Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of metformin (metformin hydrochloride) in
combination with cytarabine in relapsed/refractory AML.

II. Define the dose limiting toxicity (DLT) of metformin in combination with cytarabine in
relapsed/refractory AML.

SECONDARY OBJECTIVES:

I. Remission rate. II. Overall survival (OS). III. Disease-free survival (DFS). IV. Length of
remission.

OUTLINE: This is a dose-escalation study of metformin hydrochloride in combination with
Cytarabine.

Patients receive metformin hydrochloride orally (PO) twice daily (BID) on days 1-15 and
cytarabine intravenously (IV) over 3 hours BID on days 4-10.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 5 years.

Inclusion Criteria:

- Patients with relapsed/refractory disease must have morphologic proof (from bone
marrow aspirate, smears or touch preps of bone marrow biopsy) of AML with >= 10%
blasts within two weeks (14 days) prior to initiation of therapy

- All immunophenotype and cytogenetic/molecular groups are eligible for
participation except for acute promyelocytic leukemia (APL) (as proven by the
presence of promyelocytic leukemia/retinoic acid receptor alpha [PML-RARα])

- Patients must demonstrate one of the following:

- Relapse after first complete remission

- Refractory to conventional induction chemotherapy (failure to respond to 1 or
more cycles of daunorubicin and cytarabine) or to re-induction

- Patients with previously untreated AML are candidates if they are unable to receive
anthracyclines, and have documented AML with >= 20% blasts within one week prior to
enrollment

- Patients with chronic myelogenous leukemia (CML) in myeloid blast crisis are eligible
if their disease has failed to respond, and/or they are intolerant, to the available
tyrosine kinase inhibitors (TKIs)

- Serum total and direct bilirubin =< upper limit of normal (ULN)

- Serum creatinine < 1.4 mg/dl in females and < 1.5 mg/dl in males, and creatinine
clearance > 60 mL/min

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase
[AST])/serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =<
ULN

- Bicarbonate within the normal range of the hospital lab (24-32 mmol/L)

- Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
of 0, 1, or 2

- Females of childbearing potential and sexually active males must agree to use an
accepted and effective method of contraception while on study

- Childbearing potential is defined as any woman (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the
following criteria:

- Has NOT undergone a hysterectomy or bilateral oophorectomy; OR

- Has NOT been naturally postmenopausal for at least 12 consecutive months (i.e.
has had menses at any time in the preceding 12 consecutive months)

- Patients with a history of central nervous system (CNS) leukemia are eligible if they
are not symptomatic from current CNS involvement

- If there is CNS involvement that is known prior to enrollment or identified
subsequently, it will be treated accordingly

- Patients may have received therapy for other malignancies, as long as they have
completed therapy at least 6 months prior to study entry and be deemed to have a life
expectancy of at least 2 years with regard to that malignancy

- All patients must have given signed, informed consent prior to registration on study

Exclusion Criteria:

- Patients who have received chemotherapy or radiotherapy within 4 weeks prior to
enrollment are NOT eligible for participation

- The exception to this is patients who are refractory to conventional initial
induction chemotherapy (=< 2 courses) or to first radiation (1 course); patients
must have morphologic proof (from bone marrow aspirate, smears, or touch preps of
marrow biopsy) of AML with > 10% blasts within 2 weeks prior to initiation of
study therapy; the last dose of cytotoxic therapy (NOT including hydrea, which is
allowed) must have been given >= 14 days prior to initiation of study therapy

- Patients with a history of diabetes mellitus (DM) treated with metformin are NOT
eligible for participation

- Patients who are pregnant or breast feeding are NOT eligible for participation due to
the lack of knowledge regarding the effects of the drugs on the fetus and during
breast feeding

- Patients with any intercurrent organ damage or medical problems that would prohibit
therapy are NOT eligible for participation

- Patients with any active, uncontrolled infection are NOT eligible for participation

- Patients who are receiving therapy for another active malignancy are NOT eligible for
participation

- The exception to this is squamous cell carcinoma or basal cell carcinoma of the
skin