Conditions: Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of oxidative phosphorylation inhibitor IACS-010759 in treating patients with acute myeloid leukemia that has come back or does not respond to treatment. Oxidative phosphorylation inhibitor IACS-010759 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you joined the study. Up to 6 groups of 3-6 participants will be enrolled in the dose escalation part of the study. Up to 18 participants will be enrolled in dose expansion.

OUTLINE: This is a dose-escalation study.

INDUCTION PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 orally (PO) once daily (QD) on days 1-7.

MAINTENANCE PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 8 and 15 of course 1 and on days 1, 8, and 15 of subsequent courses. Treatment repeats every 21 days for subsequent courses for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients may receive additional courses of oxidative phosphorylation inhibitor IACS-010759 at the discretion of study doctor.

After completion of study treatment, patients are followed up every 3-6 months for up to 5 years.

If you are enrolled in dose escalation, the dose of IACS-010759 you receive will depend on when you join this study. The first group of participants will receive the lowest dose level of IACS-010759. Each new group will receive a higher dose of IACS-010759 than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of IACS-010759 is found.

If you are enrolled in the dose expansion part of the study, you will receive the dose level of IACS-010759 that was found to be the best dose in the escalation part of the study.

In the dose expansion part of the study, 6 participants will also be enrolled in a food-effect group (described in more detail below) to help researchers understand the effects of taking the study drug with food.

Study Drug Administration Each study cycle is 21 days. Cycle 1 only is 28 days. You will take IACS-010759 by mouth one (1) time every day. On Day 1 of Cycle 1 only, you will take your first dose of IACS-010759 and then wait 7 days to take your next dose. Starting on Day 8 of Cycle 1, you will take the study drug every day for the next 21 days.

You will be admitted to the hospital on Day 1 of Cycle 1 for 24 hours and on Day 8 of Cycle 1 for 7 days. This is done so that you can be checked on for any side effects.

Length of Study You may continue to take IACS-010759 for up to 12 cycles. If the doctor thinks it is in your best interest, you may be able to continue receiving the study drug beyond 12 cycles. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Arms:
arm 1: IACS-010759 Starting dose: 0.5 mg

INDUCTION PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 1-7. arm 2: IACS-010759 Starting dose: 1 mg

INDUCTION PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 1-7. arm 3: IACS-010759 Starting dose: 2 mg

INDUCTION PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 1-7.

MAINTENANCE PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 8 and 15 of course 1 and on days 1, 8, and 15 of subsequent courses. Treatment repeats every 21 days for subsequent courses for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients may receive additional courses of oxidative phosphorylation inhibitor IACS-010759 at the discretion of study doctor. arm 4: IACS-010759 Starting dose: 2.5 mg

INDUCTION PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 1-7.

MAINTENANCE PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 8 and 15 of course 1 and on days 1, 8, and 15 of subsequent courses. Treatment repeats every 21 days for subsequent courses for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients may receive additional courses of oxidative phosphorylation inhibitor IACS-010759 at the discretion of study doctor.

Interventions: intervention 1: Oxidative Phosphorylation Inhibitor IACS-010759 intervention 2: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 1 of 59 
 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID
2016-0250
Protocol Title
Phase 1 Study of IACS-010759 in Subjects with Relapsed or Refractory 
AML 
Protocol Phase
1
Protocol Version
11
Version Date
January 21, 2020
Protocol PI
Marina Konopleva, M.D.
Department
Leukemia
IND Sponsor
MD Anderson Cancer Center
IND #
128,639
 
 
 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 2 of 59 
Study Protocol: IACS2015-001  
MDACC Protocol ID: 2016-0250 
Version: Amendment #11 
Version Date: 01-21-20 
 
Phase 1 Study of IACS-010759 in Subjects with relapsed or refractory AML 
Study Synopsis and Objectives
This is an open label Phase 1 study of IACS-10579 utilizing a 3+3 dose-escalation phase followed 
by an expansion phase in subjects with relapsed or refractory AML and no available treatment 
options with known benefit. 
In cohorts 1 and 2, in the first cycle, IACS-010759 will be administered on Day 1 followed by 
continuous dosing starting on day 8 through day 28; cycles 2 and beyond will be continuous daily 
dosing. Based on PK analysis and modeling of preliminary data from cohorts 1 and 2, the study 
design has been amended.  In cohort 3 and subsequent cohorts, in the first cycle, IACS-010759 
will be administered daily for up to 7 days during an initial Induction Phase (Day 1-7) followed 
the Maintenance Phase (Day 8-21), which will use a lower dose to maintain steady state drug 
levels.  For cohort 3, the maintenance dose will be administered once weekly on Day 8 and Day 
15 of the 21-day cycle in cycle 1; in subsequent cycles, doses will be administered on Days 1, 8 
and 15 of each cycle, unless alternate schedules are recommended by the SMC.  In subsequent 
cohorts, the induction and maintenance doses and/or the dosing interval during the 
maintenance phase may be further modified by the SMC based on safety, PK and PD data 
observed.  Dosing will continue until confirmed progressive disease, initiation of alternative 
cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment prematurely at 
the dose levels given below: 
Original Dose Escalation Regimen, Cohorts 1 and 2: 
PHASE 
COHORT 
NO OF SUBJECTS 
IACS-010759 DOSE LEVEL  
(DAILY EXCEPT  
CYCLE 1, DAY 2-7) 
* 
Dose-
escalation 
Cohort 1 
3-6 
0.5 mg 
Cohort 2 
3-6 
1 mg 
*Intermediate doses of IACS-010759, not to exceed 8 mg, not listed above may also be pursued with SMC approval 
depending on the safety, PK and PD data observed. 
Revised Dose Escalation Regimen for Cohorts 3-6 and Expansion Regimen for Cohort 7: 
PHASE 
COHORT 
NO OF 
SUBJECTS 
INDUCTION DOSE* 
(FREQUENCY#) 
MAINTENANCE DOSE* 
(FREQUENCY) 
Dose-
escalation 
Cohort 3 
3-6 
2 mg (daily, Cycle 1 Day 1-7) 
0.5 mg (once per week) 
Cohort 4** 
3-6 
2.5 mg (daily, Cycle 1 Day 1-7) 
1.0 mg (three times per week) 
Cohort 5 
3-6 
2.5 mg (daily, Cycle 1 Day 1-5) 
1.5 mg (three times per week) 
Cohort 6 
3-6 
3 mg (daily, Cycle 1 Day 1-5) 
2 mg (three times per week) 
Expansion 
Cohort 7 
12 
RP2D 
RP2D 
*Intermediate induction or maintenance doses of IACS-010759, not to exceed 6 mg, and #alternative duration of 
induction doses or other maintenance schedules not listed above may also be pursued with SMC approval depending 
on the safety, PK and PD data observed.   
**Following their review of Cohort 3, the SMC recommended implementation of the following dose schedule for 
subjects who enroll in Cohort 4 of the study: 
Induction dose: 2.5 mg, administered daily, Cycle 1 Day 1 through Day 7 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 3 of 59 
Phase 1 Study of IACS-010759 in Subjects with relapsed or refractory AML 
Study Synopsis and Objectives
Maintenance dose: 1 mg, administered 3x/week (for a total weekly dose of 3 mg) with the first maintenance dose 
starting on Cycle 1 Day 8 
 
Subjects in the expansion phase will be treated at the recommended phase 2 dose (RP2D) 
identified in the dose-escalation phase, using the induction + maintenance regimen. 
 
Up to 48 subjects will be enrolled in the study: a maximum of 36 subjects in the dose-escalation 
and a maximum of 18 subjects in the expansion phase (12 additional subjects and the 6 subjects 
from the dose-escalation phase at the cohort of the highest dose level shown to be well 
tolerated or the recommended phase 2 dose). 
The primary objective is to determine safety and tolerability of IACS-010759, the maximum 
tolerated dose (MTD) and recommended phase 2 dose (RP2D).  
The secondary objectives are IACS-010759 pharmacokinetics, food effect, and preliminary clinical 
efficacy (overall response rates, duration of response, progression-free survival, overall survival). 
The exploratory objective is to evaluate pharmacodynamic (PD) and exploratory biomarkers of 
activity of IACS-010759. 
 
 
 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 4 of 59 
Table of Contents 
1 
Protocol Amendments ............................................................................................................ 6 
2 
Background Information ....................................................................................................... 14 
2.1 
AML ................................................................................................................................ 14 
2.2 
IACS-010579 .................................................................................................................. 14 
2.2.1 
IACS-010759 Preclinical Biology ............................................................................ 14 
2.2.2 
IACS-010759 Nonclinical Experience ..................................................................... 15 
2.2.3 
IACS-010759 Chemical Properties ......................................................................... 17 
3 
Study Rationale ..................................................................................................................... 17 
3.1 
Rationale for IACS-010759 Dose Selection .................................................................... 17 
3.2 
Rationale for Study Design ............................................................................................ 18 
4 
Experimental Plan ................................................................................................................. 18 
4.1 
Study Design .................................................................................................................. 18 
4.1.1 
Study Phase ........................................................................................................... 18 
4.1.2 
Enrollment/Randomization ................................................................................... 18 
4.1.3 
Subject Population................................................................................................. 18 
4.1.4 
Number of Sites and Subjects................................................................................ 18 
4.1.5 
Sample Size Considerations ................................................................................... 18 
4.1.6 
Treatment Cohorts and Treatment Schema .......................................................... 19 
4.1.7 
Dose-escalation ..................................................................................................... 20 
4.1.8 
Expansion Phase .................................................................................................... 21 
4.1.9 
Dosing Adjustments, Delays and Discontinuations ............................................... 22 
4.1.9.1 
IACS-010759 Dose Adjustments for Drug-Related Hematological AEs ............. 22 
4.1.9.2 
IACS-010759 Dose adjustments for Non-Hematologic Drug-Related AEs ........ 23 
4.1.9.3 
Intra-Subject Dose Escalation ........................................................................... 24 
4.1.9.4 
Other Allowable Modifications of Dose Schedules ........................................... 24 
4.1.10 
DLT, MTD and RP2D definitions............................................................................. 25 
4.1.11 
Assessment of Elevated Lactic Acid Levels ............................................................ 26 
4.1.12 
Subject Withdrawal ............................................................................................... 27 
4.1.13 
Subject Evaluability and Replacement .................................................................. 27 
4.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 28 
4.1.14.1 Study Stopping Rules ........................................................................................ 28 
4.1.14.2 Protocol Violations and Deviations ................................................................... 28 
4.1.15 
Follow-Up at Treatment Discontinuation or Early Withdrawal ............................. 28 
4.1.16 
Long-Term Follow-Up ............................................................................................ 29 
4.2 
Study Flowcharts ........................................................................................................... 30 
4.3 
Safety and tolerability ................................................................................................... 38 
4.3.1 
Endpoints & Assessment Methods ........................................................................ 38 
4.3.2 
Subject Evaluation & Statistics .............................................................................. 38 
4.4 
Clinical Efficacy .............................................................................................................. 39 
4.4.1 
Subject Evaluation & Statistics .............................................................................. 39 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 5 of 59 
4.4.2 
Endpoints & Assessment Methods ........................................................................ 39 
4.5 
IACS-010759 Plasma Drug Levels .................................................................................. 40 
4.5.1 
Subject Evaluation & Statistics .............................................................................. 40 
4.5.2 
Endpoints & Assessment Methods ........................................................................ 41 
4.6 
Biological activity of IACS-010759 ................................................................................. 41 
4.6.1 
Subject Evaluation & Statistics .............................................................................. 41 
4.6.2 
Endpoints & Assessment Methods ........................................................................ 41 
5 
Subject Eligibility ................................................................................................................... 41 
5.1 
Inclusion Criteria ............................................................................................................ 41 
5.2 
Exclusion Criteria ........................................................................................................... 44 
6 
Study Drug ............................................................................................................................ 45 
6.1 
Study Drug Administration ............................................................................................ 45 
6.2 
Study Drug Information ................................................................................................. 46 
6.3 
Drug Overdose Management ........................................................................................ 46 
7 
Concurrent and Supportive Therapies .................................................................................. 47 
7.1 
Non-Permitted Concomitant Therapies ........................................................................ 47 
7.2 
Supportive Care Guidelines & Permitted Concomitant Therapies ................................ 47 
7.2.1 
Concomitant medication/therapies ...................................................................... 47 
7.2.2 
Use of Blood Products ........................................................................................... 48 
7.2.3 
Lactic Acidosis and Severe Acidemia Management .............................................. 49 
8 
Administrative, Legal & Ethical Requirements ..................................................................... 49 
8.1 
Adverse Event, serious adverse event and reporting.................................................... 49 
8.1.1 
Adverse Event (AE): ............................................................................................... 49 
8.1.2 
Reporting of Adverse Events ................................................................................. 50 
8.1.3 
Assessing Severity of Adverse Events .................................................................... 50 
8.1.4 
Assessing Relationship to Study Treatment .......................................................... 51 
8.1.5 
Classification of Causality ...................................................................................... 51 
8.1.6 
Reporting Requirements ....................................................................................... 52 
8.1.7 
Serious Adverse Event Reporting (SAE) ................................................................. 52 
8.1.8 
Reporting to FDA: .................................................................................................. 54 
8.1.9 
Unexpected Adverse Event ................................................................................... 54 
9 
Appendices ........................................................................................................................... 55 
9.1 
Causes of elevated lactate ............................................................................................. 55 
9.2 
List of abbreviations ...................................................................................................... 56 
9.3 
ECOG Performance Status* ........................................................................................... 57 
9.4 
New York Heart Association (NYHA) Functional Classification...................................... 57 
9.5 
References ..................................................................................................................... 57 
 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 6 of 59 
1 Protocol Amendments 
 
Section 
Text 
Amendments 
Rationale for Change 
Amendment #10 
(dated 21 January 2019) 
Synopsis, 3.1, 
4.1.6, 4.1.7, 4.2 
Revised 
Revised the induction phase duration from 7 days to 
up to 7 days 
SMC recommendation at 
end of cohort 4 to reduce 
the daily induction phase 
dosing from 7 days to 5 
days starting in cohort 5 
Synopsis, 4.1.6 
Revised 
Modified the cohort 5 dosing regimen to 2.5 mg 
induction (daily, Cycle 1 Day 1 through Day 5) and 
1.5 mg maintenance (3 times per week starting on 
Cycle 1 Day 8) 
SMC recommendation 
Synopsis, 4.1.6 
Revised 
Modified the cohort 6 dosing regimen to 3 mg 
induction (daily, Cycle 1 Day 1 through Day 5) and 2 
mg maintenance (3 times per week starting on Cycle 
1 Day 8) 
Original dose regimen for 
cohort 6 not likely to be 
tolerated based on 
available interim data 
4.2 
Revised 
Changed Cycle 1 Day 7 visit to Cycle 1 Day 5 visit 
starting with subjects enrolled in cohort 5 
Collection of PK data 
based on revised dosing 
regimen 
4.2 
Added 
Added PK assessment 24 hours post study drug 
administration on Cycle 1 Day 5 starting with 
subjects enrolled in cohort 5 
Revised dosing regimen 
4.2 
Removed 
Removed days allowable for Cycle 1 Day 5 and Cycle 
1 Day 8 
Consistency of PK data 
based on revised dosing 
regimen 
Throughout 
Clarification 
Corrected typographical errors 
Consistency and 
readability of protocol 
Amendment #9 
(dated 13 September 2018) 
4.2 
Added 
Added baseline dilated eye exam with fundus 
photos and neurology & exam (prior to Cycle 1 Day 
1 study drug administration) 
SMC recommendation 
5.2 
Added 
Updated eligibility to exclude patients with ≥ grade 
1 peripheral neuropathy 
SMC recommendation 
Amendment #8  
(dated 06 June 2018) 
4.1.3, 5.1 
Removed 
Removed eligibility requirement that subjects must 
have failed to achieve CR to standard induction 
therapy 
Increased flexibility at site 
based on available subject 
safety information from 
this study and ongoing 
solid tumor study 
(IACS2016-002) 
Amendment #7  
(dated 27 February 2018) 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 7 of 59 
Section 
Text 
Amendments 
Rationale for Change 
Synopsis, 4.1.6 
Added 
Added dosing schedule to be implemented in Cohort 
4, based on SMC recommendation 
SMC Recommendation  
Synopsis, 3.1, 4.1.6 
Clarification 
Clarified that modified induction or maintenance 
doses or alternative maintenance schedules may be 
pursued with SMC approval depending on the 
safety, PK and PD data observed 
Informational 
6.1 
Clarification 
Corrected typographical error   
Informational 
Amendment #6  
(dated 04 January 2018) 
4.2 
Revised 
Revised days allowable for Cycle 1 Day 17 and Cycle 
2 Day 16 from ±1 day to ±2 days (Cohorts 3-7) 
Increased flexibility at site 
4.2 
Revised 
Revised days allowable for Cycle 1 Day 21 to allow 
+2 days (Cohorts 3-7) 
Increased flexibility at site 
4.2 
Revised 
Revised definition of “pre-dose” from within 3 hours 
of dosing to same calendar day of dosing (Cohorts 3-
7) 
Increased flexibility at site 
4.2 
Revised 
Revised window for collection of vital signs on Cycle 
1 Day and Cycle 1 Day 7 from ± 30 minutes to ± 60 
minutes (Cohorts 3-7) 
Increased flexibility at site 
4.2 
Removed 
Removed vital signs and physical exam assessments 
on Cycle 1 Day 17 (Cohorts 3-7) 
Minimize subject time at 
site as changes are not 
anticipated in specified 
timeframe 
4.2 
Deleted 
Removed 4-hour post study drug administration 
blood hematology on Cycle 1 Days 7, 8 and 15 and 
removed requirement to perform pre-dose testing 
within 3 hours of study drug administration (Cohorts 
3-7) 
Minimize subject 
discomfort as changes are 
not anticipated in 
specified timeframe 
4.2 
Deleted 
Removed 4-hour post study drug administration , 
chemistry, coagulation, lipase, amylase & urinalysis 
on Cycle 1 Days 7, 8, 15 and Cycle 2 Days 8 and 15 
and removed requirement to perform pre-dose 
testing within 3 hours of study drug administration 
(Cohorts 3-7) 
Minimize subject 
discomfort as changes are 
not anticipated in 
specified timeframe 
5.1 
Revised 
Revised timeframe since relapse for subjects who 
previously received SCT (inclusion criterion #3) 
Increased screening 
flexibility at site 
5.1 
Revised 
Revised serum creatinine eligibility requirement 
(inclusion criterion #5) 
Increased screening 
flexibility at site 
5.1 
Revised 
Revised interval from time of previous 
investigational or non-investigational product 
treatment to start of IACS-010759 (inclusion 
criterion #9 and exclusion criterion #7) 
Increased screening 
flexibility at site 
Amendment #5  
(dated 21 July 2017) 
Synopsis, 3.1, 
4.1.6, 4.1.7, 7.1 
Revised 
Revised the dosing regimen to include an initial 
Induction Phase in Cycle 1 (Day 1-7) and 
Maintenance Phase (Day 8-21 of Cycle 1 & Days 1-21 
PK analysis and modeling 
of data from cohorts 1 
and 2 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 8 of 59 
Section 
Text 
Amendments 
Rationale for Change 
of all subsequent cycles) to start with subjects 
enrolled in Cohort 3 
Synopsis 
Revised 
Revised the authority of the SMC to approve 
intermediate doses to include induction or 
maintenance and alternative duration of induction 
doses or other maintenance schedules, not to 
exceed 6 mg (rather than 8 mg) based on the 
revised dosing regimen to be initiated with subjects 
in Cohort 3 
Allows SMC to approve 
changes to the 
intermediate induction or 
maintenance doses, 
duration or schedules 
based on safety, PK & PD 
data without requiring a 
protocol amendment 
2.2.2 
Revised/ 
Added 
Added description of results of transporter and 
drug-drug interaction studies 
Studies complete & final 
data available  
2.2.2, 3.1,  
Added 
Added description of preliminary human PK data  
PK analysis and modeling 
of data from cohorts 1 
and 2 
4.1.2, 4.1.7 
Revised 
Revised days that PK data will be evaluated when 
making dose escalation decisions 
Plasma concentrations 
will be evaluated at the 
end of the induction 
phase and again at the 
end of the 1st cycle, as 
well as at intermediate 
time points, based on the 
revised dosing regimen 
4.1.7 
Clarification 
Provided steady state plasma levels in ng/mL  
Informational 
4.1.7 
Revised 
Revised stopping rules to assess mean plasma 
concentrations at the end of the induction phase of 
dosing (Days 7 and 8), with additional assessments 
at the end of each cycle 
Revised dosing regimen 
4.1.9 
Added 
If dose interruptions occur at the end of a cycle, the 
new cycle will start on the first day dosing resumes  
Allows appropriate 
collection of assessments 
based on study drug 
administration 
4.1.10, 4.1.11 
Deleted 
Removed requirement to perform arterial blood gas 
(ABG) testing for all abnormal venous blood pH 
results 
Minimize subject 
discomfort/ will obtain for 
DLT confirmation, where 
needed, only 
4.1.11 
Added 
Added anion gap calculation to be used for arterial 
blood collection 
Informational 
4.2 
Added 
Added new study flowchart based on revised dosing 
regimen to be implemented for subjects enrolled in 
Cohort 3-6 of the dose escalation phase and Cohort 
7 of the dose expansion phase 
PK analysis and modeling 
of data from cohorts 1 
and 2 
7.1 
Revised 
Revised requirement for in-hospitalization from 
Cycle 1 Day 1 and Day 8-14 to Cycle 1 Day 7 
PK and clinical safety data 
from cohorts 1 and 2   
8.1.3 
Deleted 
Removed reference to severity grading scale for AEs 
not defined in the NCI CTCAE Ver 4.03 
Will assess all AEs 
according to CTCAE 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 9 of 59 
Section 
Text 
Amendments 
Rationale for Change 
8.1.3 
Added 
Hospitalizations to observe subjects with elevated 
lactate who remain asymptomatic and would not 
otherwise require hospitalization will be not be 
considered a grade 3 toxicity for purposes of AE 
severity grading 
Distinguishes between 
hospitalization being 
indicated due to severity 
of AE rather than for 
observation as required 
per protocol 
7.2, 7.2.1 
Clarification 
Corrected typographical errors 
Consistency and 
readability of protocol 
Amendment #4  
(dated 10 March 2017) 
Synopsis, 4.1.6 
Added 
Added that intermediate doses of IACS-010759, not 
to exceed 8 mg, may also be pursued with SMC 
approval, depending on the safety, PK and PD data 
observed 
Allows intermediate 
doses to be evaluated 
during the dose escalation 
phase based on the 
observed safety, PK and 
PD data 
4.1.7 
Added 
Added that a cohort may be expanded to include up 
to 6 subjects, in the absence of a DLT in the first 3 
subjects of a cohort, with SMC approval; in that 
instance, allocation into simultaneously enrolling 
cohorts will alternate between cohorts. 
Recommendation by SMC 
during Cohort #1 review.  
Allows potential to 
further explore safety, PK 
and PD activity; allocation 
specified to reduce bias 
4.1.10, 4.1.11 
Clarification 
Clarified that venous or arterial blood may be used 
to monitor lactate and blood pH; abnormal venous 
blood pH results will require confirmation from 
arterial blood. Arterial blood lactate testing will also 
be used to confirm a potential DLT if an abnormal 
venous lactate level constitutes a DLT. 
Recommendation by SMC 
during Cohort #1 review.  
Not previously specified. 
Clarification is to ensure 
accuracy of lactate and 
blood pH results while 
minimizing subject 
discomfort, as agreed 
with FDA 
4.1.10, 4.1.11 
Revised 
Revised the requirements for monitoring subjects 
with elevated lactate and use in DLT definition of 
subjects with pH between 7.30 to 7.35 who remain 
asymptomatic  
pH results in leukemia 
patients can be variable 
and are typically lower 
than normal subjects.   
Definition revised, using 
recommendations from 
SMC during Cohort #1 
review and as modified 
based on FDA feedback.  
4.1.10 
Revised 
Revised the lactic acid DLT definition to include 
presence of clinical symptoms and specify time 
frame (>24 hours) to determine second episode of 
elevated blood lactic acid 
Recommendation by SMC 
during Cohort #1 review.  
Minimum time frame 
added to define 2 
separate episodes of 
elevated lactate; clinical 
symptoms added to 
reduce potential to define 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 10 of 59 
Section 
Text 
Amendments 
Rationale for Change 
a DLT based on 
asymptomatic subjects 
with laboratory results 
that may be indicative of 
disease status only, as 
agreed with FDA 
4.1.15, 4.2 
Added 
Additional PK and/or PD blood draws may be 
obtained ~every 4 days, when possible, for up to 4 
weeks after last study drug administration in 
subjects who discontinue the study 
Recommendation by SMC 
during Cohort #1 review.  
Allows potential to 
further explore PK and PD 
activity of IACS-010759 
following discontinuation 
of study drug 
4.2 
Added 
Additional PK blood draws on Days 8 and 14 of Cycle 
2  
Allows more frequent PK 
monitoring beyond Day 
28, based on review of 
available cohort 1 PK data 
4.2 
Added 
Further additional PK blood draws during Cycle 2 at 
the discretion of the Principal Investigators 
Allows for additional PK 
monitoring during Cycle 2 
if needed 
4.2 
Added 
Additional PK blood draws, weekly for the first cycle 
after dose-escalation 
Allows monitoring of PK 
levels after intra-subject 
dose escalation 
4.2 
Deleted/ 
Revised 
Removed Cycle 1/Day 2, Day 4, Day 9, Day 17 PD 
assessments and changed Cycle 1/Day 10 to also 
collect PD 6 hours following dosing 
Revised based on review 
of available cohort 1 PD 
data 
5, 5.1.2, 5.2.1 
Added, 
Clarification 
Added SAS version to be used for statistical analysis; 
confirmed that a Statistical Analysis Plan will be 
prepared and finalized prior to data base lock. 
Clarified statistical analysis plans, including moving 
descriptions to different section of protocol. 
Provides further 
information regarding 
planned statistical 
analysis; consistency and 
readability of protocol 
1, 4.1.9.2, 4.1.11 
Clarification 
Corrected typographical errors 
Consistency and 
readability of protocol 
Amendment #3  
(dated 14 December 2016) 
4.1.9, 4.2 
Added 
Added additional PK, lactate and blood pH testing 
following a dose reduction or interruption 
Additional safety 
monitoring 
4.2 
Added 
Added PD prior to dosing and 6 hours following 
dosing and PK, lactate and blood pH testing 6 hours 
following dosing on Cycle 1, Day 17 and Cycle 1, Day 
22 
Additional safety 
monitoring 
4.1.10, 4.1.11, 4.2 
Clarification 
Clarified total CO2 results will be used where 
bicarbonate testing is indicated 
Consistency with site 
practice 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 11 of 59 
Section 
Text 
Amendments 
Rationale for Change 
4.1.11 
Revised 
Updated anion gap reference range based on using 
total CO2 results (where bicarbonate testing is 
indicated)  
Use of total CO2 results 
4.2 
Revised 
ECOG testing to be performed only at Screening, 
Day 1 of each cycle, and End of Study visits 
Consistency with site 
practice 
4.2 
Clarification 
Clarified coagulation testing to include INR 
Inadvertently omitted in 
previous version 
4.2 
Clarification 
Clarified that blood hematology results below the 
level of quantitation will be recorded as 0 
Informational 
4.2 
Clarification 
Overall Response Rate assessment (as described in 
Section 5.2) included in study flowchart 
Reminder to study 
personnel 
4.2 
Revised 
Bone marrow assessments during additional cycles 
(beyond cycle 3) will be collected one day prior to 
D21 assessments 
Allows bone marrow 
results to be available for 
review when performing 
D21 assessments 
4.2 
Revised 
Corrected footnote 5 from 96 hours to 72 hours  
Typographical error 
Amendment #2  
(dated 28 October 2016) 
4.2, 9.1.2, 9.1.6, 
9.1.7 
Clarification 
All AEs including SAEs, should be collected, 
beginning from the time of the first protocol-specific 
intervention (study drug administration).  New 
information regarding signs and symptoms that 
occurred prior to the first study medication dose on 
Day 1 should be recorded under the subject’s 
Medical History. 
Clarification of Adverse 
Event Reporting 
Amendment #1  
(dated 29 August 2016) 
Synopsis, 4.1.6, 
4.1.7, 7.1 
Clarification 
Clarified cycle 1 length is 28 days (dosing occurs on 
Day 1 followed by continuous dosing starting on day 
8) 
FDA request 
4.2 
Added 
Added CPK to chemistry testing 
FDA request 
4.2 
Clarification 
Clarified coagulation testing to include PT, PTT, 
fibrinogen 
FDA request 
4.2 
Added 
Added weekly laboratory testing during second 
cycle 
FDA request 
4.1.9.2, 4.2 
Added 
Added weekly laboratory monitoring during 1st cycle 
of increased dose for intra-subject dose escalation 
FDA request 
4.1.3, 6.1 
Added 
Added “no available treatment options with known 
benefit” to subjects to be enrolled in the expansion 
phase 
FDA request 
4.1.3, 6.1 
Clarification 
Clarified definition of relapsed or refractory for 
eligibility 
FDA request 
6.3 
Revised 
Revised lactate exclusion criterion 
FDA request 
7.2 
Added 
Added description for each capsule strength 
FDA request 
4.1.10 
Revised 
Revised DLT definition 
FDA request 


 
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Section 
Text 
Amendments 
Rationale for Change 
4.1.11 
Revised  
Revised requirements for management of elevated 
lactate levels, including definition of lactic acidosis 
symptoms 
FDA request 
4.1.14, 4.1.7 
Clarification 
Clarified PK will be evaluated in each cohort prior to 
dose escalation 
FDA request 
4.1.7 
Added 
Added PK levels which will pause or stop dose 
escalation 
FDA request 
4.1.9 
Revised 
Revised dose modification criteria to permanently 
discontinue study drug in any subject that develops 
DLT related to lactic acid 
FDA request 
4.1.9.3 
Revised 
Revised intra-subject dose escalation criteria 
FDA request 
4.1.8 
Revised 
Revised stopping rule probability statement for 
expansion phase 
FDA request 
4.1.2, 4.1.7 
Added 
Added safety stopping criteria to encompass 
toxicities beyond cycle 1 
FDA request 
4.1.8 
Revised 
Revised the stopping boundaries for DLT monitoring 
to correct discrepancy 
FDA request 
7.1 
Revised 
Revised the food effect dose description to indicate 
the dose may be lower than R2PD 
FDA request 
4.2 
Added 
Added ECG monitoring at pre-dose and around the 
anticipated maximal plasma concentrations on Day 
1, Day 14 and Day 28 of Cycle 1  
FDA request 
4.2 
Revised 
Research bone marrow sample will be collected at 
Screening rather than Cycle 1, Day 1 
Reduce frequency of bone 
marrow sampling 
6.1 
Clarification 
Revised inclusion criterion #9 to clarify the interval 
from prior treatment to time of initiation of study 
drug will be at least 2 weeks for biological/immune-
based therapies  
Clarification of wash-out 
period for prior treatment 
8.1 
Added 
Added strong cytochrome P450 (CYP450) inhibitors 
or inducers as non-permitted concomitant 
medications 
FDA request 
2.1 
Amended 
Amended AML response rate reference 
To ensure consistency 
with IND 
Synopsis, 4.1.6 
Clarification 
Clarified that cycles occur on a continual basis 
Readability of protocol 
4.1.4 
Clarification 
Specified number of sites 
Number of sites not 
previously provided 
4.1.14 
Revised 
Revised Safety Monitoring Committee 
representatives description to specify study-specific 
Medical Monitor 
Responsibility transferred 
to CRO 
4.2 
Clarification 
Clarified in study flow chart which study days 
subjects are inpatient; timing of study drug 
administration; cycle days 
Readability of protocol 
4.2, 5.2 
Clarification 
Clarified bone marrow aspirate/biopsy will be 
performed clinically as indicated, at least once per 3 
cycles 
To ensure consistency of 
testing across study 
subjects 
4.2, 10.2 
Clarification 
Clarified the QTc correction formula 
Informational 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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Section 
Text 
Amendments 
Rationale for Change 
5.1.2 
Added 
Added name of clinical data base to be used for 
study data collection 
New study information 
7.2 
Clarification 
Clarified the planned starting dose capsule strength 
Informational 
9.1.2 
Revised 
Revised clinical data base and safety data base to be 
used for data collection 
Responsibility transferred 
to CRO 
9.1.3 
Added 
Added reference to recommended AE recording 
guidelines 
Readability of protocol 
9.1.7, 9.1.8 
Revised 
Revised safety reporting procedures and contact 
information 
Responsibility transferred 
to CRO 
Synopsis, 4.1.7, 
5.2.2, 6.1, 10.2 
Clarification 
Corrected typographical errors 
Consistency and 
readability of protocol 
Original Protocol  
(dated 12 April 2016) 
 


 
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2 Background Information 
2.1 AML 
Acute myeloid leukemia (AML) is a malignancy of immature granulocytes or monocytes.  The 
malignancy is characterized by accumulation of leukemic blasts and blockade of normal bone 
marrow production resulting in thrombocytopenia, anemia, and neutropenia.  There are 
approximately 13,000 new cases of AML per year in the United States, with an estimated 10,000 
deaths occurring in the same time period[1].  Almost all newly diagnosed cases, as well as 
deaths, will be in adults[2].  Standard treatment for AML includes systemic combination 
chemotherapy to control bone marrow and systemic disease.  Treatment is generally divided 
into an induction phase, to attain remission, and a consolidation/maintenance phase[2].  
Traditional induction chemotherapy can produce complete remissions in most (50% to 75%) 
subjects with AML[3, 4].  Unfortunately, between 60% and 80% of subjects with AML (especially 
those with adverse cytogenetic features, adverse molecular mutations or antecedent 
hematological disorder) will be refractory or relapse after initial response to induction therapy 
relapse so only 20% to 30% will achieve long-term disease-free survival.  For subjects with AML 
refractory to initial therapy or who relapse after a brief remission (< 12 months), outcomes are 
more dismal.  We have previously reported a median OS of 3.8 months for subjects with AML 
who are refractory to induction therapy [5]. Similarly subjects with relapsed AML have a poor 
outcome with response rates ranging from 10% to 30% and overall survival <6 months with 
salvage therapy[6, 7]. 
These results emphasize the need to explore alternate salvage regimens for subjects with 
relapsed/refractory AML. The development of novel and effective anti-AML agents and/or 
combinations is crucial to improving the outcome of AML.  
Tumors frequently rewire their metabolism to ensure a steady supply of metabolites for 
generation of ATP and for a biosynthesis of cell constituents.  While aerobic glycolysis, also 
known as the Warburg effect, is a common metabolic alteration in cancer, recent studies 
indicate that some tumors are highly dependent on oxidative phosphorylation (OXPHOS) for 
survival [8-13]. Several recent reports demonstrate that oxidative metabolism generates 
intracellular energy and metabolic intermediates necessary to promote the growth of tumor 
cells [14-18].  It has previously been reported that leukemia cells have increased rates of fatty 
acid oxidation[16] and that inhibition of fatty acid oxidation rapidly inhibits oxygen consumption 
and sensitizes leukemia cells to induction of apoptosis, substantiating the idea that 
mitochondrial oxidative metabolism supports leukemia cell survival.  Another ground-breaking 
study has demonstrated that leukemic stem cells (LSC) are unable to utilize glycolysis when 
mitochondrial respiration is inhibited, indicating that the maintenance of mitochondrial function 
is essential for LSC survival [15]. In contrast, normal murine [19] and human hematopoietic stem 
cells (HSC)[15] predominantly utilize glycolysis for energy homeostasis.  Therefore, inhibiting 
oxidative phosphorylation in the context of AML could have therapeutic potential. 
2.2 IACS-010579 
2.2.1 IACS-010759 Preclinical Biology 
IACS-010759 inhibits complex I of mitochondria oxidative phosphorylation (OXPHOS). IACS-
010759 is a potent inhibitor of the proliferation of human cancer cells, including AML cell lines, 
human primary AML cells, and glycolysis-deficient NB-1 neuroblastoma cells.  Both primary AML 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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cells and established cell lines demonstrated dose-dependent growth inhibition and reduction of 
cell viability in response to IACS-010759, with IC50 values ranging from 1-10 nM.  Ectopic 
expression of the yeast complex I protein NDI-1 partially restored AML cell viability, indicating 
that the effects of IACS-010759 were mechanism-based via OXPHOS inhibition.  In contrast to 
the potent effect of IACS-010759 on the viability of tumor cells, the compound had minimal 
effects on the viability of bone marrow cells obtained from healthy subjects, suggesting that the 
compound has a therapeutic window for tumor cells vs. normal leukocytes.  
The sensitivity of NB-1 cells, which lack the gene that encodes the essential glycolytic pathway 
enzyme phosphogluconate dehydrogenase (PGD), to IACS-010759 was reduced upon ectopic 
expression of PGD.  This suggests that the sensitivity of NB-1 cells to IACS-010759 is due to their 
inability to upregulate glycolysis in response to energy stress conferred by IACS-010759 
treatment.  This is consistent with the OXPHOS inhibitory mechanism of IACS-010759 and with 
the observed increase in potency of IACS-010759 to kill AML cells compared to normal bone 
marrow cells. 
IACS-010759 inhibits tumor growth and extends survival in AML xenograft models.  IACS-
010759 caused dose-dependent tumor regression or substantial tumor growth inhibition (TGI) in 
both orthotopic and subcutaneous xenograft models with human AML and NB-1 neuroblastoma 
cells, while overall survival was increased in both primary AML and OCI-AML3 cell line orthotopic 
xenograft models. 
In these in vivo efficacy experiments, increases in dose or shortening of the dosing interval 
corresponded to increases in efficacy, measured as TGI or regressions.  Notably, in all studies, 
decreases in dosing frequency at a given dose correspond to decreases in efficacy, with QD 
dosing being more effective than intermittent dosing of the same dose of IACS-010759.   
Trough plasma levels at steady state of 10-20 nM (5.6-11.3 ng/mL) were associated with efficacy 
in these xenograft studies, regardless of the dosing regimen.  This concentration correlates well 
with the IACS-010759 concentrations of 1-10 nM that are required to inhibit cancer cell 
proliferation and to inhibit the OXPHOS pathway in cell based assays in vitro.  Based on these 
preclinical efficacy studies, it seems reasonable to target sustained trough steady state plasma 
levels of 10-20 nM (5.6-11.3 ng/mL) IACS-010759 for efficacy in human clinical trials. 
2.2.2 IACS-010759 Nonclinical Experience 
The pharmacological, pharmacokinetic, and toxicological properties of IACS-010759 were 
characterized in a series of completed and ongoing nonclinical studies.  These studies 
demonstrate that: 
 
IACS-010759 inhibits proliferation and reduces the viability of primary human AML samples 
treated ex vivo and in AML cell lines with IC50 values ranging from 1-10 nM, and has minimal 
effects on the viability of bone marrow cells obtained from healthy subjects. These studies 
suggest that IACS-010759 has a therapeutic window for tumor cells vs. normal leukocytes. 
 
IACS-010759 caused dose-dependent tumor regression or substantial tumor growth 
inhibition (TGI) in both orthotopic and subcutaneous xenograft models with human AML 
and NB-1 neuroblastoma cells.  In addition, survival was increased in both primary AML and 
OCI-AML3 cell line orthotopic xenograft models.  Several oral dosing regimens were 
explored in these studies, and efficacy was consistently observed with steady state trough 
plasma levels of 10-20 nM (5.6-11.3 ng/mL) IACS-010759. 


 
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 
IACS-010759 had negligible inhibitory activity (estimated IC50 > 30 µM) at hERG K+ channels 
and did not prolong the QTc interval in monkeys at doses up to 1.5 mg/kg/day for up to 28 
days.   
 
IACS-010759 did not elicit central nervous system effects in rats treated with oral doses up 
to 2 mg/kg based on neurobehavioral parameters (functional observation battery). 
 
IACS-010759 exhibited low plasma clearance, a high volume of distribution, and a long half-
life (42 to 57 hours) in mice, rats, dogs, and monkeys. Upon oral dosing, the compound was 
absorbed relatively slowly, with Tmax values in the range of 3 to 8 hours and bioavailability 
of ~100% in mouse and rat and ~36% in monkey.   
 
IACS-010759 exhibited low/moderate metabolic turnover following incubation with liver 
microsomes and hepatocyte preparations from mouse, rat, dog, monkey and human. No 
metabolites unique to human were identified. IACS-010759 was found to be a moderate 
competitive inhibitor of CYP 2C19 (IC50 = 4 uM), but did not inhibit any other CYP isoforms 
tested.  No time dependent inhibition of CYPs 1A2 or 3A4 was observed.   
 
The potential for CYP enzyme induction by IACS-010759 could not be assessed in standard 
hepatocyte enzyme induction assays, likely because of the mechanism-based effects of 
IACS-010759 on oxidative phosphorylation.  Therefore, the potential of IACS-010759 to 
reduce the levels of drugs metabolized by CYP450 enzymatic pathways is unknown. 
 
In transporter studies, IACS-010759 had no effect on BSEP-, MDR1-, OAT1-, OAT3-, 
OATP1B1-, OATP1B3- and OTC1-mediated probe substrate transport. IACS-010759 
moderately inhibited the BCRP- and OCT-2 mediated probe transport by 27% and 36%, 
respectively, at 1 M.  IACS-010759 is likely a substrate of the BCRP and MDR1 transporters. 
 
A drug-drug interaction (DDI) study was conducted with IACS-010759 and pentagastrin or 
the histamine H2 blocker famotidine in dogs. Neither pentagastrin nor famotidine affected 
the plasma levels of IACS-010759 after oral administration, indicating low potential for DDI 
with drugs that affect stomach pH. 
 
IACS-010759 was nongenotoxic in a bacterial reverse mutation assay without or with 
metabolic activation, and in a bone marrow micronucleus test conducted after 28-days of 
oral administration in rats at doses up to 2 mg/kg/day, the highest dose tested. 
 
Single-dose IV administration of IACS-010759 to monkeys showed that sporadic emesis 
observed following oral and IV administration was a systemic rather than a local GI effect. 
Plasma levels of IACS-010759 associated with acute emesis were higher than those not 
associated with emesis. 
 
IACS-010759 was well tolerated in GLP-compliant 28-day oral toxicity studies in rats and 
monkeys at doses up to 1 mg/kg/day and 1.5 mg/kg/day, respectively.  Higher doses in the 
28-day studies and/or 14-day dose range-finding studies resulted in adverse effects in both 
species, including moribundity requiring euthanasia and/or mortality in rats at ≥2 
mg/kg/day and in monkeys at ≥3 mg/kg/day.  There were no treatment-related 
histopathological findings in tissue sections from the 28-day studies.   
 
Cmax on Day 28 from pivotal toxicity studies was 61.3 ng/mL in rats and 99.3 ng/mL in 
monkeys at doses of 1 mg/kg/day and 1.5 mg/kg/day, respectively.  These Cmax values, which 
were observed at doses that were well tolerated for 28 days in each species, were notably 
higher than steady state trough plasma levels of 5.6 – 11.3 ng/mL at which efficacy was 
consistently observed in nonclinical xenograft models of human tumor cells.  Because the 
human peak:trough plasma levels with daily oral dosing are projected to be <2-fold based 
on projected human clearance and on the preliminary data from cohorts 1 and 2 of the 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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present study, this represents a significant exposure multiple above the projected human 
exposure required for efficacy. 
2.2.3 IACS-010759 Chemical Properties 
IACS-010759 is available as a crystalline hydrochloride salt, with the chemical name 5-(5-methyl-
1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-
(trifluoromethoxy)phenyl)-1,2,4-oxadiazole  hydrochloride salt.  
The molecular formula of IACS-010759 hydrochloride salt is C25H25F3N6O4S.HCl and the molecular 
weight is 599.024 g/mole (562.564 g/mole as the free base). This compound has not yet been 
assigned a generic name.  
3 Study Rationale 
3.1 Rationale for IACS-010759 Dose Selection 
The starting dose of IACS-010759 has been selected as the human equivalent dose 
corresponding to no more than 1/10 the no observed adverse effect level (NOAEL) in nonclinical 
toxicology studies.  Additional considerations for dose selection include avoiding Cmax-associated 
emesis and anticipation of achieving plasma levels associated with preclinical efficacy within a 
reasonable number of escalation steps. IACS-010759 was well tolerated in 28-day oral toxicology 
studies in the monkey and rat and the NOAEL in those studies were 1.5 mg/kg/day and 1 
mg/kg/day, respectively. Based on these considerations, our projection is that a human starting 
dose of 0.5 mg will allow a thorough exploration of safety and tolerability in humans while 
minimizing the exposure of subjects to doses not anticipated to be effective. Using a model 
based on allometric scaling, a human dose of 0.5 mg, given once daily, would be anticipated to 
produce a Cmax of ~2.3 ng/mL and to give a projected steady state exposure ratio, animal-to-
human, of approximately 27-fold based on the 1 mg/kg/day dose in the rat and 43-fold based on 
the 1.5 mg/kg/day dose in the monkey for Cmax and approximately 7-fold based on the rat and 
11-fold based on the monkey for AUC.  Therefore, the human starting dose of 0.5 mg of IACS-
010759, administered orally once daily, would be anticipated to be safe and well tolerated, 
while allowing attainment early in the dose-escalation studies of doses that may be projected to 
show benefit in patients. 
 
Limited PK data from subjects in cohorts 1 and 2 showed unexpected levels of accumulation of 
IACS-010759 throughout the dosing period, consistent with a model in which the clearance of 
IACS-010759 decreases exponentially with time, leading to an increasingly long terminal T1/2 and 
accumulation upon multiple dosing.  A mathematical model and simulation has been developed 
based on data from the subjects treated with IACS-010759 to date that predicts the observed 
human PK.   Based on this model, a modified dosing regimen is being implemented for the dose 
escalation phase with cohorts 3-6 and for the dose expansion phase with cohort 7, consisting of 
an induction phase in which IACS-010759 is administered daily for up to 7 days, followed by a 
maintenance phase in which a lower dose is administered weekly to maintain steady state 
plasma levels (or as otherwise specified by the SMC based on safety, PK and PD data observed).   


 
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3.2 Rationale for Study Design 
Current treatment options for relapsed or refractory AML reflect an unmet medical need and 
additional options for treatment are needed.   
Preclinical data reviewed above strongly suggest a robust antitumor activity with IACS-010759 in 
AML. The current study focuses on evaluating the maximum tolerated dose (MTD), 
recommended phase 2 dose (RP2D) and safety profile of IACS-010759 and preliminary clinical 
efficacy in subjects with confirmed relapsed or refractory AML and no available treatment 
options with known benefit.   
The results from this study will form the basis for decisions for future studies. 
4 Experimental Plan 
4.1 Study Design 
4.1.1 Study Phase 
Phase 1 study with a dose-escalation phase followed by an expansion phase. 
4.1.2 Enrollment/Randomization 
This open label study will employ a sequential-cohort, non-randomized, single site enrollment. 
The study will be under ongoing review by a Safety Monitoring Committee (see section 4.1.14). 
In the dose-escalation phase, all subjects in a cohort will be monitored for DLT for the first cycle 
before proceeding with subsequent cohorts.  To assess toxicities that may occur beyond cycle 1, 
cohorts of up to 6 subjects will be assessed following completion of 4 cycles of study drug.  If 
two or more subjects in the cohort did not receive at least 80% of the planned dose due to 
adverse events, dose escalation will be paused and an evaluation will be performed. 
4.1.3 Subject Population 
For complete subject eligibility please see section 5. 
Dose-escalation phase: Subjects with confirmed relapsed or refractory AML and no available 
treatment options with known benefit. 
Expansion phase: Subjects with relapsed or refractory AML who have failed therapy with up to 
one prior salvage regimen and no available treatment options with known benefit. 
Exception:  stem cell transplant [SCT] or stem cell therapy for subjects who previously 
underwent SCT/stem cell therapy, and are currently in remission will not be considered a 
salvage regimen. 
Relapsed or refractory status is defined by the failure of at least one prior cycle of 
chemotherapy (including but not limited to cytotoxic chemotherapy, hypomethylator therapy, 
immune-based therapy, stem cell transplant or stem cell therapy, FLT3-inhibitor therapy, 
investigational therapy, and others).  Patients in first relapse and less than 12 months from 
diagnosis [short first remission] or in second or later relapse are eligible.   
4.1.4 Number of Sites and Subjects 
 2 to up to 48 subjects will be enrolled at one site. 
4.1.5 Sample Size Considerations 


 
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The dose-escalation phase of the study will enroll 3-6 subjects in each cohort, based on a 3+3 
dose-escalation design to assess the MTD level. A maximum of 36 subjects will enroll in the 
dose-escalation phase. 
A maximum of 18 subjects will enroll in the expansion phase (12 additional subjects and the 6 
subjects from the dose-escalation phase at the cohort of the highest dose level shown to be well 
tolerated or the RP2D). The expansion phase sample size of 18 subjects is not based on a formal 
sample size calculation.  Rather, 18 subjects are deemed to be sufficient for the assessment of 
safety and tolerability as the primary objective and the exploration of clinical anti-tumor activity 
and other secondary and exploratory endpoints. 
4.1.6 Treatment Cohorts and Treatment Schema 
In cohorts 1 and 2, IACS-010759 was administered orally daily on a continual 21-day schedule (1 
cycle = 21 days of daily dosing), with the exception that the first cycle for each subject contains a 
7-day single dose lead-in (first cycle = 28 days).  Starting on day 8 of cycle 1 for subjects enrolled 
in cohorts 1 and 2, dosing is on a 21 day schedule until confirmed PD, initiation of alternative 
cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment prematurely 
occur as defined in Section 4.1.9.   
 
Based on PK modeling of data from cohorts 1 and 2, the dose regimen for cohort 3 and 
subsequent cohorts will change to include an induction phase with daily dosing, followed by a 
maintenance phase at a dose sufficient to maintain the steady state levels achieved during the 
induction phase.  In these cohorts, IACS-010759 will be administered orally daily (up to 7 days) 
during the induction phase(Cycle 1, Days 1-7).  Starting on day 8 of cycle 1 for all cohorts, 
maintenance dosing will be administered on a 21-day schedule until confirmed PD, initiation of 
alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment 
prematurely occur as defined in Section 4.1.9.   
The planned dose levels are given in Table 1 and 2, below: 
 
Table 1: Dosing schema for Cohorts 1 and 2 
PHASE 
COHORT 
NO OF SUBJECTS 
IACS-010759 DOSE LEVEL * 
Dose-
escalation 
Cohort 1 
3-6 
0.5 mg 
Cohort 2 
3-6 
1 mg 
*Intermediate doses of IACS-010759, not to exceed 8 mg, not listed above may also be pursued with SMC approval, 
depending on the safety, PK and PD data observed.   
 
Table 2: Revised dosing schema for Cohorts 3-6 (Dose-Escalation) and 
 
Cohort 7 (Dose Expansion) 
PHASE 
COHORT 
NO OF 
SUBJECTS 
INDUCTION DOSE* 
(FREQUENCY#) 
MAINTENANCE DOSE* 
(FREQUENCY#) 
Dose-
escalation 
Cohort 3 
3-6 
2 mg (daily, Cycle 1 Day 1-7) 
0.5 mg (once per week) 
Cohort 4** 
3-6 
2.5 mg (daily, Cycle 1 Day 1-7) 
1.0 mg (three times per week) 
Cohort 5 
3-6 
2.5 mg (daily, Cycle 1 Day 1-5) 
1.5 mg (three times per week) 
Cohort 6 
3-6 
3 mg (daily, Cycle 1 Day 1-5) 
2 mg (three times per week) 
Expansion 
Cohort 7 
12 
RP2D 
RP2D 
*Intermediate induction or maintenance doses of IACS-010759 may be pursued with SMC approval, not to exceed 6 
mg, and  
# alternative duration of induction doses or other maintenance schedules not listed above may also be pursued with 
SMC approval depending on the safety, PK and PD data observed.   
**Following their review of Cohort 3, the SMC recommended implementation of the following dose schedule for 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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subjects who enroll in Cohort 4 of the study: 
Induction dose: 2.5 mg, administered daily, Cycle 1 Day 1 through Day 7 
Maintenance dose: 1 mg, administered 3x/week (for a total weekly dose of 3 mg) with the first maintenance dose 
starting on Cycle 1 Day 8 
 
4.1.7 Dose-escalation 
A standard 3+3 dose-escalation design will be used to determine MTD. The potential dose 
schedule is shown in section 4.1.6. In the first cohort, as a safety precaution, each new subject 
began treatment only after the safety analysis for DLTs and evaluation of PK data during the first 
cycle (28 days) was completed for the previous subject.  In subsequent cohorts of the dose-
escalation phase, new subjects will be entered and treated only after the previous subject has 
been treated with IACS-010759 for up to 7 days (e.g., has completed the induction phase) and 
DLT safety analysis for each subject will be performed after completion of cycle 1.  PK data will 
be monitored for each subject and evaluated for each cohort during the study and plasma levels 
will be considered when making dose escalation decisions. 
 
The following dose-escalation rules will be applied: 
- 
If 0 out of the 3 subjects have a DLT, the next cohort may be started.  
- 
If 1 out of the 3 subjects has a DLT, an additional 3 subjects will be enrolled in the same 
cohort.  If none of these 3 additional subjects have a DLT after being observed for 28 
days (i.e., cycle 1), the next dose escalation cohort may be started. 
- 
If 2 or more out of 6 subjects in Cohort 1 develop a DLT, enrollment will cease 
immediately and the study will be halted.  No MTD can be determined. 
- 
If 2 or more out of 6 subjects in the following Cohorts (2-6) develop a DLT, enrollment 
into the cohort will cease, and the prior cohort’s dose level will be deemed as MTD 
level.  All subjects from the non-tolerated cohort will be de-escalated to the prior 
cohort’s dose level. 
If at least 2 of 3 or 2 of up to 6 patients experience a DLT at a given dose, then the MTD 
has been exceeded (stopping dose).  Once the MTD has been exceeded, treat another 3 
patients at the previous dose if there were only 3 patients treated at that dose. 
 
During dose escalation, if necessary, cohorts may be expanded in the absence of a DLT, to a 
total of up to 6 subjects to further explore safety, PK and PD activity of IACS-010759 at each 
dose level with the approval of the SMC. Such an expansion may occur concurrently with dose 
escalation to the next dose level.  A predetermined allocation to cohorts that minimizes 
selection bias will be used when enrolling into two open cohorts simultaneously.  Allocation to 
simultaneously open cohorts will be performed in an alternating random manner, based on 
entry into the study.  During dose escalation, intermediate (including induction or maintenance) 
doses and alternative duration of induction doses or other maintenance schedules of IACS-
010759, not to exceed 6 mg, may also be pursued with SMC approval, depending on the safety, 
PK and PD data observed.   
The dose escalation phase of the study will be paused after the dose at which the mean steady 
state plasma levels, measured as pre-dose concentrations on Day 28 for cohorts 1 and 2 and as 
pre-dose concentrations on Day 8 (e.g. the end of the induction phase) for cohorts 3 onwards, 
reach levels of ≥20 nM (11 ng/mL).  A full review of the safety, PK and efficacy data from that 


 
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cohort will be performed and escalation may be continued if the MTD has not been reached, 
and the Sponsor obtains agreement with FDA to continue dose escalation.   
The dose escalation phase of the study will stop after the dose for which the mean Cmax on Day 
28 for cohorts 1-2 or Day 7 for cohorts 3 and onwards is ≥100 nM, or after the dose for which 
the mean steady state concentration for the cohort, as measured on the last day of any 21 day 
Cycle, is >100 nM, whichever dose is lower. 
To assess toxicities that may occur beyond cycle 1, cohorts of up to 6 subjects will be assessed 
following completion of 4 cycles of study drug.  If two or more subjects in the cohort did not 
receive at least 80% of the planned dose due to adverse events, dose escalation will be paused 
and an evaluation will be performed. 
Once the MTD has been established or the dose-escalation completed without identifying a 
MTD, the RP2D will be defined based on an assessment the safety, pharmacokinetic (PK), 
pharmacodynamic (PD), biomarker, and response data.  
At the discretion of the sponsor, dose-escalation may be stopped before an MTD is reached. In 
this case, the RP2D may be chosen based on an assessment of the safety, PK, PD, biomarker, 
and response data evaluable up to that time. An MTD does not have to be reached to expand a 
dose cohort if the available data demonstrate that a lower dose level may provide antitumor 
activity while minimizing potential risk. Upon completion of the dose-escalation, the cohort with 
either the highest dose level shown to be well tolerated or the RP2D will be expanded to a total 
of 6 subjects (if not already expanded to 6 subjects due to either observation of a DLT or to 
further explore safety, PK and PD activity of IACS-010759 at that dose level). 
Late onset DLTs that could not be taken into consideration prior to scheduled dose escalations 
will be ad-hoc evaluated on a case-by-case basis, and may lead to enrollment of additional 
subjects in specific cohorts or to revision of the previously determined MTD. 
4.1.8 Expansion Phase  
Subjects in the expansion phase will be treated at the RP2D level determined in the dose-
escalation phase.  
The primary objective of the expansion phase is to determine safety of IACS-010759.  
Additionally, as part of the expansion phase, the effect of a high fat meal on the PK of IACS-
010759 (Food Effect) will be evaluated in a total of 6 subjects (Food Effect cohort), as described 
in Section 7.1.  After the first 6 subjects have been enrolled in the expansion cohort, the next 6 
subjects will be enrolled in the Food Effect cohort.     
To evaluate safety, the method of Thall, Simon and Estey [20] will be used for monitoring DLTs 
occurring in the first cycle. The probability of DLT is denoted by PT. We assume PT ~ beta (0.4, 
1.6).  Our stopping rule is given by the following probability statement:  Pr(PT > 0.20 | 
data)>0.80. 
That is, if at any time during the study we determine that there is more than 80% chance that 
the unacceptable toxicity rate is more than 20% during the expansion phase, then the 
enrollment will be stopped. Subjects will be monitored by a cohort size of 6 during the 
expansion phase according to the following stopping boundaries for DLTs, starting from the 12th 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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subject. The monitoring rule for DLTs, based on these assumptions and monitoring conditions is 
found in Table 3. For example, accrual in the expansion phase will cease if 4 or more subjects 
experience DLTs among the first 12 subjects. The operating characteristics are summarized in 
Table 4. The design software Multc Lean Desktop (version 2.1) developed by the Department of 
Biostatistics at M. D. Anderson Cancer Center was used to generate the toxicity stopping 
boundaries and the operating characteristics tables. 
Table 3 Stopping boundaries for DLT monitoring 
# Subjects evaluated
12
18
# Subjects with DLTs
4-12
6-18
 
Table 4 Operating characteristics of toxicity monitoring 
True DLT Rate
Early Stopping Probability
Average Sample Size
0.10
0.0256
17.8
0.15
0.0922
17.4
0.20
0.2054
16.8
0.25
0.3512
15.9
0.30
0.5075
15.0
 
4.1.9 Dosing Adjustments, Delays and Discontinuations 
IACS-010759 dose reduction/interruption/discontinuation decisions should be based on the 
CTCAE version 4.03 of the toxicity and according to the guidelines shown below. If toxicity is not 
covered in the table, doses may be reduced or held at the discretion of the investigator for the 
subject’s safety.  Additional PK, blood pH and lactate testing will be performed following a dose 
reduction or resumption of dosing following a dose interruption, as described in Section 4.2.  
IACS-010759 should be permanently discontinued in any subject that develops DLT due to lactic 
acid. 
If a dose interruption occurs at the end of a cycle, the next cycle will be delayed and start on the 
first day of dosing of the next cycle.  Dose interruptions which occur during a cycle will not 
change the study days during the cycle.  
4.1.9.1 IACS-010759 Dose Adjustments for Drug-Related Hematological AEs 
 
Subjects with acute leukemias usually present with abnormal peripheral blood counts at the 
time therapy is started and myelosuppression is an expected event during the course of 
therapy for acute leukemias. Thus, no dose adjustments or treatment interruptions for 
myelosuppression will be planned for the first 4 cycles and/or in the presence of residual 
leukemia. After that, treatment interruptions and dose adjustments may be considered 
according to the following guidelines only when there is no evidence of residual leukemia.  
 
Subjects with a response (e.g., no evidence of residual leukemia or cytopenias not 
considered to be related to leukemia) and pre-cycle counts of neutrophils >1.0 x 109/L and 
platelets >50 x 109/L who have sustained low counts of neutrophils <0.5 x 109/L or a platelet 
count <20 x 109/L for more than 2 consecutive weeks in the current cycle, may have the 
treatment with IACS-010759 interrupted at the discretion of the treating physician after 
discussing with the PrincipaI Investigator (PI) until neutrophils recover to ≥0.5 x109/L and 
platelets to ≥30 x 109/L. If prolonged myelosuppression defined as ANC < 0.5 x 109/L and 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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platelets < 20 x109/L (more than 6 weeks) with evidence of a hypocellular marrow (marrow 
cellularity less than 5% without evidence of leukemia) is observed, IACS-010759 will be 
discontinued in these subjects. Delays in the start of subsequent cycles greater than 6 weeks 
will be acceptable only for subjects who are deriving clinical benefit and after discussion 
with the Principal Investigator (PI) of potential risk/benefit ratio and complete 
documentation of the degree of clinical benefit and reason for continuation on this regimen.   
 
If there are persistent peripheral blood blasts, or the bone marrow shows >5% blasts or 
evidence of leukemia, treatment may be continued regardless of neutrophil and platelet 
count with supportive care as needed. Dose-interruptions of IACS-010759 in these subjects 
should be considered on an individual case and discussed with the PI and the sponsor.  
 
Subjects with a response (no marrow evidence of leukemia) and pre-cycle counts of 
neutrophils <1x109/L and platelets <50 x109/L may be continued regardless of neutrophil 
and platelet count with supportive care as needed. Dose-interruptions in these subjects 
should be considered on an individual case and discussed with the PI and the sponsor. 
4.1.9.2 IACS-010759 Dose adjustments for Non-Hematologic Drug-Related AEs 
Dose adjustments for AEs will be performed using dose levels suggested in Table 1 and 2 in 
Section 4.1.6. Thus, if cohort 6 is established as the MTD, one and two dose level reductions of 
IACS-010759 will be the doses specified in cohort 5 and cohort 4, respectively. If the MTD is 
below cohort 3 further dose reduction levels of IACS-010759 will be defined before moving to 
the expansion phase of the study to allow for the below specified dose-reductions.  


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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Table 5: Dose adjustments for non-hematologic drug-related AEs, clinically significant in the 
opinion of the investigator 
Grade
Occurrence
Dose modification
1 or 2
Any time
No dose reduction.
3 
1st and 2nd 
time 
Hold treatment with IACS-010759.
Resume IACS-010759 at pre-interruption dose if 
recovery to ≤ Grade 1 or baseline occurs within 14 days.
(Persistent grade 2: 
Consider similar 
dose adjustments if 
persistent and not 
responding to 
optimal 
management in the 
opinion of PI and 
treating physician) 
If toxicity persists for >14 days, hold therapy and 
resume at ONE dose level below current dose for IACS-
010759 ONLY after recovery of toxicity to ≤ Grade 2. 
Dose re-escalation to prior dose of IACS-010759 is not 
permitted. 
3rd time 
Stop treatment with IACS-010759 and discontinue 
subject. 
(For subjects with clinical benefit/response from IACS-
010759 we will consider continuation if toxicities 
resolve to ≤ grade 1 and with proper dose adjustments 
after consultation with the PI and the sponsor) 
4 
Any time 
Stop treatment with IACS-010759 and discontinue 
subject. 
(For subjects with clinical benefit/response from IACS-
010759 we will consider continuation if toxicities 
resolve to ≤ grade 1 and with proper dose adjustments 
after consultation with the PI and the sponsor) 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor in specific cases. 
4.1.9.3 Intra-Subject Dose Escalation 
Intra-subject dose escalation of IACS-010759 (in accordance with the dosing schema in Table 1 
and 2) will be permitted provided: 
 
Subject has completed ≥2 cycles at their current dose level and has not achieved a CR or 
Cri 
 
Subject has not experienced any grade 3 or higher non-hematologic drug-related 
toxicity, and 
Subject has not experienced DLT, 
 
The dose may be escalated by one dose level no more frequently than every 2 cycles. 
 
The escalated dose level must have been fully evaluated and shown not to exceed the 
MTD (0 DLT of 3 or ≤1 DLT of 6)  
If an intra-subject dose escalation occurs, laboratory monitoring will be increased to weekly 
during the first cycle of the increase dose. 
4.1.9.4 Other Allowable Modifications of Dose Schedules 
Other modifications of dose schedules than the above will be allowed within the following 
guidelines: 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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 
Further dose reductions can be made to keep clinically significant toxicities grade < 2. 
Dose adjustments by more than 1 dose level at a time (e.g., from cohort 6 dose to 
cohort 4 dose) can be considered when judged in the best interest of the subject (e.g. 
severe myelosuppression, lactic acidosis) when the toxicity has resolved. The reason for 
this reduction will be discussed with the PI or Co-PI and documented in the medical 
record. 
 
Treatment interruptions and dose modifications other than the ones mentioned above 
can be considered after discussion with the PI, sponsor and proper documentation of 
the rationale.  
4.1.10 DLT, MTD and RP2D definitions 
The MTD is defined as the highest dose studied for which the observed incidence of DLT is less 
than 33%. Frequencies of toxicities will be tabulated according to the NCI Common Toxicity 
Criteria version 4.03. 
The RP2D will be determined based on the safety data and all available correlative data from the 
escalation phase by the Safety Monitoring Committee. 
Dose-limiting toxicity (DLT) is defined as a clinically significant non-hematologic adverse event or 
abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or 
concomitant medications and is possibly, probably or definitely related to the study drug and 
occurring during the first cycle (21 days) on study that meets any of the following criteria:  
 
All Grade 4 non-hematologic toxicities of any duration 
 
All grade 3 non-hematologic toxicities. Exceptions are as follow:  
o Grade 3 nausea, vomiting and diarrhea that does not require hospitalization or 
TPN support and can be managed with supportive care to ≤ grade 2 within 48 
hours. 
o Grade 3 electrolyte abnormalities that are corrected to ≤ grade 2 within 24 
hours. 
 
Lactic Acid: 
o Blood lactic acid levels [>4.0 mmol/L]) and decreased blood pH (>7.2 to <7.30) 
and no clinical symptoms of metabolic acidosis [nausea, vomiting, generalized 
muscle weakness, tachycardia, hypotension and rapid breathing] and normal 
potassium maintained in two consecutive laboratory assessments separated by 
>12 hours despite management as described in Section 4.1.11. To qualify as a 
DLT, the blood lactic acid levels [>4.0 mmol/L]) and decreased blood pH (<7.30) 
should be confirmed on arterial blood draws. Patients who develop pH between 
7.30 - 7.35 while on therapy who are asymptomatic, and have other etiologies 
for metabolic acidosis ruled out, may be permitted to continue on 
treatment.  These patients will have an increased monitoring of pH and lactate 
levels minimally at approximately 6 hours, 12 hours and 24 hours, until 
normalization of pH is established, so as to rule out any worsening 
acidosis.  Patients with a baseline normal pH (>7.35) and no clinical evidence of 
progressive leukemia (defined by >50% blasts in the bone marrow or peripheral 
blood, white count >20K, requiring hydroxyurea to control WBC counts, or new 
extramedullary leukemia) who develop acidosis that fulfills the criteria for a DLT 
during the DLT window, should be considered a DLT. 
o Blood lactic acid levels [>4.0 mmol/L]), decreased blood pH (<7.35 if the 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 26 of 59 
baseline pre-therapy pH was >7.35 or blood pH <7.30 if the baseline pre-therapy 
pH was ≤7.35), with bicarbonate >LLN and anion gap elevated, abnormal 
potassium and/or, in the opinion of the investigator, the subject is symptomatic 
for lactic acidosis [nausea, vomiting, generalized muscle weakness, tachycardia, 
hypotension and rapid breathing (Section 4.1.11, point 3).  To qualify as a DLT, 
the blood lactic acid levels [>4.0 mmol/L]) and decreased blood pH <7.35 if the 
baseline pre-therapy pH was >7.35 or blood pH <7.30 if the baseline pre-therapy 
pH was ≤7.35), should be confirmed on arterial blood draws. 
o Second episode of blood lactic acid level > 4.0 mmol/L, confirmed as lactic acid 
level > 4.0 mmol/L on arterial blood, separated by >24 hours blood draw, in the 
presence of clinical symptoms attributable to lactic acidosis [nausea, vomiting, 
generalized muscle weakness, tachycardia, hypotension and rapid breathing] 
Myelosuppression and associated complication are expected events during leukemia therapy. 
Only prolonged myelosuppression, as defined as ANC <500 through day 42 or later (6 weeks) 
from start of therapy without any evidence of leukemia, will be considered in defining the MTD 
and DLT. 
4.1.11 Assessment of Elevated Lactic Acid Levels   
Lactic acidosis is a potential mechanism-based side effect resulting from inhibition of 
mitochondrial oxidative phosphorylation by IACS-010759 and has been observed at high doses 
in preclinical studies.  Peripheral venous or arterial lactate levels will be monitored during the 
trial as detailed in section 4.2 study flowchart.  (Note: Venous or arterial blood may be used to 
monitor lactate and blood pH. Arterial blood lactate testing will also be used to confirm a 
potential DLT if an abnormal venous lactate level constitutes a DLT.) 
A recent review by Kruse et al. [21] on the measurement of lactate concluded that peripheral 
venous lactate levels are highly correlated with arterial blood lactate levels.  In the setting of 
elevated lactate, a complete physical exam and directed history will be performed to rule out 
other causes of elevated lactate levels (see appendix 9.1) 
Subjects will have their lactic acid levels, blood pH as well as electrolytes including chloride and 
bicarbonate (reported as total CO2) levels measured according to section 4.2.  Subjects with 
lactate levels >4 mmol/L and pH <7.30 and symptoms attributable to lactic acidosis [nausea, 
vomiting, generalized muscle weakness, tachycardia, hypotension and rapid breathing] will be 
hospitalized for monitoring of lactate levels and pH, electrolytes and symptoms of lactic acidosis 
[nausea, vomiting, generalized muscle weakness, tachycardia, hypotension and rapid breathing] 
for a minimum of 24 hours.  The lactic acid and blood pH levels will be assessed as follows: 
1. If lactic acid is > ULN but below 4.0 mmol/L, pH >7.35 and subject is asymptomatic, 
treatment can be continued.  Patients with pH between 7.30 - 7.35 who are 
asymptomatic, and have other etiologies for metabolic acidosis ruled out, may be 
permitted to continue on treatment.  These patients will have an increased monitoring 
of pH and lactate levels minimally at 6 hours, 12 hours and 24 hours, until normalization 
of pH is established, so as to rule out any worsening acidosis.  Patients with a baseline 
normal pH (>7.35) and no clinical evidence of progressive leukemia (defined by >50% 
blasts in the bone marrow or peripheral blood, white count >20K, requiring hydroxyurea 
to control WBC counts, or new extramedullary leukemia) who develop acidosis that 
fulfills the criteria for a DLT during the DLT window, should be considered a DLT. 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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2. If lactic acid >ULN but below 4.0 mmol/L, and subject is symptomatic (nausea, vomiting, 
generalized muscle weakness, tachycardia, hypotension and rapid breathing), treatment 
should be interrupted as indicated and lactic acidosis workup performed. 
3. If lactic acid is above 4.0 mmol/L, blood pH ≥7.35 and bicarbonate (reported as total 
CO2) is <LLN, potassium is normal and anion gap <14, and subject is asymptomatic, 
dosing should be interrupted.  Lactic acid and blood pH and electrolytes should be 
reassessed within 12 hours on arterial and/or venous blood draw until the lactic acid 
level is <4.0 mmol/L.  Once the lactic acid level is <4.0 mmol/L on arterial and/or venous 
draw, the subject can continue therapy at the discretion of the investigator. 
4. If lactic acid is above 4.0 mmol/L, blood pH <7.35 if the baseline pre-therapy pH was 
>7.35 or blood pH <7.30 if the baseline pre-therapy pH was ≤7.35) and the bicarbonate 
(reported as total CO2) is <LLN and anion gap is elevated, and/or the subject is 
symptomatic, this will be considered a DLT.  Treatment should be interrupted and lactic 
acidosis workup performed (See Section 7.2.3).  
 
Anion gap via venous blood collection can be calculated as follows: Anion Gap= [Na+] - [Cl-] - 
[total CO2]; normal range 4-14 mmol/L. 
Anion gap via arterial blood collection can be calculated as follows:  Anion Gap= [Na+] - [Cl-] - 
[HCO3-]; normal range 8-16 mEq/L. 
Symptoms of lactic acidosis include nausea, vomiting, generalized muscle weakness, 
tachycardia, hypotension and rapid breathing.  Subjects with clinical symptoms concerning for 
lactic acidosis should have an arterial blood gas assessment. Lactic acidosis is characterized by 
an elevated blood lactate concentration [>4.0 mmol/L]), decreased blood pH (<7.35), and 
electrolyte disturbances with an increased anion gap.  
4.1.12 Subject Withdrawal 
In the absence of treatment delays due to adverse events, treatment may continue until one of 
the following criteria applies: 
1. Clinically significant progressive disease, or 
2. Intercurrent illness that prevents further administration of treatment, or 
3. Subject request, or 
4. General or specific changes in the subject's condition render the subject unacceptable 
for further treatment in the judgment of the investigator, or 
5. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to continue 
therapy. 
It is planned that up to a total of 12 cycles of therapy will be administered for subjects deriving 
benefit from this regimen. Continuation of therapy for subjects completing 12 cycles of therapy 
may be considered on a case-by-case basis after discussion with the Principal Investigator.  
4.1.13 Subject Evaluability and Replacement 
In the escalation phase, subjects who are not considered fully evaluable per protocol for the 
primary objective of safety and tolerability per Section 4.3 will be replaced. Subjects who have 
taken 75% or more of the planned IACS-010759 treatment in cycle 1 will be considered 
evaluable for MTD.  Subjects who have taken less than 75% of planned medication in cycle 1, 
but who came off study due to a DLT will also be considered evaluable.   


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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4.1.14 Safety Monitoring and Study Stopping Rules 
Safety monitoring, including analysis of PK, will be performed by a Safety Monitoring 
Committee, consisting of the Principal Investigator (and co-investigators as needed) and sponsor 
representatives (e.g., a designee from the IND Office) and the study-specific Medical Monitor. 
Additional investigators and staff shall participate in reviews as indicated. 
An Independent Data Monitoring Board will not be utilized for this open label study. 
4.1.14.1  Study Stopping Rules 
The Safety Monitoring Committee has the right to recommend to terminate or alter the study 
design of this clinical study at any time. The principal investigator will be involved in any 
decisions regarding terminating the study, temporarily suspending enrollment, or stopping 
ongoing treatment with study treatment.  MD Anderson/IND Office (as the sponsor) has the 
right to terminate the clinical study at any time.   
Reasons for terminating the clinical study or a study site’s participation include, but are not 
limited to, the following: 
 
The incidence or severity of an adverse reaction related to treatment in this study or 
other studies indicates a potential health hazard to subjects 
 
Data recording is significantly inaccurate or incomplete 
 
Study site personnel are noncompliant with study procedures 
4.1.14.2  Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required processes or 
procedures that affect subject safety or benefit potential, or confound assessments of safety or 
clinical activity. A protocol deviation is a departure from the protocol that does not meet the 
above criteria. Protocol violations or deviations may be grouped into the following classes: 
 
Enrollment criteria 
 
Study activities (missed evaluations or visits) except for those allowed per protocol 
 
Noncompliance with dose or schedule, including dose calculation, administration, 
interruption, reduction, or delay; or discontinuation criteria 
 
Investigational product handling, including storage and accountability 
 
Informed consent and ethical issues 
 
Every effort will be made to adhere to the schedule of events and all protocol requirements. 
Variations in schedule of events and other protocol requirements that do not affect the rights 
and safety of the subject will not be considered as deviations. Such variations may include 
laboratory assessments completed outside of schedule, occasional missed required research 
samples such as correlative assays. 
4.1.15 Follow-Up at Treatment Discontinuation or Early Withdrawal 
Subjects who discontinue treatment for any reason should complete end-of-treatment 
procedures when possible. End of treatment procedures will include a physical examination, 
CBC with differential and platelets and chemistry. A bone marrow aspiration may be 
recommended only if non-response or progressive disease cannot be unequivocally diagnosed 
from peripheral blood. Although treatment will be discontinued at that time, all subjects who do 
not die, withdraw consent for follow-up, or become lost to follow-up, will remain on study for 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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follow-up evaluations. Subject will be followed for possible delayed emergence of IACS-010759 
related toxicity at least 30 days after the last protocol treatment.  Subjects who discontinue the 
study will be requested to return for additional PK and/or PD blood daws, approximately every 4 
days, when possible, for up to 4 weeks after the last study drug administration to further 
explore the PK and PD activity of IACS-010759 following discontinuation of study drug.  The 30-
day (+/-7 days) follow-up visit will be scheduled as a clinic visit for clinical evaluation and 
physical examinations. If the subject cannot make it to the site for this visit, the required follow 
up treatment procedures may be performed by a local physician and the records forwarded to 
the site. The research nurse will also contact the subject by telephone and obtain a verbal 
assessment of the subject’s condition. The phone conversation will then be documented in the 
subject’s charts.  
4.1.16 Long-Term Follow-Up 
Subjects who achieve any response will be followed for overall survival and response duration 
for up to 12 cycles. Patients who are responding well to therapy may continue therapy beyond 
12 cycles after approval from the PI and sponsor.   
If the disease appears to be responding to the study drug, a member of the study staff will call 
the subject once every 3-6 months for up to 5 years to assess the subject’s health.   


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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4.2 Study Flowcharts   
         Cohorts 1 and 2 
Screen
Cycle 1  
(28 days) 
Cycle 2  
(21 days) 
Cycle 3 
(21 days) 
Additional 
Cycles  
(21 days) 
End of Study 
or Early 
Termination 
Study Day 
-7 to 
-1 
1*+ 2* 
4 
8*
9* 
10* 12* 14*
17    22   28   29    36 
42 
49   50    
70 
Every 21 days  
30 after 
last Dose 
Name of Cycle Day  
 
C1 
D1 
C1 
D2 
C1 
D4 
C1
D8 
C1
D9 
C1 
D10
C1 
D12
C1 
D14
C1 
D17  
C1 
D22   
C1D
28   
C2
D1 
C2
D8 
C2 
D14
C2 
D21 
C3
D1 
C3 
D21
CX 
D20 
CX 
D21 
51 
+/- days allowable 
 
 
 
 
 
 
 
 
 
1 
1 
1 
2 
2 
2 
2 
3 
3 
4 
4 
7 
Study Drug§ 
  
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
X 
  
Disease Assessment 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
 
  
Bone marrow aspirate and/or biopsy¥  
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
X 
Every 
2-3 
cycle 
 
X 
Overall Response Rate‡ 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X ‡ 
X 
Study Procedures & Examinations 
 
 
 
Eligibility Assessment & Informed Consent 
X 
DemographicsA  
X 
Medical historyB 
X 
MUGA/ECHO 
X 
12-lead ECG (QTcF) 
X 
X2 
X 
X2 
X 
X2 
Phys. Exam (inc. weight) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ECOG 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
Vital Signs (Temp., HR, BP, RR) 
X 
X2 
X4 
X5 
X2 
X1 
X1 
X1 
X2 
X3 
X3 
X2 
X3 
X6 
X6 
X3 
X3 
X3 
 
X 
X 
Concomitant MedicationC  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
 
X 
X 
Adverse EventsD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
 
X 
X 
Labs 
Pregnancy test 
X 
Blood HematologyE, I, J 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ChemistryF, I   
X 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
X 
X6 
X6 
X 
X 
X 
 
X 
X 
Coagulation, lipase, amylase & urinalysisG, I 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
X 
X6 
X6 
X 
 
 
X 
X 
Lactate and blood pH I, K 
X 
X1 
X4 
X5 
X1 
X3 
X3 
X1 
X1 
X1 
X1 
X1 
X3 
X6 
X6 
X3 
X3 
X3 
 
X 
X 
Research Labs
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection- pharmacodynamicsH 
X 
X1 
 
 
X1 
 
X1 
 
X1 
  
X1 
X1 
 
 
 
 
 
XL 
Research Bone marrow aspirate/or biopsy 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
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Pharmacokinetics Blood samples I,K,M 
 
X2 
X4 
X5 
X2 
X1 
X1 
X1 
X2 
X1 
X1 
X2 
X3 
X6
X6
X3 
X3 
X3 
 
XL 
Notes and abbreviations provided on following page. 
 
A including Date of Birth; sex; height; race; ethnicity 
 
 
 
 
 
B including oncology history, radiation history 
C name, indication, dose, route, start and end dates 
D starting or worsening after study drug administration (signs and symptoms occurring prior to the first dose of study medication on Day 1 should be recorded 
under the subject’s Medical History). 
E complete blood count, differential, platelets 
F glucose, total protein, albumin, electrolytes [sodium, potassium, chloride, total CO2], calcium, phosphorus, magnesium, uric acid, bilirubin (total, direct), SGPT 
(ALT) or SGOT (AST), alkaline phosphatase, creatinine, blood urea nitrogen, CPK 
G PT, PTT, fibrinogen, INR 
H Oxygen consumption, metabolites, protein, mRNA analysis 
I  To be performed weekly during the first cycle of the increased dose for any intra-subject dose escalation 
J For purposes of data collection, test results below the limit of quantitation will be reported as “0” 
K If the Investigator determines that the dose of study drug should be interrupted, additional PK, lactate and blood pH assessments will be collected pre-dose 
(within 2 hours of dosing) and 6 hours +/- 30 minutes post study drug administration upon resumption of dosing.  If the dose of study drug is reduced, additional 
PK assessments will be collected pre-dose (within 2 hours of dosing) and 2, 4, 6, 8, 12 (+/- 15 mins) and 72 hours (+/- 4 hours) after starting the reduced study 
drug dose. 
L Additional PK and/or PD draws from peripheral blood may be obtained ~every 4 days, when possible, for up to 4 weeks after last study drug administration in 
subjects who discontinue the study.  
M In addition to the time points indicated in the Table, additional draws from peripheral blood for PK analysis may be obtained during Cycle 2 and beyond at the 
discretion of the Investigator.   
1 collected pre-dose (within 2 hours of dosing) and 6 hours +/- 30 minutes post study drug administration 
2 collected pre-dose (within 2 hours of dosing) and 2, 4, 6, 8 and 12 hours (+/- 15 mins) post study drug administration 
3 collected pre-dose (within 2 hours of dosing) 
4 collected 24 hours +/- 2 hours post study drug administration 
5 collected 72 hours +/- 4 hours post study drug administration 
6 collected pre-dose 
 
* Treatment will be administered as an inpatient for 24 hours on Day 1 of Cycle 1 and then starting again on Day 8 for the next 7 days. 
+ Subjects enrolled in the Food Effect group will consume a high fat meal within 30 minutes prior to study drug administration on Day 1 blood sample collection.   
§ Study drug will be administered without food, at least 1 hour before and at least 2 hours after eating, with the exception of Day 1 of Cycle 1 for subjects 
enrolled in the Food Effect group. 
¥    Bone marrow aspirate/biopsy will be performed as clinically indicated, at least once every 3 cycles. 
‡   Overall Response Rate (ORR) assessment will be performed on the same schedule as bone marrow aspirate/biopsy (every 2-3 cycles during additional cycles).  
ORR definitions are provided in Section 5.2.2.


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 32 of 59 
Cohorts 3-4 Dose-Escalation  
Screen
Cycle 1  
(21 days) 
Cycle 2  
(21 days) 
Cycle 3  
(21 days) 
Additional 
Cycles  
(21 days) 
End of Study 
or Early 
Termination 
 
Study Day 
-7 to 
-1 
1+
2 
4 
7*
8 
12
15
17   21    22    29 
36 
37 
42   
43     
63 
Every 21 days  
30 after 
last Dose 
Name of Cycle Day  
 
C1 
D1 
C1 
D2 
C1 
D4 
C1
D7 
C1
D8 
C1 
D12
C1 
D15
C1 
D17 
C1 
D21   
C2
D1 
C2
D8 
C2 
D15 
C2 
D16 
C2 
D21 
C3 
D1 
C3 
D21 
CX 
D20 
CX 
D21 
51 
+/- days allowable 
 
 
 
1 
1 
1 
1 
1 
2 
+2 
1 
1 
1 
2 
1 
3 
3 
4 
4 
7 
Study Drug§ 
 
INDUCTION 
MAINTENANCE 
  
X 
X  
 X 
X 
X 
X 
X 
X
X
X 
 
  
Disease Assessment 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
 
  
Bone marrow aspirate and/or biopsy¥  
X 
  
  
  
  
  
  
  
  
X 
  
  
  
X 
Every 2-3 
cycle 
 
X 
Overall Response Rate‡ 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X ‡ 
X 
Study Procedures & Examinations 
 
 
 
 
Eligibility Assessment & Informed Consent 
X 
 
DemographicsA  
X 
 
Medical historyB 
X 
 
MUGA/ECHO 
X 
 
Dilated eye exam with fundus photosN 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurology review and examO 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG (QTcF) 
X 
X2 
X1 
X1 
X 
 
Phys. Exam (inc. weight) 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
ECOG 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Vital Signs (Temp., HR, BP, RR) 
X 
X2 
X3 
X3 
X2 
X1 
X 
X1 
X 
X3 
X3 
X1 
X 
X 
X3 
X 
 
X 
X 
Concomitant MedicationC  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
 
X 
X 
Adverse EventsD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
 
X 
X 
Labs 
 
Pregnancy test 
X 
 
Blood HematologyE, I, J 
X 
X1 
X3 
X3 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ChemistryF, I   
X 
X1 
X3 
X3 
X 
X3 
X 
X 
X 
X3 
X3 
X 
X 
X 
X 
 
X 
X 
Coagulation, lipase, amylase & urinalysisG, I 
X 
X1 
X3 
X3 
X 
X3 
X 
X 
X 
X3 
X3 
X 
X 
 
 
X 
X 
Lactate and blood pH I, K 
X 
X1 
X3 
X3 
X1 
X1 
X 
X1 
X 
X 
X3 
X3 
X1 
X 
X 
X3 
X 
 
X 
X 
Research Labs
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 33 of 59 
Notes and abbreviations provided on following page. 
 
A including Date of Birth; sex; height; race; ethnicity 
 
 
 
 
 
B including oncology history, radiation history 
C name, indication, dose, route, start and end dates 
D starting or worsening after study drug administration (signs and symptoms occurring prior to the first dose of study medication on Day 1 should be recorded 
under the subject’s Medical History). 
E complete blood count, differential, platelets 
F glucose, total protein, albumin, electrolytes [sodium, potassium, chloride, total CO2], calcium, phosphorus, magnesium, uric acid, bilirubin (total, direct), SGPT 
(ALT) or SGOT (AST), alkaline phosphatase, creatinine, blood urea nitrogen, CPK 
G PT, PTT, fibrinogen, INR 
H Oxygen consumption, metabolites, protein, mRNA analysis 
I  To be performed weekly during the first cycle of the increased dose for any intra-subject dose escalation 
J For purposes of data collection, test results below the limit of quantitation will be reported as “0” 
K If the Investigator determines that the dose of study drug should be interrupted, additional PK, lactate and blood pH assessments will be collected pre-dose 
(within 2 hours of dosing) and 4 hours +/- 30 minutes post study drug administration upon resumption of dosing; additional PK assessments may be performed 
during the interruption at the description of the Investigator.  If the dose of study drug is reduced, additional PK assessments will be collected pre-dose (within 2 
hours of dosing) prior to starting the reduced study drug dose. Additional unscheduled PK, lactate and pH blood draws may be collected per PI judgement when 
indicated for further safety follow-up. 
L Additional PK and/or PD draws from peripheral blood may be obtained ~every 4 days, when possible, for up to 4 weeks after last study drug administration in 
subjects who discontinue the study.  
M In addition to the time points indicated in the Table, additional draws from peripheral blood for PK analysis may be obtained at the discretion of the 
Investigator.   
N Baseline dilated eye exam with fundus photos, including distance acuity (visual acuity charts using refraction-based visual acuity measurement), 
ophthalmoscopy and slit lamp exam, may be performed up to 14 days prior to study drug administration. 
O Baseline neurology review and exam to be performed by consultant neurologist up to 14 days prior to study drug administration.  The baseline neurology exam 
may include, but is not limited to, gait and station, cerebellar functions (coordination), upper and lower extremity reflexes, upper and lower muscle strength and 
sensation. 
1 collected pre-dose (same calendar day of dosing) and 4 hours +/- 30 minutes post study drug administration 
2 collected pre-dose (same calendar day of dosing) and 2, 4, 6, 8 hours (+/- 30 mins) post study drug administration.  Note: vitals may be collected (+/- 60 mins) 
post study drug administration. 
3 collected pre-dose (same calendar day of dosing) 
 
Blood collection- pharmacodynamicsH 
X 
X1 
 
 
X1 
 
 
X1 
  
X 
 
 
 
 
 
 
XL 
Research Bone marrow aspirate/or biopsy 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics Blood samples I,K,M 
 
X2 
X3 
X3 
X2 
X1 
X 
X1 
X 
X 
X3 
X3 
X2 
X 
X 
X3 
X 
 
X 
XL 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 34 of 59 
* Treatment will be administered as an inpatient for 24 hours on Day 7 of Cycle 1. 
+ Subjects enrolled in the Food Effect group will consume a high fat meal within 30 minutes prior to study drug administration on Day 1 blood sample collection.   
§ Study drug will be administered without food, at least 1 hour before and at least 2 hours after eating, with the exception of Day 1 of Cycle 1 for subjects 
enrolled in the Food Effect group.  Induction or maintenance doses and alternative duration of induction doses or other maintenance schedules of IACS-010759, 
not to exceed 6 mg, may be pursued depending on the safety and PK/PD data observed. 
¥    Bone marrow aspirate/biopsy will be performed as clinically indicated, at least once every 3 cycles. 
‡   Overall Response Rate (ORR) assessment will be performed on the same schedule as bone marrow aspirate/biopsy (every 2-3 cycles during additional cycles).  
ORR definitions are provided in Section 5.2.2. 
 
 
 
 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 35 of 59 
Cohorts 5-6 Dose-Escalation and Cohort 7 Dose-Expansion 
Screen
Cycle 1  
(21 days) 
Cycle 2  
(21 days) 
Cycle 3  
(21 days) 
Additional 
Cycles  
(21 days) 
End of Study 
or Early 
Termination 
 
Study Day 
-7 to 
-1 
1+
2 
4 
5*
8 
12
15
17   21    22    29 
36 
37 
42   
43     
63 
Every 21 days  
30 after 
last Dose 
Name of Cycle Day  
 
C1 
D1 
C1 
D2 
C1 
D4 
C1
D5 
C1
D8 
C1 
D12
C1 
D15
C1 
D17 
C1 
D21   
C2
D1 
C2
D8 
C2 
D15 
C2 
D16 
C2 
D21 
C3 
D1 
C3 
D21 
CX 
D20 
CX 
D21 
51 
+/- days allowable 
 
 
 
1 
 
 
1 
1 
2 
+2 
1 
1 
1 
2 
1 
3 
3 
4 
4 
7 
Study Drug§ 
 
INDUCTIONP 
MAINTENANCEP 
 
Disease Assessment 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
 
  
Bone marrow aspirate and/or biopsy¥  
X 
  
  
  
  
  
  
  
  
X 
  
  
  
X 
Every 2-3 
cycle 
 
X 
Overall Response Rate‡ 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X ‡ 
X 
Study Procedures & Examinations 
 
 
 
 
Eligibility Assessment & Informed Consent 
X 
 
DemographicsA  
X 
 
Medical historyB 
X 
 
MUGA/ECHO 
X 
 
Dilated eye exam with fundus photosN 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurology review and examO 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG (QTcF) 
X 
X2 
X1 
X1 
X 
 
Phys. Exam (inc. weight) 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
ECOG 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Vital Signs (Temp., HR, BP, RR) 
X 
X2 
X3 
X3 
X2 
X1 
X 
X1 
X 
X3 
X3 
X1 
X 
X 
X3 
X 
 
X 
X 
Concomitant MedicationC  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
 
X 
X 
Adverse EventsD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
 
X 
X 
Labs 
 
Pregnancy test 
X 
 
Blood HematologyE, I, J 
X 
X1 
X3 
X3 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ChemistryF, I   
X 
X1 
X3 
X3 
X 
X3 
X 
X 
X 
X3 
X3 
X 
X 
X 
X 
 
X 
X 
Coagulation, lipase, amylase & urinalysisG, I 
X 
X1 
X3 
X3 
X 
X3 
X 
X 
X 
X3 
X3 
X 
X 
 
 
X 
X 
Lactate and blood pH I, K 
X 
X1 
X3 
X3 
X1 
X1 
X 
X1 
X 
X 
X3 
X3 
X1 
X 
X 
X3 
X 
 
X 
X 
Research Labs
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection- pharmacodynamicsH 
X 
X1 
 
 
X1 
 
 
X1 
  
X 
 
 
 
 
 
 
XL 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 36 of 59 
Notes and Abbreviations: 
A including Date of Birth; sex; height; race; ethnicity 
 
 
 
 
 
B including oncology history, radiation history 
C name, indication, dose, route, start and end dates 
D starting or worsening after study drug administration (signs and symptoms occurring prior to the first dose of study medication on Day 1 should be recorded 
under the subject’s Medical History). 
E complete blood count, differential, platelets 
F glucose, total protein, albumin, electrolytes [sodium, potassium, chloride, total CO2], calcium, phosphorus, magnesium, uric acid, bilirubin (total, direct), SGPT 
(ALT) or SGOT (AST), alkaline phosphatase, creatinine, blood urea nitrogen, CPK 
G PT, PTT, fibrinogen, INR 
H Oxygen consumption, metabolites, protein, mRNA analysis 
I  To be performed weekly during the first cycle of the increased dose for any intra-subject dose escalation 
J For purposes of data collection, test results below the limit of quantitation will be reported as “0” 
K If the Investigator determines that the dose of study drug should be interrupted, additional PK, lactate and blood pH assessments will be collected pre-dose 
(within 2 hours of dosing) and 4 hours +/- 30 minutes post study drug administration upon resumption of dosing; additional PK assessments may be performed 
during the interruption at the description of the Investigator.  If the dose of study drug is reduced, additional PK assessments will be collected pre-dose (within 2 
hours of dosing) prior to starting the reduced study drug dose. Additional unscheduled PK, lactate and pH blood draws may be collected per PI judgement when 
indicated for further safety follow-up. 
L Additional PK and/or PD draws from peripheral blood may be obtained ~every 4 days, when possible, for up to 4 weeks after last study drug administration in 
subjects who discontinue the study.  
M In addition to the time points indicated in the Table, additional draws from peripheral blood for PK analysis may be obtained at the discretion of the 
Investigator.   
N Baseline dilated eye exam with fundus photos, including distance acuity (visual acuity charts using refraction-based visual acuity measurement), 
ophthalmoscopy and slit lamp exam, may be performed up to 14 days prior to study drug administration. 
O Baseline neurology review and exam to be performed by consultant neurologist up to 14 days prior to study drug administration.  The baseline neurology exam 
may include, but is not limited to, gait and station, cerebellar functions (coordination), upper and lower extremity reflexes, upper and lower muscle strength and 
sensation. 
P The dose regimen for the induction and maintenance doses are provided in Table 2. 
1 collected pre-dose (same calendar day of dosing) and 4 hours +/- 30 minutes post study drug administration 
2 collected pre-dose (same calendar day of dosing) and 2, 4, 6, 8 hours (+/- 30 mins) post study drug administration.  Note: vitals may be collected (+/- 60 mins) 
post study drug administration. 
3 collected pre-dose (same calendar day of dosing) 
4 collected pre-dose (same calendar day of dosing) and 2, 4, 6, 8 hours (+/- 30 mins) and 24 hours (+/- 2 hours) post study drug administration.  Note: vitals may 
be collected (+/- 60 mins) post study drug administration. 
 
Research Bone marrow aspirate/or biopsy 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics Blood samples I,K,M 
 
X2 
X3 
X3 
X4 
X1 
X 
X1 
X 
X 
X3 
X3 
X2 
X 
X 
X3 
X 
 
X 
XL 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 37 of 59 
 
* Treatment will be administered as an inpatient for 24 hours on Day 5 of Cycle 1. 
+ Subjects enrolled in the Food Effect group will consume a high fat meal within 30 minutes prior to study drug administration on Day 1 blood sample collection.   
§ Study drug will be administered without food, at least 1 hour before and at least 2 hours after eating, with the exception of Day 1 of Cycle 1 for subjects 
enrolled in the Food Effect group.  Induction or maintenance doses and alternative duration of induction doses or other maintenance schedules of IACS-010759, 
not to exceed 6 mg, may be pursued depending on the safety and PK/PD data observed. 
¥    Bone marrow aspirate/biopsy will be performed as clinically indicated, at least once every 3 cycles. 
‡   Overall Response Rate (ORR) assessment will be performed on the same schedule as bone marrow aspirate/biopsy (every 2-3 cycles during additional cycles).  
ORR definitions are provided in Section 5.2.2. 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 38 of 59 
 Study Objectives & Endpoints 
Primary Objectives
Safety & Tolerability
Determine Dose Limiting Toxicities 
Establish MTD and RP2D 
Secondary Objectives
IACS-010759 pharmacokinetics and food effect
Preliminary Clinical Efficacy (overall response rates, duration of 
response, progression-free survival, overall survival) 
Exploratory objectives
Pharmacodynamic and exploratory biomarkers of activity of IACS-
010759 
 
Clinical study data will be entered into Medidata Rave, the clinical data base, via electronic case 
report forms.  The Statistical Analysis Plan (SAP) will include detailed and specific description of 
all analysis to be performed on the clinical data from this study.  The SAP will be finalized prior 
to database lock. 
All statistical analyses will be performed using Version 9.4 or later of Statistical Analysis Software 
(SAS®).  Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum, and maximum) for continuous variables, and 
frequency and percentage for categorical and ordinal variables.  If there are missing values, the 
number missing will be presented, but without a percentage.   All data collected will be included 
in by-subject data listings. 
Unless otherwise specified, all tests will be two-tailed using a 0.05 level of significance.  All 
confidence intervals (CIs) will be two-sided 95% confidence intervals. 
All subjects who received any study drug and who had any on-treatment evaluation will be 
included in the Full Analysis Set (FAS). 
4.3 Safety and tolerability 
4.3.1 Endpoints & Assessment Methods 
Laboratory tests, vital sign measurements, physical exams and subject interviews will be 
performed to detect new abnormalities and deteriorations of any pre-existing conditions.  All 
“treatment-emergent” clinically significant abnormalities and deteriorations that begin or 
worsen in severity after initial administration of IACS-010759 and documented as such in the 
medical records should be recorded in the Case Report Forms as Adverse Events and graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. 
The MTD will be determined in accordance with Section 4.1.7. 
4.3.2 Subject Evaluation & Statistics 
The FAS will be used for evaluation of safety.   
Adverse events will be coded using the MedDRA dictionary. Incidences of treatment-emergent 
adverse events (TEAE, those events that started after dosing or worsened in severity after 
dosing) will be presented overall and by maximum severity (according to CTCAE Ver 4.03) and 
relationship to study medication. 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 39 of 59 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges. Frequencies and percentages will be presented by 
cohort for the shifts in these categories (i.e., low to normal, low to high, high to low, etc.) from 
baseline to each post-treatment assessment time point. Additionally, for each continuous 
hematology and chemistry parameter, descriptive statistics will be presented by cohort for the 
changes from baseline to each post-treatment assessment time point.   Descriptive statistics will 
be presented by cohort for the changes in vital signs from baseline to each post-treatment 
assessment time point.   
4.4 Clinical Efficacy 
4.4.1 Subject Evaluation & Statistics 
The FAS will be the basis for the evaluation of clinical efficacy. 
Disease assessment will be performed at the end of Cycles 1, 3, and thereafter every 2-3 cycles 
at the discretion of the treating physician.   While the bone marrow aspirate/biopsy will be 
performed as clinically indicated, testing will occur at least once every 3 cycles. 
Descriptive statistics will be provided for continuous variables and frequency tables will be used 
to summarize categorical variables. The Overall Response Rate and the proportions of subjects 
who experienced CR, Cri, PR, MLFS (morphologic leukemia-free state), hematologic 
improvements, Recurrence of Disease (RD) and Best Response measurement along with the 
corresponding exact 95% confidence intervals will be displayed.  
Kaplan-Meier method will be used to estimate the duration of response, progression-free 
survival and overall survival. These time to event variables will be summarized using the 25th 
percentile, Median, and 75th percentile as well as the minimum and maximum time to event, 
calculated by Kaplan-Meier method, and will be displayed graphically.  
4.4.2 Endpoints & Assessment Methods 
Objective Overall Response Rate (ORR) for subjects with AML include CR, CRi, PR and 
morphologic leukemia-free state [22] with or without cytogenetic response and hematologic 
improvements.  The responses are defined as below: 
 
Complete Remission (CR) 
For subjects to be classified as being in CR, they must have bone marrow regenerating 
normal hematopoietic cells and achieve a morphologic leukemia-free state and must 
have an ANC > 1 × 109/L and platelet count ≥ 100 × 109/L, and normal marrow 
differential with < 5% blasts, and subjects will be red blood cell (RBC) and platelet 
transfusion independent (defined as 4 weeks without RBC transfusion and 1 week 
without platelet transfusion). There should be no evidence of extramedullary leukemia. 
 
Complete Remission with Incomplete Hematological Recovery (CRi) 
For subjects to be classified as being in CRi, they must fulfill the criteria for CR except for 
incomplete hematological recovery with residual neutropenia (ANC ≤ 1 × 109/L) with or 
without thrombocytopenia (platelet count < 100 × 109/L). In addition, subjects do not 
need to be RBC or platelet transfusion independent (modification to Cheson criteria). 
 
Partial Remission (PR) 
For subjects to be classified as being in PR, they must have bone marrow regenerating 
normal hematopoietic cells with evidence of peripheral recovery with no (or only a few 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 40 of 59 
regenerating) circulating blasts and with a decrease of at least 50% in the percentage of 
blasts in the bone marrow aspirate with the total marrow blasts between 5% and 25%. 
 
Morphologic leukemia-free state (MLFS):  
Bone marrow: 5% myeloblasts   
 
Hematologic Improvement (HI): 
Hematologic response must be described by the number of positively affected cell lines. 
o Erythroid response (E) (pretreatment Hgb <11 g/dL) 
o Hgb increase by 1.5 g/dL 
o Platelet response (P) (pretreatment platelets <100 x109/L) 
o Absolute increase of 30 x 109/L for subjects starting with > 20 x 109/L platelets 
o Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
o Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
o At least 100% increase and an absolute increase > 0.5 x 109/L 
o Blast response (B)≥50% reduction in peripheral blood or bone marrow blasts but 
still >5% 
 
Recurrence of Disease (RD) 
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral blood 
or ≥ 5% blasts in the bone marrow aspirate not attributable to any other cause or 
reappearance or new appearance of extramedullary leukemia. Relapse after PR is 
similarly defined with reappearance of significant numbers of peripheral blasts and an 
increase in the percentage of blasts in the bone marrow aspirate to > 25% not 
attributable to any other cause or reappearance or new appearance of extramedullary 
leukemia. 
 
Best Response measurement: Response will be measured and defined for primary 
endpoints as the best response achieved during the first 3 cycles of therapy, or at time 
off study, for those subjects discontinuing treatment before the completion of 3 cycles 
of therapy. Best response is defined to be the best-measured response 
(ORR=CR+CRp+PR+MLFS) post-treatment up to that time. Best response will also be 
evaluated for the full treatment period using all assessments up to and including 
treatment discontinuation. 
Duration of Response: length of time from the first objective evidence of response to the first 
objective evidence of disease progression.   
 
Progression-Free Survival:  length of time (up to 5 years) from the date of first treatment to the 
first objective evidence of disease progression or death, whichever is earlier.   
 
Overall Survival:  length of time from the date of first administration of study drug to the date 
of death from any cause.   
 
4.5 IACS-010759 Plasma Drug Levels 
4.5.1 Subject Evaluation & Statistics 
Only subjects who received at least one dose of IACS-010759, and provided both the baseline 
sample and at least one post-treatment sample, will be evaluated. 


 
IACS2015-001: Protocol Amendment #11 (01-21-20)  
Page 41 of 59 
4.5.2 Endpoints & Assessment Methods 
Collection of samples to assess the plasma concentration of IACS-010759 will be required for all 
subjects. Peripheral blood (5 mL) will be collected at the time points indicated in section 4.2. 
A validated LC-MS/MS bioanalytical method will be used at the MDACC, Institute for Applied 
Cancer Science (IACS) research labs, located at 4SCRB2.1175, 1901 East Road, Houston, TX to 
quantify IACS-010759 in human plasma.  
Pharmacokinetic parameters will be calculated using Phoenix WinNonlin 6.3 software package.   
4.6 Biological activity of IACS-010759 
4.6.1 Subject Evaluation & Statistics 
Only subjects who received at least one dose of IACS-010759, and provided the baseline and at 
least one post-treatment sample, will be evaluated. 
PD data will be summarized graphically and with descriptive statistics by time and dose.  
4.6.2 Endpoints & Assessment Methods 
To evaluate PD biomarkers, approximately 30 cc of peripheral blood will be collected in green 
top tubes and 5 cc of bone marrow will be collected at the time points indicated in section 4.2. 
Upon isolation of blasts cells, baseline and post-treatment biological activity will be assessed 
using assays that are informed by preclinical studies using AML cell line and subject derived 
models.  These include but are not limited to: 
- 
Pre and post-treatment measurement of OXPHOS inhibition, using Seahorse Seahorse 
XF bioanalyzer to measure oxygen consumption in blast cells isolated from the 
peripheral blood.   
- 
Pre and post-treatment measurement of metabolites related to mitochondria 
metabolism, glycolysis, amino acid and nucleotide biosynthesis, to measure changes 
that have been associated with inhibition of OXPHOS and response in preclinical models.   
- 
Pre and post treatment measurement of mRNAs using gene expression profiling or 
other quantitative methods to assess mRNA signatures that has been identified utilizing 
preclinical models treated with IACS-010759.  
 
Any leftover sample or tissue including bone marrow, if available, will be stored for potential 
future exploratory research into factors that may influence development of AML and/or 
response to IACS-010759 (where response is defined broadly to include efficacy, tolerability or 
safety) or additional exploratory pharmacogenetic evaluations, including RNA microarray 
analyses or DNA, and xenografting into immunodeficient mice. Excess samples will be stored at 
MD Anderson Cancer Center, IACS laboratory, located at 4SCR6.1100, 1901 East Road, Houston, 
TX. 
5 Subject Eligibility 
5.1 Inclusion Criteria 
Eligible subjects must fulfill all of the following criteria: 
1.
Subjects with AML should have failed any prior induction therapy regimen or have 
relapsed after prior therapy (defined as patients in first relapse and less than 12 months 
from diagnosis [short first remission] or in second or later relapse 


 
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Dose-escalation phase: Subjects with confirmed relapsed or refractory AML and no 
available treatment options with known benefit 
Expansion phase: Subjects with relapsed/refractory AML who have failed therapy with 
up to one prior salvage regimen and no available treatment options with known benefit 
Exception:  stem cell transplant [SCT] or stem cell therapy for subjects who previously 
underwent SCT/stem cell therapy, and are currently in remission will not be considered 
a salvage regimen. 
2.
Eastern Cooperative Oncology Group (ECOG) ≤ 2 (see appendix 9.3)
3.
Patients who have had prior SCT are eligible if they have a relapse > 3 months since 
autologous or allogeneic stem cell transplantation provided, 
 
No clinically significant active graft-versus-host disease (GVHD > grade 1). 
 
No treatment with high dose steroids for GVHD (i.e. >20 mg Prednisolone or 
equivalent per day). 
 
No treatment with immunosuppressive drugs with the exception of cyclosporine 
and tacrolimus. 
4.
Subjects with history of CNS disease are allowed if at the time of day 1 of the study
there is no evidence of active CNS disease as documented by negative imaging or spinal 
fluid analysis carried out at least 2 weeks prior to the first study drug administration in a 
subject with no clinical signs of CNS disease. 
5.
Adequate renal and hepatic function:
 
Serum creatinine ≤ 2.0 X ULN  
 
Total bilirubin ≤ 2 times the upper limit of normal (ULN) (or </= 3.0 x ULN if deemed 
to be elevated due to Gilbert’s disease or leukemia) 
 
ALT and AST ≤ 2.5 times ULN (≤ 5.0 x ULN if due to leukemic involvement). 
6.
Negative urine pregnancy test within 72 hours prior to the first dose of study therapy 
for women of child-bearing potential (WCBP), defined as a sexually mature woman who 
has not undergone a hysterectomy or who has not been naturally post- menopausal for 
at least 24 consecutive months (i.e., who has had menses any time in the preceding 24 
consecutive months).  
7.
Have been informed of other treatment options and is not a candidate for standard 
treatment options or stem cell transplant at the time of enrollment. 
8.
Age 18 years. 
9.
In the absence of rapidly progressing disease, the interval from prior treatment to time 
of initiation of IACS-010759 administration will be at least 2 weeks or 5 half-lives 
(whichever is shorter) for cytotoxic/noncytotoxic agents and biological/immune-based 
therapies, including investigational agents. The half-life for the therapy in question will 
be based on published pharmacokinetic literature (abstracts, manuscripts, investigator 
brochures, or drug-administration manuals) and will be documented in the protocol 
eligibility document. The use of chemotherapeutic or anti-leukemic agents is not 
permitted during the study with the following exceptions: (1) intrathecal (IT) therapy 
for subjects with controlled CNS leukemia at the discretion of the PI and with the 
agreement of the Sponsor. (2) Use of hydroxyurea for subjects with rapidly proliferative 
disease is allowed before the start of study therapy and for the first 2 cycles on therapy. 
These medications will be recorded in the case-report form. 


 
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10.
Women of childbearing potential must agree to use an adequate method of 
contraception during the study and until 3 months after the last treatment. Males must 
be surgically or biologically sterile or agree to use an adequate method of contraception 
during the study until 3 months after the last treatment. 
Adequate methods of contraception include: 
 
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) or tubal ligation at least six weeks before taking 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). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 
 
Combination of any of the two following (a+b or a+c or b+c) 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 
       In case of use of oral contraception, women should have been stable on the same 
pill before taking study treatment. 
Note: Oral contraceptives are allowed but should be used in conjunction with a barrier method 
of contraception due to unknown effect of drug-drug interaction. Women are considered post-
menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
11.
Able and willing to give valid written informed consent.
 
 
 


 
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5.2 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1.
Prior exposure to IACS-010759 or other oxidative phosphorylation Inhibitors.
2.
Unstable cardiovascular function:
 
Symptomatic ischemia, or  
 
Uncontrolled clinically significant conduction abnormalities (i.e., ventricular 
tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular (AV) 
block or asymptomatic left anterior fascicular block/right bundle branch block 
(LAFB/RBBB) will not be excluded), or 
 
Congestive heart failure (CHF) NYHA Class ≥ 3 (Appendix 9.5), or 
 
Myocardial infarction (MI) within 6 months.  
 
Left ventricular ejection fraction < 40 %. 
 
Hypertension > 160 mm Hg systolic or > 100 mm Hg diastolic with or without 
antihypertensive therapy. 
3.
Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without 
complete recovery from the surgical procedure 
4.
Presence of ≥ CTCAE grade 2 toxicity (except alopecia or peripheral neuropathy) due to 
prior cancer therapy. 
5. 
Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface 
antigen (HBsAg), or hepatitis C virus (HCV). 
6.
Active uncontrolled infection. Infections controlled on concurrent anti-microbial agents 
are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable. 
7.
Participation in any other clinical trial involving another investigational agent for the 
treatment of AML within 2 weeks prior to day 1 of the study or at least 5 half-lives of 
the investigational agent, whichever is shorter. 
8.
Lactate levels > 2 mmol/L and or and serum pH <7.35 at screening.
9.
Subject currently being treated with biguanides or other agents known to increase risk 
of lactic acidosis (reference Appendix 10.1). 
10.
Subject has significant gastrointestinal abnormalities, including ulcerative colitis, 
chronic diarrhea associated with intestinal malabsorption, Crohn's disease, and/or prior 
surgical procedures affecting absorption or requirement for intravenous (IV) 
alimentation. 
11.
Subjects with uncontrolled Type I or II diabetes mellitus
12.
Mental impairment that may compromise the ability to give informed consent and 
comply with the requirements of the study. 
13.
Women who are breast-feeding or pregnant as evidenced by positive urine pregnancy 
test done within 72 hours of first dosing.  
14.
Subject has a concurrent active malignancy under treatment, with the exception of:
-Adequately treated carcinoma in situ of the breast or cervix uteri 
-Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin 
-Low-grade, early-stage prostate cancer with no requirement for therapy 
-Previous malignancy confined 
15.
Acute promyelocytic leukemia.


 
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16.
Any concomitant disease or condition that, in the clinical judgment of the treating 
physician, is likely to prevent the subject from complying with any aspect of the 
protocol or that may put the subject at unacceptable risk. 
17.
Subjects with ≥ grade 1 peripheral neuropathy at screening.
 
6 Study Drug 
6.1 Study Drug Administration 
Cohorts 1 and 2:  For each cycle 1, a single oral dose of IACS-010759 will be administered on 
day 1.   The next dose of IAC-010759 will be administered on day 8, and daily continuously 
for the duration of the study with no interruptions unless there are adverse events as 
described in Section 4.1.9.  IACS-010759 doses will be separated by intervals of 
approximately 24 hours (+/- 3 hours).  
Cohorts 3-6 and Dose Expansion:  Based on the observed accumulation of IACS-010759 
throughout the dosing period in cohorts 1 and 2, a modified dosing regimen is being 
implemented, consisting of an induction phase in which IACS-010759 is administered daily 
for up to 7 days, followed by a maintenance phase in which a lower dose is administered 
weekly (or as otherwise specified by the SMC based on safety, PK and PD data observed) to 
maintain steady state plasma levels.  Dosing will proceed on this schedule for the duration of 
the study with no interruptions unless there are adverse events as described in Section 
4.1.9.   
IACS-010759 will be administered without food, at least 1 hour before and at least 2 hours 
after eating. Each dose of IACS-010759 should be administered with 8 ounces of water.  If a 
dose is missed, the next dose will not be increased to account for missing a dose. The 
subject will take the next regular dose at the scheduled time.  Following cycle 1 (28-day cycle 
for cohorts 1 and 2, 21 day cycle for subsequent cohorts), subjects will receive one cycle of 
therapy every 21 days (+/- 4 days). 
In cohorts 1 and 2, treatment was administered as an inpatient for 24 hours on day 1 and 
then starting on day 8 for the next 7 days for all enrolled subjects.  In cohorts 3 and 4, 
treatment will be administered as an inpatient for 24 hours on Day 7 of Cycle 1 for all 
enrolled subjects.  In subsequent cohorts, treatment will be administered as an inpatient for 
24 hours on Day 5 of Cycle 1 for all enrolled subjects.  IACS-010759 will be self-administered 
and subjects instructed not to dose on days when PK/PD samples are collected until advised 
by the research staff. Self-administration can occur on days without PK/PD and subjects will 
record administration in a provided diary. 
In the expansion phase, after the first 6 subjects have been enrolled in the expansion cohort, the 
next 6 subjects will be enrolled in the Food Effect group where the effect of a high fat meal on 
the PK of IACS-010759 will be evaluated on day 1 of cycle 1 for the cohort (Food Effect group).  
The dose level to be administered will be the single agent RP2D induction dose as determined in 
the escalation phase or may be lower than the RP2D if clinical safety concerns prevent the use 
of RP2D for the food effect evaluation. Subjects in the Food Effect group will consume the high-
fat meal within 30 minutes prior to IACS-010759 administration and blood samples collected at 


 
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the timepoints listed in the Study Flowchart for PK analysis.  After this day 1 dose, subsequent 
doses of IACS-010759 will be administered without food as described above for the remainder 
of the cycle.   The plasma levels in these subjects will be compared to those of the other subjects 
in the expansion cohort to determine whether consumption of a meal affects the plasma levels 
of IACS-010759. 
 
6.2 Study Drug Information 
MDACC, IACS has defined a chemical synthesis process, specific purity profile and release 
specifications for the manufacture of IACS-010759.  WuXi AppTec Co, Ltd. is producing GMP 
material on a 2.5 kg scale. The final drug product will be a dry filled capsule (DFC) formulation 
for oral administration.   
Study drug will be packaged in 28-count bottles of 4 strengths: 0.1 mg, 0.5 mg, 1.0 mg and 5.0 
mg, as described in Table 6.  The first dose strength to be administered in cohort 1 of the dose 
escalation phase is 0.5 mg.  Study drug may be stored at room temperature. 
Table 6: IACS-010759 Drug Product Appearance by Strength 
Strength
Appearance
0.1 mg
Hard Gelatin capsules, Size 3, white opaque cap, white opaque body
0.5 mg
Hard Gelatin capsules, Size 3, light green opaque cap, white opaque body
1.0 mg
Hard Gelatin capsules, Size 3, light blue opaque cap, white opaque body
5.0 mg
Hard Gelatin capsules, Size 3, dark blue opaque cap, white opaque body
 
The active ingredient in IACS-010579 is manufactured under GMP conditions by:  
Shanghai SynTheAll Pharmaceutical Co. Ltd., 
9 Yuegong Road, 
Jinshan District, 
Shanghai 201507, China  
 
The finished drug product is manufactured under GMP conditions by:  
WuXi AppTec Co., Ltd, 
299 FuTe Zhong Road, 
Waigaoqao Free Trade Zone, 
Shanghai, 200131, P. R. China 
 
6.3 Drug Overdose Management 
There are no known antidotes available for the IACS-010759.  Any overdoses with this drug 
should be managed symptomatically. 
 
 


 
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7 Concurrent and Supportive Therapies 
7.1 Non-Permitted Concomitant Therapies 
Subject may not receive the following concomitant therapies during the study: 
1.
Biguanides or other agents known to increase risk of lactic acidosis (Appendix 10.1) 
2.
High dose steroids (>20 mg prednisolone or equivalent per day) including for GVHD
3.
Immunosuppressive drugs with the exception of cyclosporine and tacrolimus
4.
Erythropoietin and growth factors are not permitted to be used prophylactically in cycle 
1 but allowed if needed in cycle 2 and onwards. However, these can be used 
therapeutically throughout the study. 
5.
Other cancer therapy (chemotherapy, radiation or immunotherapy) other than the 
exceptions mentioned in Inclusion Criteria #9. 
6.
Strong cytochrome P450 (CYP450) inhibitors or inducers, as specified below:
 
CYP Enzyme
Strong Inhibitors
Strong Inducers
CYP1A2
Ciprofloxacin, clinafloxacin, enoxacin, 
fluvoxamine, zafirlukast  
CYP2C8
Gemfibrozil 
CYP2C19
Fluconazole, fluvoxamine, ticlopidine 
CYP3A
Clarithromycin, conivaptan, grapefruit 
juice, itraconazole, ketoconazole, mibefradil, 
nefazodone, posaconazole, telithromycin, 
troleandomycin, voriconazole 
Avasimibe, carbamazepine, 
phenobarbital, phenytoin, 
pioglitazone, rifbatun, 
rifampin, St. John’s wort 
CYP2D6
Bupropion, fluoxetine, paroxetine, quinidine
 
7.2 Supportive Care Guidelines & Permitted Concomitant Therapies 
7.2.1 Concomitant medication/therapies 
In general, the use of any concomitant medication/therapies deemed necessary for subject 
supportive care and safety are permitted. Subjects with high WBC counts may receive 
hydroxyurea prior to study entry and during the first 2 cycles. Concurrent therapy for CNS 
prophylaxis or continuation of therapy for controlled CNS disease is permitted as defined in the 
inclusion criteria. With the exception of these agents, concomitant systemic chemotherapy is 
not permitted. 
Concomitant medications are recommended as prophylaxis for nausea, vomiting, and infections, 
and are allowed for managing myelosuppression as shown in the table below.  Concomitant 
medications will be recorded in the Case Report Form. 


 
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Table 8: Instructions for the use of concomitant medications and therapies 
Category of 
Use 
Medication
Comment on Use
Restriction on 
Use 
Recommended
Prophylactic antibiotics, 
antifungal agents, and 
antiviral agents. 
Strongly encouraged
Agents known to 
increase risk of 
lactic acidosis 
(see Appendix 
10.1) 
Antiemetic agents
According to standard of 
care at MDACC 
None
Allowed
Oral allopurinol or 
rasburicase 
At investigators 
discretion 
None
Leukapheresis
According to standard of 
care at MDACC 
Before induction 
1 day 1 only 
Red blood cell transfusion
None
None
Platelet transfusion
None
None
White blood cell transfusion
At investigators 
discretion according to 
standard of care at 
MDACC 
None
Myeloid growth factors or 
platelet growth factor 
At investigators 
discretion according to 
standard of care at 
MDACC 
None
Erythropoietin or 
darbepoetin 
 
At investigators 
discretion according to 
the standard of care at 
MDACC 
None
Any other medication for 
supportive care 
At investigators 
discretion according to 
standard of care at 
MDACC  
Agents known to 
increase risk of 
lactic acidosis 
(see Appendix 
10.1) 
 
7.2.2 Use of Blood Products 
During the administration of IACS, subjects may receive red blood cell (RBC) or platelet 
transfusions, if clinically indicated, per institutional guidelines.  
Myelosuppression is expected in subjects with AML due to underlying disease. Most subjects 
will have neutropenia, thrombocytopenia, or both at study entry. Significant or life-threatening 
myelosuppression may be managed with growth factor support including G-CSF, GM-CSF and 
platelet growth factors and erythropoietin/darbopoietin/blood transfusion according to 
institutional standard of care, American Society of Clinical Oncology (ASCO) Practice Guidelines, 
and/or NCCN Practice Guidelines.  


 
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7.2.3 Lactic Acidosis and Severe Acidemia Management 
Subjects with lactic acidosis and severe acidemia (pH < 7.1) should be seen by a nephrology 
specialist as soon as possible and receive bicarbonate therapy. When using bicarbonate therapy 
in subjects with lactic acidosis and severe acidemia, the aim is to maintain the arterial pH above 
7.1.  Rapid infusions of sodium bicarbonate may increase the pCO2, accelerate the production of 
lactate, lower the ionized calcium, expand the extracellular space, and raise the serum sodium 
concentration. There is little evidence that any alternative buffering agents are superior to 
bicarbonate therapy. In adequately ventilated subjects with lactic acidosis and severe acidemia, 
1 to 2 mEq/kg sodium bicarbonate is given as an intravenous bolus. This dose is repeated after 
30 to 60 minutes if the pH is still below 7.1. 
 
8 Administrative, Legal & Ethical Requirements 
8.1 Adverse Event, serious adverse event and reporting 
8.1.1 Adverse Event (AE): 
Any untoward medical occurrence in a subject or clinical investigation subject administered an 
investigational product.  An AE does not necessarily have a causal relationship with the 
medicinal product.   
The criteria for identifying AEs are: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease 
 
Any deterioration in non-protocol-required measurements of laboratory value or other 
clinical test (e.g., ECG or X-ray) that results in symptoms, a change in treatment, or 
discontinuation from study drug 
 
Recurrence of an intermittent medical condition (e.g. headache) not present at Baseline. 
An abnormal laboratory test result may be considered as an adverse event if the identified 
laboratory abnormality leads to any type of intervention whether prescribed in the protocol or 
not. 
A laboratory result should be considered by the Investigator to be an adverse event if it: 
 
Results in the withdrawal of study treatment 
 
Results in withholding of study treatment pending some investigational outcome 
 
Medical evaluation, results in the initiation of an intervention (e.g. potassium 
supplement for hypokalemia) 
 
Any out of range laboratory value that in the Investigator’s judgment, fulfills the 
definitions of an AE with regards to subject’s medical profile 
 
Increases in severity compared to Baseline by ≥ 2 NCI grades (see Appendix C for NCI 
CTCAE Ver 4.03 criteria), with the exception of lymphocytes, albumin, cholesterol, 
glucose and phosphate.  For these tests, a change of ≥ 2 grades will be evaluated by the 
Investigator to determine if they are of clinical significance and if so, will be considered 
an adverse event. 


 
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Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  Any laboratory abnormality 
considered to constitute an adverse event should be reported on the Adverse Event Case Report 
Form (CRF). 
It is the responsibility of the Investigator to review all laboratory findings, including laboratory 
assessments performed at outside labs, in all subjects and determine if they constitute an 
adverse event.  Medical and scientific judgment should be exercised in deciding whether an 
isolated laboratory abnormality should be classified as an adverse event.  The Investigator will 
assess external laboratory findings and determine clinical significance of any which are deemed 
adverse events.  In these instances, the laboratory reports should be signed and dated by the 
Investigator. 
8.1.2 
Reporting of Adverse Events 
Adverse events will be recorded by the research personnel on the CRF.  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. 
For this protocol, adverse events and protocol specific data will be entered into the electronic 
case report form.   Serious adverse events will be entered into ARISg and reconciled against the 
clinical data base at the end of the study. All AEs encountered during the clinical study will be 
reported on the CRF.  All AEs, regardless of relationship to study drug or procedure, should be 
collected, beginning from the time of the first protocol-specific intervention (study drug 
administration).  New information regarding signs and symptoms that occurred prior to the first 
study medication dose on Day 1 should be recorded under the subject’s Medical History.  
Adverse events in clinical investigation subjects include any change in the subject’s condition.  
This includes symptoms, physical findings, or clinical syndromes. 
Subjects with AEs that are ongoing at the subject’s last study visit must be followed until 
resolution or for 30 days after the subject’s last study visit, whichever comes first.  Adverse 
events that are reported during the Follow-up Period will be recorded on the Adverse Events 
CRF and followed until resolution or for up to the 30 days after the subject’s last study visit, 
whichever comes first, with the exception that SAEs will be followed until the event resolves or 
the event or sequelae stabilize. 
Every effort must be made by the Investigator to categorize each AE according to its severity 
and its relationship to the study treatment. 
8.1.3 
Assessing Severity of Adverse Events 
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE Ver 
4.03; http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf) 
is used to assign severity scales to AEs.   
They are: 
Grade 1 = Mild 
Grade 2 = Moderate 
Grade 3 = Severe 
Grade 4 = Life Threatening 
Grade 5 = Death 
Elevated lactate levels are an anticipated pharmacodynamic effect of OXPHOS inhibitors. It is 
currently unknown if such effects may lead to biological consequences, such as lactic acidosis or 


 
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associated symptoms. Safety and tolerability of IACS-010759 is the primary objective of this 
phase 1 clinical trial. During this study, if elevated lactate levels are observed and subjects are 
hospitalized for observation of signs and symptoms (as described in Section 4.1.11), such 
hospitalization (or prolongation of hospitalization) for observation of signs and symptoms that 
would not otherwise require hospitalization will not be considered as a grade 3 toxicity when 
grading the severity of the adverse event if subjects remain asymptomatic and pH remains 
normal. 
In addition, all AEs reported using the NCI CTCAE Ver 4.03 classification and graded as 4 or 5 are 
to be considered serious.  The recommended Adverse Event Recording Guidelines are provided 
in Section 8.1.7. 
The criteria for assessing severity are different than those used for seriousness. 
8.1.4 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
 
Temporal relationship of the onset of the event to the initiation of the study 
treatment 
 
The course of the event, considering especially the effect of discontinuation of study 
treatment or reintroduction of study treatment, as applicable 
 
Whether the event is known to be associated with the study treatment, or with 
other similar treatments 
 
The presence of risk factors in the study subject known to increase the occurrence 
of the event 
 
The presence of non-study treatment related factors which are known to be 
associated with the occurrence of the event 
8.1.5 
Classification of Causality 
Causality is a determination of whether there is a reasonable possibility that the drug may have 
caused or contributed to an adverse event. It includes assessing temporal relationships, 
dechallenge/rechallenge information, association (or lack of association) with underlying 
diseases, and the presence (or absence) of one or more likely causes. 
The investigator must attempt to determine whether an adverse event is in some way related to 
the use of the study drug.  This relationship should be described as follows: 
Unlikely:  The event is clearly due to causes distinct from the use of the study drug, such as a 
documented pre-existing condition, the effect of a concomitant medication, or a new condition 
that, based on the pathophysiology of the condition and the pharmacology of the study drug, is 
unlikely to be related to the use of the study drug. 
Possible: The event follows a reasonable temporal sequence from administration of the study 
drug or the event follows a known response pattern to the study drug, but the event could have 
been produced by a concomitant medication or an intercurrent medical condition which, based 
on the pathophysiology of the condition and the pharmacology of the study drug, is unlikely to 
be related to the use of the study drug.  
Probable: The event follows a reasonable temporal sequence from administration of the study 
drug and the event follows a known response pattern to the study drug and the event cannot be 


 
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reasonably explained by an intercurrent medical condition or the event cannot be the effect of a 
concomitant medication. 
Definite: The event follows a reasonable temporal sequence from administration of the study 
drug, the event follows a known response pattern to the study drug, and based on the known 
pharmacology of the study drug, the event is clearly related to the effect of the study drug. 
Unknown:  Based on the evidence available, causality cannot be ascribed. 
8.1.6 
Reporting Requirements 
Reporting requirements will be as per institutional guidelines. 
Adverse events (AE) related to study conditions 
The serious adverse event (SAE) reporting period will begin with the time of the first protocol-
specific intervention (study drug administration)  Regardless of severity or seriousness, new 
information regarding signs and symptoms that occurred prior to the first study medication dose 
on Day 1 should be recorded under the subject’s Medical History. 
AEs should be followed to resolution or stabilization, and reported as SAEs if they become 
serious.  This also applies to subjects experiencing AEs that cause interruption or discontinuation 
of investigational product, or those experiencing AEs that are present at the end of their 
participation in the study.  Such subjects should receive post-treatment follow-up as 
appropriate. 
8.1.7 
Serious Adverse Event Reporting (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
Death 
 
A life-threatening adverse drug experience – any adverse experience that places the 
subject, 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. 
 
Subject 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 subject 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 subject 
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, to the PROMETRIKA Safety 
Manager. 


 
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 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the PROMETRIKA Safety Manager, 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 PROMETRIKA Safety Project Manager.  
 
Unless otherwise noted, the entry of an AE that is designated as serious in the EDC 
system will automatically prompt an automated email alert for a newly entered case or 
for an existing case where a change in status of the AE fields has been made by the site.  
The email alert will be sent to relevant personnel involved with the SAE case 
management, including the PROMETRIKA Safety Manager.  In the event that the site is 
unable to send the information through the EDC, the site will contact the Drug Safety 
Management department at PROMETRIKA by phone (617.844.0205) or fax 
(617.868.2122) and forward the SAE Form and other related documents to the 
PROMETRIKA Safety Manager.  The site will be responsible for safety reporting to the 
MDACC IRB.  
 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention (study drug administration), 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, all serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the Sponsor and the PROMETRIKA 
Safety Manager. This may include the development of a secondary malignancy. 
 
 


 
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Recommended Adverse Event Recording Guidelines 
Recommended Adverse Event Recording Guidelines  
Attribution
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
 
  
  
  
  
Unrelated 
Phase I 
 Phase I 
 Phase I        
Phase II   
 
Phase I        
Phase II  
Phase III 
 
Phase I         
Phase II  
Phase III 
Unlikely 
Phase I 
 Phase I 
 Phase I        
Phase II   
 
Phase I        
Phase II  
Phase III 
 
Phase I         
Phase II  
Phase III 
Possible 
Phase I       
Phase II 
 
Phase I        
Phase II  
Phase III 
 
Phase I        
Phase II  
Phase III 
 
Phase I        
Phase II  
Phase III 
 
Phase I         
Phase II  
Phase III 
Probable 
Phase I       
Phase II 
 
Phase I        
Phase II  
Phase III 
 
Phase I        
Phase II  
Phase III 
 
Phase I        
Phase II  
Phase III 
 
Phase I         
Phase II  
Phase III 
Definitive 
Phase I       
Phase II 
 
Phase I        
Phase II  
Phase III 
 
Phase I        
Phase II  
Phase III 
 
Phase I        
Phase II  
Phase III 
 
Phase I         
Phase II  
Phase III 
 
8.1.8 
Reporting to FDA: 
PROMETRIKA will submit all SAE reports to the IND Office via e-mail to 
MDACCSafetyReports@mdanderson.org.  Serious adverse events will be submitted 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. 
8.1.9 
Unexpected Adverse Event 
An unexpected adverse event is one that is not listed in the current Clinical Investigator’s 
Brochure (CIB) / Package Insert or that differs from the event mentioned in the CIB / Package 
Insert because of greater severity or specificity.  
 
 


 
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9 Appendices 
9.1 Causes of elevated lactate 
 
Shock 
Pharmacological agents*
Distributive
Linezolid
Cardiogenic
Nucleoside reverse transcriptase inhibitors
Hypovolemic
Metformin
Obstructive
Epinephrine
Post-cardiac arrest 
Propofol
Regional tissue ischemia 
Acetaminophen
Mesenteric ischemia
Beta2 agonists
Limb ischemia
Theophylline
Burns
Trauma
Anaerobic muscle activity 
Compartment syndrome
Seizures
Necrotizing soft tissue infections
Heavy exercise
Diabetic ketoacidosis 
Excessive work of breathing
Drugs/toxins 
Thiamine deficiency 
Alcohols
Malignancy 
Cocaine
Liver failure 
Carbon monoxide 
Mitochondrial disease 
Cyanide
Adapted from [23] 
 
 


 
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9.2 List of abbreviations 
 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
CBC 
Complete Blood Chemistry 
CR 
Complete Remission 
CRi 
Complete Remission with Incomplete Hematological Recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDI
DLT 
Drug-drug interaction
Dose-limiting Toxicity 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
HI 
Hematologic Improvement 
IACS 
Institute for Applied Cancer Science 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
LC-MS 
Liquid Chromatography–Mass Spectrometry 
LLN 
Lower Limit of Normal  
LSC 
Leukemic Stem Cells  
MDACC 
MD Anderson Cancer Center 
MTD 
Maximum Tolerated Dose 
MLFS 
Morphologic leukemia-free state 
NOAEL 
No Observed Adverse Effect Level  
ORR
OXPHOS 
Overall Response Rate
Oxidative Phosphorylation 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
pAMPK 
Adenosine Monophosphate Activated Protein Kinase  
PI 
Principal Investigator 
PR 
Partial Remission 
RD
RP2D 
Recurrence of Disease
Recommended Phase 2 Dose 
QTcF
SAE 
Fridericia Correction Formula
Serious Adverse Event 
SCT  
Stem Cell Transplant 
SD 
Standard Deviation 
ULN 
Upper Limit of Normal  
 


 
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7. Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
 
9.3 ECOG Performance Status* 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
9.4 New York Heart Association (NYHA) Functional Classification 
 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest.  If any physical activity is undertaken, discomfort increases. 
 
9.5 References 
 
1. 
Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2013. CA Cancer J Clin, 2013. 
63(1): p. 11-30. 
2. 
Heerema-McKenney, A. and D.A. Arber, Acute myeloid leukemia. Hematol Oncol Clin 
North Am, 2009. 23(4): p. 633-54. 


 
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3. 
Kadia, T.M., et al., Toward Individualized Therapy in Acute Myeloid Leukemia: A 
Contemporary Review. JAMA Oncol, 2015. 1(6): p. 820-8. 
4. 
Estey, E., Acute myeloid leukemia and myelodysplastic syndromes in older subjects. J Clin 
Oncol, 2007. 25(14): p. 1908-15. 
5. 
Ravandi, F., et al., Characteristics and outcome of subjects with acute myeloid leukemia 
refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy. Blood, 
2010. 116(26): p. 5818-23; quiz 6153. 
6. 
Giles, F., et al., Outcome of subjects with acute myelogenous leukemia after second 
salvage therapy. Cancer, 2005. 104(3): p. 547-54. 
7. 
O'Brien, S., et al., Outcome of adults with acute lymphocytic leukemia after second 
salvage therapy. Cancer, 2008. 113(11): p. 3186-91. 
8. 
Caro, P., et al., Metabolic signatures uncover distinct targets in molecular subsets of 
diffuse large B cell lymphoma. Cancer Cell, 2012. 22(4): p. 547-60. 
9. 
Haq, R., et al., Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. 
Cancer Cell, 2013. 23(3): p. 302-15. 
10. 
Muller, F.L., et al., Passenger deletions generate therapeutic vulnerabilities in cancer. 
Nature, 2012. 488(7411): p. 337-42. 
11. 
Roesch, A., et al., Overcoming intrinsic multidrug resistance in melanoma by blocking the 
mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell, 2013. 
23(6): p. 811-25. 
12. 
Vazquez, F., et al., PGC1alpha expression defines a subset of human melanoma tumors 
with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell, 
2013. 23(3): p. 287-301. 
13. 
Viale, A., et al., Oncogene ablation-resistant pancreatic cancer cells depend on 
mitochondrial function. Nature, 2014. 514(7524): p. 628-32. 
14. 
Birsoy, K., et al., An Essential Role of the Mitochondrial Electron Transport Chain in Cell 
Proliferation Is to Enable Aspartate Synthesis. Cell, 2015. 162(3): p. 540-51. 
15. 
Lagadinou, E.D., et al., BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively 
Eradicates Quiescent Human Leukemia Stem Cells. Cell stem cell, 2013. 
16. 
Samudio, I., et al., Pharmacologic inhibition of fatty acid oxidation sensitizes human 
leukemia cells to apoptosis induction. The Journal of clinical investigation, 2010. 120(1): 
p. 142-56. 
17. 
Sriskanthadevan, S., et al., AML cells have low spare reserve capacity in their respiratory 
chain that renders them susceptible to oxidative metabolic stress. Blood, 2015. 125(13): 
p. 2120-30. 
18. 
Sullivan, L.B., et al., Supporting Aspartate Biosynthesis Is an Essential Function of 
Respiration in Proliferating Cells. Cell, 2015. 162(3): p. 552-63. 
19. 
Simsek, T., et al., The distinct metabolic profile of hematopoietic stem cells reflects their 
location in a hypoxic niche. Cell stem cell, 2010. 7(3): p. 380-90. 
20. 
Thall, P.F., R.M. Simon, and E.H. Estey, Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Stat Med, 1995. 14(4): p. 357-79. 
21. 
Kruse, O., N. Grunnet, and C. Barfod, Blood lactate as a predictor for in-hospital 
mortality in subjects admitted acutely to hospital: a systematic review. Scand J Trauma 
Resusc Emerg Med, 2011. 19: p. 74. 
22. 
Cheson, B.D., et al., Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol, 2003. 21(24): 
p. 4642-9. 


 
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23. 
Andersen, L.W., et al., Etiology and therapeutic approach to elevated lactate levels. 
Mayo Clin Proc, 2013. 88(10): p. 1127-40.