AZD6244 (Selumetinib) in Treating Patients With Multiple Myeloma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2 Study of AZD6244 in Multiple Myeloma

Conditions
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Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Selumetinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD6244 (Selumetinib) Treatment<br>Participants receive AZD6244 (Selumetinib) orally (PO) twice a day (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Selumetinib<br>* AZD6244 (Selumetinib), 75 mg was administered orally, twice a day, continuously for 28-day cycles<br>* Other names: MEK Inhibitor AZD6244;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall Response: Stringent Complete Response (sCR) + Complete Response (CR) + Very Good Partial Response (VGPR) + Partial Response (PR). | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Mean duration of response in months. Estimated using the method of Kaplan-Meier. | From response to disease progression or death, assessed up to 2 years | 
| Incidence of Toxicity That May Be Treatment Emergent | Participants with Grade 3, 4, and 5 toxicities possibly, probably, or definitely related to study treatment. Toxicity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). | 1 year, 11 months | 
| Progression Free Survival (PFS) | Median PFS in months. Progressive Disease (PD): Increase of >= 25% from baseline. Estimated using the method of Kaplan-Meier. | From registration to progression or death, assessed up to 2 years |