8-Chloro-Adenosine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (recommended phase II dose, [RP2D]) of
8-chloro-adenosine, when given as a single agent, in patients with relapsed or refractory
acute myeloid leukemia. (Phase I) II. To assess tolerability and safety of 8-chloro-adenosine
at each dose level by evaluation of toxicities including: type, frequency, severity,
attribution, time course and duration. (Phase I) III. To estimate the response rate and to
evaluate the antitumor activity of 8-chloro-adenosine, when given as a single agent, as
assessed by complete remission rate (complete remission [CR] + complete remission with
incomplete blood count recovery [CRi]). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate for disease response to 8-chloro-adenosine in refractory/relapsed acute
myeloid leukemia (AML) on each dose level tested. (Phase I) II. To obtain estimates of
remission duration and survival probabilities (overall and event-free). (Phase II) III. To
obtain an estimate of the overall response rate (CR + CRi + partial response [PR]). (Phase
II) IV. To summarize and evaluate toxicities by type, frequency, severity, attribution, time
course and duration. (Phase II)

TERTIARY OBJECTIVES:

I. To describe the plasma, urinary and cellular pharmacokinetics of 8-chloro-adenosine and
metabolites.

II. To determine the impact of 8-chloro-adenosine on cellular adenosine triphosphate (ATP)
pool in AML blasts.

III. To assess the impact of 8-chloro-adenosine therapy on select short-lived messenger
ribonucleic acids (mRNAs) and corresponding proteins in circulating AML blasts.

IV. To correlate clinical responses and toxicity with plasma/urine 8-chloro-adenosine level
(pharmacokinetic [PK]), cellular 8-chloro-ATP (PK) and cellular ATP pool.

V. To determine the cytotoxicity of 8-chloro-adenosine toward leukemic progenitor cells in
vitro.

VI. To generate a preliminary pre-treatment RNA/micro ribonucleic acid (miRNA) signature in
leukemic progenitor cells, and explore its possible association with in vitro cytotoxicity to
8-chloro-adenosine.

VII. To explore the possible association between the preliminary RNA/miRNA signature and
clinical response to 8-chloro-adenosine.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive 8-chloro-adenosine intravenously (IV) over 4 hours on days 1-5. Treatment
repeats every 28 days for up to 4 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3
months for up to 2 years.

Inclusion Criteria:

- All subjects must have the ability to understand and the willingness to sign a written
informed consent

- Patients must have a life expectancy of > 3 months

- Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
of 0-2

- Patients must have a diagnosis of AML as per World Health Organization (WHO)
Classification of Hematologic Neoplasms

- Patients must meet one of the three treatment history criteria:

- Relapsed AML who have failed at least 1 line of salvage therapy

- De novo AML who have not achieved CR after 2 lines of therapy

- AML evolving from myelodysplastic syndrome (MDS) or myeloproliferative disorder
who have failed hypomethylating agent or induction chemotherapy

- Patients who have relapsed after allogeneic hematopoietic cell transplant (HCT)
are eligible if they are at least 3 months after HCT, do not have active graft
vs. host disease (GVHD) and are off immunosuppression except for maintenance dose
of steroids (prednisone 10 mg/day or less)

- At least 2 weeks from prior chemotherapy or radiation therapy to time of start of
treatment, except for hydroxyurea or corticosteroid therapy, which may be continued
through Cycle 1

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN)

- Total bilirubin =< 1.5 X ULN

- Calculated creatinine clearance (CrCl) >= 50 mL/min per 24 hour urine collection or
the Cockcroft-Gault formula

- Negative serum or urine beta-human chorionic gonadotropin (beta-HCG) test (female of
childbearing potential only), to be performed locally within the screening period

- Agreement by females of childbearing potential and sexually active males to use an
effective method of contraception (hormonal or barrier method of birth control or
abstinence) prior to study entry and for three months following duration of study
participation; should a woman become pregnant or suspect that she is pregnant while
participating on the trial, she should inform her treating physician immediately

Exclusion Criteria:

- Current or planned use of other investigational agents, or concurrent biological
chemotherapy, or radiation therapy during the study treatment period

- Expected to undergo HCT within 120 days of enrollment

- Current of planned use of agents that prolong or suspected to prolong QTc

- Diagnosis of acute promyelocytic leukemia

- Active central nervous system leukemia

- Active fungal infection or bacterial sepsis

- Active peptic ulcer disease

- History of heart failure or cardiac arrhythmia

- Other active malignancy except for localized skin cancer, bladder, prostate, breast or
cervical carcinoma in situ

- Pregnant women and women who are lactating; breastfeeding should be discontinued if
the mother is treated with 8-chloro-adenosine

- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures

- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)