Phase 2 Study of Carfilzomib in Relapsed Multiple Myeloma

An Open-label, Single-arm, Phase 2 Study of Carfilzomib in Patients With Relapsed or Refractory Multiple Myeloma

To evaluate the best overall response rate, safety and tolerability of carfilzomib in patients with relapsed or refractory 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