Propylene Glycol-Free Melphalan Hydrochloride (Evomela) in AL Amyloidosis Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Single-Center, Open-Label, Safety and Efficacy Study of Propylene Glycol-Free Melphalan Hydrochloride (Evomela) in AL Amyloidosis Patients Undergoing Autologous Stem Cell Transplantation

Conditions
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Amyloidosis; Systemic

Intervention / Treatment
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* Drug: Propylene Glycol-Free Melphalan Hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evomela<br>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 | Drug: Propylene Glycol-Free Melphalan Hydrochloride<br>* Intravenous Propylene Glycol-Free Melphalan Hydrochloride<br>* Other names: Evomela;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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.). | 100 days | 
| 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). | 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Engraftment | time to neutrophil engraftment | 3 weeks | 
| Platelet Engraftment | Assess time to platelet engraftment | 100 days | 
| Treatment Related Mortality | Number of patients who expire within 100 days of transplant | 100 days | 
| 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 | 6 months | 
| 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. | 12 months | 
| Participants With Peri-transplant Hospitalizations | Number of participants with peri-transplant hospitalizations | 100 days |