Safety, Tolerability, and Efficacy of TAK-659 in Adults With Relapsed or Refractory Acute Myelogenous Leukemia (AML)

The drug being tested in this study is called TAK-659. TAK-659 is being tested to treat
people who have relapsed or refractory acute myelogenous leukemia (AML). This study will be
conducted in 2 phases. The first phase will determine a safe and well-tolerated dose of
TAK-659 to be used in the second phase, and the second phase will look at response to
treatment in people who take TAK-659.

The study will enroll approximately 106 participants (up to 40 in the first phase and 66 in
the second phase). There will be two separate cohorts during Phase 2 portion of the study,
one for participants with FLT-3 ITD mutations and the other for FLT-3 wild-type participants.

Phase 1b:

• TAK-659 60 milligram (mg) tablet starting dose escalated in 20 mg or higher increments to a
maximum tolerated dose or RP2D

Phase 2:

• TAK-659 tablet at the maximum tolerated dose or RP2D determined in Phase 1b.

All participants will be asked to take their prescribed tablets at the same time each day
throughout the study.

This multi-center trial will be conducted in the United States and Canada. The overall time
to participate in this study is up to 24 months (12 months of treatment and 12 months of
follow up) unless the treating physician believes the participant would continue to derive
benefit from the study drug.

Inclusion Criteria:

1. Male or female participants 18 years or older.

2. Must have a histopathologically documented diagnosis of primary or secondary AML
(excluding acute promyelocytic leukemia), as defined by World Health Organization
(WHO) criteria (Jaffe et al, 2001), for whom no standard therapies are anticipated to
result in a durable remission according to the clinical judgment of the principal
investigator, or who refuses standard therapies (phase 1b and 2).

3. Participants for the phase 2 portion of the study must, in addition, meet the
following:

o Must be refractory to or relapsed after no more than 2 prior chemotherapy regimens.
Re-induction with the same regimen or stem cell transplant will not be considered a
separate regimen.

4. Eastern Cooperative Oncology Group performance status of 0 to 1.

5. Female participants who:

- Are postmenopausal for at least 1 year before the screening visit, or

- Are surgically sterile, or

- If they are of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent
through 180 days after the last dose of study drug, or

- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [example, calendar,
ovulation, symptothermal, postovulation methods], withdrawal, spermicides only,
and lactational amenorrhea are not acceptable methods of contraception. Female
and male condoms should not be used together).

Male participants, even if surgically sterilized (that is, status postvasectomy), who:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 180 days after the last dose of study drug, or

- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [example, calendar,
ovulation, symptothermal, postovulation methods for the female partner],
withdrawal, spermicides only, and lactational amenorrhea are not acceptable
methods of contraception. Female and male condoms should not be used together).

6. Voluntary written consent must be given before performance of any study-related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the participant at any time without prejudice to future medical care.

7. In the absence of rapid progressive disease, the interval from prior systemic
anticancer treatment to time of TAK-659 administration should be at least 2 weeks for
cytotoxic agents (other than hydroxyurea), or at least 5 half-lives for noncytotoxic
agents, and participants have to have recovered from acute toxicities of these
therapies. Participants who are on hydroxyurea may be included in the study and may
continue on hydroxyurea for the first 28 days while participating in this study.

8. Suitable venous access for the study-required blood sampling, including
pharmacokinteic (PK) and pharmacodynamic (PD) sampling and blood transfusion support.

9. Clinical laboratory values as specified in the following:

- Total bilirubin must be less than or equal to (<=) 1.5* the upper limit of normal
(ULN).

- Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be
less than or equal to (<=) 2.5*the ULN.

- Lipase <=1.5*ULN and amylase <=1.5*ULN with no clinical symptoms suggestive of
pancreatitis or cholecystitis.

- Creatinine clearance greater than or equal to (>=) 60 milliliter per minute
(mL/min) either as estimated by the Cockcroft-Gault equation or based on urine
collection (12 or 24 hours).

Exclusion Criteria:

1. Clinically active central nervous system leukemia.

2. Female participants who are lactating and breastfeeding or have a positive serum
pregnancy test during the Screening period or a positive urine pregnancy test on Day 1
before first dose of study drug.

3. Any serious medical or psychiatric illness, including drug or alcohol abuse that
could, in the investigator's opinion, potentially jeopardize the safety of the
participant or interfere with the objectives of the study.

4. Systemic anti-cancer treatment (including investigational agents) <=21 days or <=
5*their half-lives before the first dose of study treatment. (For example, if the
5*the half-life is shorter than 21 days, 5*half-life should be used as the washout
period. However, a minimum of 10 days should elapse from prior therapy to initiating
protocol therapy.)

5. Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or
higher by the National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) (v4.03).

6. Receipt of hematopoietic stem cell transplant (HSCT) within 60 days of the first dose
of TAK-659; clinically significant graft-versus-host disease (GVHD) requiring ongoing
immunosuppressive therapy post HSCT at the time of screening (use of topical steroids
for ongoing skin GVHD is permitted).

7. Active, systemic infection requiring intravenous (IV) antibiotic, antifungal, or
antiviral therapy or other serious infection within 14 days before the first dose of
study drug.

8. Major surgery within 14 days before the first dose of study drug and have not
recovered fully from any complications from surgery.

9. Radiotherapy less than 2 weeks before the first dose of study treatment or have not
recovered from acute toxic effects from radiotherapy.

10. Known human immunodeficiency virus (HIV) positive (testing not required).

11. Known hepatitis B surface antigen-positive, known or suspected active hepatitis C
infection (testing not required).

12. Evidence of currently uncontrolled cardiovascular conditions as listed in the
protocol; acute myocardial infarction with 6 months before starting study drug;
baseline QT interval (QTcF) greater than (>) 450 milliseconds (msec) (males) or > 475
msec (females); or abnormalities on baseline 12-lead electrocardiogram (ECG) that are
considered clinically significant per investigator.

13. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of TAK-659 including difficulty swallowing tablets; diarrhea >
Grade 1 despite supportive therapy.

14. Use or consumption of any of the following substances:

- Medications or supplements that are known to be inhibitors of P-glycoprotein
(P-gp) or strong inhibitors or inducers of Cytochrome (CY) P3A within 5 times the
inhibitor half-life (if a reasonable half-life estimate is known) or within 7
days (if a reasonable half-life estimate is unknown) before the first dose of
study drug. In general, the use of these agents is not permitted during the study
except for AE management.

- Medications or supplements that are known to be strong CYP3A mechanism based
inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days or within
5 times the inhibitor or inducer half-life (whichever is longer) before the first
dose of study drug. In general, the use of these agents is not permitted during
the study except for AE management.

- Grapefruit-containing food or beverages within 5 days before the first dose of
study drug. Note that grapefruit-containing food and beverages are not permitted
during the study.

15. White blood cell count > 50,000 per micro liter (/µL); hydroxyurea may be used to
control the level of circulating leukemic blast cell counts prior to study entry and,
if needed, concomitantly while on TAK-659 treatment during the first 28 days of the
study. Hydroxyurea can be used up to a maximum dose of 5 gram per (g/) day.