative dose reductions can be made to keep clinically significant, 
ABL001-related toxicity grade ≤2. However, the lowest acceptable dose 
level is -2 and the highest is what is established as MTD in the ongoing 
phase 1 study for each combination.  

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4.4.2.5. 
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 and the sponsor 
and documented in the medical record. 
 
4.4.2.6. 
A patient who has had a dose reduction because of any of the reasons 
mentioned above may have their dose re-escalated provided the patient 
has remained free of toxicity requiring dose adjustments as defined above 
for at least 1 month. Escalation will be made by 1 dose-level increments 
only, and not more frequent than every month. 
 
4.4.2.7. 
Occasional missed doses of ABL001 will not be considered a deviation. 
Missed dosed of ≥ 2 consecutive weeks without adequate justification will 
be considered a protocol deviation. 
 
4.4.2.8. 
All toxicities requiring dose interruptions and/modifications will be collected. 
 
Table 1: Dose reduction steps for ABL001  
Dose reduction 
Dose level 0 
Dose level -1 
Dose level -2 
ABL001 BID  
40 mg BID 
20 mg BID 
20 mg QD 
Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
 
4.3.3 Variations to the dose adjustment rules described above for either agent can be 
considered after discussion with the PI and approval from the sponsor. The rationale for this 
variation should be clearly documented.  
4.4.3. Duration of Therapy  
 
4.4.3.1. Patients may receive therapy for up to 36 months. After completion of the 36th month 
patients may continue therapy if in the opinion of the investigator there is clinical 
benefit provided there has been no grade 3 or higher persistent toxicity attributable to 
ABL001 at the doses being administered.  
 
4.4.3.2. Patients who achieve MR4.5 sustained for at least 2 years with at least 2 PCR 
assessments per year can hold therapy with ABL001 and/or TKI and be monitored 
with PCR. If there is reappearance of transcripts detectable by PCR, therapy with one 
or both agents can be resumed at the doses being administered at the time treatment 
was interrupted. Resumption should be particularly strongly considered for patients 
with loss of MMR in any one determination or with loss of MR4 confirmed in 2 
consecutive assessments separated by at least 1 month. 
 
4.4.4. 
Concomitant Medications 
 

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4.4.1 Patients may not receive any other treatment for CML while on study (aside from the TKIs).  
4.4.2 The use of other medications for management of comorbidities or adverse events is 
allowed, as clinically indicated. Concomitant medications will be captured as part of the 
medical record but will not be entered in the case report form.  
4.4.3 Potent CYP3A4 inhibitors should be avoided whenever possible. When the administration 
of such agents is considered indispensable for the patients’ health administration of these 
agents may be allowed after discussion with the principal investigator and approval from 
the sponsor.  
 
5. STUDY PROCEDURES  
 
5.1. Pretreatment Evaluation (Within 14 days prior treatment start, unless otherwise specified) 
5.1.1. A complete history and physical examination including performance status. 
5.1.2. CBC, platelet count and differential (differential not required if WBC <0.5 x109/L), total 
bilirubin, AST/ALT, amylase, lipase and creatinine within 1 week. 
5.1.3. Bone marrow aspirate (within 30 days [+/-7 days] from treatment start). 
5.1.4. Cytogenetic analysis or FISH in bone marrow or peripheral blood (within 30 days [+/-7 
days] from treatment start ). 
5.1.5. Pregnancy test (blood or urine) for female patients of childbearing potential within 14 days 
before initiation of study drug dosing. 
5.1.6. Peripheral blood for PCR. 
5.1.7. Peripheral blood and bone marrow for correlative studies.  
5.1.8. EKG (within 30 days prior to treatment start). 
5.1.9. Echocardiogram or MUGA scan (within 30 days prior to treatment start). 
 
5.2 
Evaluation During Study (Table 3) 
 
5.2.1. Physical exam and evaluation of toxicity (clinic visit or telephone interview) after 2 weeks 
(+/-3 days), 4 weeks (+/-7 days), 8 weeks (+/-7 days), 3 months (+/-7 days), 6 months (+/-
1 month), 12 months (+/-1 month), 18 months (+/-1 month) from the start of therapy, then 
every 6 to 12 months. 
5.2.2. If the evaluation for toxicity is done by phone, a report of physical exam from home 
physician is acceptable provided there is a physical exam at MDACC at least every 6 
months (+/- 1 month) during the first 2 years and every 12 months (+/- 1 month) thereafter. 
5.2.3. Through interview and pill diary, we will review the patient's adherence with therapy (TKI 
and ABL001). Failure to complete pill diary or occasional missed doses will not be 
considered a deviation.  
5.2.4. CBC, platelet, differential after 2 weeks (+/-3 days), 4 weeks (+/-7 days), 8 weeks (+/-7 
days), 3 months (+/-7 days), 6 months (+/-1 month), 12 months (+/-1 month), 18 months 
(+/-1 month) from the start of therapy, then every 6 to 12 months. Differential not 
required if WBC ≤0.5 x109/L. 
5.2.5. Total bilirubin, ALT or AST, amylase, lipase, creatinine after 2 weeks (+/-3 days), 4 weeks 
(+/-7 days), 8 weeks (+/-7 days), 3 months (+/-7 days), 6 months (+/-1 month), 12 months 
(+/-1 month), 18 months (+/-1 month) from the start of therapy, then every 6 to 12 months. 
EKG at day 8 of treatment start (+/- 2 days).  EKG and Echocardiogram/MUGA after 4 
weeks (+/-7 days).  

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5.2.6. PCR (peripheral blood and/or bone marrow), after 4 weeks (+/-7 days), 8 weeks (+/-7 
days), 3 months (+/-7 days), then every 3 months (+/-1 month) until one year, then every 
6months (+/-1 month). 
5.2.7. Bone marrow aspirate with cytogenetic and/or FISH every 6 months (+/- 1 months) in year 
1 (+/- 1 months), then as clinically indicated. 
5.2.8. Patients who permanently discontinue therapy with TKI will have PCR every 4 weeks (+/-
1 week) for the first 6 months after discontinuation of TKI, Then every 2 months (+/-1 
month) for the next 6 months, then every 3 months (+/-3 weeks) for 12 months, then every 
6 months (+/-2 months). 
5.2.9. Peripheral blood for correlative studies at study start, 4 weeks (+/-7 days), 8 weeks (+/-7 
days), 3 months (+/-7 days), 6 months (+/-1 month), 12 months (+/-1 month), 18 months 
(+/-1 month) from the start of therapy, then every 6 to 12 months . Bone marrow samples 
for correlative studies at study start, at 6 months (+/-1 month), at 12 months (+/- 1 month), 
then every 6-12 months. Missed collections at any or all times for correlative studies will 
not constitute a protocol deviation as they have no impact on patient safety.   
5.2.10. CBC, blood chemistries, EKG’s may be done at outside facilities. Under exceptional 
circumstances other tests might be done at outside facilities after discussion with PI. All 
outside lab results will be faxed or mailed to MDACC and reviewed and signed by the 
investigator. 
5.2.11. Patients that come off therapy with evidence of adverse events related to study drugs will 
continue follow-up for toxicity (clinic visit or telephone interview) every 2 weeks for 30 days 
(+/- 7 days) after end of therapy or until resolution of adverse events to grade 1 or less. 
 
5.3 
Outside Physician Participation During Treatment 
 
5.3.1 MDACC Physician communication with the outside physician is required prior to the 
patient returning to the local physician. This will be documented in the patient record.  
5.3.2 A letter to the local physician outlining the patient's participation in a clinical trial will 
request local physician agreement to supervise the patient's care (Appendix C) 
5.3.3 Protocol required evaluations outside MDACC will be documented by telephone, fax or e-
mail. Fax and/or e-mail will be dated and signed by the MDACC physician, indicating that 
they have reviewed it. 
5.3.4 Changes in drug dose and/or schedule must be discussed with and approved by the 
MDACC physician investigator, or their representative prior to initiation, and will be 
documented in the patient record. 
5.3.5 A copy of the informed consent, protocol abstract, treatment schema and evaluation 
during treatment will be provided to the local physician. 
5.3.6 Documentation to be provided by the local physician will include drug administration 
records, progress notes, reports of protocol required laboratory and diagnostic studies and 
documentation of any hospitalizations. 
5.3.7 The home physician will be requested to report to the MDACC physician investigator all 
life-threatening events within 24 hours of documented occurrence. 
5.3.8 Patients will return to MDACC every 3 months for 6 months, at 12 months, at 18 months 
then every 6-12 months thereafter for evaluation. If necessary, patients may have the first 
3 months evaluation conducted through their local physician if approved by the MDACC 
physician investigator. 
 

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5.4 Exploratory Objectives and Analysis  
5.4.1. To determine the rate of MRD clearance using droplet digital polymerase chain 
reaction (ddPCR) detecting the BCR-ABL1 fusion transcript 
Rationale: It is important to detect and quantify leukemia cells at low levels in order to safely 
discontinue therapy. It has been suggested that ddPCR allows for detection of low BCR-ABL1 
transcript levels. This method is based on isolation of the PCR reaction into single droplets, tested 
independently for the presence of the target. 
Hypothesis: ddPCR allows for an improved quantification of BCR-ABL1 transcripts at low levels.27 
Experimental approach: RNA will be extracted from pre and post-combination therapy (12 months 
from therapy start) from bone marrow samples with TRIzol reagent. Subsequently, it will be 
reserved transcribed to complementary deoxyribonucleic acid (cDNA) using the QuantiTect 
Reverse Transcription kit (Qiagen). Primers and probes used for each patient will be determined 
depending on the type of transcript identified with the RT-PCR clinical assay. Reactions will be 
performed on a QX200 ddPCR System (Biorad) and evaluated in technical duplicates. They will 
be partitioned into a median of ~16,000 droplets per well using the QX200 droplet generator and 
run on a 96-well thermal cycler. Analysis will be conducted using the QuantaSoft v1.7 software. 
In line with the manufacturer's recommendations, samples yielding ≥3 positive droplets from the 
10-16,000 analyzed will be scored as positive. We will also investigate reducing this cut-off to ≥2 
positive droplets. 
5.4.2 To determine the effect of therapy on quiescent leukemic Ph+ stem cells 
(CFSEmax/CD34+) 
Rationale: CML stem cells are quiescent with decreased dependence on BCR-ABL1.28,29 
Strategies aimed at eradicating this disease should be able to target those cells. 
Hypothesis: Dual targeting of BCR-ABL1 by adding the allosteric inhibitor ABL001 to a TKI 
significantly reduces the tumor burden and increases the likelihood of tumor eradication through 
elimination of quiescent leukemic Ph+ stem cells. 
Experimental approach: The goal is to assess the effect of adding ABL001 on apoptosis in 
quiescent leukemic stem cells, and on pCRKL levels (a surrogate of BCR-ABL1 activity) pre and 
post-combination therapy (12 months from therapy start) from bone marrow samples. Quiescent 
cells will be identified by staining C34+ cells with carboxyfluorescein diacetate succimidyl diester 
(CFSE, CellTrace CFSE proliferation Kit, Invitrogen).35,36 Cell proliferation will be determined 
using flow cytometric measurement of CFSE intensity (halves with cell division) in these cells 
compared to non-dividing cells treated with Colcemid (100ng/ml, Sigma; in order to induce cell 
cycle arrest). After approximately 6 days of culture, quiescent cells will be identified as CFSEbright 
(fluorescence in the region of Colcemid-treated cells), and proliferative cells will be identified as 
CFSEdim (fluorescence less than that of Colcemid-treated cells). Apoptosis will be estimated 
using measurement of phosphotidylserine externalization with annexin V staining (BD 
Biosciences), in bulk, proliferating, and quiescent cells.37 Levels of p-CRKL will also be compared 
in these cell populations by staining with anti-pCRKL (pY207) (Cell Signaling Technology).38 
5.4.3 To determine the effect of this combination on mutations in ABL1 and mutations in 
clonal hematopoiesis of indeterminate potential (CHIP)-associated genes using molecular 
barcode sequencing. 

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Rationale: Though presence of mutations in ABL1 using clinical next-generation sequencing 
assays is rare in CML patients with evidence of molecular response, it is unknown whether small 
subclones carrying these mutations could be present at low allelic frequency. In addition, there is 
growing evidence that CHIP leads to adverse outcomes in various hematological malignancies. 
However, the prognostic impact of CHIP in CML is relatively unexplored. It’s unknown whether 
patients with residual low levels of CML cells also have mutations in CHIP-associated genes at 
low allelic frequency. Molecular barcode sequencing allows for detection of ultralow-frequency 
mutations while minimizing sequencing error rates.39 
Hypothesis: Adding ABL001 leads to eradication of small clones carrying ABL1 mutations. We 
postulate that persistence of clones with CHIP-associated mutations is associated with 
persistence of the disease despite combination therapy. 
Experimental approach: DNA will be extracted from bone marrow samples pre and post-
combination therapy (12 months from therapy start). We expect that mutations will be present at 
low variant allelic frequencies (VAF), thus we propose molecular barcode sequencing, an 
amplicon-based targeted deep sequencing method that allows for consensus calls of low 
frequency alleles (Haloplex High Sensitivity technology; Agilent Technologies).39 This custom-
designed panel will include genes frequently mutated in CML and CHIP. Somatic mutations will 
be called against virtual normal sequence, followed by an automatic annotation to select non-
polymorphism, protein-coding changing mutations using our standard algorithm as previously 
described.40 
 
5.4.4 To determine the effect of therapy on bone marrow progenitors in clonogenic 
assays 
Rationale: deep levels of response in CML are maintained if therapy is able to affect primitive 
leukemic stem cells.  
Hypothesis: Dual targeting of BCR-ABL1 by adding the allosteric inhibitor ABL001 to a TKI 
significantly increases the likelihood of tumor eradication through inhibiting proliferation in 
leukemia stem cells.  
Experimental approach: we will assess a) the serial re-plating colony forming efficiency (CFC/re-
plating assay) of CD34+/CD38- cell from untreated and treated patients on protocol, and the 
frequency of long term culture-initiating cells (LTC-IC assays), respectively. D-FISH and/or RT-
PCR for BCR-ABL1 will be performed on plucked colonies to specifically determine the 
percentage of Ph+ colonies. We expect the emerging colonies to be Ph-negative or to have a 
marked decrease of the Ph-positive colonies. Methylcellulose colony formation assays will be 
carried out by plating 103 CD34+/CD38- cell sorted from CML patient samples in 0.9% MethoCult 
H4435 (containing rhKL, rhGCSF, rhGM-CSF, rhIL-3, rhIL-6, rhEpo) (Stem Cell Technologies). 
Colonies will be scored after 14 days in culture. To assess self-renewal individual colonies will be 
plucked in 50μl of IMDM/2%FBS, mixed with 150μl of Methocult and re-plated in 96-well plates 
and analyzed 14 days later. Single wells containing at least one secondary colony will be scored 
as positive for self-renewal as previously described.41  
5.4.5 To describe immune effects of the combination of TKI and ABL001 
We will characterize the effects of dual therapy on different hematopoietic compartments including 
various immune effects. A variety of exploratory markers will be explored such as markers of T 

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cell activation, differentiation and exhaustion in addition to expression of immune checkpoints on 
various hematopoietic cells.  
5.4.6 To describe patient reported outcomes (PRO) using the MDASI-CML instrument 
The MD Anderson Symptom Inventory – Chronic Myeloid Leukemia (MDASI-CML)42 is a 26 item 
self-administered questionnaire for adult CML patients. Twenty of the items measure the severity 
of disease-related symptoms and are scored from 0 (Not present) to 10 (As Bad as you can 
imagine) and 6 items that measure symptom interference with daily life scored from 0 (Did not 
interfere) to 10 (Interfered completely).  
The MDASI CML will be used to compare data on the patient’s disease-related symptoms and 
health-related quality of life from baseline, on study and at the end of the study. Patients with an 
evaluable baseline score and at least one evaluable post baseline score during the treatment 
period will be included in the change from baseline analyses. 
The patient should be given the questionnaire(s) to be completed at the scheduled visit before 
clinical assessments by the physician. Patient’s refusal to complete all or any part of a 
questionnaire should be documented in the EMR and study data capture system and should not 
be captured as a protocol deviation. Patient questionnaires should be completed in the language 
most familiar to the patient. Completion of the questionnaire when patients are evaluated by local 
physicians is optional.  
Patient’s refusal to complete all or any part of a questionnaire should be documented in the 
subject’s medical record; study data capture system; and should not be captured as a protocol 
deviation. 
 
Table 2: Summary of objectives and related endpoints  
 
Objective  
Endpoint 
Primary  
To determine the clinical activity of the combination of asciminib 
(ABL001) and a tyrosine kinase inhibitor (TKI) in patients with CML in 
complete cytogenetic response (CCyR) but detectable BCR-ABL1 
transcript 
Molecular response at 
12 months*  
Secondary  
1. To determine the effect of the combination of ABL001 and TKI on 
the rate of MR4, MR4.5, and sustained MR4.5 (MR4 and MR4.5 
rates will include only patients with a molecular response inferior to 
MR4 or MR4.5 respectively upon enrollment) 
MR4, MR4.5, sustained 
MR4.5  
2. To investigate treatment-free remission (TFR) after at least 2 years 
of sustained deep molecular remission 
TFR 
3. To determine the safety of the combination of asciminib and 
tyrosine kinase inhibitors 
Adverse events 
4. To determine the event-free survival (EFS), survival free from 
transformation to accelerated and blast phase (TFS), and overall 
survival (OS) 
EFS, TFS, OS 
Exploratory  
1.  To determine the rate of MRD clearance using droplet digital 
polymerase chain reaction (ddPCR) detecting the BCR-ABL1 fusion 
transcript 
 
2. To determine the effect of therapy on quiescent leukemic Ph+ 
stem cells (CFSEmax/CD34+) 
 
3. To determine the effect of therapy on bone marrow progenitors in 
clonogenic assays 
 

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4. To describe immune effects of the combination of TKI and ABL001 
 
5. To describe patient reported outcomes (PRO) using the MDASI-
CML instrument 
 
* A favorable response is defined as ≥1 log reduction of the BCR-ABL1 transcript levels from baseline or 
disappearance of the BCR-ABL1 transcripts (see Statistical Considerations section) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 3: Evaluation schedule  
Evaluation 
Pre-treatment  
(within 14 days) 
Week 2 
Week 4 
Week 6 
Week 8 
Month 3 
Month 6 
Month 9 
Month 12 
Month 18  
After Month 18 
At therapy  
Discontinuation ¥ 
After therapy 
discontinuation  
History, 
physical exam, 
performance 
status^ 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
Q 6-12 months 
x 
Q 4-8 weeks,  
Q 3-6 months* 
CBC** 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
Q 6-12 months 
x 
Q 4-8 weeks,  
Q 3-6 months* 
Chemistries 
(including total 
bilirubin, 
creatinine, 
electrolytes, 
ALT or AST, 
amylase, 
lipase)** 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
Q 6-12 months 
x 
Q 4-8 weeks,  
Q 3-6 months* 
Pregnancy 
Test (blood or 
urine) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
EKG, 
Echo/Muga # 
x 
~ 
x 
 
 
 
 
 
 
 
 
 
 
PCR (PB)1 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
Q 6 months 
x 
Q 4-8 weeks,  
Q 3-6 months*  
Cytogenetics 
and/or FISH^^ 
x 
 
 
 
 
 
x 
 
x 
 
As clinically indicated  
x 
 
Bone marrow 
aspiration^^  
x 
 
 
 
 
 
x 
 
x 
 
As clinically indicated  
x 
After 6 and 12 
months 
Research 
sample (PB) 
x 
 
x 
 
x 
x 
x 
 
x 
x 
 
x 
After 6 and 12 
months 
Research 
sample (BM) 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
After 6 and 12 
months 
MDASI 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
Q 6-12 months 
x 
Q 6-12 months 
^ Pre-treatment visit (within 14 days), after 2 weeks (+/-3 days), 4 weeks (+/-7 days), 8 weeks (+/-7 days), 3 months (+/-7 days), 6 
months (+/-1 month), 12 months (+/-1 month), 18 months (+/-1 month) from the start of therapy, then every 6 to 12 months. If the 
evaluation for toxicity is done by phone, a report of physical exam from home physician is acceptable provided there is a physical 
exam at MDACC at least every 6 months (+/- 1 month) during the first 2 years and every 12 months (+/- 1 month) thereafter.  
* Patients who permanently discontinue therapy with TKI will have these evaluations done every 4 weeks (+/-1 week) for the first 
6 months after discontinuation of TKI, Then every 2 months (+/-1 month) for the next 6 months, then every 3 months (+/-3 weeks) 
for 12 months, then every 6 months (+/-2 months).  
# EKG and Echo/Muga within 30 days of specified timeline. ~EKG at day 8 of treatment start (+/- 2 days).  
^^ Bone marrow aspiration with cytogenetics and/or FISH within 30 days [+/-7 days] from treatment start .  
¥ Patients that come off therapy with evidence of adverse events related to study drugs will continue follow-up for toxicity (clinic 
visit or telephone interview) every 2 weeks for 30 days (+/- 7 days) after end of therapy or until resolution of adverse events to 
grade 1 or less. 
** Screening blood tests to be obtained within 1 week of treatment start. 
1 PCR (peripheral blood and/or bone marrow), after 4 weeks (+/-7 days), 8 weeks (+/-7 days), 3 months (+/-7 days), then every 3 
months (+/-1 month) until one year, then every 6months (+/-1 month) 
 
 

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6 
RESPONSE DEFINITIONS  
 
6.4 Criteria for Response  
 
6.4.2 A favorable response for the primary endpoint is defined as a greater than a one-log 
reduction of BCR-ABL transcript levels from the baseline level or disappearance of BCR-
ABL transcripts after 12 months of combination. 
6.4.3 For the purposes of this study, progression will be defined as a confirmed loss of 
complete cytogenetic response (CCyR) (i.e., >0% Ph+ metaphases among 20 
metaphases counted by karyotype; or by FISH; or, if not cytogenetic or FISH available, 
by increase in BCR-ABL1/ABL1 to >1% IS) as assessed in two consecutive analyses 
separated by at least a month. 
6.4.4 Survival endpoints (overall, event-free and free from blast transformation) will be 
measured from the time of start of ABL001 therapy. 
 
6.5 Criteria for Removal from Study 
 
6.2.1 The patient receives CML-directed therapy other than TKI and ABL001.  
6.5.2 The patient develops disease progression defined as confirmed loss of CCyR, 
confirmed loss of CHR or transformation to accelerated or blast phase of CML. 
6.5.3 The dose of TKI is increased beyond the dose being used at the time of study entry or 
new therapies for their leukemia are added. 
6.5.4 The patient has a continuous, non-planned interruption of TKI therapy for greater than 
8 weeks (e.g., for non-compliance or toxicity). Interruptions for surgery, accidents or 
other unrelated reasons are not grounds for removal from study.  
6.5.5 The patient withdraws consent. 
6.5.6 The treating physician considers it in the best interest of the patient. 
6.5.7 Pregnancy or suspected pregnancy. 
6.5.8 The trial will be stopped at any time during the study if we determine that there 
is ≥80% chance that the unacceptable toxicity is ≥30%. Specifically, the study will 
be stopped early if (N of unacceptable toxicities) / (N patients evaluated) ≥ 3/4, 
4/8, 6/12, 7/16.   The operating characteristics of this monitoring rule are listed in 
Table 4. These rules will be applied starting from the 4th patient and in cohorts 
of 4. 
 
7 
INVESTIGATIONAL AGENT PACKAGING AND LABELING  
ABL001 will be provided as global clinical open-label supply and will be packed and labeled under 
the responsibility of Novartis, Drug Supply Management. 
Study treatment labels will include storage conditions and a unique medication number 
(corresponding to study treatment and strength). Site personnel will add the patient number on 
the label. If the label has 2-parts (base plus tear-off label), immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the package and 
affix it to the patient’s source document. 

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Study treatment 
Packaging 
Labeling and dose frequency 
ABL001 (20 mg and  
40 mg tablets) 
Tablets in bottle 
Labeled as “ABL001 20mg / 
ABL001 40 mg BID” 
 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the ABL001 should be stored according to the 
instructions specified on the drug labels. 
Handling and Storage: Investigational product must be dispensed or administered according to 
procedures described herein. Only subjects enrolled in the study may receive investigational 
product, in accordance with all applicable regulatory requirements. Only authorized site staff may 
supply or administer investigational product. All investigational products must be stored in a 
secure area with access limited to the Principal Investigator and authorized site staff and under 
physical conditions that are consistent with investigational product-specific requirements. Any 
unused or expired investigational product will be returned to MDACC to be disposed per 
institutional policy. 
Importantly, for the purposes of this study, the TKI agents (nilotinib, dasatinib) are not considered 
investigational agents and they will be supplied by commercial sources (per routine clinical care). 
 
8 
REGULATORY AND REPORTING REQUIREMENTS  
 
8.4 Adverse Event Reporting 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
8.1.1 Adverse events will be documented in the medical record and entered into Prometheus. 
Prometheus will be used as the electronic case report form for this protocol. 
 
8.4.2 Adverse event is any untoward medical occurrence that may present during treatment with 
a pharmaceutical product but which does not necessarily have a causal relationship with 
this treatment. 
 
Adverse drug reaction (ADR) is a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of 
disease or for the modification of physiologic function.  
 

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Assessing causal connection between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) the event 
would not have happened at all, 2) the event would have occurred later than it actually 
did, or 3) the event would have been less severe.  
 
The Investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial. 
 
8.4.3 Adverse Events (AEs) will be evaluated according to CTC version 5 and documented in 
medical record. Adverse events will be recorded in the Case Report Form (CRF) in 
accordance with Leukemia-specific Adverse Event Recording and Reporting Guidelines 
as below: 
 
8.4.3.1 Baseline events will be recorded in the medical history section of the case report 
form and will include the terminology event name, grade, and start date of the 
event.  The medical history section of the case report form will serve as the source 
document for baseline events once signed and dated by the principal investigator.  
 
8.4.3.2 Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
 
8.4.3.3 Hematologic laboratory abnormalities will not be recorded as baseline events for 
patients with acute leukemia, myelodysplastic syndrome, chronic lymphocytic 
leukemia, or chronic myeloid leukemia in blast phase. 
 
8.4.3.4 If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event. 
 
8.4.4 The maximum grade of the adverse event will be captured per course or protocol defined 
visit date. 
 
8.4.5 
All adverse events regardless of attribution will be recorded in the case report form.  
 
8.4.6 Hematologic adverse events will not be recorded or reported for studies in patients with 
acute leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic 
myeloid leukemia in blast phase except for: 
 
8.4.6.1 Prolonged myelosuppression as defined by the NCI-CTCAE .v5 criteria specific for 
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of DLT or SAE. 
 
8.4.7 Serious adverse events will be reported according to institutional policy. 
 

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8.5 Serious Adverse Event Reporting (SAE) 
Serious Adverse Event Reporting (SAE) for MD Anderson-Sponsored IND Protocols 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
- 
Death. 
- 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death. 
- 
Inpatient hospitalization or prolongation of existing hospitalization. 
- 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
- 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
- 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
- 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas MD 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. 
Reporting to FDA: 

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- 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
Investigator Communication with Supporting Companies: 
Reporting procedures: 
The principal investigator has the obligation to report all serious adverse events to the FDA 
(if applicable), 
IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology 
Department (DS&E). All events reported to the FDA by the investigator are to be filed utilizing 
the Form FDA 3500A (MedWatch Form), if applicable to ensure patient safety, every SAE, 
regardless of suspected causality, from the time of the first protocol-specific intervention, until 
at least 30 days after the patient has stopped study treatment must be reported to Novartis 
according to institutional policies. Information about all SAEs is collected and recorded 
on a Serious Adverse Event Report Form. The investigator must assess and record the 
relationship of each SAE to each specific study treatment (if there is more than one study 
treatment), complete the SAE Report Form in English, and send the completed, signed 
form along with the Novartis provided fax cover sheet to the Novartis Oncology Drug 
Safety and Epidemiology (DS&E) department by fax (fax: 877-778-9739) within 24 hours. 
An acceptable alternative to the FAX coversheet is an e-mail to an approved Novartis 
Patient Safety (NPS) mail box (e.g. clinicalsafetyop.phuseh@novartis.com). 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode according to 
institutional policies.  
Any SAEs experienced after the 30- day safety evaluation follow-up period should only 
be reported to Novartis if the investigator suspects a causal relationship to the study 
treatment. 
Follow-up information is submitted in the same way as the original SAE Report. Each 
re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of 
when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether the 
blind was broken or not, and whether the patient continued or withdrew from study 
participation.  
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need 
to issue an Investigator Notification (IN), to inform all investigators involved in any study 
with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 

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Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.  
Pregnancy should be reported by the investigator to the oncology Novartis Drug Safety and 
Epidemiology Department (DS&E) by fax (fax : 877-778-9739). Pregnancy follow-up should 
include an assessment of the possible relationship to the investigational/study treatment and 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the 
SAE Report Form. 
 
Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date. 21 CRF 312.33 provides 
the data elements that are to be submitted in the report. The Annual Report (AR) should be filed 
in the study's Regulatory Binder, and a copy provided to Novartis as a supporter of this study as 
follows:  
Alok Shrestha 
Sr. Clinical Research Scientist 
T: +1-862-778-0700 
M: +1-201-704-8746 
alok.shrestha@novartis.com 
 
Adverse events will be captured from the time of the first protocol-specific intervention, until 30 
days after the last dose of drug. 
9 
STATISTICAL CONSIDERATIONS  
This is a phase II, single-arm, open-label study to evaluate the efficacy of ABL001 in patients with 
CML and CCyR but with detectable MRD while continuing to receive TKI. There will be two cohorts 
of patients based on the TKI they are receiving prior to enrolment: 1) dasatinib + ABL001: patients 
have received treatment of dasatinib as standard TKI for 2 years with detectable MRD and 2) 
nilotinib + ABL001: patients have received treatment of nilotinib as standard TKI for 2 years with 
detectable MRD. Up to 20 evaluable patients will be enrolled per cohort at the MD Anderson 
Cancer Center, at a rate of 1 to 2 patients per month. Patients lost to follow-up or those who stop 
therapy for personal or financial reasons need to be replaced and do not count as failure. Patients 
who discontinue because of unacceptable toxicity are included in the stopping rule for toxicity and 
will also be counted as failures in efficacy calculations. The primary endpoint of this trial is to 
determine the rate of molecular response at 12 months from the start of the study. A favorable 
response is defined as ≥1 log reduction of the BCR-ABL1 transcript levels from baseline or 
disappearance of the BCR-ABL1 transcripts (CMR). In this setting, it would be difficult to do an 
interim monitoring for futility. Patients who lose CCyR within 12 months will be counted as 
treatment failures. For each cohort, we will estimate the response rate and 95% confidence 
interval. It is expected that the combination treatment could reach a response rate of ≥20%.  A 
sample size of 20 can achieve a 95% exact CI of (5.73%, 43.66%). 

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Summary statistics will be used to describe the clinical and demographic characteristics of the 
study population. For secondary endpoints or exploratory endpoints, frequency, percentage and 
95% confidence interval will be tabulated for binary outcomes e.g. MR4 etc. The Kaplan-Meier 
method will be used to estimate time to event outcomes e.g. EFS etc.  Descriptive statistics will 
be provided for the MDASI-CML symptom score and interference score, and the change in the 
MDASI-CML symptom score and interference score from baseline to all available time points to 
the end of study. For each arm, we will follow a Bayesian design with early stopping rules for 
toxicity42. Treatment-related unacceptable toxicity will be defined as grade 3 or 4 toxicity that 
prevents patients from continuing combination therapy despite optimal management. This will be 
determined according to the following rule: Probability (PE > 0.30 | data) > 0.80, where PE is the 
probability of toxicity; assuming that PE ~ beta (0.6, 1.4). In other words, the trial will be stopped 
at any time during the study if we determine that there is ≥80% chance that the unacceptable 
toxicity is ≥30%. Specifically, the study will be stopped early if (N of unacceptable toxicities) / (N 
patients evaluated) ≥ 3/4, 4/8, 6/12, 7/16.   The operating characteristics of this monitoring rule is 
listed in Table 4. These rules will be applied starting from the 4th patient and in cohorts of 4.  
The Investigator is responsible for completing an efficacy/safety summary report, and submitting 
it to the IND Office Medical Affairs and Safety Group, for review and approval.  This should be 
submitted after the first 4 evaluable patients complete 1 cycle (28 days) of study treatment, and 
every 4 evaluable patients per cohort, thereafter. On every report submission, the information 
from previous reported patients will need to be updated. A copy of the cohort summary should be 
placed in the Investigator’s Regulatory Binder under “sponsor correspondence”. 
Table 4: Operating characteristics for monitoring of toxicities 
True Toxicity Rate 
Early Stopping Probability 
Avg. N treated 
0.1 
0.0077 
19.89 
0.2 
0.0795 
19.02 
0.3 
0.2824 
16.75 
0.4 
0.5776 
13.36 
0.5 
0.8297 
9.93 
 
 
 
 
 
 
 
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10. APPENDIX 
Appendix 1: List of CYP3A4 inducers, inhibitors and substrates 
These lists were compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table; from the FDA’s “Guidance for Industry, Drug Interaction Studies” and from the University 
of Washington’s Drug Interaction Database. These lists may not be comprehensive and may be 

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updated periodically. Refer to Novartis Oncology Clinical Pharmacology Internal Memorandum, 
Drug-drug interactions (DDI) Database (last updated 2016) for update or more details. 
Table 11.1: CYP3A4 inducers 
Category 
Drug Names 
Strong inducers of CYP3A41 
avasimibe, carbamazepine, enzalutamide, mitotane, 
phenobarbital, phenytoin, rifabutin, rifampin, St. John’s 
wort (HYPERICUM PERFORATUM)5 
Moderate inducers of CYP3A42 
bosentan, efavirenz, etravirine, lersivirine, lopinavir, 
modafinil, nafcillin, ritonavir/tipranavir, semagacestat4, 
talviraline4, thioridazine 
Weak inducers of CYP3A43 
amprenavir, aprepitant, armodafinil bexarotene, 
boceprevir, brivacetam, clobazam, danshen5, 
dexamethasone, echinacea5, eslicarbazepine, gingko 
(ginkgo biloba)5, ginseng5, glycyrrhizin5, honey6, 
quercetin6, methylprednisolone, nevirapine, 
oxcarbazepine, pioglitazone, pleconaril4, prednisone, 
primidone, raltegravir, ritonavir, rufinamide, sorafenib, 
Stribild (combo of elvitegravir, cobicistat, emtricitabine, 
and tenofovir), sulfinpyrazone, telaprevir, terbinafine, 
ticagleror, ticlopidine, topiramate, troglitazone4, 
vemurafenib, vicriviroc/ritonavir, vinblastine, yin zhi 
huang5 
1 A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate for 
that CYP by equal or more than 80%. 
 
2 A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that 
CYP by 50-80%. 
 
3 A weak inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that CYP 
by 20-50%. 
 
4 Drugs not available in the US Market. 
 
5 Herbal product. 
 
6 Food product. 
 
 
 
 
 
Table 11.2: CYP3A4 inhibitors  
Category 
Drug Names 
Strong inhibitors of CYP3A41 
boceprevir, 
cobicistat 
(GS-9350), 
conivaptan, 
clarithromycin, 
danoprevir/ritonavir12, 
delalisib, 
darunavir/ritonavir12, elvitegravir/ritonavir12, grapefruit 
product11, indinavir, indinavir/ritonavir12, itraconazole, 

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ketoconazole, LCL161, lopinavir/ritonavir12, mibefradil, 
nefazodone, 
nelfinavir, 
posaconazole, 
ritonavir, 
saquinavir, 
saquinavir/ritonavir12, 
telaprevir, 
telithromycin, 
tipranavir/ritonavir12, 
troleandomycin, 
VIEKIRA PAK2, voriconazole 
Moderate inhibitors of CYP3A42 
ACT-178882, amprenavir, aprepitant, atazanavir, 
casopitant, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, Erythromycin, darunavir, diltiazem, 
dronedarone, FK1706Ferula asafetida resin (Ferula 
assa-foetida)4, faldaprevir, fluconazole7, imatinib, 
isavuconazole, netupitant, nilotinib, schisandra, 
sphenanthera, tofisopam, verapamil 
Weak inhibitors of CYP3A43 
almorexant, alprazolam, AMD070, amiodarone, 
amlodipine, atorvastatin, AZD2327, azithromycin, 
berberine, bicalutamide, blueberry juice5, 
chlorzoxazone, cilostazol, clotrimazole, cranberry 
juice5, daclatasvir, delavirdine, evacetrapid, 
everolimus, fosaprepitant (IV), fluvoxamine8, 
fostamatinib, Garden Cress seeds (Lepidium 
sativum)5, ginkgo4, goldenseal4, Guan Mai Ning13, 
GSK1292263, GSK2248761, isoniazid, ivacaftor, 
lacidipine, linagliptin, lomitapide, M100240, oral 
contraceptives, palbociclib, pazopanib, peppermint oil, 
propiverine, ranitidine, ranolazine, resveratrol, 
roxithromycin, Seville orange juice5, simeprevir, 
sitaxentan, suvorexant, tabimorelin, tacrolimus, 
teriflunomide, ticagrelor, tolvaptan, Tong Xin Luo13 
1 A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by equal or more than 5-fold. 
2 A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold. 
3 A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by less than 2-foldbut equal to or more than 1.25-fold. 
4 Herbal product. 
5 Food product. 
6 Gemfibrozil also inhibits OATP1B1. Applicable for another class of CYP inhibitor. 
7 Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also 
metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor. 
8 Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A. 
9 Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2. The inhibition of CYP3A4 
by ticlopidine is not strong although the actual class of its inhibition on CYP3A4 (moderate vs weak) has yet to be 
defined. 
10 Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. Applicable for another class of CYP inhibitor. 
11 The effect of grapefruit product varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation 
was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was 
used (e.g., low dose, single strength). 
12 Combination therapy.(in some cases combinations with ritonavir have been listed as moderate inhibitors of 
CYP3A in the UW database, the have all been listed as strong in the DDI guide to avoid any potential confusion). 
13 Traditional Chinese medicine. 
 
Table 14.3: CYP3A4 substrates: Narrow therapeutic index, sensitive, and others 
Category 
Drug Names 
Narrow Therapeutic index substrates of CYP3A41 
alfentanil, 
astemizole, 
cisapride, 
cyclosporine, 
dihydroergotamine, ergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, terfanadine, 
thioridazine 

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Sensitive substrates of CYP3A42 
alpha-dihydroergocryptine, alfentanil, almorexant, 
alisoporivir, aplaviroc, aprepitant, atazanavir, 
atorvastatin, avanafil, bosutinib, brecanavir, 
brotizolam, budesonide, buspirone, capravirine, 
casopitant, conivaptan, danoprevir, darifenacin, 
darunavir, dasatinib, dronedarone, ebastine, eletriptan, 
elvitegravir, eplerenone, everolimus, felodipine, 
fluticasone, ibrutinib, indinavir, ivacaftor, levomethadyl, 
lomitapide, lopinavir, lovastatin, lumefantrine, 
lurasidone, maraviroc, midazolam, midostaurin, 
naloxegol, neratinib, nisoldipine, perospirone, 
quetiapine, ridaforolimus, saquinavir, sildenafil, 
simeprevir, simvastatin, tacrolimus, terfenadine, 
ticagrelor, tilidine,tipranavir, tolvaptan, triazolam, 
ulipristal, vardenafil, vicriviroc, voclosporin. 
Other Substrates of CYP3A43 
alprazolam, ambrisentan, amlodipine, antipyrine, 
aripiprazole, artemether, avosentan, boceprevir, 
bosentan, buprenorphine, carbamazepine, 
dexloxiglumide, dextromethorphan, diazepam, 
docetaxel, enzalutamide, gemigliptin, halofantrine, 
imipramine, lansoprazole, lidocaine, linagliptin, 
operamide, loratadine, losartan, lurasidone, 
macitentan, methadone, mirodenafil, montelukast, 
morphine, nelfinavir, netupitant, nevirapine, nifedipine, 
nilotinib, nitrendipine, omeprazole, ospemifene, 
oxycodone, paclitaxel, pazopanib, pioglitazone, 
quinine, ranolazine, repaglinide, rifabutin, ritonavir, 
roflumilast, saxagliptin, selegiline, sertraline, 
sibutramine, sotrastaurine, telaprevir, theophylline, 
tirilazad, tolterodine, udenafil, ulipristal, vincristine, 
voriconazole 
Narrow Therapeutic index substrates of CYP2C9 
warfarin (also sensitive), phenytoin 
Narrow Therapeutic index substrates of CYP2C8 
paclitaxel 
1 Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de 
Pointes). 
3 Other substrates are these that have shown an in vivo ≥2-fold increase in AUC with co-administration of an inhibitor 
based on the UW database.