Phase 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma

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

To evaluate the overall response rate and safety and tolerability of carfilzomib in subjects with relapsed and refractory multiple myeloma.

Patients must have received prior treatment with bortezomib and either thalidomide or lenalidomide and be refractory to their last treatment.

Inclusion Criteria:

• Disease Related

  • Multiple myeloma

  • Subjects must have measurable disease defined as one of the following:

    • Serum M-protein ≥ 1 g/dL
    • Urine M-protein ≥ 200 mg/24 hours
    • Serum FLC ≥ 10 mg/dL with abnormal ratio (A0 Only)
    • Quantitative immunoglobulin levels using nephelometry or turbidometry (only if protein electrophoresis was felt to be unreliable for M-protein measurement) (A0 Only)

  • Subjects must have been responsive (i.e., achieved an MR or better) to first-line, standard of care therapy

  • Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy.

  • Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen (A1 Only)

  • Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide

  • Subjects must have received an alkylating agent either alone or in combination with other myeloma treatments (history of stem cell transplant is acceptable) (A1 Only)

  • Subjects must have received an anthracycline either alone or in combination with other myeloma treatments, unless not clinically indicated (A1 Only)

• 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 less than 2.0 times the upper limit of normal, and AST and ALT of less than 3.0 times the upper limit of normal

  • Uric acid within normal range (A0 Only)

  • Total white blood cell (WBC) count ≥ 2.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50.0 × 109/L (A0 Only)

  • Absolute neutrophil count > 1,000/mm3, hemoglobin > 8.0 g/dL, and platelet count > 50,000/mm3 (A1 Only)

    • Subjects should be platelet transfusion independent
    • Screening ANC should be independent of G-CSF or GM-CSF support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks
    • Subjects may receive red blood cell (RBC) or platelet transfusions or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines

  • Calculated and 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.

• 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.

Exclusion Criteria:

• Disease Related

  • Multiple Myeloma IgM (A1 Only)
  • Subjects who failed to achieve at least a confirmed MR(≥ 25% reduction in M-protein for ≥ 6 weeks) (A1 Only)
  • Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum and < 200 mg/24 hr M-protein in urine
  • Subjects with disease measurable only by serum free light chain (SFLC) analysis (A1 Only)
  • 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 Day 1, 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 cardiac ischemia, cardiomyopathy, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months, LVEF < 40
  • Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose
  • Known or suspected 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 PSA
  • Subjects with treatment related myelodysplastic syndrome
  • Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation
  • 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 (A1 Only)
  • Subjects with known or suspected amyloidosis (A1 Only)
  • Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis (A1 Only)
  • 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 (A1 Only)

• Ethical / Other

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