AZD6244 (Selumetinib) in Treating Patients With Multiple Myeloma

A Phase 2 Study of AZD6244 in Multiple Myeloma

This phase II trial studies how well selumetinib works in treating patients with multiple myeloma, a type of cancer in which a specific protein is over active. Selumetinib may stop the growth of cancer cells by blocking this protein.

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