A Phase II Study of Carfilzomib in Relapsed Waldenström's Macroglobulinemia (WM) IST-CAR-531

A Phase II Study of Carfilzomib in Relapsed Waldenström's Macroglobulinemia (WM) IST-CAR-531

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.

Waldenström's macroglobulinemia (WM) is a rare low-grade B-cell lymphoplasmacytic lymphoma. Overall reported incidences approximately 3 cases per million persons per year with about 1500 and cases diagnosed annually in United States. There is a higher incidence in males compared to females (3.4 vs 1.7 cases per 1 million person-years at risk) and WM is nearly twice as common among whites compared to blacks.[1] A familial form of the disease is also recognized. WM is an indolent disease with an overall median survival of 5 years although more recent data suggest a disease-specific median survival of 11.2 years, given the frequently older age (median 63 years) and accompanying co-morbidities at diagnosis(1). WM is characterized by infiltration of lymphoplasmacytic cells and bone marrow and by serum immunoglobulin M (IgM) monoclonal gammopathy. B-cell origin and some clinical cellular and epidemiological features are shared among WM arises from intermediately mature B cells (somatically mutated post germinal center the lymphocytes that have not yet undergone isotype switching), as opposed to immature B cells from which chronic lymphocytic leukemia arises in the fully mature, somatically mutated, from which cells multiple myeloma arises.

There is no standard of care for WM (2). Therefore, involving the patient's in clinical trials is strongly recommended whenever possible.

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.