A Study of the Effectiveness of Armodafinil to Treat Cancer-Related Fatigue in Patients With Multiple Myeloma

This is a Phase III, multi-center, double-blind, randomized, placebo-controlled, crossover study to evaluate the efficacy of armodafinil at a dosage of 150 mg/day for the treatment of cancer-related fatigue (CRF) in adult patients with multiple myeloma. The study consists of a screening period, followed by a 56 day treatment phase, and a final assessment to occur 28 days after the end of the last treatment.

The screening period will occur within 14 days before baseline, where "baseline" refers to day 1 when assessments will be made before drug administration. During this period, a medical history will be obtained along with a complete physical examination including vital sign measurements and Eastern Cooperative Oncology Group (ECOG) performance status. Clinical laboratory tests including hematology, clinical chemistry (blood urea nitrogen [BUN], serum creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), electrolytes (potassium, sodium, chloride and calcium), random glucose, total protein, albumin, and urinalysis will also be performed during the screening period as well as serum pregnancy tests for women of childbearing potential.

During the screening period, patients will also be assessed for the presence of cancer-related fatigue using the International Classification for Disease Tenth Edition (ICD-10) diagnostic criteria and the Brief Fatigue Inventory (BFI). Only those patients showing evidence of cancer-related fatigue will be enrolled in the study. The criteria for inclusion for any given patient consist of meeting the International Classification for Disease Tenth Edition (ICD-10) criteria for cancer-related fatigue and a score ≥ 4 on the BFI. ICD-10 CRF classification will be established using a standard interview guide.

Patients eligible for the study will be randomized to either receive armodafinil at an initial fixed dosage of 150 mg/day (Group A) or a placebo (Group B) during the first 28 days of the treatment phase. On day 29, patients randomized to receive placebo will then cross over to receive armodafinil at a dosage of 150 mg/day until day 56. Group A patients randomized to receive armodafinil will continue their current treatment with the drug until day 56. The duration of the treatment phase is 56 days.

Assessments for CRF will be conducted on day 1 (baseline) prior to drug treatment, and after drug administration on days 15, 28, 43, and 56. These assessments will be conducted as verbal interviews, paper-and-pencil surveys, paper-and-pencil tests, and electronic tests as appropriate per assessment.

During the treatment phase, each patient will also have clinical laboratory tests performed on days 1, 15, 28, 43 and 56 to monitor for potential toxicity. Additional procedures performed at these visits will include monitoring for adverse events, review of concomitant medications and other support therapies (e.g., growth factors and transfusion), ECOG performance status, vital signs measurements, and physical examinations.

Twenty-eight days after the last dose of study drug, patients are to complete a final assessment (herein referred to as the end-of-treatment visit). Procedures to be conducted at this visit include measurement of vital signs, a complete physical examination, assessment of adverse events, a review of concomitant medications, assessment of ECOG performance status, hematology and clinical chemistry laboratory tests including electrolytes, total protein and albumin. Patients who withdraw from the study before the completion of the 56 day cycle will still have all end-of-treatment assessments performed 28 days after their last dose of study drug.

Inclusion criteria

• The patient has been diagnosed with multiple myeloma based on standard criteria
• The patient is diagnosed with cancer-related fatigue based on ICD-10 diagnostic criteria
• The patient shows signs of severe fatigue as evidenced by a Brief Fatigue Inventory score of at least 4
• The patient is a man or woman aged 18 years or older at the time of informed consent
• The patient has given voluntary written informed consent before any study-related procedure is performed which is not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care
• Women of child bearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study.
• Men must agree to use an acceptable method of contraception throughout the study and for 90 days after last dose study drug
• The patient must be willing and able to comply with study restrictions
• The patient must have an ECOG performance status not greater than 2
• The patient must have a life-expectancy of greater than 3 months
• The patient must meet the following laboratory criteria within 14 days of enrollment:

• Platelet count greater than 50 x 109/L
• Absolute neutrophil count greater than 0.5 x 109/L
• Hemoglobin greater than 8 g/dL
• AST and ALT not greater than 3.0 x the upper limit of normal (ULN)
• Serum bilirubin not greater than 2.0 x ULN
• Calculated or measured creatinine clearance of at least 10 mL/minute

Exclusion criteria

• The patient has been concurrently diagnosed with clinically significant depression
• The patient is concurrently enrolled in another investigational study that does not apply to the specific treatment of multiple myeloma
• The patient is receiving an investigational agent (non-FDA-approved) for any reason within 28 days of starting treatment on this study
• The patient has previously received armodafinil
• The patient has received modafinil or a psychostimulant within 14 days of enrollment
• The patient has received a blood transfusion within 14 days of enrollment
• The patient has impaired cardiac function or clinically significant cardiac diseases
• The patient has other concurrent severe and/or uncontrolled medical or psychiatric conditions including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
• The patient has known positivity for human immunodeficiency virus (HIV) or hepatitis B or C; baseline testing for HIV and hepatitis B or C is not required
• The patient has undergone major surgery within 28 days of enrollment or has not recovered from side effects of such therapy (Kyphoplasty is not considered to be a major surgery; however, the investigator is to discuss enrollment of a patient with a recent history of kyphoplasty with Oncotherapeutics' medical monitor)
• The patient has a significant history of noncompliance to medical regimens or unwilling or unable to comply with the instructions given to him or her by the study staff
• The patient has a history of skin reactions and/or known sensitivity attributable to compounds of similar chemical or biological composition to modafinil, armodafinil, or the inactive ingredients in armodafinil including lactose monohydrate, starch, microcrystalline cellulose, croscarmellose, sodium, magnesium stearate or povidone
• The patient is a pregnant or lactating woman. Any women becoming pregnant during the study will be withdrawn from the study
• The patient is male whose sexual partner is a woman of childbearing potential not using effective birth control