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.

Study Overview

• Status: Completed
• Conditions: Refractory Plasma Cell Myeloma; Recurrent Plasma Cell Myeloma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Selumetinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University/Winship Cancer Institute
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health
    • Bethesda, Maryland, United States, 20892
      • Mark O Hatfield-Warren Grant Magnuson Clinical Center
  • Montana
    • Billings, Montana, United States, 59107
      • Billings Clinic Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD6244 (Selumetinib) Treatment; 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; Correlative studies; Drug: Selumetinib; AZD6244 (Selumetinib), 75 mg was administered orally, twice a day, continuously for 28-day cycles; Other Names: AZD6244; ARRY-142886; MEK Inhibitor AZD6244

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Bone Marrow Microenvironment	Effect of AZD6244 on the bone marrow microenvironment in MM.	Baseline to up to 20-30 hours after receiving the first dose of AZD6244
Level of Key Regulators	The level of key regulators of the MEK/MAPK and PI3K pathways and HSP90 and cell cycle regulators may determine the anti-tumor response to AZD6244 in vivo in multiple myeloma (MM).	Up to 20-30 hours after receiving the first dose of selumetinib

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Steven Grant, M.D., Massey Cancer Center

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: March 10, 2010
• First Submitted That Met QC Criteria: March 10, 2010
• First Posted (Estimate): March 11, 2010

Study Record Updates

• Last Update Posted (Estimate): August 19, 2015
• Last Update Submitted That Met QC Criteria: July 24, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell
• Other Study ID Numbers: NCI-2012-02929 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); N01CM00071 (U.S. NIH Grant/Contract); P30CA076292 (U.S. NIH Grant/Contract); N01CM00100 (U.S. NIH Grant/Contract); N01CM62208 (U.S. NIH Grant/Contract); CDR669144; NCI-8631; 10-C-0079 (Other Identifier: Moffitt Cancer Center); 8631 (Other Identifier: CTEP)