Multiple Myeloma
Conditions
Brief summary
The purpose of this study is to find out what effects carfilzomib has on relapsed multiple myeloma when administered in combination with cyclophosphamide and dexamethasone.
Detailed description
Multiple Myeloma is a cancer that affects the bone marrow where the cells in our blood system are formed. This includes the white cells, red cells, platelets and lymphoid cells. In multiple myeloma the plasma cell (one of the lymphoid cells) starts to reproduce out of control. This results in crowding of the bone marrow with abnormal production of all the cells and a malfunction of the plasma cells. They can also cause damage to the normal bone resulting in pain, fractures and other complications. The standard or usual treatments for your disease are lenalidomide (an immunomodulatory drug) or bortezomib (a proteasome inhibitor) based treatments. Carfilzomib is a new type of proteasome inhibitor that is approved for the treatment of relapsed multiple myeloma in the United States.
Interventions
DRUGCarfilzomib
DRUGCyclophosphamide
DRUGDexamethasone
Sponsors
Amgen
Canadian Myeloma Research Group
Canadian Cancer Trials Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Relapsed symptomatic multiple myeloma as per the International Myeloma Working group criteria \[Palumbo 2009\]. * Measurable disease, as defined by one or more of the following (assessed within 21 days prior to registration): * Serum M-protein ≥ 5 g/L (0.5g/dL) * Urine Bence-Jones protein ≥ 200 mg/24 hours * Involved serum free light chain (FLC) measurement ≥ 100 mg/L (10 mg/dL), provided serum FLC ratio is abnormal (abnormal if FLC ratio is \<0.26 or \>1.65) * Biopsy proven plasmacytoma * For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL) * Prior treatment with at least one, but no more than three, regimens for multiple myeloma * Documented relapse or progressive disease on or after any regimen (subjects refractory to the most recent line of therapy are eligible except those who are refractory to bortezomib and cyclophosphamide as described in
Exclusion criteria
1. * Achieved a response to at least one prior regimen (defined as ≥ 25% decrease in M-protein) * Age ≥ 18 years. * Life expectancy ≥ 3 months. * ECOG performance status 0-2. * Laboratory Requirements (must be done within 21 days of registration): * Hematology: * Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L * Hemoglobin ≥ 8 g/dL (80 g/L) (subjects may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines) * Platelet count ≥ 50 × 10\^9/L, independent of platelet transfusions for 7 days. (≥ 30 × 10\^9/L if myeloma involvement in the bone marrow is ≥ 50%) * Biochemistry: * ALT ≤ 3.5 x UNL * Serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) (only required if total bilirubin ≥ 2mg/dL (34μmol/L) * Creatinine clearance (CrCl) ≥ 30 mL/minute (Crockcroft and Gault formula) and not on dialysis. * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate. * Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating centre. * In accordance with CRO policy, protocol treatment is to begin within 2 working days of patient registration. * Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate After 4 Cycles | 4 months | Response rate to protocol treatment after 4 cycles is define by stringent complete response, complete response, partial response, very good partial response, minimal response. Complete response: Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow biopsy Stringent complete response: Complete response plus Absence of clonal cells in bone marrow d by immunohistochemistry or immunofluorescence Very good partial response: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein with urine M-protein level \<100 mg/24 hours. Partial response: ≥50% reduction in serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours Minimal response: 25-49% reduction in serum M-protein, and 50-89% reduction in 24-hour urinary M-protein, if ≥ 200 mg/24 hours at baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 3 years | Median time to progression or death assessed by biochemistry, radiology and immunology tests will be reported. Progression is evaluated in this study using the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) with any one or more of the following: 1. Increase of ≥ 25% from lowest response value in: Serum M-component and/or Urine M-component and/or Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels or Bone marrow plasma cell percentages. 2. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas 3. Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL (0.115 g/L) or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder. |
| Overall Survival | 3 years | Median time to death in months will be reported |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone 20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (\< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg
Carfilzomib
Cyclophosphamide
Dexamethasone | 75 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 1 |
Baseline characteristics
| Characteristic | Carfilzomib Plus Cyclophosphamide Plus Dexamethasone |
|---|---|
| Age, Continuous | 66.0 years |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 68 Participants |
| Region of Enrollment Canada | 75 participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 31 / 75 |
| other Total, other adverse events | 28 / 75 |
| serious Total, serious adverse events | 39 / 75 |
Outcome results
Primary
Overall Response Rate After 4 Cycles
Response rate to protocol treatment after 4 cycles is define by stringent complete response, complete response, partial response, very good partial response, minimal response. Complete response: Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow biopsy Stringent complete response: Complete response plus Absence of clonal cells in bone marrow d by immunohistochemistry or immunofluorescence Very good partial response: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein with urine M-protein level \<100 mg/24 hours. Partial response: ≥50% reduction in serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours Minimal response: 25-49% reduction in serum M-protein, and 50-89% reduction in 24-hour urinary M-protein, if ≥ 200 mg/24 hours at baseline
Time frame: 4 months
Population: All eligible patients how have received treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone | Overall Response Rate After 4 Cycles | stringent complete response | 4 Participants |
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone | Overall Response Rate After 4 Cycles | complete response | 3 Participants |
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone | Overall Response Rate After 4 Cycles | very good partial response | 32 Participants |
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone | Overall Response Rate After 4 Cycles | partial response | 21 Participants |
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone | Overall Response Rate After 4 Cycles | minimal response | 1 Participants |
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone | Overall Response Rate After 4 Cycles | no response | 14 Participants |
Secondary
Overall Survival
Median time to death in months will be reported
Time frame: 3 years
Population: All treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone | Overall Survival | 27.43 months |
Secondary
Progression-free Survival
Median time to progression or death assessed by biochemistry, radiology and immunology tests will be reported. Progression is evaluated in this study using the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) with any one or more of the following: 1. Increase of ≥ 25% from lowest response value in: Serum M-component and/or Urine M-component and/or Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels or Bone marrow plasma cell percentages. 2. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas 3. Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL (0.115 g/L) or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
Time frame: 3 years
Population: All treated patients were included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib Plus Cyclophosphamide Plus Dexamethasone | Progression-free Survival | 17.15 months |