Leukemia, Plasma Cell, Multiple Myeloma
Conditions
Keywords
Autologous Transplant, Proteasome Inhibitor, Melphalan, Filgrastim
Brief summary
Background: \- Plasma cell myeloma is a type of cancer that affects the plasma cells in the bone marrow. It can be difficult to treat with chemotherapy. One possible treatment combines chemotherapy with a stem cell transplant. To make this treatment more effective, researchers want to give another drug along with the transplant. This drug, carfilzomib, is often used to help treat plasma cell myeloma. However, it is not usually given along with the transplant. Researchers want to see if it is safe and effective to combine the stem cell transplant with carfilzomib, and if it improves the results of the transplant. Objectives: \- To test the safety and effectiveness of carfilzomib given with stem cell transplant for plasma cell myeloma. Eligibility: \- Individuals between 18 and 75 years of age who are having a stem cell transplant to treat plasma cell myeloma. Design: * Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and a bone marrow biopsy will also be performed. * Participants will have their own stem cells collected for the transplant. The transplant will be performed according to the standard of care. * All participants will receive carfilzomib on the first 2 days after transplant. The study doctors will determine the number of additional doses that they may have. * Treatment will be monitored with frequent blood tests and imaging studies.
Detailed description
Background: * Despite very significant progress in therapy for plasma cell myeloma (PCM) in the last decade, the disease remains mostly incurable. * High-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) continues to be a critical component of early treatment for PCM, but it is clear that the disease is not eradicated by the present high-dose therapy strategy, while intensifying the preparative regimen has, to this day, resulted in either no improvement in disease control or increased toxicity. * Carfilzomib (CFZ) is a newer proteasome inhibitor with increased activity and a safer toxicity profile than bortezomib in PCM. The favorable toxicity profile makes it a likely candidate for increasing anti-PCM drug exposure in the early post-AHCT period. Objectives: Primary Objectives -Evaluate feasibility and toxicity of an increasing number of doses of CFZ administered in the early period post-AHCT for PCM Secondary Objective * Evaluate the immune reconstitution post-AHCT following CFZ therapy * Evaluate the effects of the addition of CFZ in the early post-AHCT period on the response rate at day 100 post-AHCT Eligibility: * Newly diagnosed subjects with PCM following induction therapy * Subjects with documentation of persistent/refractory disease who have received no more than 2 salvage regimens following relapse and who have not undergone AHCT * Adequate organ functions with no major co-morbidity * Age greater than 18 years and less than or equal to 75 years Design: * Phase I/II study on the backbone of high-dose melphalan on day -2 pre-AHCT * Addition of an increasing number of doses of CFZ in the early post-AHCT period introduced in a step-wise fashion in 3 successive cohorts of 3 to 15 subjects: Cohort 1: add CFZ 20 mg/m\^2 on days +1, +2 Cohort 2 : add CFZ 20 mg/m\^2 on days: +1, +2, +8, +9 Cohort 3: add CFZ 20 mg/m\^2 on days: +1, +2, +8, +9 and add an early post-AHCT consolidation following engraftment: CFZ 20 mg/m\^2 given on days 42-43 then CFZ 56 mg/m\^2 given on days 49-50, 56-57, then on days 70-71, 77-78 and 84-85 -Dose-limiting toxicity, incidence of engraftment failure and treatment-related mortality are the objects of early stopping rules for safety purposes
Interventions
DRUGCarfilzomib
DRUGMelphalan
DRUGFilgrastim
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Multiple myeloma criteria for newly or recently diagnosed subjects * Presence of clonal plasma cells in the bone marrow greater than or equal to 10% or a documented clonal plasmacytoma (either by immuno-histochemistry or by Ig gene rearrangement), AND * Presence of an M-component; an M-component (immunoglobulin G (IgG) or immunoglobulin A (IgA)) in serum greater than or equal to 1g/dl or in urine greater or equal to 200 mg/24 h. ALTERNATIVELY, if the M-component criterion is not met: * An abnormal serum free light chain (FLC) ratio on the serum FLC assay, or if the FLC ratio is normal, * Baseline bone marrow must have 10% or greater clonal plasma cells AND, IN ADDITION, presence of one or more of the following attributable to the disease (in the presence or absence of an M-component): * Calcium elevation greater than 11.5 mg/dl (2.65 mmol/l) * Renal insufficiency: serum creatinine greater than 2 mg/dl (177 mmol/l) or less than 60ml/min. * Hemoglobin less than 10 g/dl (12.5 mmol/l) or 2 g/dl (1.25 mmol/l) below lower normal * Bone disease (lytic lesions or osteopenia) * Other evidence of disease activity: repeated infections, secondary amyloidosis, hyperviscosity, hypogammablobulinemia Criteria for subjects with persistent or recurrent disease Subjects with recurrent or persistent disease are eligible if: * Criteria for initiating therapy for plasma cell myeloma (PCM) had been present at the time of initiation of therapy or there is clear clinical indication for salvage therapy. * They have not undergone an autologous transplant for the treatment of PCM * They have received no more than two salvage regimens for the treatment of recurrent or persistent PCM (each regimen may include more than one cycle) Other eligibility criteria -Age \> 18 years and less than or equal to 75 years. In subjects between 65 and 75 years of age, physiologic age and co-morbidity will be thoroughly evaluated before enrolling. Specifically, any history of cardiovascular pathology or symptoms not clearly fitting the
Exclusion criteria
of Section 2.1.2 will prompt an evaluation by a Clinical Center Cardiologist and eligibility will be considered on a case-by-case basis. * Karnofsky performance status of 70% or greater (Eastern Cooperative Oncology Group (ECOG) 0 or 1) * Ejection fraction (EF) by multi-gated acquisition scan (MUGA) or 2-D echocardiogram within institution normal limits. In case of low ejection fraction (EF), the subject may remain eligible after a stress echocardiogram is performed if the EF is more than 35% and if the increase in EF with stress is estimated at 10% or more. * creatinine clearance \> 25ml/min (measured on a 24 hour urine collection) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x upper limit of normal * Bilirubin less than or equal to1.5 (except if due to Gilbert's disease) * Corrected carbon dioxide diffusing capacity (DLCO) greater than or equal to 40% on pulmonary function tests
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment Failure Transplant Related Mortality | up to day 100 | Engraftment failure is defined as the failure to achieve neutrophil engraftment by day 21; defined from day 0, day of autologous hematopoietic cell transplantation (AHCT), as the first of three consecutive days on which the patient's absolute neutrophil count is greater than 0.5x10(9)/l following the nadir. Transplant related mortality is defined as any subject who dies in the first 100 days post-AHCT of any non-relapse related cause. |
| Number of Participants With Adverse Events | 8 months and 15 days | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. |
Secondary
| Measure | Time frame |
|---|---|
| Evaluate the Immune Reconstitution Post-Pre-autologous Hematopoietic Cell Transplantation (AHCT) Following Carfilzomib (CFZ) Therapy | Post-AHCT following CFZ therapy |
| Evaluate the Effects of the Addition of Carfilzomib (CFZ) in the Early Post-Pre-autologous Hematopoietic Cell Transplantation (AHCT) Period on the Response Rate at Day 100 Post-AHCT | Day 100 post-AHCT |
Countries
United States
Participant flow
Pre-assignment details
The study did not progress to the phase II portion. The study was closed prematurely because the investigator left the National Institutes of Health.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1- CFZ 20 mg/m^2 (Day 1,2) Phase I/II study on the backbone of high-dose melphalan on day -2 pre-autologous hematopoietic cell transplantation (AHCT)
•Addition of an increasing number of doses of Carfilzomib (CFZ) in the early post-AHCT period introduced in a step-wise fashion in 3 successive cohorts of 3 to 15 subjects:
Cohort 1: add CFZ 20 mg/m\^2 intravenous (IV) on days +1, +2
Cohort 2 : add CFZ 20 mg/m\^2 IV on days: +1, +2, +8, +9
Cohort 3: add CFZ 20 mg/m\^2 IV on days: +1, +2, +8, +9 and add an early post-AHCT consolidation following engraftment: CFZ 20 mg/m\^2 IV given on days 42-43 then CFZ 56 mg/m\^2 IV given on days 49-50, 56-57, then on days 70. | 3 |
| Cohort 2- CFZ 20 mg/m^2 (Day 1,2,8,9) Phase I/II study on the backbone of high-dose melphalan on day -2 pre-autologous hematopoietic cell transplantation (AHCT)
•Addition of an increasing number of doses of Carfilzomib (CFZ) in the early post-AHCT period introduced in a step-wise fashion in 3 successive cohorts of 3 to 15 subjects:
Cohort 1: add CFZ 20 mg/m\^2 intravenous (IV) on days +1, +2
Cohort 2 : add CFZ 20 mg/m\^2 IV on days: +1, +2, +8, +9
Cohort 3: add CFZ 20 mg/m\^2 IV on days: +1, +2, +8, +9 and add an early post-AHCT consolidation following engraftment: CFZ 20 mg/m\^2 IV given on days 42-43 then CFZ 56 mg/m\^2 IV given on days 49-50, 56-57, then on days 70. | 0 |
| Cohort 3-CFZ 20 mg/m^2 (Day1,2,8,9/AHCT) Phase I/II study on the backbone of high-dose melphalan on day -2 pre-autologous hematopoietic cell transplantation (AHCT)
•Addition of an increasing number of doses of Carfilzomib (CFZ) in the early post-AHCT period introduced in a step-wise fashion in 3 successive cohorts of 3 to 15 subjects:
Cohort 1: add CFZ 20 mg/m\^2 intravenous (IV) on days +1, +2
Cohort 2 : add CFZ 20 mg/m\^2 IV on days: +1, +2, +8, +9
Cohort 3: add CFZ 20 mg/m\^2 IV on days: +1, +2, +8, +9 and add an early post-AHCT consolidation following engraftment: CFZ 20 mg/m\^2 IV given on days 42-43 then CFZ 56 mg/m\^2 IV given on days 49-50, 56-57, then on days 70. | 0 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Principal Investigator discretion | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1- CFZ 20 mg/m^2 (Day 1,2) | Total |
|---|---|---|
| Age, Categorical <=18 years | 0 participants | 0 participants |
| Age, Categorical >=65 years | 0 participants | 0 participants |
| Age, Categorical Between 18 and 65 years | 3 participants | 3 participants |
| Age, Continuous | 49.6 years STANDARD_DEVIATION 10.39 | 49.6 years STANDARD_DEVIATION 10.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 participants | 0 participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 participants | 3 participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 participants | 0 participants |
| Gender Female | 1 participants | 1 participants |
| Gender Male | 2 participants | 2 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 participants | 0 participants |
| Race (NIH/OMB) Asian | 0 participants | 0 participants |
| Race (NIH/OMB) Black or African American | 1 participants | 1 participants |
| Race (NIH/OMB) More than one race | 0 participants | 0 participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 participants | 0 participants |
| Race (NIH/OMB) White | 2 participants | 2 participants |
| Region of Enrollment United States | 3 participants | 3 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 3 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 3 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Engraftment Failure Transplant Related Mortality
Engraftment failure is defined as the failure to achieve neutrophil engraftment by day 21; defined from day 0, day of autologous hematopoietic cell transplantation (AHCT), as the first of three consecutive days on which the patient's absolute neutrophil count is greater than 0.5x10(9)/l following the nadir. Transplant related mortality is defined as any subject who dies in the first 100 days post-AHCT of any non-relapse related cause.
Time frame: up to day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1- CFZ 20 mg/m^2 (Day 1,2) | Engraftment Failure Transplant Related Mortality | 0 participants |
Primary
Number of Participants With Adverse Events
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Time frame: 8 months and 15 days
Population: Analysis of dose limiting toxicities (DLTs) was planned but not performed due to study termination; this Outcome Measure captures any events that occurred.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1- CFZ 20 mg/m^2 (Day 1,2) | Number of Participants With Adverse Events | 1 participants |
Secondary
Evaluate the Effects of the Addition of Carfilzomib (CFZ) in the Early Post-Pre-autologous Hematopoietic Cell Transplantation (AHCT) Period on the Response Rate at Day 100 Post-AHCT
Time frame: Day 100 post-AHCT
Population: This outcome measure was not done because the study was closed prematurely because the investigator left the National Institutes of Health.
Secondary
Evaluate the Immune Reconstitution Post-Pre-autologous Hematopoietic Cell Transplantation (AHCT) Following Carfilzomib (CFZ) Therapy
Time frame: Post-AHCT following CFZ therapy
Population: This outcome measure was not done because the study was closed prematurely because the investigator left the National Institutes of Health.