Lithium Carbonate and Tretinoin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the safety and maximum tolerated dose of the combination of tretinoin with
lithium carbonate in subjects with non promyelocytic acute myeloid leukemia.

SECONDARY OBJECTIVES:

I. To describe the dose limiting toxicities associated with the combination of lithium
(lithium carbonate) and tretinoin.

II. To determine the ability of lithium to inhibit glycogen synthase kinase-3 (GSK3)
activity in circulating acute myeloid leukemia (AML) cells and to enhance the retinoic acid
receptor expression.

III. To determine the ability of lithium and tretinoin to induce differentiation and/or
growth inhibition of AML cells.

IV. To determine the response rate of acute myeloid treatment to treatment with the
combination of Tretinoin and Lithium.

OUTLINE: This is a dose-escalation study of tretinoin.

Patients receive tretinoin orally (PO) every 12 hours on days 1-7 and 15-21 and lithium
carbonate PO three times daily (TID) on days 1-28. Treatment repeats every 28 days for up to
6 courses in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed non-acute promyelocytic
leukemia (APL) acute myeloid leukemia (AML)

- AML patients must either:

- Be ineligible to receive standard intensive induction chemotherapy (based upon
judgement of the treating physician, based on parameters such as comorbidities,
cytogenetic studies as well as), or

- Have relapsed or refractory disease to previous chemotherapy (induction and/or
consolidation) for acute myeloid leukemia; patients must have recovered from
acute toxicities of AML chemotherapy

- Prior treatment for pre-existing hematologic conditions is allowed and includes
hydroxyurea, thalidomide, hematopoietic growth factors, Zarnestra, lenalidomide,
arsenic trioxide, imatinib, corticosteroids, histone deacetylase inhibitors,
azacytidine, midostaurin; hydroxyurea is allowed up to 24 hours before starting the
experimental treatment

- A minimum of 4 weeks must have elapsed since the administration of all other
investigational agents

- A minimum of 5 days must have elapsed since the administration of hematopoietic
growth factors with short half life (filgrastim, erythropoietin), while for longer -
acting hematopoietic growth factors, the minimum time elapsed is 20 days

- Performance status Eastern Cooperative Oncology Group (ECOG) 0 - 2

- Life expectancy of > 12 weeks, in the opinion of and as documented by the
investigator

- Total bilirubin =< 1.5 times the institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5
X institutional upper limit of normal

- Serum creatinine =< 1.5 the institutional upper limit of normal

- There is no exclusion for the presence of cytopenias

- The effects of tretinoin and lithium on the developing human fetus are unknown; for
this reason and because retinoid agents as well as other therapeutic agents used in
this study are known to be teratogenic, women of child-bearing potential and men must
agree to use adequate contraception (double barrier method of birth control or
abstinence) from the time of study entry, for the duration of study participation and
for 3 months after completing treatment; should a woman become pregnant or suspect
that she is pregnant while she or her partner is participating in this study, she
should inform the treating physician immediately

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document

Exclusion Criteria:

- Prior treatment toxicities must be resolved to =< grade 1 according to National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version
4.0

- Patients who are currently receiving any other investigational agents

- Patients with untreated central nervous system involvement by AML should be excluded
from this clinical trial because of their poor prognosis and because they often
develop progressive neurologic dysfunction that would confound the evaluation of
neurologic and other adverse events; this is an uncommon situation in AML and
therefore a lumbar puncture for cerebrospinal fluid (CSF) sampling or magnetic
resonance imaging (MRI) imaging are NOT necessary to rule out central nervous system
(CNS) involvement in the absence of clinical suspicion by the treating physician

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to tretinoin or lithium carbonate or other agents used in this study

- Prohibited medications, supplements and herbal medications:

- Tetracycline and its derivatives (enhance the risk of retinoic acid toxicity)

- Live vaccines

- Vitamin A

- St. John's wort

- Dong quai: Herbal supplement, (Angelica sinensis)

- Cytochrome P450 2C8 (CYP2C8) inhibitors: gemfibrozil, trimethoprim,
thiazolinediones, montelukast, quercetin

- CYP2C8 inducers: rifampicin

- Patients receiving any medications or substances that are moderate and strong
inhibitors of CYP2C8 or inducers of CYP2C8 are ineligible

- Patients with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

- Pregnant or breastfeeding women are excluded from this study because tretinoin is a
retinoid derivative agent with the potential for teratogenic or abortifacient
effects; because there is an unknown, but potential risk for adverse events in
nursing infants secondary to treatment of the mother with tretinoin, breastfeeding
should be discontinued if the mother is treated with tretinoin; these potential risks
may also apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
tretinoin; in addition, these patients are at increased risk of lethal infections
when treated with marrow suppressive therapy; appropriate studies will be undertaken
in patients receiving combination antiretroviral therapy when indicated

- Chronic active hepatitis B or C infection

- Previous diagnosis of bipolar disorder

- Known hypersensitivity to lithium or tretinoin

- Personal or family history of established Brugada syndrome; if pre-enrollment
electrocardiogram (ECG) demonstrates abnormal findings (ST elevation in precordial
leads), cardiology consultation should be obtained to rule out presence of this
inherited syndrome; patients with family history of unexplained sudden death before
the age 45 years; personal history of unexplained syncope or history of unexplained
ventricular tachycardia or fibrillation should have a cardiology evaluation to rule
out the diagnosis of Brugada syndrome