AZD6244 (Selumetinib) in Treating Patients With Multiple Myeloma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01085214
• Collaborator: (none)
• Enrollment: 37
• Locations: 9
• Arm: 1
• Duration (Months): 24
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma	Other: Laboratory Biomarker Analysis; Drug: Selumetinib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the response rate of AZD6244 (selumetinib) hydrogen sulfate capsules in patients with relapsed or refractory multiple myeloma (MM).

SECONDARY OBJECTIVES:

1. 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 Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of AZD6244 in Multiple Myeloma
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

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: ARRY-142886 AZD6244 MEK Inhibitor AZD6244

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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).

3. 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 Outcome Measures

1. 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.

2. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Moffitt Cancer Center	Tampa	Florida	United States	33612
2	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322
3	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
4	Mark O Hatfield-Warren Grant Magnuson Clinical Center	Bethesda	Maryland	United States	20892
5	National Institutes of Health	Bethesda	Maryland	United States	20892
6	Billings Clinic Cancer Center	Billings	Montana	United States	59107
7	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
8	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
9	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Steven Grant, M.D., Massey Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01085214
• Other Study ID Numbers: NCI-2012-02929; NCI-2012-02929; CDR669144; NCI-8631; 10-C-0079; 8631; N01CM00071; N01CM00100; N01CM62208; P30CA076292
• First Posted: Mar 11, 2010
• Last Update Posted: Aug 19, 2015
• Last Verified: May 1, 2015

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 6 sites in the United States, from April 1, 2010 through July 28, 2011.

Arm/Group Title	AZD6244 (Selumetinib) Treatment
Arm/Group Description	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.
Period Title: Overall Study
STARTED	37
COMPLETED	36
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	AZD6244 (Selumetinib) Treatment
Arm/Group Description	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.
Overall Participants	37
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	18 48.6%
>=65 years	19 51.4%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	19 51.4%
Male	18 48.6%
Region of Enrollment (participants) [Number]
United States	37 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received study treatment

Arm/Group Title	AZD6244 (Selumetinib) Treatment
Arm/Group Description	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.
Measure Participants	36
Response: Total	2 5.4%
Response: sCR	0 0%
Response: CR	0 0%
Response: VGPR	1 2.7%
Response: PR	1 2.7%
Other Status: Stable Disease	17 45.9%
Other Status: Progressive Disease	13 35.1%
Could not be assessed	4 10.8%

2. Secondary Outcome

Title	Duration of Response
Description	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

Outcome Measure Data

Analysis Population Description

All participants with response

Arm/Group Title	AZD6244 (Selumetinib) Treatment
Arm/Group Description	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.
Measure Participants	2
Mean (Full Range) [months]	4.95

3. Secondary Outcome

Title	Incidence of Toxicity That May Be Treatment Emergent
Description	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

Outcome Measure Data

Analysis Population Description

All participants who received study treatment

Arm/Group Title	AZD6244 (Selumetinib) Treatment
Arm/Group Description	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.
Measure Participants	36
Hematologic - Any Grade 3	6 16.2%
Hematologic - Any Grade 4	2 5.4%
Hematologic - Any Grade 5	0 0%
Non-Hematologic - Any Grade 3	14 37.8%
Non-Hematologic - Any Grade 4	1 2.7%
Non-Hematologic - Any Grade 5	3 8.1%

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

All participants who received study treatment

Arm/Group Title	AZD6244 (Selumetinib) Treatment
Arm/Group Description	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.
Measure Participants	36
Median (Full Range) [months]	3.52

5. Other Pre-specified Outcome

Title	Changes in Bone Marrow Microenvironment
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Level of Key Regulators
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 year, 11 months
Arm/Group Title	AZD6244 (Selumetinib) Treatment
Arm/Group Description	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.
All Cause Mortality
	AZD6244 (Selumetinib) Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	AZD6244 (Selumetinib) Treatment
	Affected / at Risk (%)	# Events
Total	23/36 (63.9%)
Blood and lymphatic system disorders
Anemia	3/36 (8.3%)	3
Febrile neutropenia	1/36 (2.8%)	1
Gastrointestinal disorders
Diarrhea	2/36 (5.6%)	2
Nausea	1/36 (2.8%)	1
General disorders
Death, NOS	3/36 (8.3%)	3
Flu like symptoms	1/36 (2.8%)	1
Pain	1/36 (2.8%)	1
Hepatobiliary disorders
Hepatic failure	1/36 (2.8%)	1
Infections and infestations
Sepsis	3/36 (8.3%)	3
Skin infection	1/36 (2.8%)	1
Injury, poisoning and procedural complications
Fall	1/36 (2.8%)	1
Fracture	1/36 (2.8%)	1
Investigations
Alanine aminotransferase increased	1/36 (2.8%)	1
Aspartate aminotransferase increased	3/36 (8.3%)	3
CPK increased	3/36 (8.3%)	3
INR increased	1/36 (2.8%)	1
Neutrophil count decreased	5/36 (13.9%)	7
Platelet count decreased	5/36 (13.9%)	5
White blood cell decreased	1/36 (2.8%)	1
Metabolism and nutrition disorders
Hypercalcemia	1/36 (2.8%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/36 (2.8%)	1
Generalized muscle weakness	1/36 (2.8%)	1
Musculoskeletal and connective tissue disorder - Other, Rhabdomyolysis	2/36 (5.6%)	2
Myalgia	2/36 (5.6%)	2
Nervous system disorders
Peripheral sensory neuropathy	2/36 (5.6%)	2
Psychiatric disorders
Confusion	1/36 (2.8%)	1
Renal and urinary disorders
Acute kidney injury	3/36 (8.3%)	3
Renal and urinary disorders - Other, Acute renal failure	1/36 (2.8%)	1
Reproductive system and breast disorders
Vaginal inflammation	1/36 (2.8%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/36 (2.8%)	1
Skin and subcutaneous tissue disorders
Pruritus	1/36 (2.8%)	1
Rash acneiform	1/36 (2.8%)	1
Skin and subcutaneous tissue disorders - Other, Angular cheilitis, unilateral	1/36 (2.8%)	1
Vascular disorders
Hypotension	2/36 (5.6%)	2
Other (Not Including Serious) Adverse Events
	AZD6244 (Selumetinib) Treatment
	Affected / at Risk (%)	# Events
Total	35/36 (97.2%)
Blood and lymphatic system disorders
Anemia	17/36 (47.2%)	27
Blood and lymphatic system disorders - Other	2/36 (5.6%)	2
Gastrointestinal disorders
Diarrhea	27/36 (75%)	46
Nausea	11/36 (30.6%)	15
Vomiting	11/36 (30.6%)	16
Abdominal pain	4/36 (11.1%)	5
Dry mouth	3/36 (8.3%)	3
Gastroesophageal reflux disease	2/36 (5.6%)	2
Gastrointestinal disorders - Other	2/36 (5.6%)	2
General disorders
Fatigue	18/36 (50%)	29
Edema, limbs	16/36 (44.4%)	20
Edema, face	7/36 (19.4%)	7
Pain	4/36 (11.1%)	4
Fever	4/36 (11.1%)	4
Localized edema	4/36 (11.1%)	6
Chills	2/36 (5.6%)	2
Infections and infestations
Sinusitis	2/36 (5.6%)	3
Upper respiratory infection	2/36 (5.6%)	2
Investigations
Aspartate aminotransferase increased	14/36 (38.9%)	18
Neutrophil count decreased	12/36 (33.3%)	33
White blood cell decreased	12/36 (33.3%)	29
Platelet count decreased	10/36 (27.8%)	16
CPK increased	9/36 (25%)	12
Alanine aminotransferase increased	6/36 (16.7%)	7
Creatinine increased	5/36 (13.9%)	5
Lymphocyte count decreased	5/36 (13.9%)	11
Alkaline phosphatase increased	3/36 (8.3%)	4
Metabolism and nutrition disorders
Hypoalbuminemia	16/36 (44.4%)	27
Hypomagnesemia	9/36 (25%)	15
Hypocalcemia	7/36 (19.4%)	12
Hyponatremia	7/36 (19.4%)	8
Hypophosphatemia	7/36 (19.4%)	9
Hypokalemia	5/36 (13.9%)	5
Hyperkalemia	4/36 (11.1%)	5
Anorexia	3/36 (8.3%)	3
Hypoglycemia	3/36 (8.3%)	4
Dehydration	2/36 (5.6%)	2
Hypercalcemia	2/36 (5.6%)	3
Hypernatremia	2/36 (5.6%)	2
Metabolism and nutrition disorders - Other	2/36 (5.6%)	2
Musculoskeletal and connective tissue disorders
Back pain	5/36 (13.9%)	6
Myalgia	2/36 (5.6%)	3
Generalized muscle weakness	2/36 (5.6%)	3
Pain in extremity	3/36 (8.3%)	3
Arthralgia	2/36 (5.6%)	2
Nervous system disorders
Dizziness	4/36 (11.1%)	5
Peripheral sensory neuropathy	4/36 (11.1%)	8
Headache	2/36 (5.6%)	3
Psychiatric disorders
Insomnia	3/36 (8.3%)	3
Renal and urinary disorders
Renal and urinary disorders - Other	2/36 (5.6%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	5/36 (13.9%)	6
Cough	3/36 (8.3%)	3
Skin and subcutaneous tissue disorders
Rash acneiform	17/36 (47.2%)	26
Dry skin	6/36 (16.7%)	6
Skin and subcutaneous tissue disorders - Other	5/36 (13.9%)	8
Periorbital edema	3/36 (8.3%)	3
Skin hypopigmentation	3/36 (8.3%)	3
Vascular disorders
Hypertension	8/36 (22.2%)	9
Hypotension	2/36 (5.6%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.