AZD6244 (Selumetinib) in Treating Patients With Multiple Myeloma

Recurrent Plasma Cell Myeloma Clinical Trial

Official title:

A Phase 2 Study of AZD6244 in Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01085214
• Other study ID #: NCI-2012-02929
• Secondary ID: NCI-2012-02929CD
• Status: Completed
• Phase: Phase 2
• First received: March 10, 2010
• Last updated: July 24, 2015
• Start date: March 2010
• Est. completion date: March 2012

Study information

• Verified date: May 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: March 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Recurrent Plasma Cell Myeloma
• Refractory Plasma Cell Myeloma

Intervention

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Selumetinib
AZD6244 (Selumetinib), 75 mg was administered orally, twice a day, continuously for 28-day cycles

Locations

Country	Name	City	State
United States	Emory University/Winship Cancer Institute	Atlanta	Georgia
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Mark O Hatfield-Warren Grant Magnuson Clinical Center	Bethesda	Maryland
United States	National Institutes of Health	Bethesda	Maryland
United States	Billings Clinic Cancer Center	Billings	Montana
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	No
Other	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	No
Primary	Overall Response Rate	Overall Response: Stringent Complete Response (sCR) + Complete Response (CR) + Very Good Partial Response (VGPR) + Partial Response (PR).	Up to 2 years	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No