Safety Study of the Proteasome Inhibitor PR-171 (Carfilzomib for Injection) in Patients With Hematological Malignancies

Inclusion Criteria

• Written informed consent in accordance with federal, local, and institutional guidelines
• Males and females ≥18 years of age
• Histologically confirmed diagnosis of one of the hematologic malignancies below:
• Multiple myeloma (MM)
• Non-Hodgkin's lymphoma (NHL)
• Waldenström's Macroglobulinemia (WM)
• Hodgkin's disease (HD)
• Subjects who are refractory or relapsed following at least two prior therapies
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Adequate cardiovascular function without symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months
• 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
• Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count (ANC) ≥ 1000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50,000/mm³
• Screening 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 receiving supportive care including erythropoietin, darbepoetin and/or bisphosphonates can continue to do so, but must be transfusion independent; subjects receiving erythropoietic support must remain on the same dose for the first 28 days of study participation
• An estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockroft and Gault
• Serum creatinine ≤ 2.0 mg/dL
• Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing
• Female subjects of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test. Male subjects must use an effective barrier method of contraception throughout the study and for three months following the last dose if sexually active with a female of child-bearing potential.

Exclusion Criteria

• Female subjects who are pregnant or lactating
• Subjects who are transfusion dependent
• Subjects with NHL or HL who have received steroid therapy in the previous seven days
• Subjects with MM or Waldenström's Macroglobulinemia who have received steroid therapy in the previous three weeks, except for MM subjects in the Carfilzomib + DEX Expansion Cohort, where previous treatment with dexamethasone will be allowed. The dose and schedule of administration of dexamethasone will be adjusted to that used in the protocol
• Radiation, chemotherapy, or immunotherapy in the previous four weeks, or subjects who, in the judgment of the Investigator, have not recovered from the effects of previous therapy
• For the Dose Escalation period, subjects who have received prior radioimmunotherapy with anti-cluster of differentiation (CD)20 monoclonal antibodies such as Bexxar® or Zevalin®; subjects treated with these products will be allowed in the Dose Expansion period
• Subjects who have received allogeneic stem cell transplant therapy
• Subjects with NHL or HL who have received autologous stem cell transplant therapy and have relapsed within 100 days of therapy
• Rituxan therapy within three months before Day 1 unless there is evidence of disease progression
• Major surgery within three weeks before Day 1
• Congestive heart failure (CHF) (New York Heart Association class III to IV)
• Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
• Subjects who are known or suspected of having human immunodeficiency virus (HIV) infection or who are HIV seropositive
• Active hepatitis A, B, or C infection; or positive for Hepatitis C ribonucleic acid (RNA) or hepatitis B antigen
• Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin ca