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