Clinical trial NCT02994784
Conditions: Amyloidosis; Systemic
Sponsor: Boston Medical Center
Start date: 2018-01-08; Completion date: 2022-07-01
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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
Interventions: intervention 1: Propylene Glycol-Free Melphalan Hydrochloride
Intervention descriptions: intervention 1: Intravenous Propylene Glycol-Free Melphalan Hydrochloride

Protocol documents:
Prot_SAP_000.pdf: 
Melphalan (Propylene Glycol-Free) in AL Amyloidosis Patients  
Protocol Version 7 (12/6/18) 
 
 
 
CONFIDENTIAL 
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This document is confidential and the property of Boston Medical Center. No part of it may be transmitted, reproduced, 
published, or used by other persons without prior written authorization from the sponsor/investigator. 
Full Title:  A Phase II Single-Center, Open-Label, Safety and Efficacy Study of Propylene Glycol-Free 
Melphalan (Evomela) in AL amyloidosis Patients Undergoing Autologous Stem Cell Transplantation 
Simple Title: Propylene Glycol-Free Melphalan (Evomela) in AL Amyloidosis Patients 
 
Sponsor Investigator:  
Shayna Sarosiek, MD 
820 Harrison Ave, FGH-1 
Boston, MA 02118  
617-638-7519 
Shayna.Sarosiek@bmc.org 
 
Co-Investigators:  
Vaishali Sanchorawala, MD 
820 Harrison Ave, FGH-1 
Boston, MA 02118  
Vaishali.sanchorawala@bmc.org 
 
 
PI- J. Mark Sloan, MD 
820 Harrison Ave, FGH-1 
Boston, MA 02118  
Mark.Sloan@bmc.org 
 
Karen Quillen, MD 
820 Harrison Ave, FGH-1 
Boston, MA 02118  
Karen.Quillen@bmc.org 
 
 
Statistician:  
Gheorghe Doros, PhD 
801 Massachusetts Avenue, Room 331 
Boston, MA 02118 
Doros@bu.edu 
 
 
Agent: Propylene Glycol-Free Melphalan (Evomela) 
 
NCT02994784 
 
Investigational agent and funding provided by: Spectrum Pharmaceuticals, Inc. 
 
 
 
ORIGINAL VERSION: 8/4/16 
 Version 2: 5/16/17 
Version 3: 9/29/17 
Version 4: 11/17/17 
Version 5: 12/6/17 
Version 6: 1/8/18 
Version 7: 12/6/18 
 
Statistical Plan- see page 18 
 


Melphalan (Propylene Glycol-Free) in AL Amyloidosis Patients  
Protocol Version 7 (12/6/18) 
 
 
 
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published, or used by other persons without prior written authorization from the sponsor/investigator. 
TABLE OF CONTENTS 
 
1. 
OBJECTIVES .................................................................................................................. 5 
1.1 
Title  .....................................................................................................................................5 
1.2 
Study Design .........................................................................................................................5 
1.3 
Patient population ................................................................................................................5 
1.4  Number of sites ....................................................................................................................5 
1.5  Number of patients ...............................................................................................................5 
1.6 
Primary Objective .................................................................................................................5 
1.7 
Secondary Objectives ............................................................................................................5 
2. 
BACKGROUND .............................................................................................................. 5 
2.1 
Study Agent ..........................................................................................................................5 
2.2 
Study Disease and Rationale .................................................................................................7 
3. 
PARTICIPANT SELECTION .............................................................................................. 8 
3.1 
Screening and Recruitment and Consenting ……………………………………………………….……8 
3.2 
Inclusion Criteria ...................................................................................................................8 
3.3 
Exclusion Criteria ..................................................................................................................9 
4. 
TREATMENT REGIMEN .................................................................................................. 9 
4.1 
Stem Cell Mobilization ..........................................................................................................9 
4.2 
Stem Cell Collection ............................................................................................................ 10 
4.3 
Conditioning Regimen ......................................................................................................... 10 
4.4 
Stem Cell Infusion ............................................................................................................... 10 
4.5 
General Concomitant Medication and Supportive Care Guidelines ....................................... 10 
4.6 
Duration of Participation .................................................................................................... 11 
4.7 
Criteria for Removal From Protocol Treatment .................................................................... 11 
5. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ........................... 11 
5.1 
Toxicity Management ......................................................................................................... 11 
6. 
DRUG FORMULATION AND ADMINISTRATION ............................................................ 12 
6.1 
Melphalan (Propylene Glycol-Free) Formulation .................................................................. 12 
6.2 
Melphalan (Propylene Glycol-Free) Package, Storage, and Handling ..................................... 12 
6.3 
Melphalan (Propylene Glycol-Free) Availability ................................................................... 12 
6.4 
Melphalan (Propylene Glycol-Free) Administration .............................................................. 12 
6.5 
Melphalan (Propylene Glycol-Free) Accountability ............................................................... 12 
7. 
STUDY CALENDAR ....................................................................................................... 13 
8. 
MEASUREMENT OF EFFECT ......................................................................................... 14 
8.1  Definitions .......................................................................................................................... 14 
8.2 
AL Amyloidosis Hematologic Response Criteria .................................................................... 14 
8.3 
Organ Response Criteria ..................................................................................................... 14 
9. 
ADVERSE EVENTS ....................................................................................................... 15 
9.1 
Adverse Event (AE) Definition ............................................................................................. 15 
9.2 
Serious Adverse Event (SAE) Definition ................................................................................ 15 
9.3 
Adverse Drug Reaction Reporting ........................................................................................ 15 
9.4 
Monitoring of Adverse Events and Period of Observation .................................................... 16 


Melphalan (Propylene Glycol-Free) in AL Amyloidosis Patients  
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10. 
DATA MANAGEMENT ................................................................................................. 16 
10.1 Analyses and Reporting ...................................................................................................... 16 
10.2 Data Monitoring Committee ............................................................................................... 16 
10.3 Study Monitoring and Auditing ........................................................................................... 16 
11. 
REGULATORY CONSIDERATIONS ................................................................................. 17 
11.1 Protocol Amendments ........................................................................................................ 17 
11.2 Protocol Deviations ............................................................................................................ 17 
11.3 Institutional Review Board/Ethics Committee Approval ....................................................... 17 
11.4 Recruitment and Informed Consent ..................................................................................... 17 
11.5 Study Records Requirements .............................................................................................. 17 
12. 
STATISTICAL CONSIDERATIONS ................................................................................... 18 
12.1 Study Design/Endpoints ...................................................................................................... 18 
12.2 Sample Size/Accrual Rate .................................................................................................... 18 
12.3 Reporting and Exclusions .................................................................................................... 18 
13. 
REFERENCES ............................................................................................................... 18 
14. 
APPENDICES ............................................................................................................... 19 
14.1 APPENDIX A: Performance Status Criteria ............................................................................ 19 
 


Melphalan (Propylene Glycol-Free) in AL Amyloidosis Patients  
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SCHEMA 
 
 
Stem cell mobilization (Standard) 
Filgrastim mobilization  
 
 
 
Stem cell collection (Standard) 
> 2.0 x 106 CD 34+/kg 
 
 
 
Conditioning regimen (Investigational) 
70-100 mg/m2/dose Melphalan (Propylene Glycol-Free); Days -3 and -2 
 
 
 
Stem cell infusion (Standard) 
D 0 
 
 
 


Melphalan (Propylene Glycol-Free) in AL Amyloidosis Patients  
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This document is confidential and the property of Boston Medical Center. No part of it may be transmitted, reproduced, 
published, or used by other persons without prior written authorization from the sponsor/investigator. 
1. 
OBJECTIVES 
 
1.1 Title:  A Phase II Single-Center, Open-Label, Safety and Efficacy Study of Melphalan (Propylene 
Glycol-Free) in AL Amyloidosis Patients Undergoing Autologous Stem Cell Transplantation 
 
1.2 Study Design: 
 
This is a single arm, open label study designed to evaluate the safety and efficacy of melphalan (propylene glycol-
free) in patients with AL amyloidosis.  Treatment will be comprised of melphalan (propylene glycol-free) administered 
intravenously at a dose of 70-100 mg/m2/day on Days -3 and -2 as conditioning prior to autologous stem cell 
transplantation.  
 
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 (Gertz et al. 2005, 
Palladini et al 2012).  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 Melphalan (Propylene Glycol-Free) will be assessed. 
 
1.3 Patient population:  (Specific inclusion and exclusion criteria are detailed in section 3) 
 
1.4 Number of sites:  One (Boston Medical Center, 820 Harrison Ave, FGH-2, Boston, MA 02118) 
 
1.5 Number of patients:  43 patients 
 
1.6 Primary Objective: 
 
• 
To determine the safety profile of melphalan (propylene glycol-free) 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.), cardiac dysfunction (new arrhythmia), or 
autonomic dysfunction (decline in sitting systolic blood pressure of ≥20mm Hg compared to baseline) 
  
1.7 Secondary Objectives: 
 
• 
To assess time until neutrophil and platelet engraftment 
• 
To assess treatment related mortality at 100 days 
• 
To assess hematologic overall response rate at 6 months after autologous stem cell transplantation 
• 
To evaluate organ response at 12 months after autologous stem cell transplantation 
• 
To monitor for number of hospitalizations 
 
2. 
BACKGROUND 
 
2.1 Study Agent 
 
2.1.1. Melphalan (propylene glycol-free) 
Melphalan (propylene glycol-free) is an alkylating agent of the bischloroethylamine type.  The chemical name is 4-
[bis(2-chloroehtyl)amino]-L-phenylalanine hydrochloride.  Its molecular formula is C13H18Cl2N2O2 and the molecular 
weight is 341.67. Cytotoxicity of the drug is related to interstrand cross-linking with DNA.  It is active against both 
resting and rapidly dividing tumor cells.   
 
 
 


Melphalan (Propylene Glycol-Free) in AL Amyloidosis Patients  
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2.1.2. Clinical experience with melphalan (propylene glycol-free) 
 
From 2010 to 2011 a phase IIa, open-label, randomized cross-over trial was performed evaluating propylene glycol-
free melphalan and melphalan hydrochloride (Alkeran) in multiple myeloma patients undergoing treatment with 
autologous stem cell transplantation.  In this trial, 24 patients with multiple myeloma were treated with 100 mg/m2 of 
melphalan in two doses prior to autologous stem cell transplantation.  Patients received one dose of melphalan 
hydrochloride (Alkeran) and one dose of melphalan (propylene glycol-free) on alternate days.  All patients achieved 
myeloablation.  Pharmacokinetic studies demonstrated that propylene-glycol free melphalan was bioequivalent to 
previously marketed melphalan hydrochloride.  Pharmacokinetic studies demonstrated a maximum plasma 
concentration (Cmax) and area under the plasma concentration-time curve (AUC) were approximately 10% higher after 
propylene-glycol free melphalan when compared with melphalan hydrochloride.   
 
The safety and efficacy of melphalan (propylene glycol-free) was evaluated in a phase IIb, open-label, multicenter study 
which enrolled 61 multiple myeloma patients (Hari).  Melphalan (propylene glycol-free) was administered over 
approximately 30 minutes intravenously as 2 doses of 100mg/m2 as conditioning prior to autologous stem cell 
transplantation on Days -3 and -2.  Data from this trial demonstrated an overall response rate of 100%, with a complete 
response rate of 21% and overall partial response rate of 79%.  Based on this data the efficacy and safety of this new 
formulation was demonstrated.   
 
2.1.3. Summary of Safety Data  
 
All patients in the phase IIb, open-label trial had at least 1 grade 4 hematologic adverse event, which was indicative 
of myeloablation.  Hematologic adverse events are depicted in the figures below.   
 
Hematologic Adverse Events 
ADVERSE EVENT (AE) 
GRADE 3  
GRADE 4 
ALL 
All hematologic AEs 
61 (100%) 
61 (100%) 
61 (100%) 
Neutropenia 
3 (5%) 
58 (95%) 
61 (100%) 
Leukopenia 
1 (2%) 
60 (98%) 
61 (100%) 
Lymphopenia 
0 (0%) 
60 (98%) 
60 (98%) 
Thrombocytopenia 
0 (0%) 
60 (98%) 
60 (98%) 
Anemia 
31 (51%) 
0 (0%) 
40 (66%) 
Febrile Neutropenia 
17 (28%) 
0 (0%) 
25 (41%) 
 
Nonhematologic adverse events were mostly grade 1 or 2.  No treatment-related deaths occurred.  The incidence of 
grade 3 oral mucositis was 13% with no grade 4 events.  Side effects occurring in more than 50% of patients included 
diarrhea, nausea, fatigue, hypokalemia, and vomiting.   
 
Nonhematologic Adverse Events experienced by ≥25% of patients 
Adverse Event 
No. of patients 
Diarrhea 
57 (93%) 
Nausea 
55 (90%) 
Fatigue 
47 (77%) 
Hypokalemia 
45 (74%) 
Vomiting 
39 (64%) 
Hypophosphatemia 
30 (49%) 
Decreased appetite 
30 (49%) 
Pyrexia 
29 (48%) 
Constipation 
29 (48%) 
Mucosal Inflammation 
23 (38%) 
Dizziness 
23 (38%) 
Peripheral Edema 
20 (33%) 
Stomatitis 
17 (28%) 
Abdominal Pain 
17 (28%) 
Dysgeusia 
17 (28%) 
Dyspepsia 
16 (26%) 
 


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Twelve patients (20%) had serious adverse events (SAEs) and all of these events resolved.  Ten of these SAEs were 
considered possibly related to the study treatment.  Serious adverse events included pyrexia (8%); febrile neutropenia, 
hematochezia, and acute renal failure (3% each); and atrial fibrillation, cellulitis, dehydration, mucosal inflammation, 
oral pain, presyncope, and staphylococcal infection (2% each).  One event, pyrexia, was the only Grade 4 SAE.   
 
2.1.4. Clinical Pharmacokinetic Data  
 
After intravenous administration, melphalan (propylene glycol-free) plasma concentrations rapidly decline in a 
biexponential manner with distribution and terminal elimination phase half-lives of approximately 10 and 75 minutes, 
respectively.  Typical values for average total body clearance range between approximately 7 to 9 mL/min/kg (250 to 
325 mL/min/m2).  Mean (±SD) peak melphalan plasma concentrations in myeloma patients given intravenous 
melphalan at doses of 10 or 20 mg/m2 were 1.2 ± 0.4 and 2.8 ± 1.9 mcg/mL, respectively.   
 
The steady-state volume of distribution of melphalan is 0.5 L/kg.  Melphalan penetrates into cerebrospinal fluid.  
Average melphalan binding to plasma proteins ranges from approximately 50 to 90%.  Serum albumin is the major 
binding protein, accounting for approximately 40 to 60% of the plasma protein binding, while α1-acid glycoprotein 
accounts for about 20% of the plasma protein binding.  Approximately 30% of melphalan is (covalently) irreversibly 
bound to plasma proteins.   
 
Melphalan is eliminated from plasma primarily by chemical hydrolysis to inactive monohydroxymelphalan and 
dihydroxymelphalan.  The contribution of renal excretion to melphalan clearance appears to be low.   
 
2.2 Study Disease and Rationale 
Immunoglobulin light-chain (AL) amyloidosis is a disease in which amyloid fibrils derived from monoclonal light-
chains are deposited in organs throughout the body resulting in multi-organ dysfunction.  The kidneys, heart, 
gastrointestinal tract, liver and nervous system are most commonly involved.  Historically, treatment with high-dose 
melphalan and autologous stem cell transplantation (HDM/ASCT) has been chosen as first-line treatment in 
qualifying AL amyloidosis patients due to durable hematologic responses, as well as organ responses, and improved 
overall survival(Mahmood, Palladini).   
HDM/ASCT is recommended in select patients with AL amyloidosis based on measures of cardiac function, 
pulmonary function and hemodynamic stability(Gertz).  Despite rigorous evaluation, some patients with AL 
amyloidosis develop significant morbidity or mortality during the peri-transplant period related to renal, autonomic 
nervous system, or cardiac dysfunction.  Data from our center demonstrates that 21% of AL amyloidosis patients 
receiving treatment with high dose melphalan and autologous stem cell transplantation develop acute renal injury 
during the peri-transplant setting, with 5% of patients requiring initiation of dialysis(Fadia).  The rate of atrial 
fibrillation in the peri-transplant period is approximately 13%, which is higher than reported in other patient 
populations undergoing treatment with high dose melphalan and autologous stem cell transplantation(Arun).  
Treatment related mortality in this population of patients has improved from ~17% in the late 1990’s, but remains 
~4% with many of these deaths related to cardiac events during or after stem cell infusion(Tsai).   
The standard protocol for high-dose conditioning prior to ASCT uses melphalan hydrochloride with propylene 
glycol as a co-solvent.  Propylene glycol has been reported to cause metabolic acidosis, sepsis-like syndrome, 
hyperosmolality, and renal dysfunction, as well as cardiac arrhythmias(Wilson, Zar, Yaucher).  Propylene glycol-
free melphalan was recently studied in a phase IIb trial that confirmed the efficacy and safety profile of this new 
formulation(Hari).  Based on this clinical trial, propylene glycol-free melphalan was approved by the Food and Drug 
Administration for use as a high-dose conditioning regimen prior to autologous stem cell transplantation in patients 
with multiple myeloma.    
Due to the known risk of renal and cardiac dysfunction in AL amyloidosis patients during the peri-transplant period, 
it is hypothesized that the newer formulation of propylene glycol-free melphalan may have decreased risk of toxicity 
in AL amyloidosis patients.   
 
 
 


Melphalan (Propylene Glycol-Free) in AL Amyloidosis Patients  
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3. 
PARTICIPANT SELECTION 
3.1  
Screening and Recruitment and Consenting 
 
 
The investigators will recruit for participants from within their own practice.  It is standard of care that 
patients scheduled for visits within the hematology/oncology clinics are "pre-screened" to determine if 
they may be "potentially eligible" for any available clinical trials. This is not specific for this study. A 
screening consent is not obtained, as the pre-screening review is conducted prior to their first 
appointment. 
 
 
No data will be collected. The medical records are reviewed and a screening note is placed in the 
medical record to indicate that the patient may or may not be "potentially eligible" for a clinical trial. 
If the patient is potentially eligible, the physician will discuss the study at the visit. No procedures are 
performed for screening until after consent is obtained.  
 
 
No data will be retained prior to obtaining consent.  No data is collected during the "pre-screening". 
During the pre-screen, if a patient is determined to be not potentially eligible for any available clinical 
trials, the patient would not be considered as a "screen fail" as they have not undergone a full screening. 
 
 
If potentially eligible, the investigator will inform the potential participant within his/her practice that 
he/she may be eligible for the research study. If the patient agrees to discuss and receive information 
about the study, an IRB-approved Informed Consent Form will be presented to the patient by a member 
of the research staff who will verbally outline the details of the procedures, risks, benefits, alternatives, 
costs, etc. The patient will be given the opportunity to bring the consent home and discuss with family 
members and/or other physicians and to ask any and all questions of the investigator and/or research 
staff. Once the patient is satisfied that all questions have been answered, if he/she wishes to participate, 
the consent form will be signed and dated by the patient and the person obtaining consent. Copies of 
the signed Informed Consent Form will be given to the patient, placed in the appropriate medical record, 
and placed in the research chart. 
 
Potential participants who are non-English speaking will be consented using the Short Form (if IRB 
approved).  A hospital translator, or a translator on the phone line, will be used throughout the consent 
process and throughout their participation in the study. 
 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process will be recorded in the subject’s source documents. The original consent form 
signed and dated by the subject and by the person consenting the subject prior to the subject’s entry 
into the study, must be maintained in the Investigator’s study files.  Participants will be enrolled 
following stem cell collection and prior to receiving the investigational agent.      
 
3.2 
Inclusion Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to participate in the study: 
   
• 
Age 18 years or older 
• 
Histologic diagnosis of primary systemic (AL) amyloidosis based on:  
o 
Deposition of amyloid material by Congo red stain showing characteristic apple green 
birefringence AND/OR characteristic appearance of fibrils on electron microscopy  
AND 
o 
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 
o 
Evidence of organ involvement 


Melphalan (Propylene Glycol-Free) in AL Amyloidosis Patients  
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• 
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 DLCO ≥ 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)  
 
3.3 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study: 
 
• 
Previous HDM/SCT  
• 
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 
• 
eGFR < 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 or planned 
during the course of the trial. 
• 
No plans for anticancer agents other than the study medication during the course of the study. If such 
agents are required for a patient then the patient must first be withdrawn from the study. 
• 
Ongoing alcohol or drug addiction 
• 
Unable or unwilling to comply with the protocol 
 
4. TREATMENT REGIMEN 
 
The investigational agent will be utilized as the conditioning regimen prior to autologous stem cell transplantation.  
Expected toxicities and potential risks as well as dose modifications for melphalan (propylene glycol-free) are 
described in Section 6.  No investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the participant’s AL amyloidosis. 
 
4.1 Stem cell mobilization (Standard): Filgrastim mobilization 
Mobilization regimen will follow transplant program standard.  
Filgrastim 16 mcg/kg/day SQ will begin 3 days before first stem cell collection through the day before the final 
day of collection. For example, first day of stem cell collection begins after filgrastim has been administered for 
3 days in a row.  The use of plerixafor 0.24 mg/kg is permitted for stem cell collection.   
 
• Central venous catheter placement:  A pheresis catheter will be placed in all patients prior to stem cell collection. 
 
4.2 Stem Cell Collection (Standard): >2.0 x 106 CD 34+/kg 
 
Stem cell collection will begin after three consecutive days of filgrastim and will continue daily for up to 5 days, 
until a yield of > 2.0 x 106 CD 34+ cells/kg is achieved. 
 
Stem Cell collection and storage will be performed utilizing standard institutional guidelines. 


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4.3 Conditioning Regimen (Investigational):  Evomela 70-100 mg/m2/dose on Days -3 and -2 
 
Melphalan (propylene glycol-free) (Evomela) will be administered as conditioning treatment prior to autologous 
stem cell transplantation.  The recommended dose is 100 mg/m2/day* by intravenous infusion on two consecutive 
days (Day -3 and Day -2) prior to autologous stem cell transplantation (Day 0).  Dose reductions to 70 mg/m2/day 
will be will be permitted at Investigator discretion due to patient functional status, age, and quantity of stem cells 
collected during mobilization.  
 
* For patients > 130% of their ideal body weight, Adjusted Ideal Body Weight will be used to calculate dose. 
 
Melphalan (propylene glycol-free) will be provided by Spectrum Pharmaceuticals, Inc. Melphalan (propylene 
glycol-free) is provided in 50mg vials which will be reconstituted for intravenous administration. 
 
Hydration and antiemetic administration will follow transplant program standard, as outlined below.  Minor 
deviations may be considered if necessary for treatment if they do not impact patient safety in the clinical 
judgment of the treating physician and the transplant team.   
 
4.4 Stem cell infusion (Standard): Day 0  
 
4.5 General Concomitant Medication and Supportive Care Guidelines 
 
Participants will be instructed not to take any additional medications (including over-the-counter products) during 
the course of the study without prior consultation with the investigator. At each visit, the investigator will ask the 
participant about any new medications he/she is or has taken after the start of the study drug. 
 
Standard supportive care medications are permitted. Institution guidelines are as outlined below.  Minor 
adjustments may be made at the treating physician’s discretion based on individual clinical situations.  Rationale 
for such adjustments will be documented in the medical record:  
 
Hydration Guidelines:  
Beginning 2 hours before propylene glycol-free melphalan and ending 2 hours after propylene glycol-free 
melphalan, IV hydration with D5 0.5NS + KCl 20 mEq/L.  Rate and composition of IV fluid hydration will be 
modified to meet individual patient needs.  
 
Antiemetic (prophylactic) Guidelines:   
To be given 30 minutes before propylene glycol-free melphalan:  
Granisetron 2mg PO 
Dexamethasone 10mg PO 
Lorazepam 0.5mg PO 
 
For Nausea/Vomiting:  
Lorazepam 0.5-1mg PO q3 hours prn and QHS 
Compazine 10 mg PO prn nausea/vomiting 
 
The following restrictions apply during the entire duration of the study: 
• 
No other investigational therapy should be given to participants. 
• 
No anticancer agents other than the study medication should be given to participants. If such agents are 
required for a patient then the patient must first be withdrawn from the study. 
 
Infection prophylaxis: 
Propylene glycol-free melphalan is used as a myeloablative treatment prior to autologous stem cell 
transplantation.  Leukopenia with compromised immune function is expected with myeloablative therapy and 
for this reason the following infection prophylaxis will be applied, which is standard for patients undergoing 
stem cell transplant.  Strengths, routes and durations will be determined as per standard of care:   


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published, or used by other persons without prior written authorization from the sponsor/investigator. 
• 
Levofloxacin for bacterial infection prophylaxis.  This will be continued until neutrophil 
engraftment or until replacement by additional anti-infectives that may be required for treatment of 
fever or infection. 
• 
Acyclovir for prophylaxis of herpes zoster infection.  This will be continued until one year after 
autologous stem cell transplantation. 
• 
Fluconazole for fungal infection prophylaxis.  This will be continued until neutrophil 
engraftment.   
 
**Anti-infective medications can be adjusted as needed based on individual patient’s organ function or 
allergy history.  
 
Growth factors: 
Filgrastim 300 mcg or 480 mcg will be administered SQ once daily from Day +1 until neutrophil engraftment 
 
Medications to avoid:  
IV medications that are known to contain higher levels of propylene glycol will be avoided (including 
diazepam, lorazepam, phenobarbital, phenytoin, nitroglycerin, and digoxin) while participating in the 
study. If those medications are determine to be clinically necessary, then the details regarding dosage, 
frequency, and duration of use will be well-documented and considered in regards to patient outcomes. 
 
4.6 Duration of Participation  
 
Participants will receive two doses of melphalan (propylene glycol-free) prior to autologous stem cell 
transplantation.  Side effects of treatment will be monitored regularly until discharge from the stem cell 
transplantation program.  Participants will be followed for one year after transplantation, wit h 
hematologic and organ responses evaluated at 6 and 12 months after transplantation.  We anticipate 1 
year duration for individual subjects.  We anticipate the study will remain active for a total of 4 years including 
enrollment, treatment, follow-up and data analysis. 
 
4.7 Criteria For Removal From Protocol Treatment: 
 
• 
Inadequate stem cell yield 
 
• 
The patient may withdraw from the study at any time for any reason. 
 
• 
Completion of all protocol therapy. 
 
5. EXPECTED TOXICITIES  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate medical treatment 
should be used (including anti-emetics, anti-diarrheals, etc.). All adverse events experienced by participants will be 
collected from the time of the first dose of study treatment, through 30 days after administration of the last dose of 
study drug or “discharge” from the stem cell transplant program, whichever comes first.  
 
 
5.1 Toxicity Management 
 
 
Participants who have an adverse event or abnormal laboratory value suspected to be related to melphalan (propylene 
glycol-free) will be followed until the adverse event or abnormal laboratory resolves or returns to grade 1.  
 
It will be documented whether or not each participant completed the clinical study. The reason either study treatment 
or observations were discontinued will be recorded. Reasons that a participant may discontinue participation in a 
clinical study are considered to constitute one of the following: 
1. Adverse event(s) 
2. Abnormal laboratory value(s) 
3. Abnormal test procedure result(s) 
4. Disease progression (including initiation of new therapy) 


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5. Protocol violation 
6. Participant withdrew consent 
7. Lost to follow-up 
8. Administrative problems (including study-related issues, IRB and other regulatory issues, and drug administration 
issues) 
9. Death 
10. General or specific changes in the participant's condition that render the participant unacceptable for further 
treatment in the opinion of the treating investigator. 
 
 
6. 
DRUG FORMULATION AND ADMINISTRATION  
 
6.1 Melphalan (propylene glycol-free) Formulation 
 
Melphalan (propylene glycol-free) is provided as a white to off-white lyophilized powder in single-dose vial 
for reconstitution.  After reconstitution the solution is clear and colorless to light yellow.  Each vial contains 
50mg melphalan free base equivalent to 56 mg melphalan hydrochloride.  
 
6.2 Melphalan (propylene glycol-free) Package, Storage and Handling  
 
Melphalan (propylene glycol-free) is supplied in a single carton containing one vial.  The medication should 
be stored at room temperature 25° C (77° F).  Temperature excursions are permitted between 15-30° C (59-
86° F).  The medication is light sensitive and should be retained in the original carton until time of use.  This 
is a cytotoxic drug and should be handled using special handling and disposal procedures.   
 
Medication labels will comply with US legal requirement and be printed in English.  The storage conditions 
for the study drug will be described on the medication label.   
 
6.3 Melphalan (propylene glycol-free) Availability 
 
Melphalan (propylene glycol-free) is commercially available, but will be supplied free-of-charge from 
Spectrum Pharmaceuticals, Inc with labeling for investigational use.   
 
Drug supplies must be requested using Spectrum’s Investigator-Initiated Study Drug Product Request Form.  
The completed form should be sent to Spectrum Pharmaceuticals at IISdrugsupply@sppirx, leaving at least 2 
weeks between request and delivery. 
 
6.4 Melphalan (propylene glycol-free) Administration 
 
Melphalan (propylene glycol-free) will be administered over 30 minutes via dual lumen apheresis catheter  as 
part of the Conditioning Regimen on Days -3 and -2 prior to autologous stem cell transplantation (Day 0).   
Treatment may be administered inpatient or outpatient.  This will be at the discretion of the investigator and 
will be discussed at the weekly Autologous Stem Cell Transplantation Team Meeting based on the patient’s 
functional status and organ function.   
 
6.5 Melphalan (propylene glycol-free) Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
inventory and disposition of the agent using the NCI Drug Accountability Record of another comparable drug 
accountability form.  (See the CTEP website at http://ctep.cancer.gov/protocolDevelopment for the “Policy 
and Guidelines for Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form.)  This will be conducted by the BMC Investigational Pharmacy Services office. 
Unused melphalan (propylene glycol-free) will be destroyed per institutional policy.  Destruction will be 
documented in the Drug Accountability Record Form.   
 
 


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7. 
STUDY CALENDAR 
 
The following testing will be performed per institutional standard for transplant patients. 
REQUIRED STUDIES 
Pre-
Treatment * 
Stem Cell 
Mobilization 
& Collectionb  
Study Drug 
(chemotherapy) 
Days -3 & -2 
Stem Cell 
Infusion 
Day 0 
Days +1 
through 
engraftment  
F/U # 
PHYSICAL 
 
 
 
 
 
 
History & Physical Exam 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight, Vital Signs & Performance Status 
X 
X 
X 
X 
X 
X 
Toxicity Notation 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
LABORATORY-Serum 
 
 
 
 
 
 
CBC with Differential  
X 
X 
X 
X 
X 
X 
BUN / Serum Creatinine / Glucose / Mg / Phos 
X 
X 
X 
X 
X 
X 
Bili / Alb / Alp / SGOT / SGPT 
X 
X 
X 
 
X 
X 
Na / K / Cl / CO2  
X 
X 
X 
 
X 
X 
COR / CRP / LD / Amy / TP/ chol / CK / Ca 
X 
 
 
 
 
X 
IRON / Uric/ TSH / D-DIMER /  Factor X 
X 
 
 
 
 
X 
-2 Microglobulin / C-reactive protein 
X 
 
 
 
 
X 
SPEP / / SIFE / BNP 
X 
 
 
 
 
X 
VITB12 / FOL / ESR / RETIC / Troponin I 
X 
 
 
 
 
X 
PT/ PTT/ INR 
X 
X 
 
 
 
X 
FLC 
X 
 
 
 
Xc 
X 
HCG (for women of childbearing potential) 
X 
 
Xa 
 
 
 
Hep B Surface AG, Hep B Core AB, Hep C AB 
X 
 
 
 
 
 
HIV - 1+2  
X 
 
 
 
 
 
Type & Screend 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
LABORATORY-Urine 
 
 
 
 
 
 
UA 
X 
 
 
 
 
X 
UTP24 / UCR24 / UKAP / ULAM 
X 
 
 
 
 
X 
UPEP / UIFE / TV 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
PATHOLOGY 
 
 
 
 
 
 
BM aspiration / biopsy 
X 
 
 
 
 
X≠ 
Fat aspirate 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
EKG  
X 
 
 
X 
 
X 
CXR 
X 
 
 
 
 
 
X 
Echocardiogram 
X 
 
 
 
 
X 
PFT’s 
X 
 
 
 
 
 
CPST  
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
Stem Cell Mobilization and collection 
 
X 
 
 
 
 
High-Dose Melphalan (propylene glycol-free)  
 
 
X 
 
 
Stem Cell Infusion 
 
 
 
X 
 
 
   Testing during pre-treatment, during treatment and at follow-up should be done per institutional standard and as clinically indicated, including 
toxicity evaluations. 
#  Follow-up evaluations for disease response will take place at 6 months and one year. 
a 
Pregnancy test to be done within 7 days prior to initiation of chemotherapy for women of childbearing potential 
b 
Dates are not specific as stem cell mobilization may take place any time prior to high dose chemotherapy and stem cell transplant.   
c 
FLC’s to be drawn weekly 
d 
Type & Screen to be done on Mondays and Thursdays (or at least twice weekly depending on patient schedule) 
*  Tests are recommended for good medical practice and only those listed in the eligibility criteria are required by the protocol. 
      If clinically indicated at physician’s discretion 
≠ 
If needed to evaluate response. 
 


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8. 
MEASUREMENT OF EFFECT  
8.1 Definitions 
 
Evaluable for toxicity: All participants who receive at least one dose of study treatment will be evaluable for 
toxicity from the time of their first treatment. 
 
Evaluable for objective response: Only those participants who have received at least one dose of melphalan 
(propylene glycol-free) and have had their disease re-evaluated will be considered evaluable for response. These 
participants will have their response classified according to the definitions stated below. (Note: Participants 
who exhibit objective disease progression or die prior to 100 days will also be considered evaluable.) 
8.2 AL Amyloidosis Hematologic Response Criteria (Gertz, Palladini) 
 
CATEGORY 
RESPONSE CRITERIA 
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  
Progressive 
Disease (PD) 
• 
From CR, an increase in serum M-protein to > 0.5 g/dL, an increase in the urine M-protein to > 200 
mg/day, or an increase in the serum monoclonal free light chain by > 10 mg/dL (100 mg/L). From 
VGPR, PR or SD, an increase in the serum M-protein from the lowest level by > 50%, as long as the 
absolute magnitude of this increase is > 0.5 g/dL; or an increase in the urine M-protein from the lowest 
level by 50%, as long as the absolute magnitude of this increase is > 200 mg/day; or an increase in 
the serum or urine monoclonal free light chain by > 50% from the lowest level, as long as the absolute 
magnitude is > 10 mg/dL (100 mg/L). 
8.3 Organ Response Criteria (Gertz) 
 
A subject will be said to have had an organ response in an involved organ if any of the following criteria are met.  
 
• 
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. 
• 
Liver: ≥ 50% decrease in normalization of an initially elevated alkaline phosphatase level or reduction in the size 
of the liver by at least 3 cm if assessed by imaging.  
• 
Neuropathy: While neurotoxicity is acceptable for determining organ involvement, it will not be adequate for 
assessing organ response; organ response will be indeterminable for subjects in which neurotoxicity is the only site 
of organ involvement.  
• 
Gastrointestinal Tract: While GI involvement is acceptable for determining organ involvement, it will not be 
adequate for assessing organ response: organ response will be indeterminable for subjects in which GI is the only 
site of organ involvement. 
 
 
 


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9. 
ADVERSE EVENTS 
 
9.1 Adverse Event Definition 
 
An adverse event is any untoward or unfavorable physical or psychological occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease 
temporally associated with the subject’s participation in the research, whether or not considered related to the 
subject’s participation in the research. 
 
9.2 Serious Adverse Event Definition 
 
Serious Adverse Event:  According to the FDA’s Code of Federal Regulations Title 21 Part 314.80, a SAE is any 
untoward medical occurrence that results in any of the following outcomes: 
• 
Death 
• 
A life-threatening event 
• 
Inpatient hospitalization or prolongation of an existing hospitalization 
• 
A persistent or significant disability / incapacity 
• 
A congenital anomaly / birth defect 
• 
Important medical events based upon appropriate medical judgment that may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition of 
serious. 
 
Expectedness:  Unexpected events include any adverse drug experience that is not listed in the current Investigator 
Brochure (IB) for the drug product (e.g., all previously unobserved or undocumented events).  
 
Relatedness:  Indicates that a determination has been made that an event had a reasonable possibility of being related 
to exposure to the product.  Examples of causality include not related, unlikely, possibly, probable, definitely related 
and unable to be determined. 
Unexpected fatal or life-threatening and related experiences associated with the use of the study treatment will be 
reported to Spectrum Pharmaceuticals, Inc within three business days of awareness of the event.  
 
Upon request from the FDA or Spectrum Pharmaceuticals additional data or information that the agency or Spectrum 
Pharmaceuticals deems necessary, must be reported as soon as possible but no later than 15 calendar days. 
 
Reporting of AEs and SAEs to the IRB will take place according to institutional IRB policy. 
 
9.3 Adverse Drug Reaction Reporting 
 
An investigator or other study personnel must forward information related to Serious Adverse Events (SAEs) to 
Spectrum Pharmaceuticals, the manufacturer, via facsimile or e-mail using the MedWatch form, whether the SAE is 
unexpected or not based on the product investigator’s brochure, and whether drug-related or not based on clinical 
investigator’s assessment, within 24 hours of becoming aware of the event. Every effort should be made to provide 
complete and accurate information on the MedWatch form. 
 
Forms should be e-mailed or faxed to: 
pharmacovigilance@aurobindo.com 
 
 
Toxicity will be scored using CTCAE Version 4.03 for toxicity and adverse event reporting. A copy of the CTCAE 
Version 4.03 can be downloaded from the CTEP homepage (HTTP://CTEP.INFO.NIH.GOV). All appropriate 
treatment areas should have access to a copy of the CTCAE Version 4.03. All adverse clinical experiences, whether 
observed by the investigator or reported by the subject, must be recorded, with details about the duration and 
intensity of each episode, the action taken with respect to the test drug, and the subject’s outcome. The investigator 
must evaluate each adverse experience for its relationship to the test drug and for its seriousness.  
 


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The investigator must appraise all abnormal laboratory results for their clinical significance. If any abnormal 
laboratory result is considered clinically significant, the investigator must provide details about the action taken with 
respect to the test drug and about the subject’s outcome.  
 
AEs and SAEs will be reported from the first dose of study drug through 30 days after administration of the last dose 
of study drug or “discharge” from the stem cell transplant program, whichever is later. All SAEs should continue to 
be monitored until they are resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).  
 
9.4 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation of study intervention, 
throughout the study, and within 30 days of the last study intervention should be followed to their resolution, or until 
the participating investigator assesses them as stable, or the participating investigator determines the event to be 
irreversible, or the participant is lost to follow-up. The presence and resolution of Grade 2 or higher AEs and SAEs 
(with dates) should be documented on the appropriate case report form and recorded in the participant’s medical record 
to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring visit to obtain 
additional case details deemed necessary to appropriately evaluate the SAE report (e.g., hospital discharge summary, 
consultant report, or autopsy report).  
 
10. 
DATA MANAGEMENT 
 
10.1 
Analyses and Reporting 
 
Data generated by the methods described in the protocol will be recorded in the subjects' medical records and/or 
study progress notes. Data may be transcribed legibly on CRFs supplied for each subject or directly inputted into an 
electronic system or any combination thereof.  Data will be analyzed and reported after study is completed or 
meaningful endpoints are reached. All subsequent data collected will be analyzed and reported in a follow-up 
clinical report.  
 
10.2 
Data Safety Monitoring  
 
Toxicity and accrual monitoring will be performed on a routine basis by the study investigators as well as the 
multidisciplinary members of the Amyloid Center at Boston University, which has over 40 years’ experience in the 
treatment of AL amyloidosis. Subjects will undergo toxicity assessment, performance status assessment and laboratory 
tests according to the study calendar in Section 7.  Organ response assessment will be conducted at the six-month and 
one year follow-up appointments. The clinical status and laboratory reports of the study participants will be reviewed 
routinely by the co-investigators at the weekly meetings of the Autologous Stem Cell Transplantation Team.  
 
In addition, a medical monitor, to be assigned prior to study activation, will review the protocol as outlined below.  
The Medical Monitor will be a qualified clinician with relevant expertise, but no direct connection with the research, 
whose primary responsibility is to provide independent safety monitoring in a timely fashion. The PI will submit a 
report to the Medical Monitor, at a minimum of once every 6 months, including a list of all adverse events and serious 
adverse events (regardless of relatedness).  In addition, any unanticipated problems involving risks to participants or 
others and participant deaths within 100 days of study intervention will be reported to the Medical Monitor within 24 
hours of the PI’s knowledge of the event.  The Medical Monitor is expected to provide a formal, unbiased written 
report evaluating individual and cumulative participant safety data when making recommendations regarding needed 
changes or continuation of the study.  Although the PI is responsible for assigning causality and expectedness, the 
medical monitor will comment on whether or not (s)he is in agreement.  Medical Monitor reports will be submitted to 
the PI following each review (at a minimum of once every 6 months), which the PI will, in turn, submit to the IRB. 
 
 
10.3 
Study monitoring and auditing 
 


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Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the US Code 
of Federal Regulations (CFR).  
 
Investigators must enter study data onto CRFs or other data collection system. The Investigator will permit study-
related monitoring visits and audits by Spectrum or its representatives, IRB/EC review, and regulatory inspection(s) 
(e.g., FDA, EMEA, TPP), providing direct access to the facilities where the study took place, to source documents, 
to CRFs, and to all other study documents.  
 
11. 
REGULATORY CONSIDERATIONS 
 
11.1 
Protocol Amendments 
 
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed and approved by 
Spectrum. Amendments should only be submitted to IRB/EC after consideration of Spectrum review. Written 
verification of IRB approval will be obtained before any amendment is implemented. 
 
11.2 
Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation will be made only 
for that subject. A decision will be made as soon as possible to determine whether or not the subject (for whom the 
deviation from protocol was effected) is to continue in the study. The subject’s medical records will completely 
describe the deviation from the protocol and state the reasons for such deviation. In addition, the Investigator will 
notify the IRB in writing of such deviation from protocol. Non-emergency minor deviations from the protocol will 
be permitted with approval of the Principal Investigator. 
 
11.3 
Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical principles outlined in the 
Declaration of Helsinki. The review of this protocol by the IRB/EC and the performance of all aspects of the study, 
including the methods used for obtaining informed consent, must also be in accordance with principles enunciated in 
the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of 
Human Subjects and Part 56 Institutional Review Boards.  
 
The Investigator will be responsible for preparing documents for submission to the relevant IRB/EC and obtaining 
written approval for this study. The approval will be obtained prior to the initiation of the study.  
The approval for both the protocol and informed consent must specify the date of approval, protocol number and 
version, or amendment number.  
 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the Investigator to the 
IRB/EC for approval. The Investigator is also responsible for notifying the IRB/EC of any serious deviations from 
the protocol, or anything else that may involve added risk to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the IRB/EC prior to 
use. 
 
11.4 
Study Records Requirements 
 
The Investigator must ensure that the records and documents pertaining to the conduct of the study and the 
distribution of the study drug, that is copies of CRFs and source documents (original documents, data, and records 
[e.g., hospital records; clinical and office charts; laboratory notes; memoranda; subject’s diaries or evaluation 
checklists; SAE reports, pharmacy dispensing records; recorded data from automated instruments; copies or 
transcriptions certified after verification as being accurate copies; microfiches; photographic negatives, microfilm, 
or magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical study; documents regarding subject treatment and study drug 
accountability; original signed informed consents, etc.]) be retained by the Investigator for as long as needed to 
comply with national and international regulations (generally 2 years after discontinuing clinical development or 
after the last marketing approval). The Investigator agrees to adhere to the document/records retention procedures by 
signing the protocol. 


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published, or used by other persons without prior written authorization from the sponsor/investigator. 
 
12. 
STATISTICAL CONSIDERATIONS  
 
This is a single arm, open label study designed to evaluate the safety and efficacy of melphalan (propylene glycol-
free) as a conditioning regimen in AL amyloidosis patients undergoing treatment with autologous stem cell 
transplantation. Patients will receive treatment with 70-100 mg/m2/day on Days -3 and -2 prior to autologous stem 
cell transplantation.   
 
12.1 
Study Design/Endpoints 
 
The primary endpoint of the current study is: 
 
• 
To determine the safety profile of melphalan (propylene glycol-free) in the conditioning regimen prior to 
autologous stem cell transplantation in AL amyloidosis patients 
 
The secondary endpoints are: 
 
• 
To assess the time until neutrophil and platelet engraftment 
• 
To evaluate organ response 
• 
To assess treatment related mortality at 100 days 
• 
To assess hematologic overall response rate at 6 months after autologous stem cell transplantation 
• 
To assess hospitalizations 
 
12.2 
Sample Size/Accrual Rate 
 
Using an optimal 2-stage design, we assume a total of 30 patients per year for 3 years meeting inclusion/exclusion 
criteria, with approximately 50% enrollment with a target of 43 patients enrolled.  Using an optimal 2-stage design, 
we assume p0 = 60% and p1 = 80%, with these values representing the patients free of unacceptable toxicity.  We 
would have a 5% bound on the type I error and 80% power to detect a statistically significant toxicity rate with 11 
patients enrolled in Stage 1 and proceeding to an additional 32 patients enrolled in Stage 2 if the toxicity rate is 
acceptable in Stage 1.  Using this design the treatment would be declared successful if at least 30 of the 43 patients 
did not have unacceptable toxicity during the study period.  A transplant related mortality (determined by the stem 
cell transplant committee to be related to the study drug) of 20% or greater would be cause for study termination at 
stage 1. Transplant related mortality is defined as mortality that occurs within 100 days of stem cell transplantation. 
 
12.3 
Reporting and Exclusions 
 
All participants who met the eligibility criteria and were enrolled in the trial will be included in the main analysis of the 
response rate. All conclusions will be based on all eligible participants. 
 
 
13. 
REFERENCES  
 
Arun M, Brauneis D, Ruberg F, Shelton A, Sloan JM, Quillen K, Sanchorawala V, Varga C.  The incidence of atrial 
fibrillation among patients with AL amyloidosis undergoing high dose melphalan and stem cell 
transplantation: Experience at a single institution.  Poster presentation 2016.  
Fadia A, Casserly LF, Sanchorawala V, et al. Incidence and outcome of acute renal failure complicating autologous 
stem cell transplantation for AL amyloidosis. Kidney Int. 2003;63:1868-1873. 
Gertz M, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, Merlini G, Moreau P, Ronco P, 
Sanchorawala V, Sezer O, Solomon A, Grateau G Definition of organ involvement and treatment response 
in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International 
Symposium on amyloid and amyloidosis. Am J Hematol. 2005;79(4):319-28.  
Gertz MA, Lacy MQ, Dispenzieri A, et al.  Refinement in patient selection to reduce treatment-related mortality 
from autologous stem cell transplantation in amyloidosis.  Bone Marrow Transplant.  2013;48(4):557-561. 


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This document is confidential and the property of Boston Medical Center. No part of it may be transmitted, reproduced, 
published, or used by other persons without prior written authorization from the sponsor/investigator. 
Hari P, Aljitawi O, Arce-Lara C, et al.  A Phase IIb, multicenter, open-label, safety, and efficacy study of high-dose, 
propylene glycol-free melphalan hydrochloride for injection (EVOMELA) for myeloablative conditioning 
in multiple myeloma patients undergoing autologous transplantation.  Biol Blood Marrow Transplant 
2015;21:2100-2105. 
Mahmood S, Palladini G, Sanchorawala V, et al.  Update on treatment of light chain amyloidosis.  Haematol 
2013;99(2):209-21. 
Palladini G, Merlini G.  Transplantation vs. conventional-dose therapy for amyloidosis.  Curr Opin Oncol. 
2011;23(2):214-220.   
Tsai SB, Seldin DC, Quillen K, et al. High-dose melphalan and stem cell transplantation for patients with AL 
amyloidosis: trends in treatment-related mortality over the past 17 years at a single referral center. 
Blood;120:4445-4446. 
Wilson KC, Reardon C, Theodore AC, et al.  Propylene glycol toxicity: a severe iatrogenic illness in ICU patients 
receiving IV benzodiazepines: a case series and prospective, observational pilot study. Chest 
2005;128:1674-81.  
Yaucher NE, Fish JT, Smith HW, et al.  Propylene glycol-associated renal toxicity from lorazepam infusion. 
Pharmacotherapy 2003;23:1094-99.  
Zar T, Graeber C, Perazella MA.  Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial 
2007;20:217-9.   
 
 
14. 
APPENDICES 
 
14.1 
APPENDIX A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly.  
5 
Dead. 
0 
Dead.