Safety Study of the Proteasome Inhibitor PR-171 (Carfilzomib for Injection) in Patients With Hematological Malignancies
Condition: Waldenstrom's Macroglobulinemia; Non-Hodgkin's Lymphoma; Hodgkin's Disease; Multiple Myeloma
MeSH terms: Multiple Myeloma; Hematologic Neoplasms; Waldenstrom Macroglobulinemia; Hodgkin Disease
Intervention: Carfilzomib; Dexamethasone
Intervention description: Administered as an IV bolus dose; Administered orally prior to carfilzomib
Intervention MeSH terms: Dexamethasone
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hematological; Proteasome; Myeloma; Lymphoma

Summary:

      The purpose of this study is to test the safety and tolerability of carfilzomib at different
      dose levels on hematological cancers such as multiple myeloma, non-Hodgkin's lymphoma,
      Hodgkin's disease, or Waldenstrom's macroglobulinemia. Carfilzomib is a proteasome inhibitor,
      an enzyme responsible for degrading a wide variety of cellular proteins.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Written informed consent in accordance with federal, local, and institutional
             guidelines

          2. Males and females ≥18 years of age

          3. 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)

          4. Subjects who are refractory or relapsed following at least two prior therapies

          5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

          6. Adequate cardiovascular function without symptomatic ischemia, conduction
             abnormalities uncontrolled by conventional intervention, or myocardial infarction in
             the previous six months

          7. 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

          8. 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

          9. An estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of
             Cockroft and Gault

         10. Serum creatinine ≤ 2.0 mg/dL

         11. Uric acid, if elevated, must be corrected to within laboratory normal range prior to
             dosing

         12. 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:

          1. Female subjects who are pregnant or lactating

          2. Subjects who are transfusion dependent

          3. Subjects with NHL or HL who have received steroid therapy in the previous seven days

          4. 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

          5. 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

          6. 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

          7. Subjects who have received allogeneic stem cell transplant therapy

          8. Subjects with NHL or HL who have received autologous stem cell transplant therapy and
             have relapsed within 100 days of therapy

          9. Rituxan therapy within three months before Day 1 unless there is evidence of disease
             progression

         10. Major surgery within three weeks before Day 1

         11. Congestive heart failure (CHF) (New York Heart Association class III to IV)

         12. Acute active infection requiring systemic antibiotics, antivirals, or antifungals
             within two weeks prior to first dose

         13. Subjects who are known or suspected of having human immunodeficiency virus (HIV)
             infection or who are HIV seropositive

         14. Active hepatitis A, B, or C infection; or positive for Hepatitis C ribonucleic acid
             (RNA) or hepatitis B antigen

         15. 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 with stable prostate specific antigen (PSA) levels for three years

         16. Subjects with treatment-related myelodysplastic disorder

         17. Subjects with known brain metastasis (active central nervous system [CNS] disease
             only)

         18. Serious psychiatric or medical conditions that could interfere with treatment

         19. Participation in an investigational therapeutic study within one month prior to Day 1

         20. Significant neurotoxicity (Grade 2 or higher with pain) at the time of study
             initiation

         21. Concurrent therapy with approved or investigative anticancer therapeutics

         22. Subjects with previous hypersensitivity to bortezomib injection

         23. Subjects with contraindications to receiving allopurinol

         24. 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

         25. Subjects with known or suspected amyloidosis

         26. Subjects with pleural effusions requiring thoracentesis or ascites requiring
             paracentesis