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

PRIMARY OBJECTIVES:

I. To determine the safety and maximum tolerated dose (MTD) of CPI-613 when administered with
high dose cytarabine, and mitoxantrone (mitoxantrone hydrochloride).

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics (PKs) of CPI-613 following intravenous (IV)
administration in combination with high dose cytarabine and mitoxantrone.

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

III. To observe the overall survival of patients treated with CPI-613 in combination with
high dose cytarabine and mitoxantrone.

OUTLINE: This is a dose-escalation study of CPI-613.

Patients receive CPI-613 intravenously (IV) over 2 hours on days 1-5, cytarabine IV over 3
hours every 12 hours for 5 doses beginning on day 3, and mitoxantrone hydrochloride IV over
15 minutes after the 1st, 3rd, and 5th doses of cytarabine. . Treatment repeats every 14 days
for up to 2 courses* in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients undergoing a second course of therapy receive CPI-613 IV over 2 hours on days
1-3, cytarabine IV over 3 hours every 12 hours for 5 doses beginning on day 2, and
mitoxantrone hydrochloride IV over 15 minutes after the 1st and 3rd doses of cytarabine.

After completion of study treatment, patients are followed up for 6 months.

Inclusion Criteria:

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

- 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; (Note: Pregnant
patients are excluded because the effects of CPI-613 on a fetus are unknown)

- 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; 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 μmol/L

- International Normalized Ratio or INR must be < 1.5

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 (because the teratogenic potential of CPI-613 is unknown)

- Lactating females because the potential of excretion of CPI-613 into breast milk
(Note: Lactating females are excluded because the effects of CPI-613 on a nursing
child are unknown)

- 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

- Albumin < 2.0 g/dL or < 20 g/L

- Evidence of ongoing, uncontrolled infection

- Patients with known human immunodeficiency virus (HIV) infection; (Note: Patients with
known HIV infection are excluded because patients with an immune deficiency are at
increased risk of lethal infections when treated with marrow-suppressive therapy, and
because there may be unknown or dangerous drug interactions between CPI-613 and
anti-retroviral agents used to treat HIV infections)

- 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)