Multiple Myeloma
Conditions
Brief summary
This is a phase I clinical trial. Patients with a diagnosis of multiple myeloma undergoing autologous transplantation will receive a preparative regimen of melphalan, bendamustine, and carfilzomib. We hypothesize that the addition of carfilzomib to a conditioning regimen of melphalan and bendamustine in the setting of autologous transplantation for multiple myeloma is feasible and safe.
Interventions
DRUGCohort 1: Carfilzomib 15 mg/m2
Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 100 mg/m2 on day -2 and day -1 Carfilzomib 15 mg/m2 on day -2, -1, + 5 and +6
DRUGCohort 2: Carfilzomib 20 mg/m2
Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 100 mg/m2 on day -2 and day -1 Carfilzomib 20 mg/m2 on day -2, -1, + 5 and +6
DRUGCohort 2b: Carfilzomib 20 mg/m2
Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 140 mg/m2 on day -1 Carfilzomib 20 mg/m2 on day -2, -1 and + 5
DRUGCohort 3b: Carfilzomib 27 mg/m2
Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 140 mg/m2 on day -1 Carfilzomib 27 mg/m2 on day -2, -1 and + 5
Sponsors
Corewell Health West
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple myeloma * At least 2 x 106 CD34+ cells/kg have been collected from the patient and cryopreserved for ASCT * Greater than 18 years * Karnofsky score greater than 70% * No evidence of progressive bacterial, viral, or fungal infection * Absolute neutrophil count above 1000 * Platelet count above 50,000 * Hemoglobin above 8 g/dL * Creatinine clearance greater than 50 mL/min * Total bilirubin, ALT, and AST less than 2 x the upper limit of normal * Alkaline phosphatase less than or equal to 250 IU/L * Left Ventricular Ejection Fraction (LVEF) greater than or equal to 45% * Adjusted Carbon Monoxide Diffusing Capacity (DLCO) greater than or equal to 60% * Negative HIV serology * Recovered from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and hematological toxicity) * Patients with a pre-transplant disease status consistent with a very good partial response (VGPR), partial response (PR), stable disease (SD), progressive disease (PD), or relapse from complete remission (CR).
Exclusion criteria
* Patients who are refractory to carfilzomib. Refractory is defined as disease progression while on carfilzomib therapy after receiving at least two cycles of treatment. * Patients with a complete response (CR) (including near CR and stringent CR) to conventional induction therapy and proceeding to transplantation. * Pregnant or nursing females or women of reproductive capability who are unwilling to use effective contraception. A woman of reproductive capability is one who has not undergone a hysterectomy (removal of the womb), has not had both ovaries removed, or has not been post-menopausal (stopped menstrual periods) for more than 24 months in a row. * Male subjects who refuse to practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse. This must be done even if they are surgically sterilized (ie, post-vasectomy). * Patient with Grade 2 peripheral neuropathy * Inability to provide informed consent * Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. * Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant. * Known allergies to any of the components of the investigational treatment regimen or required ancillary treatments. * Serious medical or psychiatric illness likely to interfere with participation in this clinical study. * Diagnosed or treated for another malignancy within 3 years of enrollment (with the exception of non-melanoma skin cancer). * Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial. * Prisoner
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absence of Dose Limiting Toxicity | Assessed daily (while inpatient) through clinical and laboratory examinations up to 90 days. | An absence of neutrophil engraftment by Day +22, absence of platelet engraftment by Day +35, and any grade 4 GI toxicity or any \>/= grade 3 non-hematologic toxicity as defined by the common toxicity criteria, which is deemed by the DSMB as probably related to the study protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neutrophil Engraftment | Assessed daily (while inpatient) through clinical and laboratory examinations up to 90 days. | Engraftment of Neutrophils: ANC recovery is defined as an absolute neutrophil count (ANC) of ≥ 0.5 x 109/L for three consecutive laboratory values obtained on different days. The day used as neutrophil engraftment is the date of the first of three laboratory values. Graft Failure: Graft failure includes failure to achieve neutrophil engraftment by day 22. |
| Platelet Engraftment | Assessed daily (while inpatient) through clinical and laboratory examinations up to 90 days. | Engraftment of Platelets: Platelet engraftment is defined as a platelet count ≥ 20 x 109/L for 3 consecutive measurements obtained on different days. The patient must not have received a platelet infusion for seven consecutive days prior to the first day being considered. The day used as platelet engraftment is the date of the first of three laboratory values. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Disease assessment at day +100, +180, and +365 (+/- 7 days). | Find the response rate of the combination of melphalan, bendamustine, and carfilzomib as a conditioning regimen in patients with multiple myeloma undergoing autologous transplantation. |
Countries
United States
Participant flow
Pre-assignment details
This study was conducted using a standard 3+3 phase I design. If dose-limiting toxicity (DLT) occurred in 1 out of 3 patients, 3 additional patients were enrolled at that same dose level. Dose escalation was permitted if DLT did not occur in more than 0 out of 3, or 1 out of 6 patients
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Carfilzomib 15 mg/m2 Carfilzomib 15 mg/m2 on days -2, -1, +5, and +6 IV over 10 minutes.
Cohort 1: Carfilzomib 15 mg/m2: Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 100 mg/m2 on day -2 and day -1 Carfilzomib 15 mg/m2 on day -2, -1, + 5 and +6 | 3 |
| Cohort 2: Carfilzomib 20 mg/m2 Carfilzomib 20 mg/m2 on days -2, -1, +5, and +6 IV over 10 minutes.
Cohort 2: Carfilzomib 20 mg/m2: Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 100 mg/m2 on day -2 and day -1 Carfilzomib 20 mg/m2 on day -2, -1, + 5 and +6 | 3 |
| Cohort 2b: Carfilzomib 20 mg/m2 Carfilzomib 20 mg/m2 on days -2, -1 and +5 IV over 10 minutes.
Cohort 2b: Carfilzomib 20 mg/m2: Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 140 mg/m2 on day -1 Carfilzomib 20 mg/m2 on day -2, -1 and + 5 | 3 |
| Cohort 3: Carfilzomib 27mgm2 Carfilzomib 27 mg/m2 on days -2, -1 and +5 IV over 10 minutes.
Cohort 3b: Carfilzomib 27 mg/m2: Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 140 mg/m2 on day -1 Carfilzomib 27 mg/m2 on day -2, -1 and + 5 | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 2: Carfilzomib 20 mg/m2 | Cohort 2b: Carfilzomib 20 mg/m2 | Cohort 3: Carfilzomib 27mgm2 | Cohort 1: Carfilzomib 15 mg/m2 |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 2 Participants | 2 Participants | 7 Participants | 3 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — | — |
| Region of Enrollment United States | 18 participants | 3 participants | 3 participants | 9 participants | 3 participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 0 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 11 Participants | 1 Participants | 3 Participants | 6 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 3 | 0 / 3 | 0 / 9 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 9 / 9 |
| serious Total, serious adverse events | 0 / 3 | 2 / 3 | 0 / 3 | 0 / 9 |
Outcome results
Primary
Absence of Dose Limiting Toxicity
An absence of neutrophil engraftment by Day +22, absence of platelet engraftment by Day +35, and any grade 4 GI toxicity or any \>/= grade 3 non-hematologic toxicity as defined by the common toxicity criteria, which is deemed by the DSMB as probably related to the study protocol.
Time frame: Assessed daily (while inpatient) through clinical and laboratory examinations up to 90 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Carfilzomib 15 mg/m2 | Absence of Dose Limiting Toxicity | 3 Participants |
| Cohort 2: Carfilzomib 20 mg/m2 | Absence of Dose Limiting Toxicity | 1 Participants |
| Cohort 2b: Carfilzomib 20 mg/m2 | Absence of Dose Limiting Toxicity | 3 Participants |
| Cohort 3: Carfilzomib 27mgm2 | Absence of Dose Limiting Toxicity | 9 Participants |
Secondary
Neutrophil Engraftment
Engraftment of Neutrophils: ANC recovery is defined as an absolute neutrophil count (ANC) of ≥ 0.5 x 109/L for three consecutive laboratory values obtained on different days. The day used as neutrophil engraftment is the date of the first of three laboratory values. Graft Failure: Graft failure includes failure to achieve neutrophil engraftment by day 22.
Time frame: Assessed daily (while inpatient) through clinical and laboratory examinations up to 90 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Carfilzomib 15 mg/m2 | Neutrophil Engraftment | 11.33 days | Standard Deviation 0.58 |
| Cohort 2: Carfilzomib 20 mg/m2 | Neutrophil Engraftment | 12.67 days | Standard Deviation 2.08 |
| Cohort 2b: Carfilzomib 20 mg/m2 | Neutrophil Engraftment | 12 days | Standard Deviation 0 |
| Cohort 3: Carfilzomib 27mgm2 | Neutrophil Engraftment | 12.11 days | Standard Deviation 0.78 |
Secondary
Platelet Engraftment
Engraftment of Platelets: Platelet engraftment is defined as a platelet count ≥ 20 x 109/L for 3 consecutive measurements obtained on different days. The patient must not have received a platelet infusion for seven consecutive days prior to the first day being considered. The day used as platelet engraftment is the date of the first of three laboratory values.
Time frame: Assessed daily (while inpatient) through clinical and laboratory examinations up to 90 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Carfilzomib 15 mg/m2 | Platelet Engraftment | 17 days | Standard Deviation 2.65 |
| Cohort 2: Carfilzomib 20 mg/m2 | Platelet Engraftment | 15.5 days | Standard Deviation 0.71 |
| Cohort 2b: Carfilzomib 20 mg/m2 | Platelet Engraftment | 15.67 days | Standard Deviation 3.51 |
| Cohort 3: Carfilzomib 27mgm2 | Platelet Engraftment | 15.89 days | Standard Deviation 1.96 |
Other Pre-specified
Response Rate
Find the response rate of the combination of melphalan, bendamustine, and carfilzomib as a conditioning regimen in patients with multiple myeloma undergoing autologous transplantation.
Time frame: Disease assessment at day +100, +180, and +365 (+/- 7 days).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Carfilzomib 15 mg/m2 | Response Rate | progressive disease | 0 Participants |
| Cohort 1: Carfilzomib 15 mg/m2 | Response Rate | very good partial response | 2 Participants |
| Cohort 1: Carfilzomib 15 mg/m2 | Response Rate | partial response | 0 Participants |
| Cohort 1: Carfilzomib 15 mg/m2 | Response Rate | complete response | 1 Participants |
| Cohort 2: Carfilzomib 20 mg/m2 | Response Rate | very good partial response | 0 Participants |
| Cohort 2: Carfilzomib 20 mg/m2 | Response Rate | complete response | 1 Participants |
| Cohort 2: Carfilzomib 20 mg/m2 | Response Rate | partial response | 1 Participants |
| Cohort 2: Carfilzomib 20 mg/m2 | Response Rate | progressive disease | 0 Participants |
| Cohort 2b: Carfilzomib 20 mg/m2 | Response Rate | progressive disease | 1 Participants |
| Cohort 2b: Carfilzomib 20 mg/m2 | Response Rate | very good partial response | 1 Participants |
| Cohort 2b: Carfilzomib 20 mg/m2 | Response Rate | complete response | 0 Participants |
| Cohort 2b: Carfilzomib 20 mg/m2 | Response Rate | partial response | 1 Participants |
| Cohort 3: Carfilzomib 27mgm2 | Response Rate | progressive disease | 3 Participants |
| Cohort 3: Carfilzomib 27mgm2 | Response Rate | complete response | 2 Participants |
| Cohort 3: Carfilzomib 27mgm2 | Response Rate | very good partial response | 2 Participants |
| Cohort 3: Carfilzomib 27mgm2 | Response Rate | partial response | 2 Participants |