Phase 2 Study of Carfilzomib in Relapsed Multiple Myeloma

Two groups of patients with multiple myeloma were initially studied: bortezomib-naïve and bortezomib-treated. Following Amendment 2, only bortezomib-naïve patients were enrolled. Study results were reported in 2 parts, depending on whether a patient received prior bortezomib.

Inclusion criteria

Disease Related

• Multiple myeloma
• Subjects must have measurable disease, defined as one or more of the following:

• Serum M-protein ≥ 1 g/dL
• Urine M-protein ≥ 200 mg/24 hours
• Subjects must have been responsive (i.e., achieve a minimal response [MR] or better) to standard, first line therapy
• Relapsed and/or refractory or progressive disease after at least one, but no more than three, prior therapeutic treatments or regimens for multiple myeloma. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Induction therapy and stem cell transplant will be considered as one regimen

Demographic

• Males and females ≥18 years of age
• Life expectancy of more than three months
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

Laboratory

• Adequate hepatic function, with bilirubin < 2.0 times the upper limit of normal, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of < 3.0 times the upper limit of normal
• Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing
• Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count > 1,000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count > 50,000/mm³
• Subjects should be platelet transfusion independent
• Screening absolute neutrophil count (ANC) should be independent of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks
• Subjects may receive red blood cell (RBC) transfusion or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines
• Calculated or measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)]. Multiply result by 0.85 if female.
• Serum creatinine ≤ 2 mg/dL

Ethical / Other

• Written informed consent in accordance with federal, local, and institutional guidelines
• Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.
• Subjects must be able to receive outpatient treatment and laboratory monitoring at the institute that administers agent.

Exclusion criteria

Disease Related

• Multiple Myeloma Immunoglobulin M (IgM)
• Subjects previously treated with any proteasome inhibitor (for Part 2 Proteasome Inhibitor - Naïve only, criteria added at Amendment 2)
• Subjects must not be primary refractory to standard first-line therapy
• Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum, < 200 mg/24 hour M-protein in urine
• Subjects with disease measurable only by serum free light chain (SFLC) analysis
• Glucocorticoid therapy (prednisone >10 mg/day orally or equivalent) within the last three weeks
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia
• Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy, within the three weeks prior to first dose
• Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose
• Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to first dose, whichever time is greater
• Prior treatment with carfilzomib

Concurrent Conditions

• Major surgery within three weeks before Day 1
• Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months
• Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose
• Known or suspected human immunodeficiency (HIV) infection or subjects who are HIV seropositive
• Active hepatitis A, B, or C infection
• Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer < Gleason Grade 6 with stable prostate-specific antigen (PSA)
• Subjects with treatment related myelodysplastic syndrome
• Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation
• Subjects with known contraindication to receiving allopurinol
• Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment
• Subjects with known or suspected amyloidosis Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis
• Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Ethical / Other

• Female subjects who are pregnant or lactating
• Serious psychiatric or medical conditions that could interfere with treatment