Amyloidosis; Systemic
Conditions
Brief summary
This is a single arm, open label study designed to evaluate the safety and efficacy of propylene glycol-free melphalan hydrochloride in patients with AL amyloidosis. Treatment will be comprised of propylene glycol-free melphalan hydrochloride administered intravenously at a dose of 70-100 mg/m2/day on Days -3 and -2 as conditioning prior to autologous stem cell transplantation.
Detailed description
After giving written informed consent, subjects will be evaluated for eligibility for enrollment in the study. Baseline evaluations will be performed as outlined in Section 7. Subjects who satisfy all inclusion and exclusion criteria will begin the study drug. Subjects will be monitored from the time of the medication administration until discharge from the transplant program for safety. Organ function and hematologic status will also be measured at 6 and 12 month follow-up visits. Standard response criteria for AL amyloidosis hematologic and organ response will be used. Overall response rate will be measured and participants will be categorized into complete response, very good partial response, partial response and progressive disease. Progression free survival, organ response, and safety and tolerability of propylene glycol-free melphalan hydrochloride will be assessed.
Interventions
DRUGPropylene Glycol-Free Melphalan Hydrochloride
Intravenous Propylene Glycol-Free Melphalan Hydrochloride
Sponsors
Spectrum Pharmaceuticals, Inc
Boston Medical Center
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
* Age 18 years or older * Eastern Cooperative Oncology Group Performance Status 0-2 * Histologic diagnosis of primary systemic (AL) amyloidosis based on: * Deposition of amyloid material by Congo red stain showing characteristic apple green birefringence AND * Evidence of a clonal plasma cell dyscrasia with monoclonal protein in the serum or urine by immunofixation electrophoresis AND/OR abnormal serum free light chain assay AND/OR clonal plasma cells in the bone marrow exam demonstrated by immunohistochemistry, flow cytometry, or in situ hybridization AND * Evidence of organ involvement * Eligible for treatment with high dose melphalan and stem cell transplantation per institutional guidelines * Ability to understand and willingness to sign informed consent * Pulmonary Function Test demonstrating a diffusion capacity of lung for carbon monoxide ≥ 50% * Left ventricular ejection fraction ≥40% * Systolic blood pressure \>90 mm Hg (supine position) * Eastern Cooperative Oncology Group Performance status of 2 or better (unless patient is diagnosed with AL amyloidosis involving the gastrointestinal and peripheral/autonomic nervous systems, then performance status of 3 is acceptable)
Exclusion criteria
* Previous high-dose melphalan and stem cell transplant * Previous total cumulative dose of oral melphalan \> 300 mg * Cytotoxic chemotherapy within the previous 28 days * New York Heart Association ≥3 * Decompensated or uncontrolled heart failure * Oxygen dependence * epidermal growth factor receptor \< 30 ml/min * Active infection (i.e HIV, Hepatitis B or C) * Pregnancy or breastfeeding * Exposure to another investigational drug within 3-4 weeks prior to start of study treatment * Ongoing alcohol or drug addiction * Unable or unwilling to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Renal Dysfunction | 100 days | To determine the safety profile of propylene glycol-free melphalan hydrochloride in the conditioning regimen prior to autologous stem cell transplantation in AL amyloidosis patients, including adverse events related to renal dysfunction (was acute renal failure is defined as either a \>/=1 mg/dL increase in serum creatinine or a doubling of serum creatinine to \>/=1.5 mg/dL for at least 2 days.). |
| Number of Participants With Cardiac Dysfunction (New Arrhythmia) | 100 days | To determine the safety profile of propylene glycol-free melphalan hydrochloride in the conditioning regimen prior to autologous stem cell transplantation in AL amyloidosis patients, including adverse events related to cardiac dysfunction (new arrhythmia). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Related Mortality | 100 days | Number of patients who expire within 100 days of transplant |
| Hematologic Overall Response Rate | 6 months | Number of patients with response based on Gertz, Palladini criteria (below) Complete response (CR): Normal serum free light chain ratio,Negative serum and urine immunofixation electrophoresis Very good partial response (VGPR): Difference in serum free light chains less than 40 mg/L Partial Response (PR): \>50% Reduction in the difference in serum free light chains Stable Disease (SD): Meets neither criteria for CR, VGPR, PR or PD |
| Neutrophil Engraftment | 3 weeks | time to neutrophil engraftment |
| Participants With Peri-transplant Hospitalizations | 100 days | Number of participants with peri-transplant hospitalizations |
| Organ Response | 12 months | Number of patients with organ response based on Gertz criteria (below) * Kidney: 50% reduction in 24-hour urine protein excretion in the absence of progressive renal insufficiency (defined as a 25% increase in serum creatinine, as long as that is \> to an absolute increase of 0.5 mg/dL). In the case of nephrotic syndrome: a decrease in proteinuria to \< 1g/24h and an improvement in one of 2 extrarenal features - normalization of serum albumin or resolution of edema and/or discontinuation of diuretics in response to improvement in edema. * Heart: ≥ 2 mm reduction in the interventricular septal (IVS) thickness by echocardiogram, improvement of ejection fraction by ≥ 20% (echocardiogram must be performed at the same institution), or decrease in 2 NYHA classes without increase in diuretic need. |
| Platelet Engraftment | 100 days | Assess time to platelet engraftment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Evomela Propylene Glycol-Free Melphalan Hydrochloride (Evomela) administered intravenously at 70-100 mg/m2/day on Days -3 and -2 prior to autologous stem cell transplantation
Propylene Glycol-Free Melphalan Hydrochloride: Intravenous Propylene Glycol-Free Melphalan Hydrochloride | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 6 Months Follow-up | Lost to Follow-up | 3 |
Baseline characteristics
| Characteristic | Evomela |
|---|---|
| Age, Continuous | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black | 6 Participants |
| Race/Ethnicity, Customized Caucasian | 20 Participants |
| Region of Enrollment United States | 27 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 27 |
| other Total, other adverse events | 25 / 27 |
| serious Total, serious adverse events | 20 / 27 |
Outcome results
Primary
Number of Participants With Cardiac Dysfunction (New Arrhythmia)
To determine the safety profile of propylene glycol-free melphalan hydrochloride in the conditioning regimen prior to autologous stem cell transplantation in AL amyloidosis patients, including adverse events related to cardiac dysfunction (new arrhythmia).
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Evomela | Number of Participants With Cardiac Dysfunction (New Arrhythmia) | 5 Participants |
Primary
Number of Participants With Renal Dysfunction
To determine the safety profile of propylene glycol-free melphalan hydrochloride in the conditioning regimen prior to autologous stem cell transplantation in AL amyloidosis patients, including adverse events related to renal dysfunction (was acute renal failure is defined as either a \>/=1 mg/dL increase in serum creatinine or a doubling of serum creatinine to \>/=1.5 mg/dL for at least 2 days.).
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Evomela | Number of Participants With Renal Dysfunction | 2 Participants |
Secondary
Hematologic Overall Response Rate
Number of patients with response based on Gertz, Palladini criteria (below) Complete response (CR): Normal serum free light chain ratio,Negative serum and urine immunofixation electrophoresis Very good partial response (VGPR): Difference in serum free light chains less than 40 mg/L Partial Response (PR): \>50% Reduction in the difference in serum free light chains Stable Disease (SD): Meets neither criteria for CR, VGPR, PR or PD
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Evomela | Hematologic Overall Response Rate | 22 Participants |
Secondary
Neutrophil Engraftment
time to neutrophil engraftment
Time frame: 3 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Evomela | Neutrophil Engraftment | 10 days |
Secondary
Organ Response
Number of patients with organ response based on Gertz criteria (below) * Kidney: 50% reduction in 24-hour urine protein excretion in the absence of progressive renal insufficiency (defined as a 25% increase in serum creatinine, as long as that is \> to an absolute increase of 0.5 mg/dL). In the case of nephrotic syndrome: a decrease in proteinuria to \< 1g/24h and an improvement in one of 2 extrarenal features - normalization of serum albumin or resolution of edema and/or discontinuation of diuretics in response to improvement in edema. * Heart: ≥ 2 mm reduction in the interventricular septal (IVS) thickness by echocardiogram, improvement of ejection fraction by ≥ 20% (echocardiogram must be performed at the same institution), or decrease in 2 NYHA classes without increase in diuretic need.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Evomela | Organ Response | 13 Participants |
Secondary
Participants With Peri-transplant Hospitalizations
Number of participants with peri-transplant hospitalizations
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Evomela | Participants With Peri-transplant Hospitalizations | 23 Participants |
Secondary
Platelet Engraftment
Assess time to platelet engraftment
Time frame: 100 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Evomela | Platelet Engraftment | 17 days |
Secondary
Treatment Related Mortality
Number of patients who expire within 100 days of transplant
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Evomela | Treatment Related Mortality | 0 Participants |