Multiple Myeloma
Conditions
Brief summary
The purpose of this study is to determine the tolerance and potential efficacy of combining dose intense melphalan with escalating doses of bortezomib in patients with multiple myeloma undergoing autologous stem cell transplantation.
Detailed description
Multiple myeloma is the second most common hematological malignancy that has affected approximately 40,000 Americans.Conventional chemotherapy has achieved limited control of this disease but studies have reported improved response rates for patients who are treated with dose-intense therapy and autologous hematopoietic stem cell transplantation. This Phase I/II study will investigate the potential of combination therapy of dose-intense melphalan with escalating doses of bortezomib.
Interventions
DRUGBortezomib 1 mg/m2
* Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line * Bortezomib will be administered any time on day -4 and 24 hrs after the start of the melphalan infusion on day -1 * Dosing will be based on actual body weight Patient weight must be measured within seven days of the start of the treatment regimen
* Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line * Bortezomib will be administered any time on day -4 and 24 hrs after the start of the melphalan infusion on day -1 * Dosing will be based on actual body weight Patient weight must be measured within seven days of the start of the treatment regimen
* Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line * Bortezomib will be administered any time on day -4 and 24 hrs after the start of the melphalan infusion on day -1 * Dosing will be based on actual body weight Patient weight must be measured within seven days of the start of the treatment regimen
DRUGMelphalan
* Melphalan is administered by rapid intravenous infusion via a central or peripheral vein over one hour * Melphalan will be dissolved with 10 ml of diluent to a concentration of 5 mg/mL which is then immediately diluted in 0.9% normal saline to a concentration NOT exceeding 0.45 mg/mL prior to administration * The final dilution of melphalan is physically and chemically stable for 60 minutes and therefore will be administered within that time period * Melphalan will be given as a single dose (not split over 2 or more days) * Dosing will be based body surface area calculated using actual body weight
Sponsors
Hackensack Meridian Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3 + 3 Dose Escalation
Eligibility
Sex/Gender
ALL
Age
18 Years to 76 Years
Healthy volunteers
No
Inclusion criteria
1. A confirmed diagnosis of multiple myeloma 2. Show progression of disease after a previous cycle of dose-intense melphalan, or less than 25% decrease in paraprotein measured at 8 weeks after a prior cycle of dose-intense melphalan * May have received intervening therapies for disease progression after dose-intense melphalan and enrollment in this protocol 3. Age:18yrs-76yrs at time of melphalan administration 4. Gender: There is no gender restriction 5. Availability of \>2x10\^6 autologous peripheral blood CD34+ cells/kg or a syngeneic donor meeting eligibility criteria for syngeneic donation * Syngeneic transplantation is preferred * For patients enrolled in the phase I part of this study, \>1x10\^6 autologous or syngeneic peripheral blood CD34+ cells/kg remaining in storage as backup in case of engraftment failure 6. Recovery from complications of salvage therapy, if administered -
Exclusion criteria
1. Diagnosis other than multiple myeloma 2. Chemotherapy or radiotherapy within 28 days of initiating treatment in this study 3. Prior dose-intense therapy within 56 days of initiating treatment in this study 4. Uncontrolled bacterial,viral,fungal or parasitic infections 5. Uncontrolled CNS metastases 6. Known amyloid deposition in heart 7. Organ dysfunction * LVEF\<40% or cardiac failure not responsive to therapy * FVC,FEV1,or DLCO\<50% of predicted and/or receiving supplementary continuous oxygen * Evidence of hepatic synthetic dysfunction, or total bilirubin\>2x or AST\>3x ULN * Measured creatinine clearance \<20ml/min * Sensory peripheral neuropathy grade 4 8. Karnofsky score\<70% unless a result of bone disease directly caused by myeloma 9. Life expectancy limited by another co-morbid illness 10. History of another malignancy in remission \<2yrs (other than basal cell carcinoma) 11. Pregnant (women)or unwilling to use acceptable birth control methods (men or women) for twelve months after treatment 12. Documented hypersensitivity to melphalan or bortezomib or any components of the formulation 13. Patients unable or unwilling to provide consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Maximum Tolerated Dose of Bortezomib (MTD) | During dosing of Bortezomib on Day -4 to Day -1 of ASCT | The Maximum Tolerated Dose of Bortezomib (MTD) Will be Defined as the Dose Level Prior to That Resulting in Two Out of Six Patients Experiencing a DLT |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Cohort - Bortezomib Dose 1 mg/m2 Bortezomib at 1 mg/m2 on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. | 6 |
| Phase I Cohort - Bortezomib 1.3 mg/m2 Bortezomib at 1.3 mg/m2 on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. | 3 |
| Phase I Cohort - Bortezomib 1.6 mg/m2 Bortezomib at 1.6 mg/m2 on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. | 3 |
| Phase II Cohort Bortezomib 1.6 mg/m2 on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. | 20 |
| Total | 32 |
Baseline characteristics
| Characteristic | Phase I Cohort - Bortezomib 1.3 mg/m2 | Phase I Cohort - Bortezomib 1.6 mg/m2 | Phase II Cohort | Total | Phase I Cohort - Bortezomib Dose 1 mg/m2 |
|---|---|---|---|---|---|
| Age, Continuous | 63 years | 58 years | 57 years | 57 years | 57 years |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants | — |
| Region of Enrollment United States | 3 participants | 3 participants | 20 participants | 32 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 9 Participants | 17 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 11 Participants | 15 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 12 | 20 / 20 |
| serious Total, serious adverse events | 6 / 12 | 6 / 20 |
Outcome results
Primary
The Maximum Tolerated Dose of Bortezomib (MTD)
The Maximum Tolerated Dose of Bortezomib (MTD) Will be Defined as the Dose Level Prior to That Resulting in Two Out of Six Patients Experiencing a DLT
Time frame: During dosing of Bortezomib on Day -4 to Day -1 of ASCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Dose Intense Melphalan With Bortezomib (MTD) | The Maximum Tolerated Dose of Bortezomib (MTD) | 1.6 mg/m2 of bortezomib |