Study of IACS-010759 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia (AML)

Study Groups:

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.

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. A new group at a higher dose level may
be started at the same time as an ongoing group receiving a lower dose. If this happens,
participants will be assigned in an alternating manner between the lower dose and higher dose
groups. 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.

You will take the drug in 2 phases: Induction Phase and Maintenance Phase.

In the Induction Phase, you will take IACS-010759 by mouth one (1) time every day on Days 1-7
of Cycle 1.

At the end of the Induction Phase, you will move on to the Maintenance Phase.

During the Maintenance Phase, you will take IACS-010759 by mouth 3 times each week. The study
doctor will tell you when to take your dose.

You should take each dose with a glass of water and at least 1 hour before or 2 hours after a
meal. If you miss a dose, you should not take another dose until the next scheduled time. If
you are enrolled in the food-effect group, you will take your first dose of IACS-010759
within 30 minutes after eating a high fat meal.

You will be admitted to the hospital on Day 7 of Cycle 1 for 24 hours. 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.

Your participation on this study will be over after long-term follow-up (described below).

Study Visits:

On Days 1 and 7 of Cycle 1:

- You will have a physical exam.

- Blood (about 8-9 teaspoons each time) will be drawn before and after the dose to test
for routine, acid/base level, and PD testing. On Day 7, you will only have blood drawn
before the dose.

- Blood (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK) testing before
the dose and then 4 more times over the next 8 hours after the dose. PK testing measures
the amount of study drug in the body at different time points.

- Urine will be collected for routine tests.

- On Day 1, you will have an EKG before your dose of study drug and then 4 more times over
the next 8 hours after the dose.

- On Day 7, you will have an EKG before your dose of study drug and then 4 hours after the
dose.

On Days 2 and 4 of Cycle 1, blood (about 2-3 teaspoons) will be drawn for routine, acid/base
level and PK testing.

On Days 8 and 12 of Cycle 1:

- Blood (about 2-3 teaspoons each time) and urine will be collected for routine and
acid/base level testing before the dose. On Day 8, you will have the blood draw again
after the dose. You will only have this blood draw 1 time on Day 12.

- Blood (about 1 teaspoon each time) will be drawn before the dose and then 4 hours after
the dose for PK testing. You will only have this blood draw 1 time on Day 12.

On Day 15 of Cycle 1:

- You will have a physical exam.

- Blood (about 2-3 teaspoons each time) and urine will be collected for routine and
acid/base level testing before the dose. You will this blood draw again after the dose.

- Blood (about 6 teaspoons each time) will be drawn before the dose and then 4 hours after
the dose for PD testing.

- Blood (about 1 teaspoon each time) will be drawn before the dose and then 4 hours after
the dose for PK testing.

- You will have an EKG before and after the dose.

On Days 17 and 21 of Cycle 1:

- Blood (about 3-4 teaspoons) will be drawn to check how well your pancreas functions and
for routine and acid/base level testing.

- Blood (about 1 teaspoon each time) will be drawn for PK testing.

- Urine will be collected for routine tests.

- On Day 21 only, blood (about 6 teaspoons) will be drawn for PD testing.

- On Day 21 only, you will have an EKG.

- On Day 21 only, you will have a bone marrow aspirate and/or biopsy to check the status
of your disease and to create a lab test to learn how well the drug works.

On Days 1 and 21 of Cycles 2 and 3:

- You will have a physical exam.

- Blood (about 2-3 teaspoons) will be drawn for routine, acid/base level, and PK testing.
°During Cycle 2 only, this blood draw will also be used to check how well your pancreas
functions.

- During Cycle 2 only, urine will be collected for routine tests. On Day 21 of Cycle 3
only, you will have a bone marrow aspirate and/or biopsy.

On Days 8 and 15 of Cycle 2:

- Blood (about 2-3 teaspoons) will be drawn before the dose for routine and acid/base
level and PK testing. This blood draw will also be used to check how well your pancreas
functions.

- Urine will be collected for routine tests.

- On Day 15 only, blood (about 1 teaspoon) will be drawn after the dose for acid/base
level testing.

- On Day 15 only, blood (about 1 teaspoon each time) will be drawn for PK testing 4 times
over the next 8 hours after the dose of study drugs.

On Day 16 of Cycle 2:

- Blood (about 2-3 teaspoons) will be drawn for routine, acid/base level, and PK testing.

- Urine will be collected for routine tests.

On Day 21 of Cycles 4 and beyond:

- You will have a physical exam.

- Blood (about 2-3 teaspoons) will be drawn to check how well your pancreas functions and
for routine, PK, and acid/base level testing.

- Urine will be collected for routine tests.

Every 2-3 cycles while you are on study, if the doctor thinks it is needed, you will have a
bone marrow aspirate and/or biopsy.

If the study doctor increases your dose of study drug, the following will be performed weekly
during the first cycle of the higher dose:

- Blood (about 2-3 teaspoons) will be drawn for routine and acid/base level and PK
testing. This blood draw will also be used to check how well your pancreas functions.

- Urine will be collected for routine tests.

If the study doctor stops and re-starts your dose of study drug, the following will be
performed:

- Blood (about 3-4 teaspoons) will be drawn for acid/base level testing and to check how
well your pancreas functions.

- Blood (about 1 teaspoon each time) will be drawn for PK testing before the dose and 6
hours after the dose.

If the study doctor lowers your dose of study drug, the following will be performed when you
start taking the lower dose:

°Blood (about 1 teaspoon each time) will be drawn for PK testing before the dose.

End-of-Study Visit:

About 30 days after your last dose of the study drug:

- You will have a physical exam.

- Blood (about 2-3 teaspoons) and urine will be collected to check how well your pancreas
functions and for routine and acid/base level testing.

- If the doctor thinks it is needed, you will have a bone marrow aspirate and/or biopsy.

If you are unable to return to the clinic for the visit, this testing can be performed by a
local doctor and the results will be sent to the study doctor. The research nurse will call
you to ask about your health. These calls should last about 5 minutes.

Long-Term Follow-up:

If the disease appears to be responding to the study drug, a member of the study staff will
call you every 3-6 months for up to 5 years to ask how you are doing and about any side
effects you may be having. Each call should last about 5 minutes.

If the doctor thinks it is needed, you may be asked to come into the clinic for a physical
exam.

Inclusion 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:
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: 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)
3. Patients who have had prior SCT are eligible if they have a relapse > 3 months since
autologous or allogeneic stem cell transplantation provided, 1) No clinically
significant active graft-versus-host disease (GVHD > grade 1); 2) No treatment with
high dose steroids for GVHD (i.e. >20 mg Prednisolone or equivalent per day); 3) No
treatment with immunosuppressive drugs with the exception of cyclosporine and
tacrolimus.

4. Subjects with history of central nervous system (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: 1) Serum creatinine bilirubin be elevated due to Gilbert's disease or leukemia); 3) Alanine Aminotransferase (ALT)
and Aspartate Aminotransferase (AST) 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 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 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.

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: 1) 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; 2) 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;

11. #10 continued: 3) 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;4) 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.

12. #11 continued: 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.

13. Able and willing to give valid written informed consent.

Exclusion Criteria:

1. Prior exposure to IACS-010759 or other oxidative phosphorylation Inhibitors.

2. Unstable cardiovascular function: 1) Symptomatic ischemia, or 2) 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 3) Congestive heart failure (CHF) NYHA Class >/= 3, or 4)
Myocardial infarction (MI) within 6 months; 5) Left ventricular ejection fraction < 40
%; 6) 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.

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.

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.