Sorafenib Tosylate Before and After Donor Bone Marrow Transplant in Treating Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. Determine the toxicity and safety of incorporation of sorafenib tosylate (sorafenib) into
the pre- or post-transplant maintenance setting for three types of transplants.

SECONDARY OBJECTIVES:

I. Improvement of 2 year disease free survival after bone marrow transplant by 25% based on a
baseline relapse free survival at two years of 30%.

II. Secondary graft failure is defined as the decline in neutrophil count to < 500/cu mm
after achieving engraftment which is unrelated to infection or drug effect (sorafenib?) and
is unresponsive to stimulation by growth factors.

III. Non-relapse mortality (NRM) is defined, as death in the absence of competing risks,
relapse or progression of disease.

IV. Survival without relapse or death (disease-free survival [DFS]) or without death (overall
survival [OS]) will be determined and presented as Kaplan-Meier estimates at 1 and 2 years
post-transplant.

V. Patients will be evaluated for chronic graft versus host disease (GVHD) both as described
in the National Institutes of Health (NIH) consensus project guidelines and by conventional
criteria.

LABORATORY CORRELATIVE OBJECTIVES:

I. Patients will undergo serial examinations of bone marrow during the maintenance treatments
evaluating minimal residual disease (MRD) by flow cytometry and FLT3 suppression by western
blot analysis and plasma inhibitory assay (PIA).

OUTLINE: This is a dose-escalation study.

Patients receive sorafenib tosylate orally (PO) twice daily (BID) beginning at least 30 days
after completion of induction therapy and/or transplant but no more than 120 days after
transplant continuing for up to 2 years after transplant in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 24 months.

Inclusion Criteria:

- Acute myeloid leukemia with a FLT3-internal tandem duplication (ITD) who are in a
complete remission or partial remission (less than 10% blasts in marrow) as documented
by bone marrow biopsy and who plan to undergo a bone marrow transplantation

- Patients who have had count recovery (absolute neutrophil count [ANC] > 500,000/mm^3;
non transfused platelet count over 30,000/mm^3) and are at least 30 days after
induction and/or transplantation but no more than 120 days post transplant

- Patients may have received any prior therapy deemed necessary for induction of
remission except for patients whom have progressed while on sorafenib; patients who
have responded to sorafenib previously are eligible for enrollment on the protocol

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than four months

- Total bilirubin less than 2 x upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 x institutional upper limit of normal

- Creatinine =< 1.5 x upper limit of normal OR creatinine clearance >= 60 mL/min/1.73
m^2 for patients with creatinine levels > 1.5 x upper limit of normal

- The effects of sorafenib on the developing human fetus are unknown; for this reason
and because tyrosine kinase inhibiting agents are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation; should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately; contraception should continue for at least 30 days after the last dose of
sorafenib

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks except for
intrathecal chemotherapy (i.e., methotrexate, cytarabine, or thiotepa)

- Patients may not be receiving any other investigational agents

- Patients with uncontrolled hypertension (i.e., persistent grade 3 while undergoing
treatment)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sorafenib

- Patients with active and/or untreated central nervous system (CNS) leukemia will not
be eligible

- Patients must not have any evidence of bleeding diathesis or be on any therapeutic
anticoagulation such as low molecular weight (LMW) heparin or warfarin for deep vein
thrombosis (DVT) treatment

- 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 women are excluded from this study because sorafenib is chemotherapeutic
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 sorafenib, breastfeeding should be discontinued if the
mother is treated sorafenib

- Human immunodeficiency virus (HIV)-positive patients are excluded because management
of these patients in the hematopoietic cell transplant setting has not yet been well
defined and is currently the subject of investigation in other studies addressing this
issue

- Patients with active acute GVHD who have been initiated on therapy or had therapy
escalation within 21 days are not eligible

- Patients with lack of engraftment (less than 90% donor deoxyribonucleic acid [DNA] in
bone marrow or peripheral blood) after bone marrow transplant as evidence by RFLP
(restriction fragment length polymorphism) are not eligible

- Patients who are unable to swallow pills are not eligible

- Patients taking strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4)
inhibitors including enzyme-inducing anti-epileptic drugs (phenytoin, carbamazepine,
or phenobarbital), rifampin, grape fruit juice, or St. John's wort are not eligible