A Phase II Study of Carfilzomib in Relapsed Waldenström's Macroglobulinemia (WM) IST-CAR-531
Overview
- Phase
- Phase 2
- Intervention
- Carfilzomib
- Conditions
- Waldenstrom Macroglobulinemia
- Sponsor
- Hackensack Meridian Health
- Enrollment
- 7
- Locations
- 1
- Primary Endpoint
- Overall Response Rate (ORR) of Carfilzomib in Bortezomib naïve and Bortezomib-exposed Relapsed WM
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief 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.
Detailed Description
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.
Investigators
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.
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.
Arms & Interventions
Carfilzomib
Carfilzomib 20 mg/m2 on day 1, 2 then 56 mg/m2 days 8, 9 and 15, 16 over 30 minutes every 28 days. Dexamethasone 4 mg (8 mg if \> 45 mg/m2) orally each day of carfilzomib therapy. If less than a partial remission (PR) after 4 cycles, add rituximab 375 mg/m2 on day 16 of each cycle. Patients who meet the criteria for progression prior to 4 cycles of therapy will have rituximab added to their treatment. For patients receiving rituximab, the carfilzomib dose will be decreased to 27 mg/m2. Patients will be treated to maximal response plus 2 additional cycles to a maximum of 12 cycles.
Intervention: Carfilzomib
Carfilzomib
Carfilzomib 20 mg/m2 on day 1, 2 then 56 mg/m2 days 8, 9 and 15, 16 over 30 minutes every 28 days. Dexamethasone 4 mg (8 mg if \> 45 mg/m2) orally each day of carfilzomib therapy. If less than a partial remission (PR) after 4 cycles, add rituximab 375 mg/m2 on day 16 of each cycle. Patients who meet the criteria for progression prior to 4 cycles of therapy will have rituximab added to their treatment. For patients receiving rituximab, the carfilzomib dose will be decreased to 27 mg/m2. Patients will be treated to maximal response plus 2 additional cycles to a maximum of 12 cycles.
Intervention: Rituximab
Carfilzomib
Carfilzomib 20 mg/m2 on day 1, 2 then 56 mg/m2 days 8, 9 and 15, 16 over 30 minutes every 28 days. Dexamethasone 4 mg (8 mg if \> 45 mg/m2) orally each day of carfilzomib therapy. If less than a partial remission (PR) after 4 cycles, add rituximab 375 mg/m2 on day 16 of each cycle. Patients who meet the criteria for progression prior to 4 cycles of therapy will have rituximab added to their treatment. For patients receiving rituximab, the carfilzomib dose will be decreased to 27 mg/m2. Patients will be treated to maximal response plus 2 additional cycles to a maximum of 12 cycles.
Intervention: Dexamethasone
Outcomes
Primary Outcomes
Overall Response Rate (ORR) of Carfilzomib in Bortezomib naïve and Bortezomib-exposed Relapsed WM
Time Frame: Participants will be evaluated every 28 days (1 cycle) until progression or a maximum of 12 cycles (1 year)
The overall response rate (ORR) (rate of patients attaining a Partial Response or a Complete Response). Responses will be based on both serum paraprotein levels by SPEP and bidimensional disease measurements on CT scan for patients with adenopathy/organomegaly/lymphadenopathy. Criteria as per the Recommended Response Criteria for Waldenstrom Macroglobulinemia Complete Response: * Absence of serum monoclonal IgM protein by immunofixation * Normal serum IgM level * Complete resolution of extramedullary disease, i.e., lymphadenopathy and splenomegaly if present at baseline * Morphologically normal bone marrow aspirate and trephine biopsy Partial response (PR) * Monoclonal IgM protein is detectable -≥50% but\<90% reduction in serum IgM level from baseline * Reduction in extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at baseline * No new signs or symptoms of active disease
Secondary Outcomes
- Progression Free Survival(Participants will be evaluated every 28 days (1 cycle) until progression, an average of 19 months)
- Time to Progression(Participants will be evaluated every 28 days (1 cycle) until disease progression, an average of 16 months)
- Number of Patients Experiencing Dose Limiting Toxicity(Participants will be evaluated for the first 28 days of cycle 1)
- Duration of Response in Patients With WM.(Participants will be evaluated every 28 days (1 cycle) until they experience disease progression, are treated with another therapy, or died, an average of 15 months)