Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma
Conditions
Brief 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.
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGSelumetinib
AZD6244 (Selumetinib), 75 mg was administered orally, twice a day, continuously for 28-day cycles
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to 2 years | Overall Response: Stringent Complete Response (sCR) + Complete Response (CR) + Very Good Partial Response (VGPR) + Partial Response (PR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | From response to disease progression or death, assessed up to 2 years | Mean duration of response in months. Estimated using the method of Kaplan-Meier. |
| Incidence of Toxicity That May Be Treatment Emergent | 1 year, 11 months | 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). |
| Progression Free Survival (PFS) | From registration to progression or death, assessed up to 2 years | Median PFS in months. Progressive Disease (PD): Increase of \>= 25% from baseline. Estimated using the method of Kaplan-Meier. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Bone Marrow Microenvironment | Baseline to up to 20-30 hours after receiving the first dose of AZD6244 | Effect of AZD6244 on the bone marrow microenvironment in MM. |
| Level of Key Regulators | Up to 20-30 hours after receiving the first dose of selumetinib | 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). |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 6 sites in the United States, from April 1, 2010 through July 28, 2011.
Participants by arm
| Arm | Count |
|---|---|
| AZD6244 (Selumetinib) Treatment Participants received AZD6244 (Selumetinib) orally (PO) twice a day (BID) on days 1-28. Courses repeated every 28 days in the absence of disease progression or unacceptable toxicity. | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Alternate treatment required | 1 |
Baseline characteristics
| Characteristic | AZD6244 (Selumetinib) Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 19 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 65 years |
| Region of Enrollment United States | 37 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 35 / 36 |
| serious Total, serious adverse events | 23 / 36 |
Outcome results
Primary
Overall Response Rate
Overall Response: Stringent Complete Response (sCR) + Complete Response (CR) + Very Good Partial Response (VGPR) + Partial Response (PR).
Time frame: Up to 2 years
Population: All participants who received study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD6244 (Selumetinib) Treatment | Overall Response Rate | Response: Total | 2 participants |
| AZD6244 (Selumetinib) Treatment | Overall Response Rate | Response: sCR | 0 participants |
| AZD6244 (Selumetinib) Treatment | Overall Response Rate | Response: CR | 0 participants |
| AZD6244 (Selumetinib) Treatment | Overall Response Rate | Response: VGPR | 1 participants |
| AZD6244 (Selumetinib) Treatment | Overall Response Rate | Response: PR | 1 participants |
| AZD6244 (Selumetinib) Treatment | Overall Response Rate | Other Status: Stable Disease | 17 participants |
| AZD6244 (Selumetinib) Treatment | Overall Response Rate | Other Status: Progressive Disease | 13 participants |
| AZD6244 (Selumetinib) Treatment | Overall Response Rate | Could not be assessed | 4 participants |
Secondary
Duration of Response
Mean duration of response in months. Estimated using the method of Kaplan-Meier.
Time frame: From response to disease progression or death, assessed up to 2 years
Population: All participants with response
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AZD6244 (Selumetinib) Treatment | Duration of Response | 4.95 months |
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).
Time frame: 1 year, 11 months
Population: All participants who received study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD6244 (Selumetinib) Treatment | Incidence of Toxicity That May Be Treatment Emergent | Hematologic - Any Grade 5 | 0 participants |
| AZD6244 (Selumetinib) Treatment | Incidence of Toxicity That May Be Treatment Emergent | Non-Hematologic - Any Grade 3 | 14 participants |
| AZD6244 (Selumetinib) Treatment | Incidence of Toxicity That May Be Treatment Emergent | Hematologic - Any Grade 3 | 6 participants |
| AZD6244 (Selumetinib) Treatment | Incidence of Toxicity That May Be Treatment Emergent | Hematologic - Any Grade 4 | 2 participants |
| AZD6244 (Selumetinib) Treatment | Incidence of Toxicity That May Be Treatment Emergent | Non-Hematologic - Any Grade 4 | 1 participants |
| AZD6244 (Selumetinib) Treatment | Incidence of Toxicity That May Be Treatment Emergent | Non-Hematologic - Any Grade 5 | 3 participants |
Secondary
Progression Free Survival (PFS)
Median PFS in months. Progressive Disease (PD): Increase of \>= 25% from baseline. Estimated using the method of Kaplan-Meier.
Time frame: From registration to progression or death, assessed up to 2 years
Population: All participants who received study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD6244 (Selumetinib) Treatment | Progression Free Survival (PFS) | 3.52 months |
Other Pre-specified
Changes in Bone Marrow Microenvironment
Effect of AZD6244 on the bone marrow microenvironment in MM.
Time frame: Baseline to up to 20-30 hours after receiving the first dose of AZD6244
Other Pre-specified
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).
Time frame: Up to 20-30 hours after receiving the first dose of selumetinib