CIP-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Granulocytic Sarcoma

PRIMARY OBJECTIVES:

I. To determine the feasibility of CPI-613 when administered with high dose cytarabine, and
mitoxantrone (mitoxantrone hydrochloride) in all three phases of salvage therapy (induction,
consolidation and maintenance).

SECONDARY OBJECTIVES:

I. To observe the response rate (complete remission [CR], and CR with incomplete recovery
[CRi]) of CPI-613 in combination with high dose cytarabine and mitoxantrone.

II. To observe the overall survival of patients treated with CPI-613 in combination with high
dose cytarabine and mitoxantrone in induction, consolidation and maintenance.

III. To monitor toxicities experienced by patients treated with CPI-613 in combination with
high dose cytarabine and mitoxantrone in induction, consolidation and maintenance.

OUTLINE:

SALVAGE INDUCTION COURSE 1: Patients receive 6,8-bis(benzylthio)octanoic acid intravenously
(IV) over 2 hours on days 1-5, cytarabine IV over 3 hours every 12 hours starting on day 3
for 5 doses, and mitoxantrone hydrochloride IV over 15 minutes after the first, third, and
fifth doses of cytarabine.

SALVAGE INDUCTION COURSE 2 (OPTIONAL, AT DISCRETION OF TREATING PHYSICIAN): Patients receive
6,8-bis(benzylthio)octanoic acid, cytarabine, and mitoxantrone hydrochloride as in course 1
or an abbreviated second course at the discretion of the treating physician. In the
abbreviated course, patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days
1-3, cytarabine IV over 3 hours every 12 hours starting on day 2 for 3 doses, and
mitoxantrone hydrochloride IV over 15 minutes after the first and third cytarabine doses.

SALVAGE CONSOLIDATION: Patients achieving response receive up to 2 courses of the abbreviated
course of 6,8-bis(benzylthio)octanoic acid, high dose cytarabine, and mitoxantrone
hydrochloride. Patients achieving response may undergo stem cell transplant at the discretion
of the treating physician. Patients may proceed to maintenance after 1, 2 or no courses of
consolidation at the discretion of the treating physician.

MAINTENANCE THERAPY: Patients achieving response receive 6,8-bis(benzylthio)octanoic acid IV
over 2 hours on days 1-5. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients must have histologically or cytologically documented relapsed and/or
refractory acute myeloid leukemia or granulocytic sarcoma

- Eastern Cooperative Oncology Group (ECOG) performance status of =< 3

- Expected survival > 3 months

- Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
sterile) must use accepted contraceptive methods (abstinence, intrauterine device
[IUD], oral contraceptive or double barrier device), and must have a negative serum or
urine pregnancy test within 1 week prior to treatment initiation

- Fertile men must practice effective contraceptive methods during the study period,
unless documentation of infertility exists

- Mentally competent, ability to understand and willingness to sign the informed consent
form

- No radiotherapy, treatment with cytotoxic agents (except CPI-613), treatment with
biologic agents or any anti-cancer therapy within the 2 weeks prior to treatment with
CPI-613; hydroxyurea and oral tyrosine kinase inhibitors being used without grade =< 2
toxicity can be taken until day 1 of therapy; patients must have fully recovered from
the acute, non-hematological, non-infectious toxicities of any prior treatment with
cytotoxic drugs, radiotherapy or other anti-cancer modalities (returned to baseline
status as noted before most recent treatment); patients with persisting,
non-hematologic, non-infectious toxicities from prior treatment =< grade 2 are
eligible, but must be documented as such

- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) =< 3 x
upper normal limit (UNL), alanine aminotransferase (ALT)/serum glutamate pyruvate
transaminase (SGPT) =< 3 x UNL (=< 5 x upper limit of normal [ULN] if liver metastases
present)

- Bilirubin =< 1.5 x UNL

- Serum creatinine =< 1.5 mg/dL or 133 umol/L

- International normalized ratio or INR must be < 1.5

- Left ventricular ejection fraction (by transthoracic echocardiography [TTE],
multigated acquisition scan [MUGA] or cardiac magnetic resonance imaging [MRI])
sufficient to safely administer mitoxantrone as determined by the treating physician

Exclusion Criteria:

- Serious medical illness, such as significant cardiac disease (e.g. symptomatic
congestive heart failure, unstable angina pectoris, myocardial infarction within the
past 6 months, uncontrolled cardiac arrhythmia, pericardial disease or New York Heart
Association class III or IV), or severe debilitating pulmonary disease, that would
potentially increase patients' risk for toxicity

- Patients with active central nervous system (CNS) or epidural tumor

- Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g.,
active peptic ulcer disease)

- Pregnant women, or women of child-bearing potential not using reliable means of
contraception

- Lactating females

- Fertile men unwilling to practice contraceptive methods during the study period

- Life expectancy less than 3 months

- Any condition or abnormality which may, in the opinion of the investigator, compromise
the safety of patients

- Unwilling or unable to follow protocol requirements

- Patients with large and recurrent pleural or peritoneal effusions requiring frequent
drainage (e.g. weekly); patients with any amount of clinically significant pericardial
effusion

- Active heart disease including myocardial infarction within previous 6 months,
symptomatic coronary artery disease, uncontrolled arrhythmias, or symptomatic
congestive heart failure

- Evidence of ongoing, uncontrolled infection

- Patients with known human immunodeficiency virus (HIV) infection

- Patients receiving any other standard or investigational treatment for their cancer,
or any other investigational agent for any indication within the past 2 weeks prior to
initiation of CPI-613 treatment (the use of Hydrea is allowed)

- Patients who have received immunotherapy of any type within the past 4 weeks prior to
initiation of CPI-613 treatment

- Requirement for immediate palliative treatment of any kind including surgery

- Patients that have received a chemotherapy regimen with stem cell support in the
previous 6 months

- A history of additional risk factors for torsade de pointes (e.g., clinically
significant heart failure, hypokalemia, family history of long QT syndrome)