Filgrastim, Cladribine, Cytarabine, and Mitoxantrone With Sorafenib Tosylate in Treating Patients With Newly-Diagnosed, Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. To assess the maximum tolerated dose (MTD) of sorafenib (sorafenib tosylate) used in
combination with dose-intensified mitoxantrone (mitoxantrone hydrochloride) as part of the
G-CSF, cladribine, cytarabine and mitoxantrone hydrochloride (G-CLAM) regimen in adults with
newly-diagnosed acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes (MDS).
(Phase 1) II. To determine if the addition of sorafenib to G-CLAM improves the rate of
minimal residual disease negative (MRDneg) complete response (CR) compared with our center's
historical control of G-CLAM alone in adults with newly-diagnosed AML/high-risk MDS. (Phase
2)

SECONDARY OBJECTIVES:

I. To estimate rates of CR, overall response rate (ORR), overall survival (OS), event-free
survival (EFS), and relapse-free survival (RFS) after the addition of sorafenib to G-CLAM in
patients with newly-diagnosed AML/high-risk MDS.

II. To describe the toxicity profile and safety (rate of adverse events) of sorafenib in
combination with G-CLAM.

III. To assess the feasibility of incorporating quality of life (QOL), cost and healthcare
resource utilization endpoints in to a phase 1/2 clinical trial for newly diagnosed AML.

IV. To investigate, within the limits of a phase 1/2 trial, the impact of study treatment and
response on quality of life, cost, and healthcare resource utilization for patients with AML
undergoing intensive chemotherapy.

OUTLINE: This is a phase I, dose-escalation study of mitoxantrone and sorafenib tosylate
followed by a phase II study.

INDUCTION: Patients receive mitoxantrone hydrochloride intravenously (IV) over 60 minutes on
days 1-3 and sorafenib tosylate orally (PO) twice daily (BID) on days 10-19 in the absence of
disease progression or unacceptable toxicity. Patients also receive filgrastim subcutaneously
(SC) once daily (QD) on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine
IV QD over 2 hours on days 1-5 in the absence of disease progression or unacceptable
toxicity. Patients achieving partial remission (including MRD positive [pos] CR, CR with
incomplete platelet recovery [CRp], and CR with incomplete count recovery [CRi]) or
persistent AML may receive up to 2 courses of induction therapy per the discretion of the
treating physician.

POST-REMISSION: Patients receive sorafenib tosylate PO BID on days 8-27 or 3 days prior to
next course of treatment, whichever occurs first. Patients also receive filgrastim
subcutaneously SC QD on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine
IV QD over 2 hours on days 1-5 in the absence of disease progression or unacceptable
toxicity. Patients achieving MRDneg CR may receive up to 4 courses of post-remission therapy.
Patients achieving disease response (MRDpos CR, CRi/CRp, or persistent disease) may receive
up to two induction courses and 1 course of post-remission therapy with mitoxantrone
hydrochloride omitted in course 3. If they then enter MRDneg CR, they can proceed with up to
a total of 4 courses of post-remission therapy.

MAINTENANCE THERAPY: Patients achieving MRDneg CR may receive maintenance therapy of
sorafenib tosylate PO BID for up to 1 year.

After completion of study treatment, patients are followed up every 3 months for up to 5
years.

Inclusion Criteria:

- Newly diagnosed disease with either a diagnosis of "high-risk" MDS (>= 10% blasts in
marrow or blood), high-risk myeloproliferative neoplasm (MPN; >= 10% blasts in blood
or bone marrow), or AML other than acute promyelocytic leukemia (APL) with
t(15;17)(q22;q12) or variants according to the 2008 World Health Organization (WHO)
classification; patients with biphenotypic AML are eligible; such "high-risk" MDS or
MPN have natural history much closer to AML than to lower risk MDS or MPN and have
responded similarly to "AML-type" therapy

- Outside diagnostic material is acceptable as long as peripheral blood and/or bone
marrow slides are reviewed at the study institution by appropriate clinical staff;
flow cytometric analysis of peripheral blood and/or bone marrow should be performed
according to institutional practice guidelines

- Treatment-related mortality (TRM) score =< 13.1 as calculated with simplified model

- The use of hydroxyurea prior to study registration is allowed; patients with
symptoms/signs of hyperleukocytosis or white blood cell (WBC) > 100,000/uL can be
treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500
mg/m^2/dose) prior to study day 0 enrollment

- Bilirubin =< 2 times institutional upper limit of normal unless elevation is thought
to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (assessed
within 10 days prior to study day 0)

- Serum creatinine =< 2.0 mg/dL (assessed within 10 days prior to study day 0)

- Left ventricular ejection fraction >= 45%, assessed within 3 months prior to study day
0, e.g. by multi gated acquisition scan (MUGA) scan or echocardiography, or other
appropriate diagnostic modality and no clinical evidence of congestive heart failure

- Women of childbearing potential and men must agree to use adequate contraception
beginning at the signing of the consent until at least 3 months after the last dose of
study drug

- Provide written informed consent (or legal representative)

Exclusion Criteria:

- Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not
considered candidate for CML-directed tyrosine kinase inhibitor treatment (excluding
sorafenib)

- Concomitant illness associated with a likely survival of < 1 year

- Active systemic fungal, bacterial, viral, or other infection, unless disease is under
treatment with anti-microbials and/or controlled or stable (e.g. if specific,
effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis,
human immunodeficiency virus (HIV)]); patient needs to be clinically stable as defined
as being afebrile and hemodynamically stable for 24-48 hours prior to study day 0,
unless fever is thought to be secondary to the underlying hematologic disease

- Active or clinically significant (or symptomatic) cardiac disease, including active
coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other
than beta blockers or digoxin within the last 3 months, unstable angina (anginal
symptoms at rest), new-onset angina within 3 months before randomization, or
myocardial infarction within 6 months before study day 0

- Previous receipt of azacitidine, decitabine, anthracyclines, cytarabine, or other
nucleoside analogues for treatment of AML or MPN/MDS other than as noted for
cytarabine

- Pregnancy or lactation

- Concurrent treatment with any other investigational agent that has anti-leukemia
activity or another drug with anti-AML-activity