Clinical trial NCT03417284
Conditions: Plasma Cell Myeloma
Sponsor: M.D. Anderson Cancer Center
Start date: 2019-10-09; Completion date: 2024-07-18
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/II trial studies the side effects and best dose of melphalan hydrochloride in treating participants with newly-diagnosed multiple myeloma who are undergoing a donor stem cell transplantation. Giving chemotherapy before a donor stem cell transplantation helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the participant, they may help the participant's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving melphalan hydrochloride before a donor stem cell transplantation may work better than standard chemotherapy in helping to prevent multiple myeloma from coming back.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the optimal dose and schedule of melphalan for injection (melphalan hydrochloride \[Evomela\]) prior to autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma (MM).

II. To collect the pharmacokinetic data and compare the exposure-response evaluations between the 2 infusion schedules.

SECONDARY OBJECTIVES:

I. To determine the incidence of treatment related mortality (TRM) at day 90 after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela.

II. To determine the rate of minimal residual disease (MRD) negative complete response (CR) rate at day 90 after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela.

III. To determine the progression-free survival (PFS) after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela.

OUTLINE: This is a phase I, dose escalation study of melphalan hydrochloride followed by a phase II study.

PREPARATIVE REGIMEN: Participants are randomized to 1 of 2 groups.

GROUP 1: Participants receive melphalan hydrochloride intravenously (IV) over 30-60 minutes on day -2.

GROUP 2: Participants receive melphalan hydrochloride IV over 8-9 hours on day -2.

TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes.

POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz subcutaneously (SC) once daily (QD) starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an absolute neutrophil count (ANC) of 0.5 x 10\^9/L.

After completion of study treatment, participants are followed up at 3 months, every 3 months for 1 year, and then annually for 1 year.

Arms: arm 1: PREPARATIVE REGIMEN: Participants receive melphalan hydrochloride IV over 30-60 minutes on day -2.

TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes.

POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz SC QD starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an ANC of 0.5 x 10\^9/L. arm 2: PREPARATIVE REGIMEN: Participants receive melphalan hydrochloride IV over 8-9 hours on day -2.

TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes.

POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz SC QD starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an ANC of 0.5 x 10\^9/L.
Interventions: intervention 1: Autologous Hematopoietic Stem Cell Transplantation intervention 2: Filgrastim-sndz intervention 3: Melphalan Hydrochloride
Intervention descriptions: intervention 1: Undergo HSCT intervention 2: Given SC intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2017-0399 
Protocol Title 
Prospective Phase I/II Trial to Jointly Optimize the Administration 
Schedule(s) and Dose(s) of Melphalan for Injection (Evomela) as 
a Preparative Regimen for Autologous Hematopoietic Stem Cell 
Transplantation in Patients with Newly Diagnosed Multiple 
Myeloma 
Protocol Phase  
I/II 
Protocol Version 11.0 
Version Date 
11 February 2022 
 
Protocol PI 
Qaiser Bashir, MD 
Department 
Stem Cell Transplantation and Cellular Therapy 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
136601 


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Prospective Phase I/II Trial to Jointly Optimize the Administration 
Schedule(s) and Dose(s) of Melphalan for Injection (Evomela) as a 
Preparative Regimen for Autologous Hematopoietic Stem Cell 
Transplantation in Patients with Newly Diagnosed Multiple Myeloma 
 
 
 
 
 
 
 
 
 
 
1 The University of Texas MD Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department 
2 The University of Texas MD Anderson Cancer Center, Pharmacy Clinical Programs 
3 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
 
Institution Study Number:  2017-0399 
Sponsor:   Acrotech Biopharma 
IND Holder:  The University of Texas MD Anderson Cancer Center 
IND Number:  136601 
Principal Investigator:  Qaiser Bashir, MD 
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy Department 
1515 Holcombe Blvd, Unit 0432 
Houston, TX 77030 
Telephone: 713.794.4422 
Fax: 713.792.8949 
qbashir@mdanderson.org 
 
Co-Chairs:  Muzaffar H. Qazilbash, MD1 
Collaborators:  Alison Gulbis, PharmD2 
  Jitesh D. Kawedia, PhD2 
Dawen Sui, MS3 
Peter F. Thall, PhD3 


 
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Table of Contents 
 
 
1.0 
OBJECTIVES ......................................................................................................................................................... 3 
2.0 
BACKGROUND AND RATIONALE ......................................................................................................................... 3 
3.0 
BACKGROUND DRUG INFORMATION .................................................................................................................. 9 
4.0 
PATIENT ELIGIBILITY .......................................................................................................................................... 12 
5.0 
PRETREATMENT EVALUATION .......................................................................................................................... 13 
6.0 
TREATMENT PLAN ............................................................................................................................................. 14 
7.0 
EVALUATION DURING STUDY ............................................................................................................................ 15 
8.0 
ADVERSE EVENTS AND REPORTING REQUIREMENTS ........................................................................................ 17 
9.0 
CRITERIA FOR RESPONSE AND PROGRESSION ................................................................................................... 22 
10.0 
CRITERIA FOR REMOVAL FROM THE STUDY ...................................................................................................... 22 
11.0 
STATISTICAL CONSIDERATIONS ......................................................................................................................... 22 
12.0 
REFERENCES ...................................................................................................................................................... 26 
 
 
 


 
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Protocol Body 
 
1.0     Objectives 
1.1 
Primary Objectives: 
 
A. To determine the optimal dose and schedule of melphalan for injection (Evomela) prior to 
autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma (MM). 
B. To collect the pharmacokinetic data and compare the exposure-response evaluations 
between the 2 infusion schedules. 
 
1.2 
Secondary Objectives: 
 
A. To determine the incidence of treatment related mortality (TRM) at day 90 after auto-HCT 
in newly diagnosed myeloma patients treated on different schedules and doses of 
Evomela. 
B. To determine the rate of minimal residual disease (MRD) negative complete response 
(CR) rate at day 90 after auto-HCT in newly diagnosed myeloma patients treated on 
different schedules and doses of Evomela. MRD negative is defined as absence of 
phenotypically aberrant clonal plasma cells by nerve growth factor (NGF) on bone marrow 
aspirates using the EuroFlow standard operation procedure for MRD detection in multiple 
myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated 
cells or higher. 
C.To determine the progression-free survival (PFS) after auto-HCT in newly diagnosed 
myeloma patients treated on different schedules and doses of Evomela. 
2.0 Background and Rationale 
2.1 
Rationale and Hypothesis 
 
The solubilizer used in alkeran (brand name melphalan) for injection is propylene glycol (PG), 
which is potentially associated with an array of side effects, such as renal failure, cardiac 
arrhythmias, hyperosmolality, increased anion gap metabolic acidosis, and sepsis like 
syndrome. In addition, melphalan has marginal solubility and limited chemical stability upon 
reconstitution and dilution that prevents the solution from being administered as a longer 
infusion. The commercial product; after reconstitution with sterile solution that contains PG; can 
develop an impurity (citrate derivative of melphalan) in <30 minutes and, when further diluted, 
melphalan loses its potency over time. 
 
Melphalan for injection (Evomela) is a PG free reformulation of alkeran. Evomela incorporates 
Captisol brand of beta-cyclodextrin sulfobutyl ethers sodium salts. The substitution of Captisol 
for the excipients found in alkeran directly overcomes the formulation limitations of alkeran. 
Evomela can be dissolved directly using saline. Results show that based on the increase in 
total impurities in Evomela at 0.45 mg/mL, admixture solutions are about 5, 9, 15 and 29 times 
more stable at concentrations of 0.45, 1.0, 2.0 and 5.0 mg/mL, respectively. Results confirmed 
that reconstituted Evomela solution can be stored in the vial for up to 1 hour at room 
temperature or for up to 24 hours at refrigerated temperature (2 – 8 °C) with no significant 
degradation. After storage in the vial, it remains stable for an additional 3 to 29 hours after 
preparation of admixture solution in infusion bags at concentrations of 0.25 to 5.0 mg/mL, 


 
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respectively. In addition, Evomela solution in saline, at concentration of 5.0 mg/mL melphalan 
was bacteriostatic through 72 hours storage at 2 – 8 °C (Evomela Investigators Brochure, 
Appendix A). 
 
Depending on the final concentration, it is stable at room temperature for up to 24-hours upon 
reconstitution followed by immediate dilution (Evomela Investigator Brochure, Appendix A). This 
results in less handling of this cytotoxic agent by pharmacy and nursing staff with a concomitant 
decrease in exposure risks and increase in convenience and administration flexibility. 
 
Based on the above observations, we hypothesize that Evomela will be easier to handle and 
administer to the patients compared to alkeran. Furthermore, Evomela may actually be less 
toxic due to the absence of PG and this will allow for the escalation of dose and prolongation of 
infusion time, in order to increase the efficacy of melphalan in patients undergoing auto-HCT. 
 
2.2 
Introduction and Background 
 
2.2.1 
Autologous Hematopoietic Stem Cell Transplantation In Multiple Myeloma 
 
A pivotal Intergroupe Francophone du Myelome (IFM) trial in 1996 showed that auto-HCT 
prolonged survival compared to the conventional chemotherapy[1]. Thereafter, several trials 
have shown that auto-HCT can prolong PFS[2, 3] or both PFS and OS[4, 5] compared to 
non-transplant based regimens (Table 1). Based on available data auto-HCT is recommended 
as consolidative therapy for patients with MM (grade A recommendation from American Society 
for Blood and Marrow Transplantation)[6]. 
 
 


 
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Table 1. Summary of prospective randomized trials comparing conventional chemotherapy with 
auto-HCT that showed prolonged PFS and OS with auto-HCT. 
 
Study 
Patients 
Regimen 
Response 
TRM 
PFS 
OS 
Child et 
al.[4] 
N=407 
<65-years 
Untreated 
*DBCM 
Vs. 
DVPC à M200 
or M140+TBI 
(N=8) 
CR rate 8% 
vs. 44% 
(p<0.001) 
6 deaths 
within 100 
days 
**19.6 mo 
vs. 31.6 mo 
(p<0.001) 
**42.3 mo vs. 
54.1 mo 
(p=0.04) 
Palumbo 
et al. [5] 
N=194 
50-70 years 
MP x 6 
Vs. 
M100 x 2 
Near CR 
6% vs. 
25% 
(p=0.002) 
At 3-year 
37% vs. 
16% 
(p<0.001) 
At 3-year 
77% vs. 62% 
(p<0.001) 
Attal et 
al.[1] 
N=200 
<65-years 
Untreated 
*VMCP 
alternating with 
BVAP 
Vs. 
VMCP 
alternating with 
BVAP à 
M140+TBI 
CR+VGPR 
rate 14% 
vs. 38% 
(p<0.001) 
18 mo vs. 
41 mo 
(p=0.01) 
37.4 mo vs. 
NR 
(p=0.03) 
TRM, Treatment-related mortality; PFS, Progression-free survival; OS, overall survival; 
CR, Complete response; VGPR, Very good partial remission; NR, Not reached 
D, Doxorubicin; B, (BCNU) Carmustine; C, Cyclophosphamide; M, Melphalan; V, 
Vincristine; P, Methylprednisolone/Prednisone; TBI, Total body irradiation; 
*Both arms received maintenance therapy with interferon alfa-2a. 
** Median. 
 
Melphalan Dose Escalation Studies 
 
Melphalan remains the mainstay of pre-transplant conditioning therapy for myeloma and no 
other drug combination has convincingly shown superiority over melphalan alone. The data 
suggests that more intense chemotherapy may be useful in prolonging survival. For instance, 
the IFM 9502 randomized study comparing total body irradiation (TBI) + melphalan 140 mg/m2 
(MEL 140) to melphalan 200 mg/m2 (MEL 200) in newly diagnosed symptomatic myeloma 
patients younger then 65-year old showed that higher dose melphalan lead to superior overall 
survival (OS), 45.6% vs. 65% at 45 months, despite equivalent treatment related mortality 
(TRM)[7]. The incidence of grade 3-4 mucositis was 30% 
 
In another study by Palumbo et al.[8], MEL 200 and MEL 100 were compared in a randomized 
manner in newly diagnosed myeloma patients assigned to receive 2 auto-HCTs. OS did not 
differ (P = .13); median PFS (31.4 vs 26.2 months, P = .01), median time to progression (34.4 
vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in 
the MEL 200 and 2.9% in the MEL 100 group. Severe neutropenia and infections were 
marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse 
events, and the overall occurrence of at least 1 non-hematologic grade 3 or 4 adverse event 
were significantly higher in the MEL200 cohort. 
 


 
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Moreau et al.[9] treated 27 patients with advanced myeloma with high-dose therapy with MEL 
220 followed by auto-HCT. No toxic deaths were observed. The major adverse side effect was 
grade 4 mucositis (WHO scale) in 63% of patients. Two patients experienced reversible 
paroxysmal atrial fibrillation after MEL 220. No liver, renal, or pulmonary toxicity was observed. 
 
Phillips et al.[10] conducted a study to define a new maximum tolerated dose (MTD) and the 
dose-limiting toxicity (DLT) of melphalan and auto-HCT when used with the cytoprotective agent 
amifostine. Escalating doses of melphalan beginning at 220 mg/m2 and advancing by 20 mg/m2 
increments were used until severe regimen-related toxicity (RRT) was encountered. Melphalan 
was given in doses up to and including 300 mg/m2. Although mucosal RRT was substantial, it 
was not the DLT, and some patients given the highest melphalan doses (ie, 300 mg/m2) did not 
develop mucosal RRT. There was no obvious increased incidence of grade I versus grade II 
mucosal toxicity at any dose level beyond melphalan 220 mg/m2. No patient developed grade 
ꞏIII mucosal or gastrointestinal RRT. The DLT was not clearly defined. Cardiac toxicity in the 
form of atrial fibrillation occurred in 3 of 36 patients treated with melphalan doses ꞏ280 mg/m2 
and was deemed fatal in 1 patient given melphalan 300 mg/m2 (Table 2). Another patient given 
melphalan 300 mg/m2 died of hepatic necrosis. The MTD of melphalan in this setting was thus 
considered to be 280 mg/m2, and 27 patients were given this dose without severe RRT. There 
was no delayed toxicity. 
 
Table 2[10]. 
Nonmucosal RRT, Graded According to the Seattle (Bearman) Criteria 
 
Melphalan 
Dose (mg/m2) 
Total No. 
Patients 
Affected 
Patients 
Organ System 
Grade 
220 
11 
1 
Cardiac 
IV 
240 
5 
0 
— 
— 
260 
6 
0 
— 
— 
280 
27 
1 
Hepatic 
I 
 
 
1 
Cardiac 
II 
300 
9 
2 
Cardiac 
II, IV 
 
 
1 
Hepatic 
IV 
All doses 
58 
6 
— 
— 
 
In a more recent trial of 19 patients, dose-escalation of melphalan administered on day -2 
began at 200 mg/m2 with palifermin administered at a fixed dose of 60 mcg/kg/day. Subsequent 
dose escalations of melphalan were done at 20 mg/m2 increments up to a maximum dose of 
280 mg/m2. There were no treatment-related deaths by day 100. The overall incidence of oral 
mucositis grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days. Grade 
4 mucositis was seen in only 1 patient who was given MEL 200 (Table 3). Two of 6 patients who 
were given MEL 280 did not develop oral mucositis. Cardiac DLT in the form of atrial fibrillation 
did occur in 1 of 6 patients treated with MEL 280. Further dose escalation was not allowed due 
previous report of cardiac toxicity with MEL 300[11]. 
 
 
 


 
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Table 3 [11] 
Melphalan Dose and Severity of Oral mucositis (OM). 
Patients 
WHO-OM 
Score Range 
Duration of Severe 
OM (Grade 3)* 
Days to Resolution 
of OM 
Level 1 = 
melphalan 200 
1* 
2-4 
5 
9 
2 
1-2 
- 
8 
3 
1-3 
6 
10 
Level 2 = melphalan 
220 
4 
0 
- 
- 
5 
1-3 
5 
10 
6 
2-3 
6 
11 
Level 3 = melphalan 
240 
7 
0 
- 
- 
8 
1-3 
5 
12 
9 
1-2 
- 
12 
Level 4 = melphalan 
260 
10 
0 
- 
- 
11 
1-3 
6 
20 
12 
2-3 
5 
16 
Level 5 = melphalan 
280 
13 
0 
- 
- 
14 
0-1 
- 
4 
15 
0-1 
- 
8 
16 
1-2 
- 
10 
17 
1-3 
3 
17 
18 
0 
- 
- 
 
Only 1 patient in the whole group receiving melphalan 200 mg/m2 developed grade 4 OM for 3 
days. 
 
In another phase II trial, myeloma patients with a median of 1 prior regimen received MEL 280 
prior to auto-HCT[12]. Two doses of amifostine 740 mg/m2 IV over 5-15 minutes were 
administered 24 hour and 15 min before MEL 280 to ameliorate mucosal toxicity. Between 
5/1999 and 10/2003, 58 MM patients received this high dose regimen after 
dexamethasone-based induction regimens. Bearman critieria were utilized for grading RRT: 
grade 1 mucositis was seen in 41%, grade 2 in 14% and grade 3 in 1.7%. Other grade 3 
toxicities included: lung (1.7%) and renal (1.7%); 1 patient died from melphalan-induced 
interstitial pneumonitis; 7% experienced atrial fibrillation or flutter. Of the 57 evaluable patients, 
CR was achieved in 28 (49%), VGPR in 6 (11%), PR in 17 (30%), SD in 4 (7%) unknown in 1 
(1.5%) and progression in 1 (1.5%). PFS and OS at 7 years was 10% and 39% respectively. 
The authors concluded that MEL 280 dose escalation increased response depth, however, 
sustainability of response was not impacted. 


 
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2.3 
Rationale For Melphalan Dose Escalation 
 
Increasing the dose of melphalan can result in improvement in response rates[12]. In order to 
investigate the pharmacokinetics of total and unbound plasma melphalan using a population 
approach, population pharmacokinetic modelling was performed with total and unbound 
concentration–time data from 100 myeloma patients (36–73 years) who had received a median 
192 mg m2 melphalan dose[13]. Total area under the curve (AUC; range 4.9–24.4 mg l-1 h) and 
unbound AUC (range 1.0–6.5 mg l-1 h) were significantly higher in patients who had oral 
mucositis (ꞏgrade 3) and long hospital admissions (P < 0.01). Patients who responded well had 
significantly higher unbound AUC (median 3.2 vs. 2.8 mg l-1 h, P < 0.05) when assessed from 
diagnosis to post-melphalan and higher total AUC (median 21.3 vs. 13.4 mg l-1 h, P= 0.06), 
when assessed from pre- to post-melphalan. 
 
Despite the hints at better efficacy of melphalan with the higher dose, the most widely used 
dose is 200 mg/m2, primarily due to concerns of toxicity and lack of prospective data. With the 
availability of a more stable and potentially less toxic Evomela, it seems reasonable to study the 
dose escalation in order to improve the outcomes. 
 
2.4 
Rationale For Prolonging Infusion Time 
 
The use of continuous infusion or frequent fractionated-dose delivery in clinical trials have been 
demonstrated to increase the antitumour activity of several drugs (for example, cytarabine in the 
treatment of acute leukemia, bleomycin in cervical carcinoma, 5-fluorouracil in colon carcinoma, 
methotrexate in acute lymphocytic leukemia)[14]. 
 
For several reasons melphalan maybe a good candidate for continuous infusion: 1) a short 
half-life, 2) a small volume of distribution, 3) a mechanism of action that is not cycle specific and 
is time-dependent, and 4) its uptake is a saturable process[14]. Indeed, pre-clinical data 
suggests that sequential exposure of melphalan was more effective than solid exposure at the 
same dose in myeloma cell lines[14]. However, due to the instability of the currently available 
alkeran at the room temperature, the infusional studies have not been possible. This limitation 
will be overcome by Evomela as the compound is stable for several hours at the room 
temperature thus allowing us to study the infusional schedules in addition to the traditional 
30-60 minute bolus doses. 
 
2.5 
Clinical Experience and Potential Benefits of Using Evomela 
 
In a phase IIa, open-label, randomized, cross-over design bioequivalence study, the 
pharmacokinetics of Evomela were compared with the marketed formulation of melphalan 
(Alkeran)[15]. Patients received half of the total dose of melphalan in the form of Alkeran and the 
other half in the form of Evomela in an alternating manner. Twenty-four patients were enrolled 
between 4 February 2010 and 16 May 2011. The median age of enrolled subjects was 58 years 
(range: 48–65). All patients achieved myeloablation 3 days post auto-HCT followed by successful 
neutrophil engraftment with a median of 11 days after transplant. Pharmacokinetic analysis 
showed that Evomela was bioequivalent with Alkeran and also revealed that maximum plasma 
concentration (Cmax) and area under the plasma concentration-time curve were higher (~10%) 
after Evomela administration. The authors concluded that Evomela is bioequivalent to Alkeran 
while also demonstrating a marginally higher systemic drug exposure. 
 
In another clinical trial Evomela (200 mg/m2) was administered as 2 doses of 100 mg/m2 each 


 
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in a phase IIb, open-label, multicenter study to confirm its safety and efficacy as a high-dose 
conditioning regimen for patients with MM undergoing auto-HCT. Sixty-one patients were 
enrolled[16]. All achieved myeloablation. Median time to neutrophil and platelet engraftment was 
12 days and 13 days, respectively. Day-100 TRM was 0%. Overall response rate (ORR) was 
100% with a CR rate of 21%. The incidence of grade 3 mucositis and stomatitis was low (10% 
and 5%, respectively) with no grade 4 mucositis or stomatitis reported (graded according to 
National Cancer Institute Common Terminology Criteria for Adverse Events). 
 
Evomela appears to be a safe alternative to Alkeran and has demonstrated that when used as 
conditioning regimen, it is able to meet the pertinent transplant related outcomes such as 
myeloablation and engraftment. 
 
In summary Evomela can potentially be associated with the following benefits: 
 
· 
Evomela results in marginally, but statistically significant, higher systemic drug levels than 
Alkeran (~110%) (P<0.05). 
· 
Evomela is more stable following reconstitution, which eliminates the time constraints that 
are imposed on pharmacists and nursing staff when preparing high-dose Alkeran for 
infusion. These timing issues might result in delivery of a less than intended dose of 
high-dose melphalan at time of transplant, which results in effective-dose variability between 
patients. 
· 
Evomela can potentially enable safe administration of higher doses of melphalan, which 
may lead to better myeloma responses. This is expected because response to high-dose 
therapy is dose dependent and has a linear, steep dose-response curve[17]. 
· 
Evomela might also be considered in situations where Alkeran is associated with suspected 
infusion reactions[18]. 
· 
 
3.0 Background Drug Information 
3.1 
Melphalan HCL for Injection (Evomela) 
Pharmacologic Category: Alkylating Agent 
Mechanism of Action: Alkylating agent which is a derivative of mechlorethamine that inhibits 
DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA; acts on 
both resting and rapidly dividing tumor cells. 
Major Excipient: 
Captisol is a substituted ß-cyclodextrin that serves as the major functional excipient in Evomela. 
Captisol performs as a solubilizing and stabilizing agent by forming reversible complexes with 
melphalan in the formulation. When the formulation is administered intravenously, the 
equilibrium between melphalan and melphalan-Captisol complex rapidly shifts in favor of  
melphalan due to its dilution by blood and the distribution and binding of melphalan to body 
tissues and blood components 
Dosage Forms: IV 
Compatibility: 
The presence of Captisol facilitates the use of an aqueous initial diluent (Sodium Chloride for 
Injection) for the resultant freeze-dried product instead of the co-solvent diluent necessary for 
the reconstitution of Alkeran. The Ligand formulation does not need a second vial of solvent for 
reconstitution and can be dissolved directly using saline. 
 
 


 
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Solvent 
Solubility (mg/mL) 
Classification 
Water 
<0.1 
Practically insoluble 
1 N HCl 
>100 
<1000 
Freely soluble 
Ethanol 
~40 
Soluble 
Methanol 
>100 
<1000 
Freely soluble 
Diethyl Ether 
<0.1 
Practically insoluble 
 
Administration: Hazardous agent and vascular irritant; use appropriate precautions for 
handling and disposal. 
 
For the purpose of this study, Evomela (2 mg/ml) will be infused using two different infusion 
schedules. Patients will be randomized to different schedule cohorts as explained in section 
11.2.1 and given either a 30-60 minute infusion or 8-9 hour infusion. Because 2 mg/ml Evomela 
is stable for 10 hours, patients receiving the 8-9 hour infusion will receive the total dose in one 
single bag to complete the infusions. 
 
Note: Melphalan is a vascular irritant; local reactions may occur. Extravasation may cause local 
tissue damage; administration via a central line is recommended; do not administer by direct 
injection into a peripheral vein. 
 
Pregnancy Risk: May cause fetal harm if administered during pregnancy. Women of 
childbearing potential should be advised to avoid pregnancy while on melphalan therapy. 
 
Lactation: Use not recommended. 
Storage and Handling: Melphalan for injection (Evomela) is a PG free reformulation of 
alkeran. Evomela incorporates Captisol brand of beta-cyclodextrin sulfobutyl ethers sodium 
salts. The substitution of Captisol for the excipients found in alkeran directly overcomes the 
formulation limitations of alkeran. Evomela can be dissolved directly using saline. Results show 
that based on the increase in total impurities in Evomela injection at 0.45 mg/mL, admixture 
solutions are about 5, 9, 15 and 29 times more stable at concentrations of 0.45, 1.0, 2.0 and 5.0 
mg/mL, respectively. Results confirmed that reconstituted Evomela solution can be stored in the 
vial for up to 1 hour at room temperature or for up to 24 hours at refrigerated temperature (2 – 8 
°C) with no significant degradation. After storage in the vial, it remains stable for an additional 3 
to 29 hours after preparation of admixture solution in infusion bags at concentrations of 0.25 to 
5.0 mg/mL, respectively. In addition, Evomela solution in saline, at concentration of 5.0 mg/mL 
melphalan was bacteriostatic through 72 hours storage at 2 – 8 °C Evomela Investigators 
Brochure, Appendix A). 
 
Adverse reactions: 
> 10%: 
Cardiovascular: Peripheral edema (conditioning: 33%) 
Central nervous system: Fatigue (³50%; conditioning: 77%), dizziness (conditioning: 38%) 
Endocrine & metabolic: Hypokalemia (³50% conditioning: 74%), hypophosphatemia 
(conditioning: 49%) 
Gastrointestinal: Diarrhea (≥50%; conditioning: 93%), nausea (≥50%; conditioning: 90%), 
vomiting (≥50%; conditioning: 64%), decreased appetite (conditioning: 49%), constipation 
(conditioning: 48%), mucositis (conditioning: 38%), abdominal pain (conditioning: 28%),  


 
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dysgeusia (conditioning: 28%), stomatitis (conditioning: 28%), dyspepsia (conditioning: 26%) 
Hematologic & oncologic: Anemia (≥50%), decreased absolute lymphocyte count (≥50%), 
decreased neutrophils (≥50%), decreased platelet count (≥50%; nadir: 14 to 21 days; recovery: 
28 to 35 days), decreased white blood cell count (·50%; nadir: 14 to 21 days; recovery: 28 to 35 
days), febrile neutropenia (conditioning: 41%; grades 3/4: 28%)  
Miscellaneous: Fever (conditioning: 48%) 
 
1% to 10%: 
Gastrointestinal: Hematochezia 
Genitourinary: Amenorrhea (9%) 
Hypersensitivity: Hypersensitivity reaction (IV: 2%; less common in oral formula; includes 
bronchospasm, dyspnea, edema, hypotension, pruritus, skin rash, tachycardia, urticaria), 
anaphylaxis (£2%) 
Renal: Renal failure 
 
Frequency not defined: 
Cardiovascular: Hepatic veno-occlusive disease (hepatic sinusoidal obstruction syndrome; 
SOS), vasculitis 
Central nervous system: Flushing sensation, tingling sensation 
Endocrine & metabolic: SIADH (dose related; Greenbaum-Lefkoe 1985) 
Genitourinary: Infertility, inhibition of testicular function 
Hematologic & oncologic: Bone marrow depression 
Hepatic: Hepatitis, increased serum transaminases, jaundice 
Renal: Increased blood urea nitrogen 
Miscellaneous: Chromosomal abnormality 
 
<1%, postmarketing, and/or case reports: Alopecia, bone marrow failure (irreversible), hemolytic 
anemia, interstitial pneumonitis, maculopapular rash, pulmonary fibrosis, skin ulceration at 
injection site, tissue necrosis at injection site (rarely requiring skin grafting) 
 
 
Supply: 
Acrotech Biopharma will supply Evomela for this study. 
 
 


 
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4.0 Patient Eligibility 
4.1 
Inclusion Criteria 
 
1. Patients with non-relapsed multiple myeloma in complete response (CR), partial remission 
(PR), very good partial remission (VGPR), or symptomatic stable disease (no evidence of 
progression) including patients with light chain MM detected in the serum by free light chain 
assay OR patients with non-secretory multiple myeloma [absence of a monoclonal protein 
(M protein) in serum as measured by electrophoresis (SPEP) and immunofixation (SIFE) 
and the absence of Bence Jones protein in the urine (UPEP) defined by use of 
conventional electrophoresis and immunofixation (UIFE) techniques] but with measurable 
disease on imaging studies like MRI, CT scan or PET scan. 
2. Patients who have received at least two cycles of initial systemic therapy and are within 2 to 
12 months of the first dose. Mobilization therapy is not considered initial therapy. 
3. Age 18 - 70 years. 
4. Karnofsky performance score 70% or higher. 
5. Cardiac function: left ventricular ejection fraction at rest > 40% within 3 months of 
registration. 
6. Hepatic function: bilirubin < 2x the upper limit of normal (except patients with Gilbert 
Syndrome in whom bilirubin level of > 2x upper normal limit will be allowed) and ALT and 
AST < 2.5x the upper limit of normal. 
7. Renal function: creatinine clearance of >/= 40 mL/min, estimated or calculated using the 
Cockcroft-Gault equation. 
8. Pulmonary function: DLCO, FEV1, FVC > 50% of predicted value (corrected for hemoglobin) 
within 3 months of registration. 
9. All female and male subjects of reproductive potential must consent to the use of effective 
contraceptive methods as advised by the study doctor during treatment. 
10. Signed informed consent form. 
 
4.2 
Exclusion Criteria 
 
1. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication 
and progression of clinical symptoms). 
2. Patients seropositive for the human immunodeficiency virus (HIV). 
3. Patients with history of 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. 
4. Patients  receiving an investigational new drug  within 14 days before enrollment. 
5. Female patients who are pregnant (positive b-HCG) or breast feeding. 
6. Prior hematopoietic cell transplantation allogeneic or autologous (a prior autologous HCT 
will be allowed as long as it was part of tandem transplantation). 
7. Prior organ transplant requiring immunosuppressive therapy. 
 
 


 
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5.0 Pretreatment evaluation 
5.1 
Disease Assessment Prior to Starting Treatment (within 30 days) 
 
Studies listed below will be done prior to starting treatment only if these were not done before 
study entry either as part of diagnostic or routine pre-transplant workup. 
 
1. Bone marrow aspirate and biopsies with cytogenetics, FISH* analysis, and multiparameter 
flow cytometry for MRD** monitoring. 
2. Bone survey with long bones within 6 months of registration unless MRI skeletal survey or 
PET/CT have been completed within 60 days of study treatment 
3. SPEP and serum IFE. 
4. UPEP and urine IFE. 
5. Serum free light chain assay, immunoglobulins IgG, IgA, IgM, IgD (if patient has IgD MM). 
6. Beta 2 microglobulin. 
 
5.2 
To be done within 14 days of study entry 
 
CBC with differential, electrolytes, BUN, creatinine, glucose, total protein, albumin, calcium, 
phosphorus, uric acid, total bilirubin, alkaline phosphatase, LDH, AST, ALT, and magnesium 
 
* The following FISH probes are recommended: TP53 gene deletion; monosomy 13; CDKN2C 
deletion; CKS1B gain/amplification; IgH/CCND1/MYEOV gene rearrangement. 
 
** MRD will be monitored on the bone marrow samples using multiparameter flow cytometry. 
We plan to collect 500,000 – 2 Million events for MRD panels. The antibodies we will use in flow 
are: 
CD138, CD38, CD19, CD20, CD45, CD56, CD81, CD117 
Gating strategy: CD138 (bright), CD38 (bright) [the MRD probes may be changed/updated to 
reflect the current practices of flowcytometry at MD Anderson]. 
 
 


 
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6.0 Treatment Plan 
6.1 
Mobilization and Collection of Peripheral Blood Progenitor Cells (PBPCs) 
 
The mobilization and collection of the PBPCs is a standard procedure for which patients sign a 
separate informed consent. This procedure does not constitute part of the proposed research 
therefore can occur prior or after protocol registration. 
 
6.2 
Treatment Plan 
 
Day -3 
Admission / IV Hydration 
 
Day -2 
Melphalan for injection (Evomela) IV (based on cohort/dose level) 
 
Pharmacokinetic samples collected 
 
Day -1 
Rest 
Day 0 
Autologous Stem Cell Infusion  
Day +5 
G-CSF (filgrastim-sndz, Zarxio) administered per SCTCT departmental Guidelines 
of Care 
 
6.3 
Chemotherapy Agents Administration and Dosing 
 
All chemotherapy will be administered inpatient. 
Evomela: 
1. The patients will be admitted on day -3 to start hydration. 
2. Evomela will be administered on day -2 (dose and schedule based on the cohort/dose 
level). 
3. Unused/expired study drug will be disposed of following Investigational Pharmacy 
SOC guidelines. 
 
Schedules 
Evomela Dose* 
Day -2 
Group 1 (30-60 minute 
infusion) 
200 mg/m2 
225 mg/m2 
Group 2 (8-9 hour infusion) 
200 mg/m2 
225 mg/m2 
 
Evomela doses and schedules to be studied: 
 
Please see Section 11.0 (Statistical Considerations) for details of trial progression and dose 
assignment in each schedule. First cohort in each schedule will be treated at 200 mg/m2. 
 
For Group 1, the 2 mg/ml concentration of Evomela will be infused over approximately 30-60 
minutes, as this is stable for 10 hours. 
 


 
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For Group 2, the 2 mg/ml concentration of Evomela will be infused over approximately 8-9 hours. 
 
* For patients who weigh more than 130% of their ideal body weight, body surface area should 
be calculated based on adjusted ideal body weight (per package insert).  Weight will be 
obtained within 7 days prior to admission for dose calculation.  Adjusted ideal body weight is 
calculated as follows: 
Adjusted ideal body weight = (Ideal body weight + actual body weight)/2 
 
6.4 
Supportive Care 
 
Supportive treatment including antibiotic prophylaxis, treatment, and blood product support will 
follow current departmental guidelines. 
 
Cryotherapy: Patients will be instructed to place approximately 1 ounce of crushed ice in the 
mouth. The ice will be allowed to melt and replenished as soon as it has completely melted. 
Patients will be instructed to begin placing the ice chips in their mouth 30 minutes before the 
start of Evomela infusion and continue this procedure as follows: 
 
· 
30 minutes prior to the infusion, during the infusion, and for at least 2 hours after the end of 
infusion (in 30-60 minute infusion group). 
· 
30 minutes prior to the infusion, during the infusion (intermittently, as tolerated), and for 2 
hours after the end of infusion (in 8-9 hour infusion group). 
 
 
7.0 Evaluation During Study 
 
Every effort will be made to adhere to the schedule of events and all protocol requirements. 
Variations in schedule of events and other protocol requirements that do not affect the rights 
and safety of the patient will not be considered as deviations. Such variations may include 
laboratory assessments completed outside of schedule and occasional missed required 
research samples. 
 
The active study follow-up period will be up to one year post-transplant. Subsequent follow up 
will be according to departmental practices. 
 
7.1 
Assessment schedule during the active study period 
 
All patients on the study will be admitted for auto-HCT. 
 
The patients will be admitted on Day -3 of transplant (day of stem cells infusion is considered 
Day 0).  
 
Evaluations during the hospital stay and until Day +30: 
 
Starting Day -2 until the day of discharge, evaluations will follow our SOC guidelines.   If clinically 
indicated these studies may be done at other time points which can replace the nearest planned 
time point.  During the treatment administration and until 30 days after Evomela administration, 
all patients will be monitored for toxicity, which will be evaluated according to CTCAE v5.0. While 


 
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admitted in the hospital, patients will be monitored daily. Once discharged, they will be followed 
per standard of care.   
 
Around 3 months post transplant. 
1. Bone marrow aspirate and biopsy for morphology with cytogenetics, FISH* analysis, and 
multiparameter flow cytometry for MRD** monitoring. 
2. PET scan (only in patients who had a PET scan prior to auto-HCT and had disease 
detectable on PET scan). 
 
Approximately every three months during the first year post transplant 
1. SPEP and serum IFE only if SPEP is negative. 
2. UPEP and urine IFE only if UPEP is negative. 
3. Serum free light chain assay, immunoglobulins IgG, IgA, IgM, IgD (if patient has IgD MM). 
4. LDH. 
 
Around one year post transplant 
1. Bone survey with long bones only if abnormal at baseline. 
2. Bone marrow aspirate and biopsy for morphology with cytogenetics, FISH* analysis, and 
multiparameter flow cytometry for MRD**monitoring. 
 
Labs at each visit or as clinically indicated 
CBC with differential, electrolytes, BUN, creatinine, glucose, total protein, albumin, calcium, 
phosphorus, uric acid, total bilirubin, alkaline phosphatase, LDH, AST, ALT, and magnesium 
 
* The following FISH probes are recommended: TP53 gene deletion; monosomy 13; CDKN2C 
deletion; CKS1B gain/amplification; IgH/CCND1/MYEOV gene rearrangement. 
 
** MRD will be monitored on the bone marrow samples using multiparameter flow cytometry. 
We plan to collect 500,000 – 2 Million events for MRD panels. The antibodies we will use in flow 
are for: 
 
CD138, CD38, CD19, CD20, CD45, CD56, CD81, CD117 
Gating strategy: CD138 (bright), CD38 (bright) [the MRD probes may be changed/updated to 
reflect the current practices of flow cytometry at MD Anderson]. 
 
7.2 
Pharmacokinetics of Evomela in different infusion schedules and their effect on 
safety and efficacy. 
 
Intense pharmacokinetic sampling will be done for the first 30 patients. Sparse sampling will be 
done for the remaining 30 patients as described below. 
 
INTENSE Sampling 
Sample collection for 30-60 minute infusion – Blood samples (10 ml) will be collected at the 
following time points: 
A) Pre-dose. 
B) After the end of infusion: At 10 min (± 5 minutes) , 30 min (± 5 minutes) , 60 min (± 5 
minutes), 90 min (± 15 minutes),120 min (± 15 minutes), 240 min (± 15 minutes), 360 min 
(± 15 minutes), and 480 min (± 60 minutes). 
 
 
 


 
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o
Sample collection for 8-9 hour infusion – Blood samples (10 ml) will be collected at the following 
time points: 
A) Pre-dose. 
B) During the infusion: At 3 hr (± 15 minutes), 5 hr (± 15 minutes), and 8 hr (± 15 minutes) after 
the start of infusion (before completing the infusion). 
C) After the end of infusion: At 60 min (± 5 minutes), 120 min (± 15 minutes), 240 min (± 15 
minutes), 360 min (± 15 minutes) and 480 min (± 60 minutes) after the end of infusion. 
 
SPARSE Sampling 
Sample collection for 30-60 minute infusion – Blood samples (10 ml) will be collected at the 
following time points: 
A) Pre-dose. 
B) After the end of infusion: At 10 min (± 5 minutes), 30 min (± 5 minutes), 90 min (± 15 
minutes), 240 min (± 15 minutes), and 480 min (± 60 minutes) after the end of infusion. 
 
Sample collection for 8-9 hour infusion – Blood samples (10 ml) will be collected at the following 
time points: 
A) Pre-dose. 
B) During the infusion: At 5 hr (± 15 minutes), and 8 hr (± 15 minutes) after the start of infusion 
(before completing the infusion). 
C) After the end of infusion: At 240 min (± 15 minutes) and 480 min (± 60 minutes) after the end 
of infusion. 
 
Plasma will be separated and stored in -80 C until further analysis. Evomela concentration will 
be determined using high performance liquid chromatography assay and ultraviolet detection as 
described previously. 
 
Melphalan concentrations over time will be modeled using non-compartmental analysis (via 
Phoenix WinOnlin) to estimate PK parameters such as melphalan exposure (AUC), Cmax, and 
clearance. 
 
7.3 Maintenance Therapy 
 
Study participants may be concurrently enrolled in other IND studies for consolidation or 
maintenance therapy, with consolidation or maintenance treatment to begin after 3 month post-
transplant evaluations are completed.   
8.0 Adverse Events and Reporting Requirements 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. The investigator (or physician designee) is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for all adverse events 
for subjects enrolled. 
8.1 
Definitions 
Active Treatment 
For the purpose of this study, the investigational component of the treatment plan is Evomela 
used for transplant conditioning. 


 
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Active treatment period 
The time of administration of this drug as per treatment plan outlined above, up to 30 days after 
the Evomela infusion. 
 
Follow-up period 
Is defined as 31 days after Evomela infusion until off study criteria is met. Thereafter patients 
will be followed per standard procedure for hematopoietic transplant recipients including 
monitoring for relapse, survival and late events. 
8.2 
Causality Assessment 
 
Evomela used for transplant conditioning is the investigational component therefore adverse 
events known to be caused by Evomela and its direct consequences will be scored as definitive 
related. 
 
When the relationship of the adverse event cannot be ruled out with certainty the AE may be 
considered probable or possible related. 
 
Adverse events known to be related to drugs used for supportive treatment will be scored as 
unrelated. 
 
8.3 
Concomitant medications 
 
Patients treated on this protocol will require supportive care treatment (concomitant 
medications). These medications are considered standard of care and have no scientific 
contribution to the protocol; therefore no data will be captured on various medications needed or 
their side effects. All concomitant meds will be captured in the medical record only. 
 
8.4 
Data collection 
Collection of adverse events will reflect the onset and resolution date and maximum grade. 
Intermittent events should be labeled as such and followed until resolution. If a patient is taken 
off study while an event is still ongoing, this will be followed until resolution unless another 
therapy is initiated. Pre-existing medical conditions will be recorded only if an exacerbation 
occurs during the active treatment period. Adverse events will be collected starting on the day of 
Evomela administration until 30 days after infusion. Adverse Events known to be definitely 
related to G-CSF and autologous stem cell transplant will not be captured. 
 
Minor electrolyte abnormalities will be captured in the medical record and corrected as per 
standard guidelines of the Stem Cell Transplantation & Cellular Therapy department. 
Electrolyte and metabolic imbalances, which are considered clinically significant and 
unexpected in routine stem cell transplant setting and are considered related to Evomela will be 
recorded. 
 
Expected adverse events in post auto transplant period: 
A. Related to myelosuppression: thrombocytopenia, bleeding, platelets and RBC transfusions. 
B. Fever: Non-neutropenic or neutropenic without infection. 
C. Infections in the presence or absence of neutropenia. 
D. Readmissions (lasting <10 days). 
E. Cytopenias post-transplant including secondary graft failure. 
F. Low blood pressure due to dehydration requiring fluid replacement. 
G. Fluid overload leading to cardiac dysfunction. 


 
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H. GI related: nausea, vomiting, diarrhea, mucositis. 
I. 
Organ dysfunction: cardiac, pulmonary, hepatic, CNS and/or renal. 
J. Fatigue. 
K. Neurologic: seizures, neuropathies. 
L. Stem Cell Transplant Syndromes: Cytokine Storm, TTP, hemorrhagic cystitis, interstitial 
pneumonitis (including pulmonary hemorrhage). 
 
Adverse Events Considered Serious: 
A. Graft failure/ rejection. 
B. Prolonged hospitalization due to infections and/or organ failure requiring extensive 
supportive care (i.e., dialysis, mechanical ventilation). 
C. Readmissions from any cause resulting in a prolonged hospitalization (>10 days). 
D. Any expected or unexpected event resulting in an irreversible condition and/ or leading to 
death. 
 
Adverse events will be documented in the medical record and entered into the electronic case 
report form in MD Anderson Cancer Center’s Clinical Oncology Research system 
(CORe)/BMTWeb. All other protocol specific data will be entered into BMTWeb/CORe. 
 
8.5 
Dose Limiting Toxicity (For dose finding in Stage I) 
 
Toxicity will be defined as grade 4 mucositis or any grade 4 or 5 non-hematologic or 
non-infectious toxicity occurring within 30 days from the start of the infusion. 
 
8.6 
Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred in 
a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
• 
Important medical events as defined above may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND Office. 
 


 
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All events occurring during the conduct of a protocol and meeting the definition of a SAE, must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. Unless stated 
otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office. If a death is possibly related to study agent 
administration, we will hold study enrollment and agent administration pending assessment 
of the event. 
• 
The electronic SAE application (eSAE) will be utilized for safety reporting to the IND Office, 
IRB, and Acrotech Biopharma. 
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent/assent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, or 
there has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. 
 
8.7 
Assessment of the Adverse Events Severity 
 
The severity of the adverse events (AEs) will be graded according to the Common Terminology 
Criteria v5.0 (CTCAE) from the day of Evomela infusion up to 30 days after the Evomela 
infusion. Events not included in the CTCAE chart will be scored as follows: 
 
General grading: 
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment required 
beyond prophylaxis. 
Grade 2: Moderate: discomfort present with some disruption of daily activity, require treatment. 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line 
treatment. 
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
 
Grading for specific syndromes: 
Veno-occlusive disease (VOD): 
Grade 3: Bili >2mg/dl with at least two of the following: increased weight >4% from 
baseline, ascites or hepatomegaly 
Grade 4: pulmonary and or renal failure 
 
Pulmonary events not caused by CHF (interstitial pneumonitis (IP), pulmonary hemorrhage 
(DAH): 
Grade 1: CXR showing mild infiltrates or interstitial changes 
Grade 2: mild SOB 
Grade 3: requires supplemental oxygen, or is a documented infection 
Grade 4: requires intubation 
 
 
 


 
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Thrombotic thrombocytopenic purpura (TTP): 
Grade 1: No treatment required 
Grade 2: Requires steroids and/or plasma transfusions 
Grade 3: Requires plasma exchange 
 
Cytokine storm or engraftment syndrome: 
Grade 1: No treatment required 
Grade 2: Treatment required 
Grade 3: Organ dysfunction 
Grade 4: Total Bilirubin >5 
 
Hemorrhagic Cystitis: 
Grade 1: minimal or microscopic bleeding/pain 
Grade 2: gross bleeding/pain and spasms 
Grade 3: transfusion/irrigation required 
Grade 4: dialysis required 
 
8.8 
Reporting to FDA 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure that serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
 
8.9 
Sponsor Reporting Requirements 
 
Acrotech will be notified of all life-threatening or fatal Serious Adverse Events within 24 hours 
after learning of the Event. All other Serious Adverse Events will be reported within 5 working 
days of knowledge. A copy of the MDACC eSAE will be submitted to: 


 
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Acrotech Pharmacovigilance via e-mail to pvg@aurobindousa.com or via fax to 
+(732) 289-6189. 
 
9.0 
Criteria for Response and Progression 
Disease response, progression, and relapse will be defined according to International Myeloma 
Working Group uniform response criteria (Appendix B). 
 
10.0 
Criteria for Removal from the Study 
1. Patient withdrawal of the informed consent. 
2. Patient's inability or unwillingness to have follow-up visits and/or laboratory tests required by 
this protocol. 
3. An unexpected toxicity that is deemed unacceptable by the study chairman. 
4. Disease progression. 
5. After one year post stem cell transplant. 
 
Patients who experience an unexpected toxicity that is deemed unacceptable by the Principal 
Investigator will not be replaced. 
 
11.0 
Statistical Considerations 
11.1 
Preliminaries 
 
This is a two-stage phase I-II trial to optimize the dose and schedule of PGF Melphalan given as 
a single agent preparative regimen for auto-HCT. Two doses will be studied, 200 and 225 
mg/m2. Two infusion schedules will be studied, 30-60 minutes and 8-9 hours, which we will 
refer to below as schedules 1 and 2, respectively. For dose-finding in stage 1, toxicity will be 
defined as grade 4 mucositis, or any grade 4 or 5 non-hematologic or non-infectious toxicity 
occurring within 30 days from the start of infusion. Complete response will be defined as 
negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow aspirates.  Schedule selection in stage 
2 is based on complete remission at day 90 (CR90). Secondary outcomes will include overall 
survival (OS) time and progression free survival (PFS) time. 
 
Stringent complete response (sCR) will be defined as complete response as defined above plus 
normal FLA ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry. 
 
11.2. 
Stage I Dose-Finding Design 
 
11.2.1 Schedule Randomization Scheme 
 
Patients will be randomized between the 2 schedules, as they are accrued, until a total of 60 
patients have been accrued. The randomization will be restricted so that the sample size is 
perfectly balanced between the 2 schedules, with 15 patients in each schedule at n=30, and 30 
patients in each schedule at n=60 patients. Within each schedule, the adaptive BMA-CRM[19] 
decision rules (either choose a dose or stop accrual in that schedule due to excessive toxicity at 


 
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the lowest dose d=200) will be applied for each new cohort of 3 patients, subject to the 
constraints given below, in section 11.2.2. If a schedule is terminated early, then, up to the total 
overall maximum of 60, thereafter patients will be treated with the remaining schedule. If both 
schedules are terminated early, then the trial will be stopped. 
 
11.2.2 Phase I BMA-CRM Adaptive Decision Rules 
 
The same phase I dose-finding design will be used for each schedule. This will be an 
application of the Bayesian Model Averaging continual reassessment method (BMA-CRM)[19], 
with target toxicity probability .20, cohort size 3, the three CRM model probability skeletons (.10, 
.21), (.05, .08), and (.07, .15), maximum sample size 30 (10 cohorts of 3 patients each), and the 
first cohort treated at 200 mg/m2. Denoting the probability of toxicity at dose 200 by p(200), 
accrual will be stopped early due to excessive toxicity for a schedule, with no dose selected for 
that schedule, if Pr[ p(200) > .20 | data ] > .90, that is, if the lowest dose is too toxic. The 
operating characteristics (OCs) were computed using the BMA-CRM application (version 2.2.3) 
from the MDACC Biostatistics department. Based on a simulation with 1000 replications per 
scenario, assuming maximum sample size 30, accrual rate 3 per month, 50% toxicities 
observed in the second half of the assessment period, the within-schedule operating 
characteristics of this design are as follows. If a schedule receives > 30 patients due to early 
termination of the other schedule, then the OCs for the remaining schedule will be improved 
over the tabulated values. 
 
Table 4. Within-schedule operating characteristics of the BMA-CRM design, with maximum sample size 
30, cohort size 3, and target ptox = .20, based on 1000 replications per scenario. 
 
Scenario 1 
Dose Level 
True 
Prob(tox) 
Selection 
Probability 
# of Subjects 
Treated 
# of 
Toxicities 
1 
0.050 
0.10 
8.0 
0.4 
2 
0.200 
0.88 
21.6 
4.2 
Probability of Early Termination: 0.02 
Toxicities per Trial: 4.6 
 
Scenario 2 
Dose Level 
True 
Prob(tox) 
Selection 
Probability 
# of Subjects 
Treated 
# of 
Toxicities 
1 
0.100 
0.20 
10.5 
1.0 
2 
0.200 
0.77 
18.7 
3.7 
Probability of Early Termination: 0.04 
Toxicities per Trial: 4.8 
 
Scenario 3 
Dose Level 
True 
Prob(tox) 
Selection 
Probability 
# of Subjects 
Treated 
# of 
Toxicities 
1 
0.020 
0.03 
5.3 
0.1 
2 
0.150 
0.97 
24.7 
3.7 
Probability of Early Termination: 0.00 
Toxicities per Trial: 3.8 
 
 
 


 
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Scenario 4 
Dose Level 
True 
Prob(tox) 
Selection 
Probability 
# of Subjects 
Treated 
# of 
Toxicities 
1 
0.020 
0.00 
3.8 
0.1 
2 
0.080 
1.00 
26.2 
2.1 
Probability of Early Termination: 0.00 
Toxicities per Trial: 2.1 
 
Scenario 5 
Dose Level 
True 
Prob(tox) 
Selection 
Probability 
# of Subjects 
Treated 
# of 
Toxicities 
1 
0.300 
0.33 
13.5 
4.0 
2 
0.390 
0.04 
3.6 
1.4 
Probability of Early Termination: 0.63 
Toxicities per Trial: 5.4 
 
Scenario 6 
Dose Level 
True 
Prob(tox) 
Selection 
Probability 
# of Subjects 
Treated 
# of 
Toxicities 
1 
0.460 
0.04 
7.8 
3.5 
2 
0.550 
0.00 
0.9 
0.5 
Probability of Early Termination: 0.96 
Toxicities per Trial: 4.0 
 
11.2.3 Pharmacokinetics analysis 
 
Pharmacokinetic data such as Evomela exposure between the 2 infusion schedules will be 
compared in first 30 patients enrolled and exposure-response will be evaluated to determine if 
there is difference in safety and efficacy between the 2 infusion schedules. Dose-escalation in 
each treatment schedule will be initiated only after the PK and safety data at each dose is 
analyzed and it is determined that there is no safety concern as per DLT guidelines specified in 
the statistical section. 
 
11.3 
Stage 2 Selection 
 
At the end of the phase I portion of the trial, for each schedule, the last patient treated at the 
optimal dose will be followed for 90 days to evaluate response. For each schedule that is not 
terminated early due to excessive toxicity, the empirical response rate will be computed for the 
subsample of patients treated at the optimal dose chosen by the BMA-CRM for that schedule. 
Among these, the (dose, schedule) combination having maximum empirical Pr(CR90) will be 
selected for future evaluation. 
 
11.4 
Implementation 
 
The BMA-CRM design will be implemented using the Clinical Trials Conduct Website in the 
MDACC Department of Biostatistics. A block randomization scheme for schedule assignments 
to achieve balance between schedules as described above will be provided to the Website 
personnel prior to trial initiation. The randomization will be conducted using the Clinical Trials 
Conduct Website. 


 
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11.5 
Statistical Data Analysis Plan 
 
Toxicity will be tabulated by dose, type, and grade. The probability of toxicity over 30 days as a 
function of dose will be estimated by fitting a Bayesian binary outcome regression model 
(Gelman, et al.)[20]. The times for overall survival (OS) and progress-free survival (PFS) will be 
computed from the date of Evomela injection to the last time of follow-up or the event of interest 
(progression or death). Unadjusted OS and PFS distributions will be estimated by the Kaplan 
and Meier method [21]. The posterior probabilities of transplant related mortality (TRM), minimal 
residual disease (MRD), and CR90 will be estimated along with 95% posterior credible intervals, 
assuming beta (.50, .50) priors. The probabilities of TRM, MRD, and CR90 from the two infusion 
schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), 
where pj denotes the probability of the event with schedule j=1,2, based on the data for patients 
treated at the optimal within-schedule dose chosen by the BMA-CRM. 
 
11.6 
Toxicity/Efficacy Summary Reports 
The Investigator is responsible for completing toxicity/efficacy summary reports and submitting 
them to the IND office Medical Affairs and Safety Group for review. These should be submitted 
as follows: 
 
Phase I (Dose Finding)/Phase II (Efficacy Assessment) 
 
Toxicity Summary, after the first cohort of 3 evaluable patients per schedule, complete 30 days 
after Melphalan infusion, and every 3 evaluable patients thereafter, IND Office approval must be 
obtained prior to advancing/changing dose levels. 
During every submission update the response data of previously submitted patients once they 
complete 90 days of treatment. 
 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
 
 


 
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12.0 
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