A Phase II Study of Carfilzomib in Relapsed Waldenström's Macroglobulinemia (WM) IST-CAR-531
Condition: Waldenstrom Macroglobulinemia
MeSH terms: Waldenstrom Macroglobulinemia
Intervention: Carfilzomib; Rituximab; Dexamethasone
Intervention description: If you decide to participate in the study, you will receive carfilzomib on Days 1, 2, 8, 9, 15, and 16 every 28 days for a minimum of 2 cycles (approximately 2 months). You may receive additional cycles for as long as your disease remains stable or improved or until your study doctor determines that you should stop receiving the study drug or you decide to stop participating in the study.; If you decide to participate in the study, in addition to the carfilzomib and possible dexamethasone administration, If less than a partial remission (PR) after 4 cycles is achieved, rituximab 375 mg/m2 on day 16 of each subsequent cycle will be added to the treatment. Subjects who meet the criteria for progression prior to 4 cycles of therapy will have rituximab 375 mg/m2 weekly for 4 consecutive weeks every 3 cycles added to the treatment. Subjects will be treated to maximal response plus 2 additional cycles to a maximum of 12 cycles.
At the beginning of every cycle, your study doctor will see if your general health is satisfactory. You will be asked to report any side effects or problems you have had since the start of the last treatment cycle as well as any medication change(s).; If you decide to participate in the study, you will receive carfilzomib on Days 1, 2, 8, 9, 15, and 16 every 28 days for a minimum of 2 cycles (approximately 2 months). You may receive additional cycles for as long as your disease remains stable or improved or until your study doctor determines that you should stop receiving the study drug or you decide to stop participating in the study.
You will also receive dexamethasone weekly on Days 1, 2, 8, 9, 15 and 16 starting with cycle 1 and continuing every cycle thereafter.
Intervention MeSH terms: Dexamethasone; Rituximab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the safety and effectiveness of an investigational
      study drug called carfilzomib. The investigators want to find out what effects, good and/or
      bad, it has on patients and their cancer if treatment continues beyond previous carfilzomib
      treatment study.

      Carfilzomib (KyprolisTM) is approved by the U.S. Food and Drug Administration (FDA) to be
      used only in certain U.S. patients with relapsed and refractory multiple myeloma that have
      tried and failed other therapies. It has not been approved to be used for any other disease
      or condition.

      In this study, carfilzomib is referred to as an investigational study drug because it is not
      approved for use in all patients with multiple myeloma in the United States, and it is not
      approved by some regulatory authorities (the agencies that are responsible for approving the
      use of a medicine in a country such as Health Canada).

      Carfilzomib is a type of drug called a proteasome inhibitor. A proteasome is a protein found
      within cells that has the important role of identifying and marking damaged proteins that are
      needed to be destroyed by the cell for survival. The inhibition of the proteasome allows for
      damaged protein to accumulate within cells. This accumulation of damaged protein causes the
      cell to die.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Biopsy proven WM with relapsed/refractory symptomatic disease are eligible for
             enrollment.

          -  Bone marrow lymphoplasmacytosis with:

               -  > 10% lymphoplasmacytic cells (measured within 28 days prior to registration OR

               -  Aggregates or sheets of one of the following: lymphocytes, plasma cells or
                  lymphoplasmacytic cells on the bone marrow biopsy (measured within 28 days prior
                  to registration).

               -  Measurable disease defined as a quantitative IgM monoclonal protein of >500 mg/dL
                  obtained within 28 days prior to registration

               -  CD20+ bone marrow or lymph node by immunohistochemistry or flow cytometry
                  obtained within 28 days prior to registration

               -  Lymph node biopsy must be done <28 days prior to registration if used as an
                  eligibility criterion for study entry.

          -  Symptomatic disease, as defined by the IWWM, includes the following criteria:
             Hemoglobin less than 10 g/dL, platelet count less than 100,000 uL, bulky adenopathy or
             organomegaly, symptomatic hyperviscosity syndrome, severe neuropathy, amyloidosis,
             cryoglobulinemia, cold agglutinin disease, or evidence of transformation high-grade
             non-Hodgkin's lymphoma.

          -  Patients must not be receiving concurrent steroids > 10 mg prednisone (or equivalent)
             per day.

          -  Prior irradiation is allowed if > 28 days prior to registration have elapsed since the
             date of last treatment.

          -  Women must not be pregnant or breast-feeding due to the fact that the reproductive
             risk to humans taking carfilzomib is unknown. All females of childbearing potential
             must have a blood test or urine study within 2 weeks prior to registration to rule out
             pregnancy. A female of childbearing potential is any woman, regardless of sexual
             orientation or whether they have undergone tubal ligation, who meets the following
             criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
             been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
             at any time in the preceding 24 consecutive months).

          -  Women of childbearing potential and sexually active males must use an accepted and
             effective method of contraception throughout the study and for 8 weeks after
             completion of the study.

          -  Patients must be > 18 years old.

          -  Patients must have ECOG performance status of < 2.

          -  Patients may have received prior bortezomib therapy.

          -  Adequate hepatic function, with serum ALT ≤ 3times the upper limit of normal and serum
             direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to randomization

          -  Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization

          -  Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be
             receiving red blood cell [RBC] transfusions in accordance with institutional
             guidelines)

          -  Platelet count ≥ 50 × 109/L (≥ 30 × 109/L if WM involvement in the bone marrow is >
             50%) within 14 days prior to randomization

          -  Creatinine clearance (CrCl) ≥ 15 mL/minute within 7 days prior to randomization,
             either measured or calculated using a standard formula (e.g., Cockcroft and Gault)

        Exclusion Criteria:

          -  Pre-existing peripheral neuropathy > grade 2 with pain (CTC version 4.0).

          -  Hematologic criteria: ANC < 500/uL, Platelets < 25,000 uL.

          -  Renal function: CrCl < 15 ml/min.

          -  Active infection requiring intravenous antibiotics

          -  Known Active hepatitis B or C

          -  SGOT (AST) and SGPT (ALT) > 3x institutional ULN

          -  Direct bilirubin > 1.5 mg/dL

          -  Patients must not have any severe and/or uncontrolled medical condition or other
             conditions that could affect their participation in the study, including, but not
             restricted to:

          -  Symptomatic congestive heart failure of New York Heart Association Class III or IV.

          -  Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
             within 3 months of start of study treatment, serious uncontrolled cardiac arrhythmia
             or any other clinically significant heart disease.

          -  Severely impaired lung function as defined as spirometry and DLCO (corrected for Hgb)
             that is <50% of the normal predicted value and/or O2 saturation <88% at rest on room
             air.

          -  Active (acute or chronic) or uncontrolled severe infections.