AZD6244 (Selumetinib) in Treating Patients With Multiple Myeloma

PRIMARY OBJECTIVES:

I. To assess the response rate of AZD6244 (selumetinib) hydrogen sulfate capsules in
patients with relapsed or refractory multiple myeloma (MM).

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of AZD6244 in patients with MM. II. To estimate progression-free
survival and duration of response to AZD6244. III. To test whether AZD6244 hydrogen sulfate
capsules downregulate tumor cell phosphorylated mitogen-activated protein kinase (pERK)1/2.

OUTLINE:

Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 weeks.

Inclusion Criteria:

- Confirmed diagnosis of multiple myeloma with relapsed or refractory disease following
at least two prior therapies

- Measurable disease defined as:

- Serum monoclonal protein >= 1 gm/dL or

- Urine monoclonal protein of >= 200 mg/24 hours, or

- Measurable free light chains by free light chain assay of >= 10 mg/dL with
abnormal kappa to lambda free light chain ratio, or

- Measurable bone disease, defined as >= 1 unidimensionally measurable lesion
(longest diameter to be recorded) >= 20 mm with conventional techniques or >= 10
mm with spiral computed tomography (CT) scan (for patients with lytic bone
disease)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Absolute neutrophil count: >= 1,000/μL (independent of blood cell growth factors)

- Platelets: >= 75,000/μL (independent of blood cell growth factors or transfusion)

- Total bilirubin: =< 1.5 x upper normal limit; however, patients with documented
Gilbert's syndrome are eligible

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
[SGPT]): < 2.5 x upper limit of normal (ULN)

- Creatinine: < 3.0 x ULN

- Known human immunodeficiency virus (HIV) infected patients meeting the following
characteristics are eligible:

- Cluster of differentiation (CD)4 cell count >= 500/mm^3

- Meeting either of the following:

- Willing to suspend antiretroviral therapy for duration of protocol therapy
or

- On stable regimen of combination antiretroviral therapy that does not
include either zidovudine or stavudine for at least 12 weeks and without
evidence of toxicity

- No HIV-associated condition that defines acquired immunodeficiency syndrome
(AIDS)

- Prior allogeneic stem cell transplant is allowed provided that all of the following
conditions are met:

- >= 6 months have elapsed since allogeneic transplant

- No graft vs. host disease (GVHD) is present

- Not currently on immunosuppressive therapy

- Women of child-bearing potential must agree to use a medically accepted form of
contraception prior to, during, and for four weeks following study treatment; men
must agree to use a medically accepted form of contraception prior to, during, and
for sixteen weeks following study treatment

- Able and willing to provide a written informed consent

- Prior palliative and/or localized radiation therapy is permitted, provided at least
14 days have passed from date of last radiation therapy

- Pulse oximetry of >= 95% on room air

Exclusion Criteria:

- Any concurrent condition or planned treatment that would compromise study objectives
or represent an unacceptable patient risk, including but not limited to:

- Planned concurrent treatment for multiple myeloma other than bisphosphonates;
ongoing corticosteroids for indications other than multiple myeloma allowed as
long as the dose does not exceed 60 mg of prednisone per day or equivalent

- Persisting effects of any previous or ongoing treatment that might compromise
delivery of study treatment or assessment of adverse events

- Planned concurrent treatment with any other investigational agents

- Cytotoxic chemotherapy less than 2 weeks, or biologic therapy less than 2 weeks, or
corticosteroids less than 2 weeks prior to registration

- No other malignancy unless the patient has been disease-free for >= 1 year

- Known multiple myeloma of central nervous system or leptomeninges

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD6244

- Previous mitogen activated protein kinase (MEK) inhibitor use

- Uncontrolled hypertension, i.e., persistent blood pressure (BP) of >= 160/95

- Significant cardiovascular disease (New York Heart Association class II, III or IV
cardiac disease), hypertrophic cardiomegaly or restrictive cardiomyopathy, myocardial
infarction within the past 6 months, unstable angina, unstable arrhythmia unstable or
a need for anti-arrhythmic therapy (use of medication for atrial fibrillation is
allowed, if stable for at least 3 months)

- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant or nursing

- Left ventricular ejection fraction (LVEF) =< 45% by echocardiogram (ECHO) or
multigated acquisition scan (MUGA) scan

- Any requirement for supplemental oxygen