TK216 and Decitabine in Treating Patients With Relapsed and Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of
Ets-family transcription factor inhibitor TK216 (TK216) in patients with relapsed and
refractory (R/R) acute myeloid leukemia (AML). (Phase I Dose Escalation) II. To determine the
safety and tolerability of TK216 combined with decitabine in patients with relapsed and
refractory AML. (Combination Cohort)

SECONDARY OBJECTIVES:

I. Safety profile of TK216 as characterized by adverse event (AE) type, severity, timing and
relationship to study drug, as well as laboratory abnormalities in the first and subsequent
treatment cycles. (Phase I Dose Escalation) II. To explore the efficacy (complete remission
[CR], complete remission without platelet recovery [CRp], complete remission without blood
count recovery [CRi], or partial remission [PR]), of TK216 as a single-agent in patients with
R/R AML. (Phase I Dose Escalation) III. To assess overall survival (OS), and disease free
survival (DFS) in patients with R/R AML treated with TK216. (Phase I Dose Escalation) IV.
Duration of disease control defined as first date of disease control identified (either
CR/CRp/CRi, PR or SD) until the date of progression. (Phase I Dose Escalation) V. To explore
biomarkers of response and resistance in patients with R/R AML treated with TK216. (Phase I
Dose Escalation) VI. Safety profile of TK216 in combination with decitabine as characterized
by adverse event (AE) type, severity, timing and relationship to study drug, as well as
laboratory abnormalities in the first and subsequent treatment cycles. (Combination Cohort)
VII. To explore the efficacy (complete remission [CR], complete remission without platelet
recovery [CRp], complete remission without blood count recovery [CRi], or partial remission
[PR], of TK216 in combination with decitabine in patients with R/R AML. (Combination Cohort)
VIII. To assess overall survival (OS), and progression free survival (PFS) in patients with
R/R AML treated with TK216 + decitabine. (Combination Cohort) IX. Duration of disease control
defined as first date of disease control identified (either CR/CRp/CRi, PR or SD) until the
date of progression. (Combination Cohort) X. To explore biomarkers of response and resistance
in patients with R/R AML treated with TK216 + decitabine. (Combination Cohort)

OUTLINE: This is a dose-escalation study.

Patients receive TK216 intravenously (IV) continuously on days 1-7 every 21 days, or
continuously on days 1-7 and 15-21 every 28 days. Patients also receive decitabine IV over 60
minutes on days 1-10 every 28 days. Treatment continues in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients with a diagnosis of histologically confirmed relapsed or refractory (R/R)
acute myeloid leukemia for which no available standard therapies are indicated or
anticipated to result in a durable response

- Patients must not have had leukemia therapy for 14 days prior to starting TK216.
However, patients with rapidly proliferative disease may receive hydroxyurea as needed
until 24 hours prior to starting therapy on this protocol and during the first cycle
of study

- Bilirubin =< 2 mg/dL

- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 3 x upper
limit of normal (ULN) -- or =< 5 x ULN if related to leukemic involvement

- Creatinine =< 1.5 x ULN

- Known cardiac ejection fraction of > or = 45% within the past 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

- A negative urine pregnancy test is required within 1 week for all women of
childbearing potential prior to enrolling on this trial

- Patient must have the ability to understand the requirements of the study and signed
informed consent. A signed informed consent by the patient or his legally authorized
representative is required prior to their enrollment on the protocol

Exclusion Criteria:

- Pregnant women are excluded from this study because the agent used in this study has
the potential for teratogenic or abortifacient effects. Because there is a potential
risk for adverse events in nursing infants secondary to treatment of the mother with
the chemotherapy agents, breastfeeding should also be avoided

- Uncontrolled intercurrent illness including, but not limited to active uncontrolled
infection, symptomatic congestive heart failure (New York Heart Association [NYHA]
class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia,
or psychiatric illness/social situations that would limit compliance with study
requirements

- Patient with documented hypersensitivity to any of the components of the therapy
program

- Patients with active, uncontrolled central nervous system (CNS) leukemia will not be
eligible

- Men and women of childbearing potential who do not practice contraception. Women of
childbearing potential and men must agree to use at least 1 form of barrier birth
control (such as condom) prior to study entry and for the duration of study
participation

- Patients with known history of serous retinopathy will not be eligible

- Prior treatment with TK216