Clinical trial NCT01897714
Conditions: Relapsed and/or Relapsed-refractory Multiple Myeloma
Sponsor: Oncopeptides AB
Start date: 2013-07-01; Completion date: 2020-03-01
Enrollment: 75 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.

Detailed description:

Arms: arm 1: Intravenous (IV) infusion of 15 milligram (mg) melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle. arm 2: IV infusion of 25 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle. arm 3: IV infusion of 40 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle. arm 4: IV infusion of 55 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle. arm 5: IV infusion of 40 mg melflufen on Day 1 of each 21-day or 28-day treatment cycles, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycles. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each treatment cycle. arm 6: IV infusion of 40 mg melflufen on Day 1 of each 28-day treatment cycle.
Interventions: intervention 1: Melflufen intervention 2: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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Confidential 
Page 3 
Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
 
Protocol Acceptance Page 
 
 
Protocol Number:  O-12-M1 
 
Protocol Title:   
An Open-Label Phase I/IIa Study of the Safety and Efficacy of 
Melphalan-flufenamide (Melflufen) and Dexamethasone Combination for 
Patients with Relapsed and/or Relapsed-Refractory Multiple Myeloma. 
 
Protocol Date: Date of Version 1.2: February 8, 2013 
 
 
  Date of Version 2.0: October 2, 2013 
  Date of Version 3.0: May 7, 2014 
  Date of Version 4.0: January 27, 2015 
  Date of Version 5.0: June 20, 2015 
 
Date of Version 6.0: July 6, 2016 
 
Date of Version 7.0: November 2, 2018 
 
By signing this protocol acceptance page, I confirm I have read, understood, and agree to 
conduct the study in accordance with the current protocol.  
 
 
 
__________________________________________ 
Principal Investigator Name (Printed) 
 
__________________________________________ 
____________ 
Principal Investigator Signature 
 
 
 
Date 
 
 
This study is to be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, Title 21 of the Code of Federal Regulations §§ 50, 56, and 312, 
the International Conference on Harmonization E6, and any applicable regulatory 
requirements. 
 
The study protocol and any amendments are to be reviewed by an Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB) before implementation. 
 
Confidential information contained in this document will not be used for any purpose other 
than the evaluation or conduct of the clinical investigation without the prior written consent of 
Oncopeptides AB. 


 
 
Confidential 
Page 4 
Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Table of contents 
List of Figures ...................................................................................................................... 8 
List of Tables ....................................................................................................................... 8 
Protocol Synopsis: ............................................................................................................... 9 
List of Abbreviations ......................................................................................................... 26 
1 
Background ........................................................................................................................ 28 
1.1 
Overview of Multiple Myeloma ............................................................................ 28 
1.2 
Overview of Melflufen .......................................................................................... 28 
1.2.1 
Melflufen Description ........................................................................... 28 
1.2.2 
Non-clinical experience ........................................................................ 29 
1.2.3 
In Vivo Studies ...................................................................................... 30 
1.2.4 
Preclinical Multiple Myeloma Studies .................................................. 31 
1.2.5 
Clinical Experience ............................................................................... 31 
1.2.6 
Clinical Pharmacokinetics ..................................................................... 33 
2 
Rationale ............................................................................................................................ 34 
2.1 
Study Rationale and Purpose ................................................................................. 34 
2.2 
Rationale for the Study Design .............................................................................. 34 
2.3 
Rationale for Dose Selection ................................................................................. 35 
2.4 
Rationale for Amendment 4 ................................................................................... 36 
2.4.1 
Rationale for 28-day cycle .................................................................... 36 
2.4.2 
Rationale for Single Agent Melflufen Cohort ....................................... 36 
2.5 
Rational for Amendment 5 .................................................................................... 36 
2.5.1 
New vial strength .................................................................................. 36 
2.5.2 
DSMC review of single agent cohort .................................................... 37 
2.6 
Rationale for Amendment 6 ................................................................................... 37 
3 
Objectives and Endpoints .................................................................................................. 38 
3.1 
Primary Objectives ................................................................................................ 38 
3.1.1 
Phase I ................................................................................................... 38 
3.1.2 
Phase IIa ................................................................................................ 38 
3.2 
Secondary Objectives ............................................................................................ 38 
3.3 
Exploratory Objective(s) ....................................................................................... 38 
3.3.1 
Correlative Studies Objective(s) ........................................................... 38 
4 
Study design ...................................................................................................................... 38 
4.1 
Description of Study Design .................................................................................. 38 
5 
Patient Population .............................................................................................................. 39 
5.1 
Patient Screening ................................................................................................... 40 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
5.1.1 
Information to Be Collected on Screening Failures .............................. 40 
5.2 
Patient Eligibility ................................................................................................... 40 
5.2.1 
Inclusion Criteria ................................................................................... 40 
5.2.2 
Exclusion Criteria .................................................................................. 42 
6 
Patient Registration, Numbering and Treatment Assignment ........................................... 43 
6.1 
Patient Registration ................................................................................................ 43 
6.2 
Patient Numbering ................................................................................................. 43 
6.3 
Treatment Assignment ........................................................................................... 44 
6.4 
Replacement Policy ............................................................................................... 44 
6.4.1 
Phase I ................................................................................................... 44 
6.4.2 
Phase IIa ................................................................................................ 44 
7 
Treatment ........................................................................................................................... 44 
7.1 
Study Treatment ..................................................................................................... 44 
7.2 
Phase I (Phase I is completed) ............................................................................... 45 
7.2.1 
Dosing Levels........................................................................................ 45 
7.3 
Phase IIa ................................................................................................................. 46 
7.4 
Concomitant Therapy ............................................................................................ 46 
7.4.1 
Recommended Concomitant Therapy ................................................... 46 
7.4.2 
Contraindicated Concomitant Therapy ................................................. 47 
7.5 
Phase I Dose Escalation Guidelines (Phase I is completed) .................................. 47 
7.6 
Definition of Maximum Tolerated Dose (Phase I only. Phase I is completed) ..... 48 
7.7 
Definition of DLT (Phase I only. Phase I is completed) ....................................... 48 
7.8 
Guidelines for Dose Escalation Decisions (Phase I only. Phase I is 
completed) ............................................................................................................. 49 
7.8.1 
Intra-Patient Dose Escalation (Phase I only. Phase I is completed) ..... 49 
7.9 
Dose Modifications ................................................................................................ 50 
7.9.1 
Phase I and Phase IIa Dose Modification and Dose Delay ................... 50 
7.9.2 
Dose Reduction Steps ........................................................................... 50 
7.9.3 
Dose Reduction Steps for Melflufen ..................................................... 50 
7.9.4 
Dose Reduction Steps for Dexamethasone ........................................... 51 
7.9.5 
Dose Modification Guidelines for Melflufen ........................................ 51 
7.9.6 
Dose Modification Guidelines for Dexamethasone .............................. 53 
7.9.7 
Initiation of a New Cycle of Treatment ................................................ 54 
7.9.8 
Treatment Duration ............................................................................... 55 
7.10 
Study Drug Preparation and Administration ......................................................... 55 
7.10.1 
Melflufen Packaging and Labeling ....................................................... 55 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
7.10.2 
Melflufen Supply .................................................................................. 55 
7.10.3 
Melflufen Storage .................................................................................. 55 
7.10.4 
Preparation of Melflufen Solution for infusion ..................................... 55 
7.10.5 
Labeling ................................................................................................. 58 
7.10.6 
Handling and storage of the Melflufen Solution for infusion ............... 58 
7.10.7 
Melflufen Administration ...................................................................... 59 
7.11 
Dexamethasone ...................................................................................................... 59 
7.11.1 
Dexamethasone Packaging and Labeling .............................................. 59 
7.12 
Dexamethasone Storage ......................................................................................... 60 
7.12.1 
Dexamethasone Administration ............................................................ 60 
7.13 
Study Drug Compliance and Accountability ......................................................... 60 
7.13.1 
Study Drug Compliance ........................................................................ 60 
7.13.2 
Study Drug Accountability ................................................................... 60 
8 
Visit Schedule and Assessments ....................................................................................... 60 
8.1 
Study Flow and Visit Schedule.............................................................................. 60 
8.2 
Study Assessments................................................................................................. 64 
8.2.1 
Efficacy Assessments ............................................................................ 64 
8.2.2 
Safety and Tolerability Assessments .................................................... 64 
8.2.3 
Electrocardiogram Assessments ............................................................ 65 
8.2.4 
Pharmacokinetic Assessments .............................................................. 65 
8.2.5 
Correlative Sample Assessments .......................................................... 65 
8.2.6 
Follow Up Assessments ........................................................................ 66 
8.3 
End of Treatment Visit Including Post Study Follow-Up and Premature 
Withdrawal ............................................................................................................ 66 
8.3.1 
Criteria for Premature Patient Withdrawal ........................................... 66 
9 
Central Lab and Correlative Sample Collection and Handling ......................................... 67 
9.1 
Central Lab Specimen Collection .......................................................................... 67 
9.1.1 
Central Lab Specimen handling and shipping ...................................... 67 
9.2 
Correlative Specimen Collection and Handling .................................................... 67 
9.2.1 
Specimen Collection ............................................................................. 68 
9.2.2 
Handling of Specimens ......................................................................... 68 
9.2.3 
Labeling and Shipping of Samples ....................................................... 68 
10 Safety Monitoring and Reporting ...................................................................................... 68 
10.1 
Adverse Events ...................................................................................................... 68 
10.1.1 
Adverse Event Reporting ...................................................................... 69 
10.1.2 
Laboratory Test Abnormalities ............................................................. 70 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
10.2 
Serious Adverse Events ......................................................................................... 70 
10.2.1 
Definitions ............................................................................................. 70 
10.2.2 
Serious Adverse Event Reporting ......................................................... 71 
10.3 
Pregnancies ............................................................................................................ 72 
10.4 
Data Safety Monitoring Committee ....................................................................... 72 
11 Data Collection and Management ..................................................................................... 73 
11.1 
Data Confidentiality ............................................................................................... 73 
11.2 
Site Monitoring ...................................................................................................... 73 
11.3 
Data Collection ...................................................................................................... 74 
11.4 
Database Management and Quality Control .......................................................... 74 
12 Statistical Methods and Data Analysis .............................................................................. 74 
12.1 
Analysis Sets .......................................................................................................... 74 
12.1.1 
Safety Analysis Set ............................................................................... 74 
12.1.2 
Efficacy Analysis Set ............................................................................ 74 
12.1.3 
Correlative Studies Analysis ................................................................. 74 
12.2 
Analysis of Objectives ........................................................................................... 75 
12.2.1 
Primary Objective ................................................................................. 75 
12.2.2 
Secondary Objective(s) ......................................................................... 75 
12.2.3 
Exploratory Objective(s) ....................................................................... 75 
12.3 
Analysis of Endpoints ............................................................................................ 75 
12.3.1 
Primary Endpoint Analysis Phase I ....................................................... 75 
12.3.2 
Primary Endpoint Analysis Phase IIa ................................................... 76 
12.3.3 
Secondary Endpoint Analysis ............................................................... 76 
12.4 
Sample Size Calculation ........................................................................................ 77 
12.4.1 
Phase I ................................................................................................... 77 
12.4.2 
Phase IIa ................................................................................................ 77 
12.4.3 
Pharmacokinetic methods ..................................................................... 77 
12.4.4 
Statistical methods for PK parameters .................................................. 78 
13 Ethical Considerations and Administrative Procedures .................................................... 78 
13.1 
Regulatory and Ethical Compliance ...................................................................... 78 
13.2 
Responsibilities of the Investigator and IRB/IEC/REB ......................................... 78 
13.3 
Informed Consent Procedures................................................................................ 79 
13.4 
Discontinuation of the Study ................................................................................. 79 
13.5 
Publication of Study Protocol and Results ............................................................ 79 
13.6 
Study Documentation, Record Keeping and Retention of Documents ................. 79 
13.7 
Confidentiality of Study Documents and Patient Records .................................... 80 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
13.8 
Audits and Inspections ........................................................................................... 80 
13.9 
Financial Disclosures ............................................................................................. 80 
14 Protocol Adherence ........................................................................................................... 81 
14.1 
Amendments to the Protocol ................................................................................. 81 
15 References ......................................................................................................................... 82 
List of Appendices 
Appendix A: ECOG Performance Status 
Appendix B: NCI CTCAE Version 4.03 
Appendix C: IMWG Response Criteria for Multiple Myeloma 
Appendix D: Definition of Lines of Therapy 
Appendix E:  Declaration of Helsinki 
Appendix F: Estimated Creatinine Clearance using Cockcroft-Gault formula 
Appendix G: QTc interval by Fridericia Formula 
List of Figures 
Figure 1.2-1 
Structure of Melflufen 
List of Tables 
Table 7-1 
Dose levels to be tested ......................................................................... 45 
Table 7-2 
Dose reduction steps for melflufen (Phase I/IIa) .................................. 50 
Table 7-3 
Dose reduction steps for dexamethasone (Phase I/IIa) ......................... 51 
Table 7-4 
Dose modification guidelines for toxicity related to melflufen ............ 51 
Table 7-5 
Dose modifications for toxicity related to dexamethasone ................... 53 
Table 7 – 6  
List of Melflufen Powder Vials ............................................................. 57 
Table 8 – 1 
Visit Schedule and Assessments ........................................................... 60 
 


 
 
Confidential 
Page 9 
Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Protocol Synopsis:   
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
Study Protocol 
Title 
An Open-Label Phase I/IIa Study of the Safety and Efficacy of 
Melflufen 
(Melphalan-flufenamide) 
and 
Dexamethasone 
Combination for Patients with Relapsed and Relapsed-Refractory 
Multiple Myeloma 
Study Sponsor 
Oncopeptides AB 
 
Sponsor’s Medical 
Expert  
 
 
Site(s) 
 
Approximately 6 - 8 international sites located in the United States 
and Europe. 
Study Period and  
Phase of 
Development 
Phase I/IIa 
FPFV – 3Q 2013  
LPFV – 1Q 2016 
LPLV – 1Q 2017 
Background and 
Rational 
Melflufen (L-melphalanyl-p-L-fluorophenylalanine ethyl ester 
hydrochloride) is an optimized derivative of the classical alkylating 
agent melphalan that has been in clinical use as an anti-tumor agent 
for nearly fifty years. Chemically melflufen may be described as the 
ethyl ester of a dipeptide with melphalan and para-fluoro-L-
phenylalanine. 
 
The transport of melflufen into cells is rapid. Once inside the 
cytoplasm melflufen will rapidly be subjected to enzymatic 
activation by cleavage of the dipeptide and ester bonds, thereby 
releasing free melphalan. Aminopeptideases like Aminopeptidase N 
(APN), (for which melflufen is a substrate) is frequently over-
expressed in tumors. Because of the differential rate of transport of 
melflufen into cells (rapid) and free melphalan out of cells (slow), a 
high intracellular concentration of melphalan is achieved as a result 
of the intracellular cleavage. Thus, treatment with melflufen 
efficiently results in the intracellular trapping of melphalan. It has 
been demonstrated that treatment with melflufen results in a 10-20 
fold higher intracellular concentration of melphalan in tumor cells 
compared with direct treatment with equal doses of melphalan.1,2 
 
When studied in cell cultures of human tumors representing 
approximately 20 different diagnoses of human cancers including 
myeloma, melflufen showed 50 to 100 fold higher potency compared 
with that of melphalan. After the targeted delivery of melphalan to 
the tumor cells, the detailed mechanism of action is naturally 
expected to be that of melphalan, i.e. alkylation of tumor cell DNA. 
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Confidential 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
neutropenia) and thrombocytopenia, which appeared dose-related 
and reversible, and appeared more pronounced in heavily pretreated 
patients. Fatigue, nausea, occasional vomiting, diarrhea and anemia 
were also observed (see Oncopeptides AB Investigator Brochure). 
 
In summary, the cell culture studies demonstrated that melflufen 
provides targeted delivery of melphalan to the cancer cells and 
therefore higher concentrations are achieved in tumors. In preclinical 
animal studies, melflufen shows equimolar bone marrow toxicity 
profile to melphalan with better tumor growth suppression. The 
phase I-II trial conducted in advanced cancer patients has established 
the recommended phase II dose (RPTD) of melflufen to be 50 mg 
every 3 weeks, at least in previously treated patients with an 
acceptable safety profile. Melphalan is currently used clinically in 
multiple myeloma (MM). Cell culture studies demonstrate a greater 
cytotoxic potency of melflufen versus melphalan against MM cells 
without significant toxicity in normal cells. Overall, these preclinical 
and clinical studies provide the rationale for clinical protocols 
evaluating melflufen in MM. 
Study Design 
This is an open-label, phase I/IIa, multicenter study which will enroll 
patients with relapsed and or relapsed-refractory MM.  Phase I will 
follow the standard 3 + 3 modified Fibonacci design with 3 to 6 
patients, depending on dose limiting toxicity (DLT) observed, at each 
dose level to be tested. Up to 5 dose levels will be tested; IV 
melflufen at 15 mg, 25 mg, 40 mg, 55 mg and 70 mg, given on Day 
1, in combination with a fixed dose of dexamethasone 40 mg PO or 
IV on Days 1, 8 and 15 of each 21-day cycle.  
Once the maximum tolerated dose (MTD) has been determined in 
Phase I, an additional 49 patients will be enrolled and treated at the 
MTD in the Phase IIa part of the study. 
  
Patients will be assessed for response after each cycle according to 
the IMWG response criteria. Patients may receive up to 8 cycles of 
therapy. However, patients who have benefit from the therapy may 
continue treatment at the discretion of the investigator and after 
approval by the study sponsor for each individual case. Doses of 
melflufen or dexamethasone may be interrupted or reduced in an 
attempt to manage toxicity according to the protocol guidelines. 
 
Amendment 4 aims to establish the single agent activity of 
melflufen, and hence the dexamethasone dose will be reduced to a 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
maximum of 24 mg per cycle for anti-emetic purpose. As 
dexamethasone alone is not regarded as an effective treatment in 
RRMM, it is important to explore if the main activity of the 
promising effect seen with the combination of melflufen and 
dexamethasone arise from the melflufen component. If so, future 
patients may be treated with melflufen with lower dose of 
dexamethasone, thus avoiding many of the well-known 
dexamethasone side effects. 8 mg dexamethasone will be 
administered on Days 1 and 2 of each cycle, and in addition 4 mg is 
allowed on Days 3 and 4 if needed for delayed emesis.     
  
 
Amendment 4 will also increase the standard cycle length of 
melflufen from 21 to 28 days. This was decided by the DSMC 18 
May 2015 after review of the available dosing and safety data. As 
this was regarded a safety precaution, this change has already been 
implemented. 
 
Amendment 5 described that in the event that the DSMC, at any time, 
determines that the risk-benefit balance of single agent melflufen is 
sub optimal, they will have the possibility to recommend that 
subsequent patients be treated with the combination of melflufen 
with weekly 40 mg dexamethasone in order to optimize efficacy, 
without any further amendment. In this case, patients will follow the 
same dexamethasone dose, schedule and dose modification 
guidelines as the combination cohort previously described in 
accordance with protocol version 4.0 Amendment 3 dated 27 January 
2015. A total of 40 patients have to date been treated with this 
combination. Patients ongoing in the single agent cohort may then 
have weekly dexamethasone added at the investigator’s discretion. 
Amendment 5 also includes an additional melflufen vial strength, 20 
mg. 
 
Amendment 6 includes an additional final OS follow-up for those 
approx. 40% of patients who were still alive 24 months after their 
last melflufen dose or progression. This is done to better understand 
the long-term benefit of melflufen treatment, where median OS is 
20.7 months. After this, the study will be closed for all patients and 
results will be reported.  
 
Objectives 
Primary Objective(s) 
Phase I (Phase 1 is complete) 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
The primary objective of the Phase I portion of the study is to 
determine the MTD of the combination of melflufen and 
dexamethasone in patients with relapsed and relapsed-refractory 
multiple myeloma (MM). 
 
Phase IIa 
To evaluate the objective response rate ≥ PR and the clinical benefit 
(including minimal response [MR]) to the combination of melflufen 
and dexamethasone and to melflufen as single agent at the MTD 
determined in Phase I. 
 
Secondary Objective(s) 
To evaluate the overall response including the complete 
response/stringent complete response (CR/sCR), very good partial 
response (VGPR), PR and clinical benefit (≥ MR), time to 
progression, duration of response, progression free survival and 
overall survival in all evaluable patients. 
 
To further explore the safety and tolerability of the combination and 
single agent melflufen at the MTD. 
Exploratory Objective(s) 
To identify mechanisms of response and or resistance to melflufen. 
Pharmacokinetics will be evaluated in patients enrolled at a select 
site with the training and expertise to collect and process the required 
samples.   
ECG assessments to screen for major effects on the QTc interval will 
be conducted at select sites. Should a signal be detected further 
evaluations will be conducted in future studies. 
 
Inclusion Criteria 
Eligible patients will be considered for inclusion in this study if they 
meet all of the following criteria: 
 
1. Male or female, age 18 years or older.  
2. Patient has a diagnosis of multiple myeloma with 
documented relapsed and/or relapsed-refractory disease. 
3. Patient has measurable disease defined as any of the 
following: 
• Serum 
monoclonal 
protein ≥ 0.5 g/dL 
by 
protein 
electrophoresis.   
• ≥ 200 mg of monoclonal protein in the urine on 24-hour 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
electrophoresis  
• Serum immunoglobulin free light chain ≥ 10 mg/dL 
AND abnormal serum immunoglobulin kappa to lambda 
free light chain ratio. 
• If no monoclonal protein is detected (non-secretory 
disease), then ≥ 30% monoclonal bone marrow plasma 
cells.  
4. Patient has had at least 2 or more prior lines of therapy 
including 
lenalidomide 
and 
bortezomib 
and 
has 
demonstrated disease progression on or within 60 days of 
completion of the last therapy. (see appendix D for the 
definition of lines of therapy);  
5. Life expectancy of ≥ 6 months; 
6. Patient has an ECOG performance status ≤ 2. (Patients with 
lower performance status based solely on bone pain 
secondary to multiple myeloma will be eligible); 
7. Females of childbearing potential (FCBP)† must have a 
negative serum or urine pregnancy test prior to initiation of 
therapy; 
8. Female patients of child bearing potential and non-
vasectomized male patients agree to practice appropriate 
methods of birth control;  
9. Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and authorization 
to use protected health information;  
10. The patient has or, accepts to have, an acceptable infusion 
device for infusion of melflufen (Port A Cath, PICC line or 
central venous catheter); 
11. 12 lead ECG with QTcF interval of ≤ 470 msec; (see 
Appendix G) 
12. The following laboratory results must be met within 21 days, 
or as specified in the table of assessments, prior to initiation 
of therapy: 
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 
x 109/L) (Growth factors cannot be used within 14 days 
prior to initiation of therapy).  


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (platelet 
count ≥ 50,000 cells/ mm3 for patients in whom ≥ 50% of 
bone marrow nucleated cells are plasma cells (without 
transfusion during the previous 7 days to initiation of 
therapy).  
• Hemoglobin ≥ 8.0 g/dL (RBC transfusions are permitted)  
• Total Bilirubin ≤ 1.5 X upper limit of normal (ULN);  
• Renal function: Estimated creatinine clearance ≥ 45 
ml/min and serum creatinine ≤ 2.0 mg/dL;  
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN.  
† (FCBP) is any sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy or 2) has not been 
naturally postmenopausal (not having menstrual cycles due to cancer 
therapy does not rule out childbearing potential) for at least 24 
consecutive months. 
 
Exclusion Criteria 
Patients will be ineligible for this study if they meet any one of the 
following criteria: 
1. Patient has evidence of mucosal or internal bleeding and/or 
is platelet transfusion refractory (i.e., unable to maintain a 
platelet count ≥ 50,000 cells/mm3);  
2. Any medical conditions that, in the Investigator’s opinion, 
would impose excessive risk to the patient or would 
adversely affect his/her participating in this study. Examples 
of 
such 
conditions are: 
a 
significant history of 
cardiovascular 
disease 
(e.g., 
myocardial 
infarction, 
significant conduction system abnormalities, uncontrolled 
hypertension, ≥  grade 3 thromboembolic event in the last 6 
months), renal insufficiency (unless felt to be secondary to 
MM);  
3. Known active infection requiring parenteral or oral anti-
infective treatment;  
4. Other malignancy within the past 3 years with the exception 
of adequately treated basal cell carcinoma, squamous cell 
skin cancer, carcinoma in-situ of the cervix; 
5. Other ongoing anti-myeloma therapy.  Patients may be 
receiving concomitant therapy with bisphosphonates and 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
low dose corticosteroids (e.g., prednisone up to but no more 
than 10 mg PO q.d. or its equivalent) for symptom 
management 
and 
comorbid 
conditions. 
Doses 
of 
corticosteroid should be stable for at least 7 days prior to 
initiation of therapy; 
6. Pregnant or breast-feeding females; 
7. Serious psychiatric illness, active alcoholism, or drug 
addiction that may hinder or confuse compliance or follow-
up evaluation; 
8. Known HIV or hepatitis B or C viral infection; 
9. Patient has concurrent symptomatic amyloidosis or plasma 
cell leukemia; 
10. POEMS 
syndrome 
(plasma 
cell 
dyscrasia 
with 
polyneuropathy, 
organomegaly, 
endocrinopathy, 
monoclonal protein and skin changes); 
11. Previous 
cytotoxic 
therapies, 
including 
cytotoxic 
investigational agents, for multiple myeloma within 3 weeks 
(6 weeks for nitrosoureas) prior to initiation of therapy. 
Biologic, novel therapy (including investigational agents in 
this class) or corticosteroids within 2 weeks prior to 
initiation of therapy.  Patient has side effects of the previous 
therapy > grade 1 or previous baseline. 
12. Prior peripheral stem cell transplant within 12 weeks of 
initiation of therapy; 
13. Radiotherapy within 21 days prior to initiation of therapy. 
However, if the radiation portal covered ≤ 5% of the bone 
marrow reserve, the patient may be enrolled irrespective of 
the end date of radiotherapy;  
14. Known intolerance to steroid therapy. 
 
Study Treatment(s) 
Treatment will be given in an outpatient treatment setting in cycles.  
Each cycle is 28 days. Melflufen concentrate for solution for infusion 
is to be diluted in 250 ml of 5% glucose solution. The study treatment 
will be administered as a 30 minute IV infusion every 4 weeks via 
central line.  (See protocol for complete guidelines on drug 
preparation and administration).  Safety precautions regarding 
preparation and handling of alkylating agents should be followed in 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
accordance with institutional guidelines. Prophylactic treatment with 
antiemetics is recommended. 
 
Dexamethasone oral tablets or IV solution is available either from 
commercial supplies or otherwise oral tablets will be supplied by 
Oncopeptides AB where required by local regulations. 
 
Phase I (Phase I is completed) 
Phase I Dose Levels to be tested: 
Dose Level 
Melflufen 
Dose (IV) 
Dexamethasone 
dose (PO or IV) 
Cycle = 21 
days 
Day 1 
Day 1, 8, 15 
Level 1 
15 mg 
40 mg 
Level 2 
25 mg 
40 mg 
Level 3 
40 mg 
40 mg 
Level 4 
55 mg 
40 mg 
Level 5 
70 mg 
40 mg 
 
The first cohort of patients enrolled in the Phase I portion of the study 
will receive dose level 1. A full safety evaluation will be conducted 
when these patients have completed one cycle (21 days) of 
combination therapy. Dose escalation for subsequent patients will 
proceed as follows: 
 
• If no DLT is reported in the first three patients at a dose level, that 
dose level will be considered safe and three patients will be 
enrolled at the next dose level. 
 
• If 1/3 patients in a cohort at a dose level has a DLT, the dose level 
will be expanded to obtain six evaluable patients. 
 
• If 2/3 patients in a cohort at a dose level has a DLT, that dose 
level will not be considered safe, no further dose escalation will 
take place, and the MTD will have been exceeded*.   
 
• If there are < 2 patients with a DLT among the expanded cohort 
of six evaluable patients a cohort of three patients will be enrolled 
in the next higher dose level. 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
 
• If there are 2 or more patients with a DLT among the expanded 
cohort of six evaluable patients, that dose level will not be 
considered safe, no further dose escalation will take place, and 
the MTD will have been exceeded*.   
 
* When the MTD has been exceeded: 
 
If less than 6 patients have been treated in the next lower dose level 
(the possible MTD level), additional patients will be entered into this 
dose level until there are 6 patients treated.  If ≤ 1 of these 6 patients 
encountered DLT, then this dose level will be declared to be the 
MTD. If 2 or more of the 6 patients encounter DLT, then the MTD 
has been exceeded.   
 
NOTE: If a patient discontinues treatment for reasons unrelated to 
adverse events such that safety in cycle one cannot be fully 
evaluated, an additional patient may be enrolled; these will be 
reviewed on a case by case basis in conjunction with the sponsor.   
 
Intra-Patient Dose Escalation: In consultation with Oncopeptides AB 
medical monitor, intra-patient dose escalation may be considered at 
the discretion of the investigator if the patient has not had a DLT in 
cycle 1, has not required a dose modification in cycle 2+ and has 
achieved only SD or MR as best response. In addition, the higher 
dose with which the patient is to be treated must be a dose that has 
completed evaluation and has not exceeded the MTD.       
 
The 6 patients treated at MTD will be the first 6 patients of the phase 
IIa component of the study. 
 
Definition of Maximum Tolerated Dose (Phase I only. Phase I is 
completed):    
The MTD of the combination of melflufen and dexamethasone in 
multiple myeloma patients shall be defined as the highest dose level 
resulting in ≤ 1 out of 6 patients experiences DLT. The dose will be 
escalated either until an MTD is identified or the maximum planned 
dose is achieved.  
 
Definition of DLT (Phase I only. Phase I is completed): 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
• Grade 3 or greater non-hematologic toxicity 
possible/probable/definite related to treatment with melflufen 
or the combination of melflufen and dexamethasone. (If a 
patient experiences a grade 3 or greater non-hematologic 
toxicity (see table 7-5 for the list of toxicities) that is clearly 
and solely related to dexamethasone during cycle one of 
therapy – this will not necessarily be counted as a DLT.  The 
event will be considered by the Data Monitoring Safety 
Committee (DSMC) upon review of all other toxicities noted 
for the given cohort and the DSMC will determine if dose 
escalation should continue or if a reduced dose of 
dexamthasone (20 mg) will be implemented for subsequent 
cohorts). 
• Grade 3-4 thrombocytopenia (platelet count < 50,000/ mm3) 
with clinically significant bleeding.    
• Platelet transfusions in the absence of bleeding will not 
be considered a DLT because thrombocytopenia is an 
anticipated effect of the disease as well as a side effect 
of treatment, particularly in a heavily pretreated patient 
population and patients can enter the study with pre-
existing thrombocytopenia.   
• Grade 4 neutropenia must occur for more than 5 days to be 
considered dose limiting. A grade 4 neutropenia with duration 
of less than 5 days or grade 3 neutropenia must result in 
neutropenic fever with elevated temperature (defined as 
ANC < 1000/mm3 with a single temperature of > 38.3°C or 
sustained temperature of ≥ 38°C for more than one hour) to be 
considered dose-limiting. 
Other grade 4 hematological toxicity (other than 
thrombocytopenia, neutropenia and lymphopenia) 
• Inability to receive Day 1 dose for Cycle 2 within 14 days from 
planned Day 1 Cycle 2, due to continued drug related toxicity 
from cycle one or drug related toxicity newly encountered on 
Day 1 of Cycle 2. 
 
Patients must meet the criteria as outlined in the protocol (see 
section 7.9.7); Initiation of A New Cycle of Therapy (including 
platelet count ≥ 50,000/ mm3 and Neutrophils ≥ 1,000 cells/ mm3 
(1.0 x 109/L); to begin cycle 2 or subsequent cycles. The DLT 
criteria will not change the adverse event reporting which will be 
done according to National Cancer Institute – Common 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
Terminology Criteria for Adverse Events Version 4.03 (CTCAE 
4.03).  
The prophylactic use of growth factors and platelet transfusions in 
cycle one of the dose escalation cohorts in Phase 1 is not permitted. 
However, at the discretion of the investigator, the use of growth 
factors and platelet transfusions to facilitate retreatment is permitted.  
Phase II 
Patients will be treated at the MTD as determined in Phase I with the 
same schedule. All patients will follow the same procedures for drug 
administration and observation as Phase I.  
Amendment 4 introduced a 28-day cycle based on the May 18, 2015 
DSMC recommendation. Ongoing patients may increase to 28-day 
schedule at investigator discretion; new patients will start therapy 
with 28-day cycles. Amendment 4 also aim to explore the effect of 
melflufen alone, and hence dexamethasone will be given as 8 mg on 
Days 1 and 2 of each cycle, and an additional 4 mg may be given on 
Days 3 and 4 at investigator discretion, if needed, for a total 
maximum of 24 mg per cycle as anti-emetic prophylaxis. 
 
Duration of 
Treatment 
Phase I and Phase II: Treatment will be administered in cycles of 21 
days (Amended to 28 days for all new patients enrolled after May 
18, 2015). Up to 8 cycles will be administered. However, patients 
who have benefit from the therapy may continue treatment at the 
discretion of the investigator after approval by the study sponsor for 
each individual case. Response will be evaluated every cycle starting 
with cycle 2 according to the IMWG response criteria.   
 
Concomitant 
Drug/Therapy 
All blood products and concomitant medications received from 
screening until the end of study visit treatment should be recorded. 
• Prophylactic treatment with anti-emetic(s) just prior to study 
treatment administration is recommended. 
• Patients should receive full supportive care while on this study 
at the investigators discretion including transfusions, anti-
emetics, anti-diarrheals, analgesics etc., and treatment of other 
concurrent medical conditions. 
• IV or PO Bisphosphonate therapy, if indicated, is permitted. 
• Colony-stimulating factors may be used if neutropenia occurs 
but should not be used prophylactically during Cycle 1 of Phase 
I. 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
• No anticancer agents other than the study medications 
administered as part of this study protocol are permitted. 
Number of Patients 
A maximum of 6 patients per dose level will be enrolled in 5 planned 
dose levels. An additional 6 patients may be required should 
dexamethasone toxicity require switching to the alternate dose levels 
regardless of the level at which the change is made. A maximum of 
36 patients can be enrolled in the Phase I part of the study.   
 
The 6 patients treated at the MTD in Phase I, will be included in the 
Phase IIa assessment. An additional 49 patients will be enrolled in 
the Phase IIa portion of the study for a total of 55 at the MTD. 
 
Amendment 4 will include a cohort of ≥20 efficacy-evaluable 
patients treated with single agent melflufen. 
All patients following approval of the amendment 4 will be treated 
with single agent melflufen. The aim is to have at least 20 patients 
treated with single agent melflufen. The overall objective is to treat 
55 efficacy-evaluable patients with 40 mg of melflufen. The 55 
efficacy-evaluable patients will therefore also include the cohort of 
≥20 single agent patients. When 55 evaluable patients have been 
obtained, further recruitment will be stopped but all patients that 
have signed informed consent will be allowed to continue. If the ≥ 
20 efficacy-evaluable single-agent cohort has NOT been fulfilled 
within the total of 55 patients, recruitment will continue until this 
cohort is complete. 
 
Assessments 
Safety Assessments: 
• Serial physical examinations with vital signs and assessment of 
performance status; 
• Routine safety laboratory tests (CBC with differential and 
platelets; clinical chemistry, coagulation tests) with calculation 
of creatinine clearance (either estimated by Cockcroft-Gault 
formula [Appendix F] or measured through 24-hour urine 
collection); 
• Chest X-ray; 
• Pregnancy testing; 
• Electrocardiogram; 
• Neurological assessments; 
• Assessment and grading of adverse events. 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
Adverse experiences, including clinical laboratory and vital sign 
abnormalities, will be graded using the NCI’s CTCAE 4.03 
(Appendix B). Patients are evaluable for toxicity if they receive one 
dose of study treatment. 
 
Efficacy Assessments 
• M-protein determination using both of the following procedures: 
o Serum protein electrophoresis (SPEP) and serum protein 
immunofixation with quantitative immunoglobulins; and  
o Urine protein electrophoresis (UPEP) and urine protein 
immunofixation (all using the same 24-hour urine 
collection);  
• Serum free light chains (SFLC); 
• Plasmacytoma evaluation; 
• Bone marrow aspirate to quantify percent myeloma cell 
involvement;  
• Skeletal survey: lateral radiograph of the skull and 
anterioposterior views of femur and humeri.  Anterioposterior 
and lateral views of the spine, and anterioposterior views of the 
pelvis and ribs. (CT/PET scan may be utilized to support 
conventional X-ray of spine, ribs and pelvis with the same 
technique to be used with each evaluation or as clinically 
indicated).   
• Beta2 microglobulin. 
 
Disease status will be assessed at screening and C1, Day 1 and 
starting with Cycle 2, response to treatment will be assessed every 
cycle by M protein quantitation and immunofixation from serum, a 
24-hour urine collection and SFLC. Full disease response 
assessment, including assessment of plasmacytomas and skeletal 
survey and/or CT/PET scan will be performed if indicated according 
to the IMWG response criteria for all patients or at the end of 
treatment for any reason. Bone marrow aspirate will be performed to 
confirm CR in patients who have achieved a CR by immunofixation. 
Additional skeletal survey and or CT/PET scan may be performed if 
the patient has bone symptoms suggested by pain and/or progression 
of lesions documented at baseline. If soft tissue plasmacytomas are 
present and measurable on physical examination they will be 
assessed at every cycle. Those extramedullary plasmacytomas 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
documented and measurable only by MRI and/or CT/PET scans will 
be assessed by the relevant modality to confirm response according 
the IMWG response criteria and the end of treatment evaluation.  
Correlative Sample Assessments 
Peripheral blood and bone marrow aspirate samples will be collected 
at pre-therapy, Cycle 1 Day 2, to confirm CR and at end of study.  
(Cycle 1 Day 2 and end of study samples are optional for consenting 
patients). Cells will be subjected to proteomics, microarray analysis, 
enzymatic assays, and Tissue Microarray Analysis (TMA). The 
studies will be oriented on biomarkers relevant to efficacy of 
melflufen.  Correlative samples will only be collected at US sites. 
Pharmacokinetic Assessments 
Plasma samples for determination of melflufen and melphalan 
concentrations will be drawn in connection to the first treatment 
cycle, prior to start of infusion (baseline), at 15 and 25 minutes post 
start of infusion, immediately before end of infusion, and at 5, 10 15, 
30, 60, 120 and 210 minutes post end of infusion. The PK samples 
will only be collected at one to two dedicated sites trained in the 
procedures for sample processing. 
Statistical Methods 
Study Endpoints 
 
Primary Endpoint 
Phase I 
The primary end point of Phase I is to determine the MTD by 
monitoring and analyzing the frequency and grade of adverse events 
occurring at each dose level of melflufen and dexamethasone to be 
tested. 
 
Phase IIa 
The primary end point of Phase IIa is the objective response rate (CR, 
sCR, VGPR, PR) and clinical benefit (≥ MR) and the rate of SD and 
PD observed in patients treated at the MTD. 
 
Secondary Endpoint(s) 
The overall response rate (CR/sCR, VGPR, PR) and clinical benefit 
(≥ MR), time to progression, duration of response, progression free 
and overall survival in all evaluable patients.   
 
To further evaluate the frequency and grade of all adverse events of 
the combination of melflufen and dexamethasone and of melflufen 
alone, including the rate and type of second primary malignancies. 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
 
Exploratory Endpoint(s) 
To identify mechanisms of response and or resistance to melflufen. 
Pharmacokinetics of melflufen and melphalan will be collected at the 
following time points: start of infusion (baseline), at 15 and 25 
minutes post start of infusion, immediately before end of infusion, 
and at 5, 10 15, 30, 60, 120 and 210 minutes post end of infusion, at 
one to two centers. 
 
Assessment of QTc interval will be conducted at select sites.  
 
Analysis Sets 
Safety Analysis: 
All patients that have initiated treatment (at least one dose) will be 
considered evaluable for safety analysis(s).  The maximum grade for 
each type of adverse event will be recorded for each patient, and 
frequency tables will be reviewed to determine patterns.  
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
 
Efficacy Analyses: 
All patients who have baseline evaluation, receive at least 2 cycles 
of therapy and have at least one post dose efficacy measurement will 
be considered evaluable for response.  The Phase IIa portion of the 
study was originally designed using a one-stage design to enter 20 
eligible patients for a total of 26 including the 6 patients treated at 
the MTD.  It was calculated that if 4 or more (≥ 15%) responses were 
reported among 26 evaluable patients, the treatment would be 
regarded as effective. However, based on initial promising response 
data in the first 10 patients treated at the MTD the patient number 
was amended to 55 patients treated at the MTD in order to 
demonstrate an ORR (≥ PR), better than previously reported for 
competitive compounds in similar patient populations. Assuming an 
ORR for melflufen of 50% and including 55 patients, the study will 
have 80% power to show that the lower limit of a 95 % confidence 
interval is above 32%.   
 
Amendment 4: At least 20 efficacy-evaluable patients will be treated 
with single agent melflufen to explore if the main activity in the 
promising effect seen with the combination of melflufen and 
dexamethasone is coming from melflufen alone. These patients will 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Compound Name 
Melflufen (J1) 
Molecular Formula C24H31CL3F N3O3 
Chemical Name 
L-melphalanyl-p-L-fluorophenylalanine ethyl ester HCl  
be included in the main efficacy analysis set, as well as be assessed 
separately. As described above, an ORR of ≥15% would suggest that 
melflufen has single agent activity. 
 
Ethics 
The study will be conducted in accordance with the International 
Conference on Harmonisation (ICH) for Good Clinical Practice 
(GCP) and the appropriate regulatory requirement(s).   


 
 
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Oncopeptides AB 
 
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Protocol Amendment 6, Version 7.0, November 2, 2018 
 
List of Abbreviations 
AE 
ALT 
ANC 
AML 
APN 
AST 
AUC 
BLQ 
CBC 
CDP 
Cmax 
CRF(e) 
CRO 
CR 
CT 
CTCAE 
CXR 
DLT 
DNA 
DOR 
DSMC 
ECG 
ECOG 
EOT 
FCBP 
GCP 
G-CSF 
IMWG 
HIV 
IV 
ICF 
ICH 
IEC 
IRB 
JNK 
MM 
MR 
MRI 
mRNA 
MTD 
NSCLC 
OS  
PD 
PET 
PFS 
Adverse Event 
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT 
Absolute neutrophil count 
Acute Myelocytic Leukemia 
Aminopeptidase N  
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT 
Area under the curve 
Below the level of quantification 
Complete blood count 
Clinical Development Plan 
Maximum plasma concentration 
Case Report Form(electronic) 
Contract Research Organization 
Complete response 
Computerized tomography 
Common terminology criteria for adverse events 
Chest X-Ray 
Dose Limiting Toxicity 
Deoxyribonucleic acid 
Duration of response 
Data Safety Monitoring Committee 
Electrocardiogram 
Eastern Cooperative Oncology Group 
End of therapy 
Female of child bearing potential 
Good Clinical Practice 
Granulocyte colony stimulating factor 
International Myeloma Working Group 
Human immunodeficiency virus 
intravenous(ly) 
Informed consent form 
International Conference on Harmonization 
Independent Ethics Committee 
Institutional Review Board 
c-Jun N-terminal kinases  
Multiple Myeloma 
Minor response 
Magnetic resonance imaging 
Messenger RNA 
Maximum tolerated dose 
Non-small cell lung cancer  
Overall survival  
Progressive disease 
Positron emission tomography 
Progression free survival 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
PHI 
PK  
PO 
POEMS 
 
PR 
PTC 
q.d. 
RBC 
REB  
RPTD 
TMA 
TTP  
SAE 
SD 
SFLC 
siRNA 
SPEP 
ULN 
UPEP 
VGPR 
Protected Health Information  
Pharmakokinetics 
Per os/by mouth/orally 
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin 
changes 
Partial response 
Peptichemio    
quaque die/one a day 
Red blood count  
Research Ethics Board  
Recommended phase two dose 
Tissue microarray analysis 
Time to progression 
Serious Adverse Event 
Stable disease 
Serum free light chain 
Small interfering RNA  
Serum protein electrophoresis 
Upper limit of normal 
Urine protein electrophoresis 
Very good partial response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Oncopeptides AB 
 
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1 
Background 
1.1 
Overview of Multiple Myeloma 
 
Multiple myeloma (MM) is a heterogeneous clonal B-cell malignancy characterized by the 
accumulation of abnormal antibody producing plasma cells in the bone marrow. The disease 
is associated with a variety of clinical manifestations including lytic bone lesions, 
hypercalcemia, renal impairment and anemia.  MM is the second most common hematologic 
malignancy and accounts for approximately 11,000 deaths per year in the United States and 
19,000 in Europe.5,6  
 
Current treatment strategies include the use of immunomodulatory drugs such as thalidomide 
and its derivatives, proteasome inhibitors such as bortezomib, synthetic steroids, alkylating 
agents such as melphalan, anthracyclines and autologous stem cell transplant. Despite recent 
therapeutic advances and the use of “novel agents”, MM remains an incurable disease with a 
median survival of approximately 5 - 7 years. 7 
Melphalan has wide spread use in the treatment of MM, both as a low dose agent in elderly 
patients and in myeloablative treatment supported by autologous stem cell transplantation. 
However, melphalan treatment is associated with significant toxicities and the development of 
drug-resistance.  Since the introduction of melphalan, nearly 50 years ago, attempts have been 
made to improve the therapeutic index and thus provide a greater margin of clinical safety 
during treatment with the drug. 
1.2 
Overview of Melflufen 
During the 1960’s six peptide derivatives of m-L-sarcolysin (the meta-isomer of melphalan) 
were tested in the clinic and marketed as a cocktail under the name Peptichemio (PTC).  PTC 
demonstrated clinical activity in a number of tumor types.8,9 However, production was stopped 
in the 1980’s. Researchers at Oncopeptides AB subsequently synthesized similar analogues of 
peptide derivatives of melphalan that showed higher anti-tumor activity in nonclinical studies. 
From a large group of synthesized compounds with different amino acid additions, 2 were 
selected by Oncopeptides AB to enter into extensive assays against primary human tumors and 
tumor cell lines in vitro and in vivo, and eventually melflufen was selected as a candidate drug. 
1.2.1 
Melflufen Description 
Melflufen (L-melphalanyl-p-L-fluorophenylalanine ethyl ester hydrochloride) is a derivative 
of the classical alkylating agent melphalan that has been in clinical use as an anti-tumor agent 
for nearly fifty years. The chemical name for Melflufen is L-melphalanyl-p-L-
fluorophenylalanine ethyl ester hydrochloride and the chemical structure is provided in Figure 
1.2-1. The molecular weight is 498 (free base). 
 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
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Figure 1.2-1: Structure of Melflufen 
1.2.2 
Non-clinical experience 
1.2.2.1 
Mechanism of Action and In Vitro Studies 
Chemically melflufen may be described as the ethyl ester of a dipeptide consisting of melphalan 
and para-fluoro-L-phenylalanine. The dipeptide is hydrolyzed by the action of peptidases (for 
example aminopeptidase N), inside or in the vicinity of tumor cells, thereby releasing free 
melphalan, which has a better ability to interact with cellular DNA. Melphalan and melflufen, 
which can be classified as nitrogen mustard derivatives, exert their cytotoxic action through 
covalent interaction with intracellular nucleophiles, especially DNA, as a result of the 
spontaneous formation of reactive cyclic aziridinium ion intermediates. Difunctional agents, 
able to crosslink a DNA strand within a double helix (intrastrand), between two strands 
(interstrand) or between DNA and proteins, are more active than monofunctional agents. Cross-
linking of DNA is probably the most important factor for the cytotoxic effect, resulting in 
inhibitory effects on DNA replication and transcription, which subsequently leads to cell death. 
The reactivity of the nucleophilic sites in DNA relates to electronic and steric properties, as 
well as to the involvement in hydrogen bonds within the DNA double helix. Detailed studies 
have suggested that the N-7 position of guanine is the most susceptible site for alkylation.10  
When evaluated on different human cancer cell lines in vitro melflufen is, on a molar level, 10 
to 139 times more potent than melphalan despite equal alkylating capacity i.e. one bis(2-
chloroethyl)amino group per molecule.11 For the RPMI8226 MM cell lines the difference in 
potency is approximately ten times, regardless of resistance mechanism in the sublines (i.e. 
Glutathione mediated or Pgp-mediated).2 Based on correlation analysis of melflufen and 
melphalan in a panel of different cell lines it is concluded that the two drugs share the same 
main mechanism of action, i.e. alkylation of cancer cell DNA  (Pearson´s correlation coefficient 
= 0.8).2 This similarity in mechanism, but discrepancy in potency favoring melflufen, has also 
been confirmed with direct measurements of DNA syntheses12, the alkaline single cell gel 
electrophoresis (Comet assay), TUNEL assay (Terminal deoxynucleotidyl transferase (dUTP) 


 
 
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Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
nick end labeling) and direct comparisons of mRNA response to treatment (cMAP assay). An 
increased DNA damage after melflufen treatment has also been observed in MM cells where an 
increased level of γ-H2AX, a marker of DNA double strand break, has been observed after 
melflufen treatment with a concomitant activation of the DNA-damage signaling component 
p53.19 
Combination studies in vitro suggest synergistic antitumoral activity of melflufen with e.g. 
etoposide in various human cancers13, or with lenalidomide and bortezomib in MM cells.19 
The potency difference between melflufen and melphalan is dependent on hydrolysis of the 
peptide bond in melflufen. If this bond is chemically modified to be non-hydrolysable (e.g. by 
using a D-amino acid, or adding a methyl group to the peptide bond) the activity is significantly 
impaired and the targeted superiority eliminated.14 In searching for possible peptidases involved 
in this activation various human tumor cell lines were pre-treated with the enzyme inhibitors 
bestatin (inhibitor of several aminopeptidases) and ebelactone A (inhibitor of esterases), both 
which significantly decreased the cytotoxic activity of melflufen, but not melphalan.15  
Hydrolysis of melflufen in the cytoplasm of the tumor cells appears to be a rapid event.  In vitro 
studies in different human cancer cell lines have shown that the maximum intracellular 
melphalan concentration (following melflufen exposure) was reached after 15 minutes, 
thereafter declining with a half-life of approximately 1 hour, closely to what is expected for 
melphalan in aqueous solution.15,16,16,17 Following equimolar exposure of melphalan to the same 
tumor cells, the levels of intracellular melphalan was below the limit of quantification. Based 
on the assay’s limit of quantification, it was estimated that the intracellular concentration of 
melphalan was at least 10 times higher after exposure to melflufen than after melphalan itself, 
consistent with the difference in potency regarding cell death.  Preincubation with bestatin, an 
aminopeptidase inhibitor, 60 minutes before melflufen exposure, resulted in lower intracellular 
concentration of melphalan and somewhat higher concentrations of melflufen.15-16 
Aminopeptidases are widely distributed enzymes catalyzing the cleavage of amino acids from 
the amino terminus of protein or peptide substrates, and may localize as subcellular organelles 
in the cytoplasm or as membrane components. Some are monomeric and others are assemblies 
of relatively high mass (50 kDa) subunits. Many, but not all, of these peptidases are zinc 
metalloenzymes and are inhibited by the transition-state analog bestatin. Aminopeptidase N 
(APN, also known as CD13) is probably the most studied aminopeptidase with respect to 
cancer, and its expression has been associated with a number of characteristics of the malignant 
phenotype (e.g. cell proliferation, secretion, invasion and most often angiogenesis). A specific 
role of APN in hydrolyzing melflufen releasing free melphalan has been demonstrated in vitro 
with: i) pure APN enzyme, ii) plasmid-based overexpression of APN, or iii) down regulation of 
endogenous APN with siRNA.17 
(See Oncopeptides AB Investigators Brochure). 
1.2.3 
In Vivo Studies 
In vivo studies show that melflufen is well-tolerated and inhibits tumor growth in mice and 
rats.4 Preclinical safety studies conducted with melflufen showed it to have a comparable 


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Oncopeptides AB 
 
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130 mg) as a 30-minute intravenous infusion every 3rd week in a total of 25 treatment cycles. 
The primary objective of the phase I part of the study was to identify the recommended Phase 
II dose. The majority of the adverse events reported during phase I were blood and lymphatic 
system disorders (46 events), gastrointestinal disorders (35 events) and general disorders 
(fatigue, pyrexia, chills and chest pain (22 events). Nausea in relation to or shortly after drug 
infusion, as well as asthenia or fatigue was also commonly observed in this population of 
terminally ill cancer patients. No hypersensitivity or allergic reactions were observed. Dose 
limiting toxicity was found to be bone marrow related, i.e. neutropenia and thrombocytopenia, 
mainly occurring at doses of 75 mg or above. The dose recommended for Phase II was 
established at 50 mg. 
This side effect profile was expected based on experience from pre-clinical toxicity testing of 
melflufen and from known information from other alkylating agents, and are similar to what is 
observed for melphalan.   
1.2.5.2 
Phase II Clinical Experience 
In the Phase IIa parts conducted in Sweden and Russia. A total of 38 patients (22 in Sweden, 
16 in Russia) were treated with a total of 116 infusions (SWE: 65 cycles at doses 25-75 mg + 
RU: 51 cycles at doses 30-50 mg).  
In the Swedish patients, doses of 25 – 75 mg were tested. The most frequently reported related 
adverse events of any common terminology criteria for adverse events (CTCAE) grade were 
neutropenia, leukopenia and thrombocytopenia experienced by 19 out of 22 patients. 
Neutropenia occurred in (16 patients, 27 events), leukopenia in (15 patients, 24 events) and 
thrombocytopenia in (11 patients, 20 events).  These events were often seen in combination (16 
patients, 28 episodes).  The onset of the events was generally within 3 weeks after 
administration of study drug. The events resulted in dose reduction in next treatment period for 
10 patients that continued treatment. Generally, the events were resolved within 1- 4 weeks of 
onset. 
Of the 22 patients, 14 were evaluated for tumor response after 3 cycles of melflufen. Of these, 
one patient had a partial response (PR), 8 had stable disease (SD), and 5 had progressive disease 
(PD). Reasons for discontinuation prior to evaluation (eight patients) was due to disease 
progression after 1 (4 patients) or 2 cycles (2 patients), or hematological toxicity (2 patients). 
In conclusion, reversible leukopenia/neutropenia and thrombocytopenia, was confirmed to be 
the dose-limiting toxicity of melflufen. During the Phase IIa part, the starting dose was reduced 
to 50 mg (from 75 mg), as hematological toxicity rendered dose reduction in several patients. 
The data suggested that several courses of previous chemotherapy was pre-disposing to bone 
marrow toxicity, and in general patients in Phase IIa were more pre-treated than those in phase 
I. 
Sixteen patients were included in the Phase IIa part of the trial conducted in St Petersburg, 
Russia. The patients were diagnosed with ovarian cancer (n=8) or non-small cell lung cancer 
(NSCLC n=8, 2 females, 6 males) all without remaining standard treatment options. All patients 
had been treated with chemotherapy prior to study inclusion and in general ovarian cancer 


 
 
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patients had received more chemotherapy than NSCLC patients (3-5 different regimens for 
ovarian cancer, 2-4 different regimens for NSCLC).  
The 16 patients were administered melflufen with a starting dose of 50 mg as a 30-minute 
infusion in a total of 51 treatment cycles. The Russian experience confirmed hematologic 
toxicity as the dose limiting toxicity of melflufen. 
Out of 16 included patients 11 were evaluated for tumor response after nine weeks (2-3 cycles) 
of melflufen. These 11 included 5 ovarian cancer patients of who 4 had SD, and 1 PD. For the 
6 NSCLC patients, evaluation showed SD in 4 and PD in 2. The three non-evaluable ovarian 
cancer patients discontinued the study before the third cycle due to hematological toxicity, one 
of these received supportive G-CSF (exclusion criteria). The two non-evaluable NSCLC 
patients discontinued the study before the third cycle due to death related to progression, and 
hematological toxicity (and G-CSF treatment), respectively. 
Four patients died during the course of the Phase II studies. The cause of death was disease 
progression in three of the patients, and this was assessed by investigator as not related to 
melflufen therapy. One patient (male breast cancer, previously treated with six palliative 
chemotherapy regimens) presented with hematological nadir (neutrophils 0.6 WBC 1.3 x 
109/L) 15 days after his first dose of melflufen 50 mg. Blood values improved by Day 22 
(neutrophils 2.1, WBC 3.1 x 109/L), but on the same day the patient developed fever. He was 
admitted to hospital on Day 24, and was diagnosed with pneumonia with effusions and 
developed a neutropenic sepsis, from which he died on the 26th day after melflufen treatment 
in spite of treatment for the infection. This patient had liver metastases and was included in the 
study with slightly abnormal liver function tests (ALAT, ASAT, PK-INR and LDH) that 
worsened during the cycle and especially during his hospitalization. 
In the Swedish patients, it was observed that previous chemotherapy treatment appeared 
predisposing to hematological toxicity. The study population was however heterogeneous with 
respect to diagnoses included and drugs given, and so no detailed analysis was possible. In the 
Russian Phase IIa patients, it was easier to identify two separate groups of patients that were 
different in this respect, and where all patients started with 50 mg melflufen. The ovarian cancer 
patients (n = 8) had received an average of 3.9 prior chemotherapy regimens, while the NSCLC 
patients only had received only 2.5. Dose reductions were done in six of seven ovarian cancer 
patients receiving more than one dose of melflufen (the remaining patient received only one 
dose), but not in any of the NSCLC patients (however, one patient discontinued after the 2nd 
dose due to the need for G-CSF support). When all patients in the Phase IIa part were considered 
(Sweden + Russia, n = 38), there were 8 patients that had received only 2 prior chemotherapy 
regimens. Among these 8 patients, hematological toxicity of grade 3 or 4 was seen in 3 patients 
receiving in average of 3.6 cycles of melflufen. In contrast, among 16 patients that had received 
5 or more prior chemotherapy regimens, the incidence of hematological toxicity grade 3-4 was 
higher (14 of 16 patients), and the number of given doses of melflufen lower (average 2.6 
cycles).  
1.2.6 
Clinical Pharmacokinetics 
The pharmacokinetics (PK) of melflufen and the active metabolite melphalan were evaluated 
after melflufen doses ranging from 25 to 130 mg administered as an IV infusion over 30 minutes 


 
 
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to patients with advanced solid tumors during the Phase I-IIa trials in Sweden. Plasma 
concentration data of melflufen and melphalan were followed up to 6 hours after start of the 30-
minute infusion. Concentration profiles were evaluated using non-compartmental methods. 
It was concluded that administration of melflufen as an IV infusion resulted in a rapid and 
extensive formation of melphalan, which was thereafter eliminated from plasma in accordance 
with the pattern seen after direct administration of melphalan. Melphalan exposure increased 
approximately in relation to the given dose and the inter-occasion variability in exposure 
between treatment cycles was limited after administration of the same dose amount. Gender and 
body weight had no influence on the PK parameters of released melphalan. Consequently, the 
PK data supports an absolute dosing regimen of melflufen as proposed in the current clinical 
trial. Furthermore, the established PK profile of melflufen and its active metabolite melphalan 
supports that no further PK measurements are required in the current Phase I/IIa clinical trial 
given the low correlation between plasma concentrations and the efficacy and toxicity profile 
of melflufen. In the PK studies of melflufen, the dose 50 mg was the most frequently 
administered (32 occasions). It would be anticipated that a large patient would have a smaller 
Cmax and AUC than a smaller patient, if both patients were given the same dose. However, 
when these parameters were measured and were analyzed in relation to the patient´s weight, no 
significant relation could be detected, thereby justifying continuous use of flat-fixed dosing 
schedules. 
2 
Rationale 
2.1 
Study Rationale and Purpose 
Melphalan has been clinically used for the treatment of malignant diseases for over fifty years, 
and has demonstrated activity in a variety of solid tumors like breast cancer, ovarian cancer and 
testicular cancer as well as in, multiple myeloma.19,20 The clinical experience of melphalan in 
the treatment of multiple myeloma is extensive, both as low dose palliative treatment as well as 
high dose regimens supported by autologous or allogenic stem cell transplantation.  
The in vitro studies demonstrated that melflufen provides targeted delivery of melphalan to the 
cancer cells and therefore higher concentrations are achieved in tumors. In preclinical animal 
studies, melflufen shows equimolar bone marrow toxicity profile to melphalan with better 
tumor growth suppression. The Phase I-II trial conducted in advanced cancer patients has 
established the recommended Phase two dose (RPTD) of melflufen, with an acceptable safety 
profile, to be 50 mg every 3 weeks, at least in previously treated patients with solid tumors. 
Melphalan is currently used clinically in MM. Cell culture studies demonstrate a greater 
cytotoxic potency of melflufen versus melphalan against MM cells without significant toxicity 
in normal cells. Overall, these preclinical and clinical studies provide the rationale for clinical 
protocols evaluating melflufen in MM. 
2.2 
Rationale for the Study Design 
In the previous clinical trials performed with melflufen, no obvious interactions or other 
associated risk factors were observed by the investigators, except a noted tendency that patients 
with several lines of previous chemotherapy treatments appeared to be more vulnerable to bone 


 
 
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marrow toxicity than patients with less previous treatments. In addition, multiple myeloma is a 
disease state that adversely affects the bone marrow. Therefore, a Phase I/IIa study design was 
chosen to evaluate the toxicity profile in this select patient population.  This is an open-label, 
Phase I/IIa, multicenter study which will enroll patients with relapsed and or relapsed-refractory 
multiple myeloma.  The Phase I part of the trial will follow the standard 3 + 3 modified 
Fibonacci design with 3 to 6 patients, depending on dose limiting toxicity (DLT) observed, at 
each dose level to be tested.   
Once the maximum tolerated dose (MTD) has been determined in Phase I, an additional 49 
patients will be enrolled and treated at the MTD in the Phase IIa portion of the study to further 
evaluate toxicity and efficacy. 
2.3 
Rationale for Dose Selection 
The primary objective of the Phase I portion of the study is to determine the MTD of the 
combination of melflufen and dexamethasone in subjects with relapsed and/or relapsed-
refractory multiple myeloma. Dose levels have been selected based on safety and tolerability 
results from the previous Phase I/II trial with melflufen in solid tumor patients.  
PK analyses conducted in patients with solid tumors concluded that administration of melflufen 
as an IV infusion resulted in a rapid and extensive formation of melphalan, which was thereafter 
eliminated from plasma in accordance with the pattern seen after direct administration of 
melphalan. For patients receiving 50 mg of melflufen the weight of the patients had no apparent 
effect on the observed Cmax or area under the curve (AUC) of neither melflufen nor melphalan. 
Consequently, the PK data support a fixed dosing regimen of melflufen as proposed in the 
current clinical trial synopsis.  
Data show that melflufen is well tolerated when used at 50 mg for first cycle treatment in 
patients with lung cancer, while more pre-treated patients (patients with ovarian cancer) where 
more sensitive to melflufen. Since patients with MM are often both heavily pre-treated and have 
a disease that could weaken the bone marrow, this study will start at a dose that is lower than 
the identified RPTD. Once the first cohort of patients has been successfully treated with this 
lower dose, the dose will be escalated in a stepwise procedure to a maximum dose that is 
approximately the previously recommended Phase 2 dose. Up to 5 dose levels will be tested; 
IV melflufen given as a 30-minute infusion on Day 1 at 15 mg, 25 mg, 40 mg, 55 mg and 70 
mg in combination with a fixed dose of dexamethasone 40 mg PO or IV on Days 1, 8 and 15 of 
each 21 day cycle. This was performed in the completed Phase I component of the study. Dose 
escalation of melflufen will occur only after that the Data Safety Monitoring Committee 
(DSMC) has reviewed each cohort and made a recommendation. Intra-patient dose escalation 
is permitted, according to guidelines in Section 7.8.1, for patients that are tolerating treatment 
and have achieved only a SD or MR as best response in order to maximize response and 
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2.4 
Rationale for Amendment 4 
2.4.1 
Rationale for 28-day cycle 
As of 20 May 2015, 29 patients had been dosed with 40 mg of melflufen in the ongoing Phase 
II portion of the trial. A total of 89 full cycles of therapy have been administered with a median 
cycle length of 23 days. However, 41 of 89 (46%) completed cycles were delayed ≥ 5 days with 
the large majority due to delayed hematologic recovery.  
The Data Safety Monitoring Committee (DSMC) convened on 18 May 2015 and reviewed the 
current safety data related to the 40 mg cohort of patients. Overall the safety profile is consistent 
and as expected with neutropenia and thrombocytopenia as the main toxicities. No new safety 
concerns were identified. A detailed review of the cycle length, dose intensity and response was 
completed. As a result of this assessment, the DSMC recommended to allow additional time for 
hematologic recovery and for some flexibility in dose modifications in order to maximize 
exposure and minimize toxicity in any given patient based on tolerability. The main objective 
is to allow more patients to stay on the scheduled dosing interval as well as allowing more 
patients to stay longer on treatment while decreasing the risk of bone marrow failure. These 
changes were implemented immediately, as they were seen as a safety precaution, prior to the 
formal amendment. 
2.4.2 
Rationale for Single Agent Melflufen Cohort 
 
Dexamethasone alone is not regarded an effective treatment for multiple myeloma. When 
combined with other anticancer agents, two aims are to achieve an antiemetic effect and to 
support adrenal function. Oncopeptides AB conducted a face-to-face meeting with the FDA 
on 18 June 2015 where preliminary data from melflufen-dexamethasone combination in the 
ongoing study O-12-M1 were presented. The FDA representatives stressed that the 
interpretation of the therapeutic benefit of the combination was pending the availability of 
single-agent data from melflufen treated patients to isolate the effect of the melflufen 
component. The FDA would accept data from ≥20 single-agent treated patients in the 
presently ongoing study. If the exploratory cohort shows that the main activity of the 
combination of melflufen and dexamethasone arise from melflufen, future patients may be 
treated with melflufen without dexamethasone, thus avoiding the well-known dexamethasone 
side effects. 
2.5 
Rational for Amendment 5 
2.5.1 
New vial strength 
Due to unexpectedly slow recruitment in the trial over the last months, the trial will have to 
continue beyond the expiry date of the IMP batches currently in use. The expiry date cannot be 
extended further since the stability studies with those batches are completed and there are no 
more vials available to extend the duration of the stability studies. As a consequence, a new 
batch will have to be shipped to the study sites. This batch will consist of 20 mg vials since the 
sponsor has decided to introduce this vial strength to be used in future clinical trials. Hence, the 


 
 
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protocol has been updated to include all three strengths (15, 20 and 25 mg). It also clarifies that 
the use of the 55 mg and 70mg doses are not applicable during the Phase 2 part of the study.  
2.5.2 
DSMC review of single agent cohort 
In the event that the DSMC, at any time, determines that the risk-benefit balance of single agent 
melflufen is sub optimal, they will have the possibility to recommend that subsequent patients 
will be treated with the combination of melflufen with weekly 40 mg dexamethasone in order 
to optimize efficacy, without any further amendment. In this case, patients will follow the same 
dexamethasone dose, schedule and dose modification guidelines as the combination cohort 
previously described in accordance with protocol version 4.0 Amendment 3 dated 27 January 
2015. A total of 40 patients have to date been treated with this combination. Patients ongoing 
in the single agent cohort may then have weekly dexamethasone added at the investigators 
discretion.   
2.6 
Rationale for Amendment 6 
Study O-12-M1 was initiated in 2013 with the objective to assess the benefits and risks of 
melflufen including overall response rate (ORR), progression free survival (PFS) and overall 
survival (OS) in a treatment experienced relapsed-refractory multiple myeloma (RRMM) 
population. Based on clinical data in similar populations available at that time, showing 10-15 
months OS with e.g. carfilzomib and pomalidomide (Mohty 2012), it was anticipated that it 
would be sufficient to follow patients for 24 months after last treatment with study drug 
(melflufen+dexamethasone) to appropriately document OS in the study.  
The results of this study, in a population with median 4 prior lines of therapy (range 2-14), 93% 
last-line refractory and 67% double-refractory to an IMiD and a PI, show a surprisingly 
powerful clinical benefit including, but not limited to, a median OS of 20.7 months with median 
28.4 months of follow-up based on data cut 9 Nov 2017. Approximately 40% of the treated 
patients in Phase 2 were still alive at 24 months after end of treatment or progression and could 
not be followed any further within the present protocol. It is of importance, not only for 
Oncopeptides but also for the medical community, that the majority of surviving patients in this 
study are followed beyond 24 months so that updated OS data can establish the real magnitude 
of benefit. Following these patients would further provide understanding of which patients may 
have the highest probability of long survival (the patients with the highest benefit/risk ratio) 
after treatment with melflufen.  The protocol is therefore amended to allow for an extended OS 
follow-up assessment period beyond 24 months. This will be performed once, and after that the 
study will be closed for all patients and the results will be reported. There are currently 4 patients 
that are still in long-term follow-up, and they will then stop the study early. They have already 
lived longer than the median OS, and will be part of the few remaining late-stage censored 
patients.  


 
 
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3 
Objectives and Endpoints 
3.1 
Primary Objectives 
3.1.1 
Phase I 
The primary objective of the Phase I portion of the study is to determine the MTD of the 
combination of melflufen and dexamethasone in patients with relapsed and or relapsed-
refractory MM. 
3.1.2 
Phase IIa 
To evaluate the objective response rate (≥ PR) and the clinical benefit (≥ MR) to the 
combination of melflufen and dexamethasone and melflufen as single agent at the MTD 
determined in Phase I.  
3.2 
Secondary Objectives 
To evaluate the overall response including the complete response/stringent complete response 
(CR/sCR), very good partial response (VGPR) partial response (PR) and clinical benefit 
(≥ MR), the time to progression (TTP), duration of response (DOR), progression free survival 
(PFS) and overall survival (OS) in all evaluable patients. 
To further explore the safety and tolerability of the combination of melflufen and 
dexamethasone and of melflufen as single agent at the MTD. 
3.3 
Exploratory Objective(s) 
3.3.1 
Correlative Studies Objective(s)  
To identify mechanisms of response and or resistance to melflufen.  
Pharmacokinetics will be evaluated on patients enrolled at a select site that will be trained in 
the process of sample handling. 
ECG assessments to screen for major effects on the QTc interval will be conducted at select 
sites. Should a signal be detected further evaluations will be conducted in future studies. 
4 
Study design 
4.1 
Description of Study Design 
This is an open-label, Phase I/IIa, multicenter study that will enroll patients with relapsed and 
or relapsed-refractory MM.  Phase I will follow the standard 3 + 3 modified Fibonacci design 
with 3 to 6 patients, depending on dose limiting toxicity (DLT) observed, at each dose level to 
be tested.  Up to 5 dose levels will be tested; IV melflufen given as 30-minute infusion on Day 
1 at 15 mg, 25 mg, 40 mg, 55 mg and 70 mg in combination with a fixed dose of dexamethasone 
40mg PO on Days 1, 8 and 15 of each 21-day cycle. Alternate dose level of dexamethasone 20 
mg PO on Days 1, 8 and 15, may be explored in the event that the DLT at any dose level is 
thought to be specifically related to the treatment with dexamethasone 40 mg (PO or IV).  


 
 
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Once the MTD has been determined in Phase I, an additional 49 patients will be enrolled and 
treated at the MTD. The evaluation of the MTD will be based on the toxicity observed during 
Cycle 1 of Phase I.   
For both Phase I and Phase II, a treatment cycle was 21 days, however 18 May 2015 the cycle 
length was increased by the DSMC to 28 days. Patients will be assessed for response after each 
cycle with confirmation of response according to the IMWG response criteria regardless of dose 
level treated. Patients may receive up to 8 cycles of therapy. Doses of melflufen or 
dexamethasone may be interrupted or reduced in an attempt to manage toxicity according to the 
protocol guidelines. However, patients who have benefit from the therapy may continue 
treatment at the discretion of the investigator and after approval by the study sponsor for each 
individual case. In this case, patients will be treated with the dose last tolerated in cycle 8 or as 
modified based on cycle 8 toxicity requiring dose modification.  
Patients in the single agent cohort will receive melflufen 40 mg on day one of each 28-day 
cycle. All study procedures will remain the same except for the administration of 
dexamethasone. Dexamethasone will be used at lower doses as an anti-emetic medication. 
Dexamethasone alone is not regarded as an effective treatment. If the exploratory cohort shows 
that the main activity of the combination of melflufen and dexamethasone arise from the 
melflufen component, future patients may be treated with melflufen without dexamethasone, 
thus avoiding the well-known dexamethasone side effects.  In the event that the DSMC, at any 
time, determines that the risk-benefit balance of single agent melflufen is sub optimal, they will 
have the possibility to recommend that subsequent patients will be treated with the combination 
of melflufen with weekly 40 mg dexamethasone in order to optimize efficacy, without any 
further amendment. In this case, patients will follow the same dexamethasone dose, schedule 
and dose modification guidelines as the combination cohort previously described in accordance 
with protocol version 4.0 Amendment 3 dated 27 January 2015. Patients ongoing in the single 
agent cohort may then have weekly dexamethasone added at the investigators discretion. 
5 
Patient Population 
This trial will enroll patients with a diagnosis of relapsed or relapsed-refractory MM. Up to 36 
patients will be enrolled in Phase I with 5 dose levels of melflufen to be tested. However, in 
the event the DSMC, upon review of all other toxicities noted for the given cohort, determines 
a reduced dose of dexamethasone (eg; 20mg) will be implemented for subsequent cohorts, 
then the lower dose of dexamethasone is to be tested with the dose level of melflufen, at 
which the dexamethasone caused the DLT. In this case up to 6 additional patients may be 
enrolled, for a maximum of 36 patients. An additional 49 patients will be enrolled in the Phase 
IIa part at the MTD determined in Phase I, for a total of 55 patients treated at the MTD. 
Patients will be enrolled from approximately 6 – 8 sites in the United States and Europe. 
 
Amendment 4 will enroll a cohort of ≥20 patients to single agent melflufen 40 mg on day 1 of 
each 28-day cycle. All patients following approval of the amendment will be treated with 
single agent melflufen until the 20 efficacy-evaluable single-agent cohort has been completed. 
The objective is to treat a total of 55 efficacy-evaluable patients with 40 mg of melflufen. The 
55 efficacy-evaluable patients will therefore also include the cohort of 20 single agent 


 
 
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patients. When 55 evaluable patients have been obtained, further recruitment will be stopped 
but all patients that have signed informed consent will be allowed to continue. If the 20 
efficacy-evaluable single-agent cohort has NOT been fulfilled within the total of 55 patients, 
recruitment will continue until this cohort is complete. 
5.1 
Patient Screening 
Written informed consent must be obtained before any protocol-specific screening tests or 
procedures are performed. Patients must have received at least 2 prior therapies for their disease 
and meet all the entry criteria detailed in Section 5.3 and 5.4. After informed consent is obtained, 
the screening assessments will be performed as detailed in Section 8 of the protocol. Table 8-1 
lists all of the screening assessments including frequency and time lines of when assessments 
are to be performed. Laboratory tests noted in the inclusion criteria must be within the limits 
specified prior to patient registration. Testing may be repeated for this purpose. The last result 
obtained prior to start of study treatment will be used to determine eligibility. Assessments 
performed as part of the subject’s routine clinical evaluation and not specifically for this study 
need not be repeated after signed informed consent has been obtained provided the assessments 
fulfill the study requirements and are performed within the specified timeframe prior to 
registration. 
5.1.1 
Information to Be Collected on Screening Failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered screen failures. The reason for not being started on treatment will be entered in the 
screening log and the eCRF.  
5.2 
Patient Eligibility 
The investigator or designee must ensure that patients meet all the following inclusion and 
exclusion criteria. 
5.2.1 
Inclusion Criteria 
 
Eligible patients will be considered for inclusion in this study if they meet all of the following 
criteria: 
 
1. Male or female, age 18 years or older.  
2. Patient has a diagnosis of multiple myeloma with documented relapsed and/or 
relapsed-refractory disease. 
 
3. Patient has measurable disease defined as any of the following: 
a. Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis.   
b. ≥ 200 mg of monoclonal protein in the urine on 24-hour electrophoresis  


 
 
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c. Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio. 
d. If no monoclonal protein is detected (non-secretory disease), then ≥ 30% 
monoclonal bone marrow plasma cells.  
4. Patient has had at least 2 or more prior lines of therapy including lenalidomide and 
bortezomib and has demonstrated disease progression on or within 60 days of 
completion of the last therapy. (See Appendix D for the definition of lines of therapy);  
5. Life expectancy of ≥ 6 months; 
 
6. Patient has an ECOG performance status ≤ 2. (Patients with lower performance status 
based solely on bone pain secondary to multiple myeloma will be eligible); 
7. Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test prior to initiation of therapy; 
8. Female patients of child bearing potential and non-vasectomized male patients agree 
to practice appropriate methods of birth control;  
9. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information;  
10. The patient has, or accepts to have, an acceptable infusion device for infusion of 
melflufen (Port-a- Cath, PICC line or central venous catheter); 
 
11. 12 lead ECG with QtcF interval ≤ 470 msec. (see Appendix G) 
12. The following laboratory results must be met within 21 days, or as specified in the 
table of assessments, of initiation of therapy: 
• Absolute neutrophil count (ANC) ≥ 1,000 cells/ mm3 (1.0 x 109/L) (Growth 
factors cannot be used within 14 days of initiation of therapy); 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (platelet count ≥ 50,000/ mm3 
for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells 
(without transfusion during the previous 7 days to initiation of therapy);  
• Hemoglobin ≥ 8.0 g/dL (RBC transfusions are permitted);  
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN);  


 
 
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• Renal function: Estimated creatinine clearance ≥ 45 ml/min and serum 
creatinine ≤ 2.0 mg/dL; (See Appendix F); 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN.  
† FCBP is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due to 
cancer therapy does not rule out childbearing potential) for at least 24 consecutive months. 
5.2.2 
Exclusion Criteria 
Patients will be ineligible for this study if they meet any one of the following criteria: 
 
1. Patient has evidence of mucosal or internal bleeding and/or is platelet transfusion 
refractory (i.e., unable to maintain a platelet count ≥ 50,000 cells/mm3);  
 
2. Any medical conditions that, in the Investigator’s opinion, would impose excessive risk 
to the patient or would adversely affect his/her participation in this study. Examples of 
such conditions are: a significant history of cardiovascular disease (e.g., myocardial 
infarction, 
significant 
conduction 
system 
abnormalities, 
uncontrolled 
hypertension, ≥ grade 3 thromboembolic event in the last 6 months), renal insufficiency 
(unless felt to be secondary to MM); 
 
3. Known active infection requiring parenteral or oral anti-infective treatment;  
4. Other malignancy within the past 3 years with the exception of adequately treated 
basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix; 
 
5. Other ongoing anti-myeloma therapy.  Patients may be receiving concomitant therapy 
with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more 
than 10 mg PO q.d. or its equivalent) for symptom management and comorbid 
conditions. Doses of corticosteroid should be stable for at least 7 days prior to initiation 
of therapy; 
 
6. Pregnant or breast-feeding females; 
 
7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or 
confuse follow-up evaluation; 
 
8. Known HIV or hepatitis B or C viral infection; 
 
9. Patient has concurrent symptomatic amyloidosis or plasma cell leukemia; 


 
 
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10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein and skin changes); 
 
11. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple 
myeloma within 3 weeks (6 weeks for nitrosoureas) prior to start of study treatment. 
Biologic, novel therapy (including investigational agents in this class) or 
corticosteroids within 2 weeks prior to initiation of therapy.  Patient has side effects of 
the previous therapy > grade 1 or previous baseline. 
 
12. Prior peripheral stem cell transplant within 12 weeks of initiation of therapy; 
 
13. Radiotherapy within 21 days prior to Cycle 1 Day 1. However, if the radiation portal 
covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of 
the end date of radiotherapy; 
 
14. Known intolerance to steroid therapy. 
6 
Patient Registration, Numbering and Treatment Assignment 
6.1 
Patient Registration 
The investigator or designated staff will contact Oncopeptides AB’s Contract Research 
Organization (CRO), and provide the requested eligibility and identifying information for the 
patient to register (Registration form).  The form will be faxed to the CRO using a dedicated 
fax line (Refer to the Study Reference Manual for procedure details). Patient’s eligibility will 
be checked by the CRO once all screening procedures are completed prior to registration and 
cohort assignment. Patients that do not meet all the eligibility criteria will be considered screen 
failures and will not be registered into the trial.  
6.2 
Patient Numbering 
Each patient will initially receive a screening number.  A Patient Number is assigned when the 
patient is registered in the study and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient Number consists of the Center 
Number with a sequential patient number suffixed to it, so that each patient is numbered 
uniquely. The time point of confirmation of eligibility and assignment of the patient number 
will be considered “registration” into the trial. 
Once assigned, the Patient Number must not be reused for any other patient and the Patient 
Number for that individual must not be changed.  


 
 
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6.3 
Treatment Assignment  
During Phase I, the assignment of a patient to a particular dose level will be coordinated by the 
CRO. Confirmation of patient registration and the dose level assignment for a particular patient 
will be communicated by the CRO to the sites via return FAX and email of the patient 
Registration Form. During Phase IIa, confirmation of patient registration and the dose selected 
for the Phase IIa will also be communicated to the sites via return FAX and email of the patient 
Registration Form. Treatment may not begin prior to receipt of the confirmation of registration. 
Once registered, treatment must begin within the remaining days of the screening period.  If the 
patient fails to start treatment for any reason, the patient will be considered a screen failure. 
6.4 
Replacement Policy  
6.4.1 
Phase I 
Patients will not be replaced on study during Phase I unless they fail to start treatment, withdraw 
from study for reasons other than an adverse event during Cycle 1 and are considered as non-
evaluable for the purposes of determining toxicity for the current cohort. Enrollment of a new 
patient to the current cohort will only be considered if there is less than the required number of 
evaluable patients to determine toxicity for the cohort. (For example; of 3 patients in a cohort, 
one withdraws due to disease progression but 2 others have DLT, there is no need to replace 
the patient for the given cohort as the MTD has already been exceeded. Alternatively; of 3 
patients in a cohort, one withdraws due to disease progression but 2 others have not experienced 
a DLT, the patient will be replaced to fully evaluate the cohort with three evaluable patients).  
Decisions regarding replacement of patients will be made by the Data Safety Monitoring 
Committee.  
6.4.2 
Phase IIa 
In Phase IIa patients will not be replaced if they are considered evaluable for response. All 
patients who have baseline evaluation, receive at least 2 cycles of therapy followed by at least 
one efficacy measurement will be considered evaluable for response.  The Phase IIa portion of 
the study uses a one-stage design and will enter 49 eligible patients for a total of 55 evaluable 
patients (including the 6 patients treated at the MTD in the Phase I portion). If sufficient 
numbers of evaluable patients are not available to evaluate response, additional patients may be 
enrolled in order to meet the secondary endpoint. Decisions regarding replacement of patients 
will be made by the Data Safety Monitoring Committee. 
Amendment 4 will enroll a cohort of 20 patients to single agent melflufen 40 mg on day 1 of 
each 28-day cycle. Replacement rules for this cohort will be the same as those described above. 
7 
Treatment 
7.1 
Study Treatment 
 
Treatment will be given in an outpatient treatment setting in cycles.  Each cycle is 21 days. As 
described in Amendment 4, DSMC 18 May 2015 increased the cycle length to 28 days.  


 
 
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Ongoing patients may increase to a 28-day schedule at investigator discretion; new patients will 
start with 28-day cycles.   
 
Patients enrolled in the single agent cohort of melflufen will follow the same guidelines for 
drug administration as the combination cohorts.   
 
All patients must have an acceptable infusion device prior to the initiation of the first dose of 
melflufen. (Port A Cath, PICC line or central venous catheter). 
 
Prior to initiation of therapy on Cycle 1 Day 1, CBC results must continue to meet the entry 
criteria: 
 
• Absolute neutrophil count (ANC) ≥ 1,000 cells/ mm3 (1.0 x 109/L) (Growth 
factors cannot be used within 14 days of initiation of therapy); 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (platelet count ≥ 50,000/ mm3 
for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells) 
(without transfusion during the previous 7 days to initiation of therapy). 
 
Melflufen will be administered as a 30-minute intravenous (IV) infusion every 21 days. As 
described in Amendment 4, DSMC 18 May 2015 increased the cycle length to 28 days.  
Ongoing patients may increase to a 28-day schedule at investigator discretion; new patients will 
start with 28-day cycles. (See protocol section 7.10 for complete guidelines on drug preparation 
and administration). 
 
Dexamethasone will be administered as oral tablets or IV infusion, at the investigators 
discretion according to the regional Package Insert.  
 
7.2 
Phase I (Phase I is completed) 
7.2.1 
Dosing Levels  
Table 7-1 
Dose levels to be tested 
Dose Level 
Melflufen Dose  
(IV) 
Dexamethasone dose  
(PO or IV) 
Cycle = 21 days 
Day 1 
Days 1, 8 and 15 
Level 1 
15 mg 
40 mg 
Level 2 
25 mg 
40 mg 
Level 3 
40 mg 
40 mg 
Level 4 
55 mg 
40 mg 
Level 5 
70 mg 
40mg 


 
 
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7.3 
Phase IIa 
Patients will be treated at the dose determined in Phase I administered according to the same 
schedule; melflufen on Day 1 and dexamethasone on Days 1, 8 and 15 of each 21 day cycle or 
the recommended Phase II dose and schedule as determined by the DSMC. As described in 
Amendment 4, DSMC 18 May 2015 increased the cycle length to 28 days. Ongoing patients 
may increase to a 28-day schedule at investigator discretion; new patients will start with 28-day 
cycles.  
Amendment 4 will enroll a cohort of ≥20 patients to single agent melflufen 40 mg on day 1 of 
each 28-day cycle. Dexamethasone will NOT be administered as an anti-tumor compound.   
However, all patients will be treated with dexamethasone as an anti-emetic prophylaxis with 8 
mg of dexamethasone on days 1 and 2 of every cycle. An additional 4 mg of dexamethasone 
may be given on days 3 and 4 if needed, at the discretion of the investigator. The total dose of 
dexamethasone may not exceed 24 mg in any cycle.   In the event that the DSMC, at any time, 
determines that the risk-benefit balance of single agent melflufen is sub optimal, they will have 
the possibility to recommend that subsequent patients will be treated with the combination of 
melflufen with weekly 40 mg dexamethasone in order to optimize efficacy, without any further 
amendment. In this case, patients will follow the same dexamethasone dose, schedule and dose 
modification guidelines as the combination cohort previously described in accordance with 
protocol version 4.0 Amendment 3 dated 27 January 2015. Patients ongoing in the single agent 
cohort may then have weekly dexamethasone added at the investigators discretion. 
7.4 
Concomitant Therapy  
All baseline medications that the patient is taking within 7 days prior to the initiation of therapy 
must be recorded. All additional medications (other than study drug) or changes in baseline 
medications and significant non-drug therapies (including physical therapy, herbal/natural 
medications and blood transfusions) administered during the study must be listed on the 
Concomitant Medications page of the eCRF.  
7.4.1 
Recommended Concomitant Therapy 
Prophylactic treatment with anti-emetic(s) prior to melflufen administration is recommended. 
Subsequent anti-emetic drugs against delayed emesis will be administered at the discretion of 
the investigator.  
Patients should receive full supportive care, including transfusions of blood and blood products 
(including platelets), antibiotics, anti-diarrheals, analgesics, etc. and prophylactic treatment for 
tumor lysis syndrome when appropriate.  
Bisphosphonate therapy IV or PO should be administered if indicated in accordance with 
institutional guidelines. 
The prophylactic use of growth factors and platelet transfusions in cycle one of the dose 
escalation cohorts in Phase I is not permitted. However, at the discretion of the investigator, the 
use of growth factors and platelet transfusions to facilitate retreatment is permitted. 


 
 
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7.4.2 
Contraindicated Concomitant Therapy 
Concurrent therapy with any approved or investigative anticancer therapeutic drug with activity 
against multiple myeloma is not allowed.  
Corticosteroids 
for 
non-malignant 
conditions 
(e.g., 
asthma, 
inflammatory 
bowel 
disease) > prednisone 10 mg/day (or its equivalent) are not permitted.   
Amendment 4 single agent melflufen cohort may not exceed a total dose of 24 mg of 
dexamethasone per cycle  
Other investigative agents should not be used during the study. 
7.5 
Phase I Dose Escalation Guidelines (Phase I is completed) 
 
The first cohort of patients enrolled in the Phase I portion of the study will receive dose level 1.  
A full safety evaluation will be conducted when these patients have completed one cycle (21 
days) of combination therapy. Based on the evaluation after the first cycle, the dose escalation 
for subsequent patients will proceed as follows: 
 
• If no DLT is reported in the first three patients at a dose level, that dose level will be 
considered safe and three patients will be enrolled at the next dose level. 
 
• If 1/3 patients in a cohort at a dose level has a DLT, the dose level will be expanded to obtain 
six evaluable patients. 
 
• If 2/3 patients in a cohort at a dose level has a DLT, that dose level will not be considered 
safe, no further dose escalation will take place, and the MTD will have been exceeded*.   
 
• If there is ≤ 1 patient with a DLT among the expanded cohort of six evaluable patients a 
cohort of three patients will be enrolled in the next higher dose level. 
 
• If there are 2 or more patients with a DLT among the expanded cohort of six evaluable 
patients, that dose level will not be considered safe, no further dose escalation will take 
place, and the MTD will have been exceeded*.   
 
* When the MTD has been exceeded: 
 
If less than 6 patients have been treated in the next lower dose level (the possible MTD level), 
additional patients will be entered into this dose level until there are 6 patients treated.  If ≤ 1 
of these 6 patients encountered DLT, then this dose level will be declared to be the MTD.  If 2 
or more of the 6 patients encounter DLT, then the MTD has been exceeded.   
 
NOTE: If a patient discontinues treatment for reasons unrelated to adverse events such that 
safety in cycle one cannot be fully evaluated, an additional patient may be enrolled; this will be 


 
 
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reviewed on a case by case basis in conjunction with The Data Safety Monitoring Committee. 
(See Section 6.4.1) 
7.6 
Definition of Maximum Tolerated Dose (Phase I only. Phase I is 
completed) 
 
The MTD of the combination of melflufen and dexamethasone in multiple myeloma patients 
shall be defined as the highest dose level resulting in ≤ 1 out of 6 patients experiencing DLT in 
Cycle 1. The dose will be escalated in a new cohort until an MTD is identified or the maximum 
planned dose is achieved.  
7.7 
Definition of DLT (Phase I only. Phase I is completed) 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as related or possibly related to study drug that occurs within the first 21 days of 
treatment and meets any of the criteria outlined below. National Cancer Institute CTCAE 
version 4.03 will be used for all grading. 
• Grade 3 or greater non-hematologic toxicity possible/probable/definite related to 
treatment with melflufen or the combination of melflufen and dexamethasone. (If a 
patient experiences a grade 3 or greater non-hematologic toxicity (see Table 7-5 for list 
of toxicities that would be considered attributable to dexamethsone) that is clearly and 
solely related to dexamethasone during cycle one of therapy – this will not necessarily 
be counted as a DLT.  The event will be considered by the DSMC upon review of all 
other toxicities noted for the given cohort and the DSMC will determine if dose 
escalation should continue or if a reduced dose of dexamethasone (20mg) will be 
implemented for subsequent cohorts). 
• Grade 3-4 thrombocytopenia (platelet count < 50,000/ mm3) with clinically significant 
bleeding.    
o Platelet transfusions in the absence of bleeding will not be considered a DLT 
because thrombocytopenia is an anticipated effect of the disease and side effect of 
treatment, particularly in a heavily pretreated patient population and patients can 
enter the study with pre-existing thrombocytopenia.   
• Grade 4 neutropenia must occur for more than 5 days to be considered a DLT.  A grade 
4 neutropenia with duration of less than 5 days or grade 3 neutropenia must result in 
neutropenic fever with elevated temperature (defined as ANC < 1000/mm3 with a single 
temperature of > 38.3°C or sustained temperature of ≥ 38°C for more than one hour) to 
be considered dose-limiting. 
• Other grade 4 hematological toxicity (other than thrombocytopenia, neutropenia and 
lymphopenia)  
• Inability to receive Day 1 dose for Cycle 2 within 14 days of planned Day 1 Cycle 2, 
due to continued drug related toxicity from cycle one or drug related toxicity newly 
encountered on Day 1 of Cycle 2. 


 
 
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Patients must meet the criteria as outlined in the protocol (Section 7.9.7, Initiation of a New 
Cycle of Therapy), including platelet count ≥ 50,000/ mm3 and Neutrophils ≥ 1,000 cells/mm3, 
to begin cycle 2 or subsequent cycles of therapy. The prophylactic use of growth factors and 
platelet transfusions in cycle one of the dose escalation cohorts in Phase I is not permitted. 
However, at the discretion of the investigator, the use of growth factors and platelet transfusions 
to facilitate retreatment is permitted.     
7.8 
Guidelines for Dose Escalation Decisions (Phase I only. Phase I 
is completed) 
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled 
patients who will be treated at the specified dose level.  
Patients must complete a minimum of 1 cycle of treatment (21 days) with the minimum safety 
evaluation or have had a DLT within the first cycle of treatment to be considered evaluable for 
dose escalation decisions.  
Dose escalation decisions will be made by the DSMC and will be based on data from the first 
cycle. Additional data from all other ongoing dose levels may also be included in the dose 
escalation decision at the discretion of DSMC. If a patient experiences a grade 3 or greater non-
hematologic toxicity that is clearly and solely related to dexamethasone (see Table 7-5 for list 
of toxicities that would be considered attributable to dexamethasone) during cycle one of 
therapy – this will not necessarily be counted as a DLT.  The event will be considered by the 
DSMC upon review of all other toxicities noted for the given cohort and the safety committee 
will determine if dose escalation should continue or if a reduced dose of dexamethasone (eg. 
20mg) will be implemented for subsequent cohorts. The DSMC may at its own discretion alter 
the dose or schedule of melflufen. In the event that a lower dose of dexamethasone is to be 
tested, the dose level of melflufen, at which the dexamethasone caused the DLT, will be 
repeated.  
Drug administration at the next higher dose level may not proceed until the DSMC determines 
that the results of the previous dose level were evaluated and that it is permissible to proceed to 
a higher dose level.  
7.8.1 
Intra-Patient Dose Escalation (Phase I only. Phase I is completed) 
Intra-patient dose escalation is not permitted at any time within the first 2 cycles of treatment. 
After the second cycle is completed, individual patients may be considered for treatment at a 
dose of melflufen higher than the dose to which they were initially assigned. In order for a 
patient to be treated at a higher dose he or she must have tolerated the lower dose for at least 2 
cycles of therapy without experiencing a DLT or requiring a dose reduction in Cycle 2 or 
subsequent cycles and have achieved only a stable disease (SD) or minor response (MR) as best 
response. In addition, the higher dose with which the patient is to be treated must be a dose that 
has completed the safety evaluation and has not exceeded the MTD. Patients may only escalate 
from one dose level to the next, without skipping a dose level. For any further increase after the 
initial intra-patient dose escalation, the following rules apply: the patient must not have 
experienced a CTCAE grade ≥ 2 drug related toxicity over at least two cycles of therapy at the 
lower dose, and the higher dose being considered must have been fully evaluated and shown 


 
 
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not to exceed the MTD. Consultation and agreement with the DSMC must occur prior to any 
intra-patient dose escalation occurring.  
7.9 
Dose Modifications 
7.9.1 
Phase I and Phase IIa Dose Modification and Dose Delay 
Dose reductions are not permitted during Cycle 1 of Phase I unless the patient experiences 
a DLT. The patient may continue on protocol therapy if the toxicity resolves and the patient 
can be managed by a dose modification as detailed in this section.  However, the occurrence of 
the DLT will be counted toward the assessment of the MTD.  Dose reductions are permitted in 
subsequent cycles of Phase I and during cycle 1 and subsequent cycles of Phase IIa. 
The prophylactic use of growth factors and platelet transfusions in cycle one of the dose 
escalation cohorts in Phase I is not permitted. However, at the discretion of the investigator, the 
use of growth factors and platelet transfusions to facilitate retreatment is permitted.  Dose 
adjustments are permitted according to rules described in this section. Dose modifications 
different from those stated in the protocol should only be made in consultation with the medical 
monitor of the designated CRO –and/or the DSMC; unless required for immediate patient 
safety.   
Administration of the study drugs will be discontinued in the event of a treatment-related 
toxicity that persists despite appropriate dose reductions or any other toxicity that, in the opinion 
of the Investigator, warrants discontinuation.   
Toxicity will be assessed using the CTCAE version 4.03 (Appendix B).   
All interruptions or changes to study drug administration must be recorded in the eCRF. 
All dose modifications should be based on the worst preceding toxicity. 
7.9.2 
Dose Reduction Steps 
7.9.3 
Dose Reduction Steps for Melflufen 
Table 7-2 outlines the dose reduction steps for melflufen based on the starting dose for Cycle 
one or subsequent cycles. Multiple dose reductions are permitted however, the lowest dose 
permitted is 15 mg. If a patient is unable to tolerate the lowest dose of melflufen due to drug 
related toxicity the patient must be withdrawn from study.  
Table 7-2 
Dose reduction steps for melflufen (Phase I/IIa) 
 
Starting 
Dose 
Dose reduction 
step - 1 
Dose reduction 
step – 2 
Dose reduction 
step - 3 
Dose 
reduction step 
- 4 
70 mg 
55 mg 
40 mg 
25 mg 
15 mg 
55 mg 
40 mg 
25 mg 
15 mg 
 
40 mg 
25 mg 
15 mg 
- 
- 
25 mg 
15 mg 
- 
- 
- 
15 mg 
- 
- 
- 
- 


 
 
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7.9.4 
Dose Reduction Steps for Dexamethasone 
Table 7-3 outlines the dose reduction steps for dexamethasone based on the starting dose for 
Cycle one or subsequent cycles. Multiple dose reductions are permitted. If a patient is unable 
to tolerate dexamethasone due to dexamethasone related toxicity, dexamethasone may be 
discontinued.  However, the patient may continue on treatment with single agent melflufen, at 
the investigators discretion.   
Table 7-3 
Dose reduction steps for dexamethasone (Phase I/IIa) 
 
Starting Dose 
Dose reduction 
step - 1 
Dose reduction 
step - 2 
40 mg 
20 mg 
12 mg 
20 mg 
12 mg 
- 
12 mg 
- 
- 
 
Amendment 4 will change the dexamethasone dosing schedule for all new patients to 8 mg 
given on Days 1 and 2 of each cycle. An additional 4 mg allowed at the discretion of the 
investigator on Days 3 and 4 only, if needed. The ongoing patients should continue with the 
initial schedule.  In the event that the DSMC, at any time, determines that the risk-benefit 
balance of single agent melflufen is sub optimal, they will have the possibility to recommend 
that subsequent patients will be treated with the combination of melflufen with weekly 40 mg 
dexamethasone in order to optimize efficacy, without any further amendment. In this case, 
patients will follow the same dexamethasone dose, schedule and dose modification guidelines 
as the combination cohort previously described in accordance with protocol version 4.0 
Amendment 3 dated 27 January 2015. Patients ongoing in the single agent cohort may then 
have weekly dexamethasone added at the investigators discretion. 
7.9.5 
Dose Modification Guidelines for Melflufen 
 
Amendment 4 Dose Modifications: 
 
The Data Safety Monitoring Committee (DSMC) convened on 18 May 2015 and reviewed the 
current safety data related to the 40 mg melflufen treatment cohort of patients. Overall the 
safety profile is consistent and as expected with neutropenia and thrombocytopenia as the 
main toxicities and no new safety concerns were identified. A detailed review of the cycle 
length, dose intensity and response was completed. As a result of this assessment, the DSMC 
made recommendations to allow additional time for hematologic recovery and for some 
flexibility in dose modifications in order to maximize exposure and minimize toxicity in any 
given patient based on tolerability. The main objective is to allow more patients to stay on the 
scheduled dosing interval as well as allowing more patients to stay longer on treatment while 
decreasing the risk of bone marrow failure. 
 


 
 
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Amendment 4 details the revised dose modifications of melflufen implemented as a safety 
precaution for all patients treated in Phase II as of 18 May 2015 and all new patients enrolled 
in the study.   
 
Dose modifications of melflufen for the Amendment 4 single agent cohort will follow the 
same rules detailed below for melflufen.   
 
Dose modifications are permitted for melflufen according to the following guidelines. If a 
patient is unable to tolerate the lowest dose of melflufen due to drug related toxicity the 
patient must be withdrawn from study. 
 
Prior to each cycle of melflufen the criteria for initiation of therapy must be met. (See section 
7.9.7). The dose of melflufen to be administered is based on the time to recovery of the 
adverse event.   
 
The cycle length is changed from 21 to 28 days. Patients currently tolerating a 21-day cycle 
may continue with a 21-day or increase to a 28-day cycle length at the investigators 
discretion. All new patients enrolled in the study will commence with a 28-day treatment 
cycle.  
 
Hematologic Toxicity: 
 
The following guidelines for dose modification should be followed:  
 
• If the criteria for initiation of a new cycle of therapy (See Section 7.9.7) are not met 
on the next scheduled Day 1 of any given cycle, re-evaluate weekly.   
• If the criteria for initiation of a new cycle of therapy are met on Day 29, 36 and/or 
Day 43, continue therapy at the same dose level.  
• If the criteria for initiation of a new cycle of therapy are met on Day 29 or Day 36, an 
additional week may be added to the cycle length at the investigators discretion to 
allow additional bone marrow recovery. However, in this circumstance, treatment 
must be initiated by 6 weeks (42 days). 
• If the criteria for initiation of a new cycle of therapy are not met on Day 36, but are 
met by Day 43, a one level dose reduction may be implemented at the investigator's 
discretion but is not required.  If the patient does not fulfill the retreatment criteria at 
Day 43, a dose reduction is required. 
• If the criteria for initiation of a new cycle of therapy are not met by day 43, continue 
to re-evaluate weekly for an additional 2 weeks.  
• If the criteria are met on days 50 or 57, a one level dose reduction of melflufen is 
required.   
• If the criteria for initiation of a new cycle of therapy are not met by day 57 due to 
drug related toxicity, then the patient must be discontinued from the study; unless in 
the investigators opinion the patient is benefitting from therapy, continuation may be 
discussed with the medical monitor or sponsor on a case by case basis.  


 
 
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Alternate dose modification may be considered in discussion with the medical monitor or the 
sponsor.   
 
Patients who discontinue the study for a study related adverse event including abnormal 
laboratory value must be followed as described in Section 8.2.6. 
 
The prophylactic use of growth factors and platelet transfusions is not permitted within 14 
days of initiation of treatment (C1D1). However, at the discretion of the investigator, growth 
factors and platelet transfusions are permitted as per institutional guidelines for the treatment 
of hematologic toxicity. 
 
Non-hematologic toxicity 
 
The resolution of all non-hematologic toxicity must be to ≤ Grade 1 or baseline and will 
follow the same criteria and time lines for dose reduction as hematologic toxicity noted above.   
7.9.6 
Dose Modification Guidelines for Dexamethasone 
Table 7-5 Dose modifications for toxicity related to dexamethasone 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1–2  
(requiring medical management) 
Treat with H2 blockers, sucralfate, 
or omeprazole. If symptoms persist 
despite above measures, decrease 
dexamethasone dose by 1 dose 
level. 
Gastrointestinal 
> Grade 3  
(requiring hospitalization or 
surgery) 
Hold dexamethasone until 
symptoms adequately controlled. 
Restart and decrease one dose level 
of current dose along with 
concurrent therapy with H2 
blockers, sucralfate, or omeprazole. 
If symptoms persist despite above 
measures, discontinue 
dexamethasone and do not resume. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone and do 
not resume 
Cardiovascular 
Edema 
> Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca) 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose 
level; if edema persists despite 
above measures, decrease dose 
another dose level. Discontinue 
dexamethasone and do not resume 


 
 
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if symptoms persist despite second 
reduction. 
Neurology 
Confusion or Mood alteration  
> Grade 2 (interfering with 
function +/- interfering with 
activities of daily living) 
Hold dexamethasone until 
symptoms resolve. Restart with one 
dose level reduction. If symptoms 
persist despite above measures, 
discontinue dexamethasone and do 
not resume. 
Musculoskeletal 
Muscle weakness  
> Grade 2 (symptomatic and 
interfering with function +/- 
interfering with activities of 
daily living) 
Decrease dexamethasone dose by 
one dose level. If weakness persists 
despite above measures, decrease 
dose by one dose level. Discontinue 
dexamethasone and do not resume 
if symptoms persist. 
Metabolic 
Hyperglycemia > Grade 3 or 
higher 
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite above 
measures, decrease dose by one 
dose level until levels are 
satisfactory. 
7.9.7 
Initiation of a New Cycle of Treatment  
Patients should be assessed at the beginning of each cycle according to the tests and evaluations 
outlined on Day 1 of each cycle in Table 8-1. To begin a new cycle of treatment the following 
criteria must be met: 
• ANC must be ≥ 1.0 x109/L (≥ 1,000/mm3) 
• Platelet count must be ≥ 50.0 x 109/L (≥ 50,000/mm3) 
• All non-hematologic toxicities must be ≤ Grade 1 or returned to baseline (except 
alopecia 
• Absence of any other DLT’s 
If these criteria are not met on the next scheduled Day 1, re-evaluate weekly. If these criteria 
are not met on the scheduled Day 1, the new cycle should be held and can only be initiated 
when the criteria are met according to the dose modifications and timelines outlined in Section 
7.9.5. Dose Modifications. 


 
 
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7.9.8 
Treatment Duration 
Patients may continue treatment in both Phase I and Phase IIa with the study drug for up to 8 
cycles or until the patient experiences unacceptable toxicity, disease progression or withdraws 
consent, and/or treatment is discontinued at the discretion of the investigator. However, patients 
who have benefit from the therapy at the end of 8 cycles may continue treatment at the discretion 
of the investigator and after approval by the study sponsor for each individual case. In this case, 
patients will be treated with the dose last tolerated in Cycle 8 or as modified based on Cycle 8 
toxicity requiring dose modification. 
7.10 
Study Drug Preparation and Administration 
7.10.1 
Melflufen Packaging and Labeling 
The study drug is packaged in 50 ml glass vials containing 15, 20 or 25 mg of melphalan 
flufenamide (melflufen). The vials will be delivered either in separate paper boxes with 
respective doses of 15, 25, 40 or 55 mg, or in paper boxes with 16 vials of 20 mg. The Phase 2 
dose of 40 mg will consist of two vials (either one 15 mg + one 25 mg or 2 x 20 mg) and the 55 
mg dose will consist of 3 vials (two 15 mg + one 25mg). The 70 mg dose will be prepared from 
two dose boxes of 40 mg (volume infused calculated to ensure correct dose given). Note: The 
55 mg and 70 mg doses are not applicable to the Phase 2 part of the study thus use of the 20 mg 
vial for these doses is also not applicable.  
Medication labels on the vials will be in the local language and comply with the legal 
requirements of each country.  
The labeling of the infusion bag for each patient is performed in connection with the preparation 
of the infusion solution at the hospital pharmacy. 
7.10.2 
Melflufen Supply 
Melflufen is formulated as a sterile lyophilized powder for solution for infusion (containing 
melflufen and the excipient sucrose). The product, lyophilized melflufen for solution for 
infusion, is filled in 50 mL glass vials. Each vial contains 15, 20 or 25 mg of melflufen. 
7.10.3 
Melflufen Storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the melflufen shall be stored at +2 - 8°C (refrigerated).   
7.10.4 
Preparation of Melflufen Solution for infusion 
The prescribed dose of melflufen will be prepared in a designated pharmacy. Safety precautions 
regarding preparation and handling of alkylating agents should be followed according to 
standard operating procedures at the pharmacy.    
Melflufen powder will be diluted in a 250 mL 5% glucose solution infusion bag (called 5% 
glucose below). The melflufen solution for infusion will be administered to the patient as a 30-


 
 
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minute IV infusion and the infusion must start within 30 minutes from start of preparation 
(initial dilution).  
This means that a well-planned preparation and handling procedure is required due to the 
relatively rapid degradation of the melflufen drug substance in water solutions.  
 
The melflufen solution is prepared by dilution of melflufen powder in 250 mL 5% glucose 
according to the prescribed dose and the dosing table below.  
7.10.4.1 Materials 
 
 
Melflufen Powder: 
15, 20 or 25 mg in a glass vial. 
Delivered in paper boxes  
Store at +2 to +8ºC (refrigerated) until preparation. Only take out 
the number of vials to be used. Allow the vial/s to equilibrate to 
room temperature (15-25°C) for 30 minutes before mixing with 
5% glucose.  
 
5% glucose:   
       Plastic infusion bag, 250 mL. 
Note! The solution should have reached room temperature (15-
25°C) at the time point for preparation.  
 
Syringe:  
PP (Poly Propylene) syringes should be used when handling the 
Melflufen Solution. The Melflufen Solution should be injected 
directly into the glucose bag from the syringe through one of the 
injection ports. A transfer device should not be used.  
 
Infusion tubing set: 
       Sites can use their standard infusion tubing sets. 
NOTE: The infusion tubing set should be pre-filled with 5% glucose.  Use of saline is 
prohibited due to the risk for precipitation. 
7.10.4.2 Preparation procedure: 
 
1. The investigator will prescribe the melflufen dose, according to protocol. 
 
2. Prepare the labels, see below; one label should be placed on the infusion bag and one label 
should be placed in the patient’s medical records. It is also to be filled in electronically in 
the eCRF at the clinic after the infusion is finished.  
 
3. Take out the melflufen vial/s from the corresponding dose/paper box. The number of vials 
will depend on the dose, as listed in the table below. Allow the vials to equilibrate to room 
temperature (15-25°C) for 30 minutes before preparation. 
 
4. Note the dose and batch number for the Melflufen Powder in the preparation protocol. 
 


 
 
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5. Notify the clinic that the preparation is about to begin, to make sure that the prepared 
infusion bag of Melflufen Solution will be collected immediately after preparation. The 
infusion must start within 30 minutes from start of preparation i.e the infusion must be 
completed within 60 minutes. 
 
6. Use standard safety precautions for preparing chemotoxic drugs (Gown, face and eye 
protection, gloves and work under a LAF).Shake or vortex the vial/s to disintegrate the 
freeze-dried melflufen powder-cake.  Add 40 mL of glucose solution from the infusion 
bag, using a polypropylene (PP) syringe, to the/each Melflufen Powder vial.  Mix 
thoroughly by shaking the vial/vials until clear solution.  If the solution is not clear within 
10 minutes, discard and take out a new dose and start over. For 40 mg doses transfer the 
solutions to the 5% glucose infusion bag.  For 15 and 25 mg doses the volume transferred 
to the infusion bag must be adjusted to ensure correct dose.  For a 25 mg dose, either use 
one 25 mg vial and transfer the full volume (40 mL) to the infusion bag, or use two 20 mg 
vials and transfer the full volume (40 mL) from the first vial to the infusion bag, but only 
transfer 10 mL from the second vial to the infusion bag. For a 15 mg dose, use only one 
vial, either 15 mg or 20 mg.  If 20 mg vial is used, only transfer 30 mL to the infusion bag.  
If 15 mg vial is used transfer the full 40 mL to the infusion bag. Do not use a transfer 
device, inject directly into the bag.  Be careful to make sure that the dissolved melflufen 
solution is transferred correctly to the glucose infusion bag. 
 
7. Turn the infusion bag upside down at least five times to ensure a good mixing of the 
solutions. Carefully check that the infusion solution is clear, without visible particles or 
colour. A non-clear solution should not be used. The Melflufen Solution should be kept at 
room temperature (15- 25°C). 
 
8. Note the exact time point (hour, min) for preparation (i.e. when the 40mL glucose solution 
is added to the Melflufen Powder) of the Melflufen Solution in all the labels, both paper 
and electronic. 
Table 7 – 6  
List of Melflufen Powder Vials List of vials of ‘Melflufen Powder’ to be added 
to 250 mL 5% glucose solution for each melflufen dose planned to be used in the clinical trial.  
 
 
Melflufen Dose  
(mg) 
 
Melflufen Powder to be added 
to 250 mL 5% glucose  
 
 
No of vials  
that will be needed 
15 
1 x 15 mg vial or 1 x 20 mg vial 
1 
25 
1 x 25 mg vial or 2 x 20 mg vials 
1 or 2 
40 
1 x 15 mg vial + 1 x 25 mg vial or 2 x 20 mg 
2 
55* 
2 x 15mg vials + 1 x 25mg vial 
3 
70* 
2 x 15mg vials + 2 x 25mg vial 
4 
*Note: the 55 mg and 70 mg doses are not applicable during the Phase 2 part of the study thus 
use of the 20 mg vial is also not applicable for these doses. 


 
 
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7.10.5 
Labeling  
 
The glucose bag should be labelled according to the description below. A second label should 
be detached and transferred to the medical records at the clinic, and be filled in electronically 
in the eCRF.  
 
For Clinical trial only            Protocol No: O-12-M1    
 
Melflufen Solution for i.v. Infusion 
Patient number [X] 
[Y] mg; Cycle number [Z] 
Infusion should start within 30 minutes from start of 
preparation 
Infusions time: 30 min. 
Store at 15-25°C 
 
Date        YYYY/MM 
 
Time of preparation       xx h: xx min         
Sign.             
 
Investigator Name: 
Sponsor: Oncopeptides AB, Phone+46 (0)70 6340211 
For Clinical trial only            Protocol No: O-12-M1    
 
Melflufen Solution for i.v. Infusion 
Patient number [X] 
[Y] mg; Cycle number [Z] 
 
Date        YYYY/MM 
 
Time of preparation        xx h: xx min      
 
 
Sign.             
 
Investigator Name: 
Sponsor: Oncopeptides AB, Phone +46 (0)70 6340211 
 
 
 
 
This label should be placed on the 
infusion bag. 
This label should be  placed in the 
medical record and the information 
completed on the appropriate eCRF 
 
 
 
 
 
7.10.6 
Handling and storage of the Melflufen Solution for infusion 
 
The labelled Melflufen solution for infusion bag should be kept at room temperature (15-
25°C) and be transported immediately to the clinic for start of the infusion to the patient 
within 30 minutes from start of preparation (initial dilution).  
 
 
Labels for vials (example): 
 
For Clinical trial only                          Protocol No: O-12-M1  
                         
 
Melflufen Powder for Solution for i.v. infusion 
X* mg 
 
Batch number:        xxxxx 


 
 
Confidential 
Page 59 
Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
Expiry date:            YYYY/MM 
 
Store at 2-8°C (refrigerated) 
 
Sponsor: Oncopeptides AB,  Phone+46 (0)70 6340211 
* 15, 20 or 25 mg 
 
In the US an additional cautionary statement will be added on the labels:  
Caution: new drug limited by United States law to investigational use. 
7.10.7 
Melflufen Administration 
The study treatment will be administered via an acceptable infusion device, which will be 
inserted according to standard local practice. All patients must have an acceptable infusion 
device for infusion prior to the initiation of the first dose of melflufen. (Port A Cath, PICC line 
or central venous catheter). The infusion tubing set should be pre-filled with 5% glucose. 
NOTE: Flushing the tubing set with saline is not allowed at any time due to the risk for 
precipitation. Glucose 5% must be used. 
The time from start of preparation to end of infusion should not exceed 60 minutes, i.e; 
• The infusion should start as soon as possible, but not later than 30 minutes from the start 
of preparation. 
• The investigational product should be administered as a 30-minute intravenous infusion. 
The exact preparation time, the administered dose as well as the start and stop time for the 
infusion, should be documented on the appropriate eCRF page.  
For the 70mg dose, the volume to be infused must be calculated to ensure the correct dose is 
given. Two dose boxes of 40mg should be used. Four vials (2 x 15mg and 2 x 25mg) should be 
dissolved in a 250 ml glucose bag according to the procedure above. From that prepared 80mg 
dose, only 87.5% or 218.75 ml should be infused in order for the patient to receive a 70mg dose. 
Prophylactic treatment with the anti-emetic drug(s) prior to melflufen solution administration 
is recommended. Subsequent anti-emetic drugs against delayed emesis will be administered at 
the discretion of the investigator. Concomitant medication shall be documented in the 
concomitant medication page in the eCRF. 
Vital signs will be recorded pre and post infusion. 
7.11 
Dexamethasone 
7.11.1 
Dexamethasone Packaging and Labeling 
Dexamethasone is a commercially available drug, available as both tablets and as various sterile 
formulations for intravenous administration. Where not readily available, oral dexamethasone 
will be supplied by Oncopeptides AB. 


 
 
Confidential 
Page 60 
Oncopeptides AB 
 
Protocol No. O-12-M1  
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
7.12 
Dexamethasone Storage 
Dexamethasone is to be stored at controlled room temperature 20 – 25oC (68-77oF).  Consult 
the package insert for the respective product for additional storage and usage instructions.  
7.12.1 
Dexamethasone Administration 
Dexamethasone may be administered orally or intravenously at the investigators discretion.  
Sites are responsible to record administration and patient compliance regarding dexamethasone 
dosing in the eCRF.  Consult the package insert for the respective product for additional 
instructions for dexamethasone administration. 
7.13 
Study Drug Compliance and Accountability 
7.13.1 
Study Drug Compliance 
Compliance will be assured by administration of the study treatment under the supervision of 
the investigator or his/her designee, and will be documented in the study drug administration 
and accountability records.   
7.13.2 
Study Drug Accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study.  
For sites where dexamethasone is provided by the sponsor, sites will be asked to return all 
unused dexamethasone on a regular basis, at the end of the study or at the time of study treatment 
discontinuation. 
At study close-out, and as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Oncopeptides AB’s selected CRO monitor.  
8 
Visit Schedule and Assessments 
8.1 
Study Flow and Visit Schedule 
Table 8-1 lists all of the assessments and indicates with an “X”, when they are to be performed. 
All data obtained from these assessments must be supported in the patient’s source 
documentation.  
Table 8 – 1 Visit Schedule and Assessments


Oncopeptides AB 
Confidential 
Page 61 
 
 
Protocol No. 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
 
 
Visit Schedule and Assessments for Phase I and Phase II  
PROCEDURES 
Screen 
 
Cycle 1 
(Days 1 – 28) 
Cycle 2 - 816 
(Days 1 – 28) 
14End of 
Treatment 
15Post 
Study 
Follow Up 
-21d to -1d 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History, Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
 
PE, Weight, Height, ECOG1 
X 
X 
 
 
 
X 
 
 
 
X 
 
Toxicity Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs (HR, Temp, RR, 
BP) 2 
X 
X 
 
 
 
X 
 
 
 
X 
 
ECG 3 
X 
X3 
 
 
 
X3 
 
 
 
X 
 
CXR 
X 
 
 
 
 
 
 
 
 
X 
 
CBC 4 
X 
X4 
X 
X 
X 
X 4 
X 
X 
X 
X 
 
Serum Chemistry 5 
X 
X5 
 
 
 
X 5 
 
 
 
X 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
 
Correlative Studies 6,11 
X6 
X (Day 2)6 
 
 
 
X 6 
 
 
 
X6 
 
Pharmacokinetics7 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test 8 
X 
 
 
 
 
X 
 
 
 
X 
 
Extramedullary disease 9 
X 
X9 
 
 
 
X9 
 
 
 
X 
X15 
Skeletal Survey 10 
X 
 
 
 
 
X10 
 
 
 
X 
 
Bone Marrow Aspiration 6,11 
X 
X(Day 2)6 
 
 
 
X6,11 
 
 
 
X6,11 
X15 
Myeloma-specific lab tests 
including 24 hour urine 
collection12 
X12 
X 
 
 
 
X12 
 
 
 
X 
X15 
Melflufen Administration13 
 
X 
 
 
 
X 
 
 
 
 
 
40 mg Dexamethasone 
Administration13 
 
Days 1, 8, 15 and 22 13 
Days 1, 8, 15 and 22 13 
 
 


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Oncopeptides AB 
Confidential 
Page 63 
 
 
Protocol No. 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
will have the possibility to recommend that subsequent patients will be treated with the combination of melflufen with weekly 40 mg dexamethasone in order to 
optimize efficacy, without any further amendment. In this case, patients will follow the same dexamethasone dose, schedule and dose modification guidelines as 
the combination cohort previously described in accordance with protocol version 4.0 Amendment 3 dated 27 January 2015. Patients ongoing in the single agent 
cohort may then have weekly dexamethasone added at the investigators discretion.   
14. End of Treatment visit should be done within 30 days and prior to initiation of any subsequent therapy (whichever occurs first).  Serious Adverse events should 
be followed until resolution or stable with no expectation of resolution.  Patients that discontinue therapy for reasons other than progression at any time will 
continue to have disease assessments done monthly (for according to IMWG for confirmation of response/PD) until progression or initiation of subsequent 
therapy.    
15. Following disease progression or initiation of subsequent therapy, Post study follow up includes documentation of second primary malignancies, subsequent 
therapy, disease status and survival. Follow-up should occur every 3 months for up to 2 years. For patients who were alive at their original End of Study, one 
additional OS follow-up will be made as part of Amendment 6.   
16. Patients that continue therapy beyond 8 cycles will continue to follow the same schedule of assessments as required for Cycles 2 – 8. 
 
A +/- 3-day window is permitted for all time points, following screening, to allow for holidays/weekends and scheduling difficulties. *Additional tests may be performed at 
the beginning of each cycle and at any reasonable time point during treatment if indicated for monitoring of drug profile/safety or for disease/health status at the discretion 
of the clinical investigator.        


Oncopeptides AB 
Confidential 
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Protocol No. O-12-M1 
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
8.2 
Study Assessments 
All assessments will be done according to the timelines outlined in Table 8-1; Visit Schedule 
and Assessments. 
8.2.1 
Efficacy Assessments 
 
Efficacy Assessments 
• M-protein determination using both of the following procedures: 
o Serum protein electrophoresis (SPEP) and serum protein immunofixation with 
quantitative immunoglobulins; and  
o Urine protein electrophoresis (UPEP) and urine protein immunofixation (all using the 
same 24-hour urine collection);  
• Serum free light chains (SFLC); 
• Plasmacytoma evaluation; 
• Bone marrow aspirate to quantify percent myeloma cell involvement;  
• Beta2 microglobulin. 
• Skeletal survey: lateral radiograph of the skull, and anterioposterior views of femur and 
humeri.  Anterioposterior and lateral views of the spine, and anterioposterior views of the 
pelvis and ribs. (CT/PET scan may be substituted for conventional X-ray of spine, ribs and 
pelvis with the same technique to be used with each evaluation).   
 
Starting with Cycle 2, response to treatment will be assessed every cycle by M protein 
quantitation and immunofixation from serum, a 24-hour urine collection and SFLC.  Full 
disease response assessment, including skeletal survey and or CT/PET scan will be performed 
according to the International Myeloma Working Group (IMWG) response criteria21 to confirm 
response and end of treatment visit. Bone marrow aspirate will be performed to confirm CR in 
patients who have achieved a CR by immunofixation. Additional skeletal survey and/or 
CT/PET scan may be performed if the patient has bone symptoms suggested by pain and/or 
progression of lesions documented at baseline. If soft tissue plasmacytomas are present and 
measurable on physical examination they will be assessed at every cycle. Those extramedullary 
plasmacytomas documented and measurable only by MRI and/or CT/PET scans will be 
assessed by the relevant modality to confirm response according to the IMWG response criteria 
and end of treatment visit. 
8.2.2 
Safety and Tolerability Assessments 
Safety Assessments: 
• 
Serial physical examinations with vital signs and assessment of performance status; 
• 
Routine safety laboratory tests (CBC with differential and platelets; clinical chemistry, 
coagulation tests) with calculation of creatinine clearance according to the Cockgroft-
Gault equation); 
• 
Chest X-ray; 


Oncopeptides AB 
Confidential 
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Protocol No. O-12-M1 
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
• 
Pregnancy testing; 
• 
Electrocardiogram; (see section 8.2.3 for details on ECG assessments) 
• 
Neurological assessments; 
• 
Assessment and grading of adverse events. 
Adverse experiences, including clinical laboratory and vital sign abnormalities, will be graded 
using the CTCAE version 4.03 (Appendix B). Patients are evaluable for toxicity if they receive 
one dose of study treatment. 
8.2.3 
Electrocardiogram Assessments 
At screening a 12-lead Electrogardiogram (ECG) assessment will be performed on all patients 
to assess the QTcF interval (Note: the QTcF interval at screening must be ≤ 470msec for the 
patient to be eligible for participation in the trial). (See Appendix G) 
Additionally, at three select sites further ECG assessments will be done to provide data to 
guide future need for QTc monitoring.  ECGs will then be performed via Holter monitor in 
Cycles 1, 2 and 3, from baseline prior to the infusion and up to 120 minutes after end of 
infusion. All ECGs, obtained at the select sites, will be read centrally.  Please refer to the ECG 
section of the Study Reference Manual. 
All cardiac events should be treated as per the local standard of care and referred to a 
specialist if clinically indicated. Treatment decisions may be based on local interpretation of 
the QTc.  The centralized readings of ECG’s by an independent ECG expert will use the 
Fridericia correction: QTcF.   
8.2.4 
Pharmacokinetic Assessments 
PK samples will only be collected at one to two designated sites that will receive training 
in the methods of sample processing.  
Plasma samples for determination of melflufen and melphalan concentrations will be drawn in 
connection to the first treatment cycle (Cycle 1, Day 1) prior to start of the infusion (baseline), 
at 15 and 25 minutes post start of infusion, immediately before end of infusion, and at 5, 10 
15, 30, 60, 120 and 210 minutes post end of infusion.  Additional specimen handling 
instructions will be provided in a site specific PK collection manual. 
8.2.5 
Correlative Sample Assessments 
Correlative samples will be collected to identify mechanisms of response/resistance to 
melflufen. 
Peripheral blood and bone marrow aspirate samples will be collected at screening, Cycle 1 Day 
2, at time of confirmation of response and end of therapy. Cells will be subjected to proteomic 
study, microarray analysis, enzymatic assays, and Tissue Microarray Analysis (TMA). Cycle 1 
Day 2 and end of therapy samples are optional for consenting patients.  


Oncopeptides AB 
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Protocol No. O-12-M1 
 
Protocol Amendment 6, Version 7.0, November 2, 2018 
 
8.2.6 
Follow Up Assessments 
All patients must have safety evaluations within 30 days after the last dose of study treatment. 
Follow-up evaluations include review of concomitant medications and ongoing adverse events 
up to 30 days post treatment and any new disease related therapy. Serious Adverse Events 
should be followed until resolution or stabilized with no expectation of resolution.  Assessment 
for second primary malignancies, disease status and survival will be done every 3 months for 
up to 2 years. For patients who were alive at their original End of Study, one additional OS 
follow-up will be made as part of Amendment 6. 
8.2.6.1 
Lost To Follow-Up 
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
8.3 
End of Treatment Visit Including Post Study Follow-Up and 
Premature Withdrawal 
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible 
(within 30 days or prior to initiation of subsequent therapy – whichever occurs first), at which 
time the End of Treatment (EOT) visit will be performed as described in Table 8-1 Visit 
schedule and Assessments. This will be followed by the Post Study Follow-Up assessments. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following the 
last dose of study treatment. 
Patients that discontinue therapy for reasons other than disease progression at any time will 
continue to have disease assessments done monthly (or according to IMWG for confirmation 
of response/PD) until progression or initiation of subsequent therapy. Post study follow up 
includes documentation of second primary malignancies, subsequent therapy, disease status and 
survival. Following disease progression or subsequent therapy, follow-up should occur every 3 
months for up to 2 years. For patients who were alive at their original End of Study, one 
additional OS follow-up will be made as part of Amendment 6. 
8.3.1 
Criteria for Premature Patient Withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. The study can be terminated at any time for any reason by 
Oncopeptides AB. Patients may be withdrawn from the study if any of the following occur: 
1. Disease Progression.   
2. Patients may choose to withdraw from the study at any time. 
3. Adverse Event(s) (AEs) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug. 


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documented AE, constitute unexpected AEs.  For example, an event more specific or more 
severe than described in the IB would be considered “unexpected”.    
Whenever possible, the CTCAE version 4.03 should be used to describe the event and for 
assessing the severity of AEs (see Appendix B).  Any events representing a change in the 
CTCAE Grade need to be reported on the AE eCRF.  This includes any abnormal laboratory 
values that the investigator considers clinically significant.  
For AEs not adequately addressed in the CTCAE, the severity table below may be used: 
Severity 
Description 
GRADE 1 – Mild 
Transient or mild discomfort; no limitation in 
activity; no medical intervention/therapy 
required. 
GRADE 2 – Moderate 
Mild to moderate limitation in activity—some 
assistance may be needed; no or minimal 
medical intervention/therapy required. 
GRADE 3 – Severe 
Marked limitation in activity, some assistance 
usually required; medical intervention/therapy 
required, hospitalizations possible. 
GRADE 4 – Life-
threatening 
Extreme limitation in activity, significant 
assistance required; life-threatening (immediate 
risk of death); significant medical 
intervention/therapy required, hospitalization or 
hospice care probable. 
GRADE 5 – Fatal 
Death 
 
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 patient's 
outcome. 
10.1.1 
Adverse Event Reporting 
All adverse events, from initiation of therapy, that are spontaneously reported by the patient or 
detected during or between visits by non-directive questioning, through physical examination, 
laboratory test, or other assessments should be reported. As far as possible, each adverse event 
should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5). 
2. Its duration (Start and end dates). 
3. Its relationship to the study treatment.  
4. Action taken with respect to study or investigational treatment (eg. none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable). 
5. Whether medication or therapy was given (eg; no concomitant medication/non-drug therapy 
or procedure, concomitant medication/non-drug therapy or procedure). 


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6. Outcome (eg; not recovered/not resolved, recovered/resolved, recovered/resolved with 
sequalae, fatal, unknown). 
7. Whether it is a serious adverse event (SAE) as defined in Section 10.2. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent up to 30 days post the last dose of study drug.  Assessment should be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study treatment, the interventions required to treat it, and the outcome. 
Progression of malignancy should not be reported as an adverse event. Progression of 
malignancy with a fatal outcome should not be reported as a serious adverse event unless the 
event meets any of the other seriousness criteria as outlined in Section 10.2. Adverse events 
associated with but separate from the progression of malignancy (example, deep vein 
thrombosis at the time of progression or hemoptysis concurrent with finding of disease 
progression) will be reported as per usual guidelines used for such events with proper attribution 
regarding relatedness to the drug. 
10.1.2 
Laboratory Test Abnormalities 
10.1.2.1 Definitions and Reporting 
Laboratory abnormalities that constitute an adverse event (are considered by the investigator to 
be clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Event eCRF.  
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
10.2 
Serious Adverse Events 
10.2.1 
Definitions 
A Serious Adverse Event (SAE) is defined as any AE, occurring at any dose, that meets any 
one or more of the following criteria: 
• Is fatal or immediately life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization,  
 


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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 if the patient 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). 
Note that hospitalizations for the following reasons should not be reported as serious adverse 
events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not 
a serious adverse event 
10.2.2 
Serious Adverse Event Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has signed informed consent and until at least 30 days after the patient has stopped study 
treatment must be reported to the Oncopeptides AB designated CRO, within 24 hours of the 
onset or after the investigator became aware of the SAE learning of its occurrence, via the 
Electronic Data Capture (EDC) system.  
Any SAEs experienced after this 30-day period should only be reported to Oncopeptides AB 
designated CRO if the investigator suspects a causal relationship to the study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded in the EDC on the electronic Serious 
Adverse Event Report Form (eSAE); all applicable sections of the form must be completed in 
order to provide a clinically thorough report. The investigator must assess and record the 
relationship of each SAE to study treatment, complete the eSAE Report Form within 24 hours 
to the Oncopeptides AB designated CRO Drug Safety department. 
SAE reporting instructions can be found in the Data Management Entry Specification 
instructions for Inform. 
In the event that the EDC system is non-functioning, fax transmission is possible.  Regional 
Fax numbers are provided in the Study Reference Manual. The original copy of the SAE Report 
Form and the fax confirmation sheet must be kept with the case report form documentation at 
the study site. 


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Each re-occurrence, change in grade, complication, or progression of the original event should 
be reported as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Oncopeptides AB study treatment, an 
Oncopeptides AB designated CRO Drug Safety department associate may urgently require 
further information from the investigator for Health Authority reporting. Oncopeptides AB may 
need to issue an Investigator Notification (IN), to inform all investigators involved in any study 
with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
10.3 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Oncopeptides AB designated CRO within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be reported by the investigator via the paper Pregnancy Report form and must 
be submitted to the Oncopeptides AB designated CRO Data Management department. 
Pregnancy follow-up should include an assessment of the possible relationship to the study 
treatment and any pregnancy outcome. Any SAE experienced during pregnancy (such as 
congenital anomaly/birth defect/spontaneous abortions) must be reported on the electronic 
Serious Adverse Event Report Form (eSAE). 
Male patients, who impregnate their female partners during study participation, will be 
requested to provide the outcome and details of the pregnancy, with details completed as above. 
10.4 
Data Safety Monitoring Committee  
A DSMC will be convened for this study and will primarily act to safeguard the interests of 
study subjects, assess safety and efficacy data, and for monitoring the overall conduct of the 
study. The committee will consist of Oncopeptides AB Chief Medical Officer, the 
Oncopeptides Medical Expert of the study, the CRO Medical Monitor and will be chaired by 
an independent multiple myeloma expert. All study investigators will be invited but are not 
mandatory participants. At the end of each cohort, the committee will meet and evaluate all the 
current safety data and make decisions regarding dose escalation or cohort expansion in the 
Phase I component of the study.  The committee will also determine when the MTD has been 
reached and make recommendations on the Phase II dose and schedule.   The DSMC may 
provide recommendations for stopping or continuing the study.  The DSMC may also make 
recommendations related to the selection, recruitment, and retention of subjects, their 
management and the procedures for data management and quality control.  Additional details 
regarding the DSMC may be found in the Oncopeptides AB DSMC Charter. 


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11 
Data Collection and Management 
11.1 
Data Confidentiality 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research patient to revoke their authorization for use of their PHI. 
In the event that a patient revokes authorization to collect or use PHI, the Sponsor and its agents, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period. 
Access to the data collection system will be controlled by user identification codes and 
passwords, made available only to authorized personnel who have completed prerequisite 
training. 
11.2 
Site Monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Oncopeptides 
AB personnel (or designated CRO) will review the protocol and eCRFs with the investigators 
and their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Oncopeptides AB (or CRO) monitoring standards require 
full source data verification for the presence of signed and dated informed consent, adherence 
to the inclusion/exclusion criteria and documentation of AE/SAEs. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. 


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11.3 
Data Collection 
An electronic Case Report Form (eCRF) is required and should be completed for each subject. 
The subject’s identity should always remain confidential. The completed original eCRF is the 
sole property of the Sponsor and should not be made available in any form to third parties 
(except to authorized representatives of appropriate regulatory authorities) without written 
permission from the Sponsor. 
The designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the electronic data 
capture (EDC) system until they have been trained. Automatic validation programs will check 
for data discrepancies in the eCRFs and allow modification or verification of the entered data 
by the investigator staff. 
The study Investigators are responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
11.4 
Database Management and Quality Control 
Oncopeptides AB personnel (or designated CRO) will review the data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
12 
Statistical Methods and Data Analysis 
12.1 
Analysis Sets 
12.1.1 
Safety Analysis Set 
All patients that have initiated treatment (at least one dose) will be considered evaluable for 
safety analysis(s).  The maximum grade for each type of adverse event will be recorded for each 
patient, and frequency tables will be reviewed to determine patterns.  Additionally, the 
relationship of the adverse event(s) to the study treatment will be taken into consideration. 
12.1.2 
Efficacy Analysis Set  
All patients in the Phase IIa part (including the 6 patients on MTD in Phase I) who have baseline 
evaluation, receive at least 2 cycles of therapy and have at least one post dose efficacy 
measurement will be considered evaluable for response.    
12.1.3 
Correlative Studies Analysis 
Correlative studies are an exploratory endpoint. Samples will be collected on consenting 
patients to identify mechanisms of response and resistance to melflufen.  


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12.2 
Analysis of Objectives 
12.2.1 
Primary Objective 
12.2.1.1 Phase I 
The primary objective(s) of the Phase I portion of the study is to determine the MTD, after one 
treatment cycle, of the combination of melflufen and dexamethasone in patients with relapsed 
or relapsed-refractory MM. 
12.2.1.2 Phase IIa 
The primary objective of Phase IIa is to evaluate the objective response rate (≥ PR) and the 
clinical benefit (≥ MR) to the combination of melflufen and dexamethasone and melflufen as 
single agent at the MTD determined in Phase I. 
12.2.2 
Secondary Objective(s) 
To evaluate the overall response including the complete response/stringent complete response 
(CR/sCR), very good partial response (VGPR), partial response (PR) and clinical benefit 
(≥ MR), the time to progression, duration of response, progression free survival and overall 
survival in all evaluable patients. 
To further explore the safety and tolerability of the combination of melflufen and 
dexamethasone and melflufen alone at the MTD. 
12.2.3 
Exploratory Objective(s) 
To identify mechanisms of response or resistance to melflufen.  
Pharmacokinetic analysis will be evaluated on patients enrolled at a select site that will have 
training in specimen handling. 
ECG assessments to screen for major effects on the QTc interval will be conducted at select 
sites. Should a signal be detected further evaluations will be conducted in future studies. 
12.3 
Analysis of Endpoints 
12.3.1 
Primary Endpoint Analysis Phase I 
The frequency and grade of adverse events and dose limiting toxicities occurring in each cohort 
will be determined. 
This dose escalation study will use a modified Fibonacci design with 3-6 patients at each dose 
level.  Depending on the dose level at which DLT is observed, a maximum of 36 eligible 
participants may be enrolled.    
Three to six patients will be entered at each dose level. If no DLT is observed in the first 3 
patients, escalation will proceed. If 2 or 3 DLTs are observed in the first 3 patients, escalation 
stops. If 1 DLT is observed in the first 3 patients, an additional 3 patients will be entered. If no 
additional DLTs are observed in the three additional patients, escalation proceeds. If any DLTs 
are observed among the 3 additional patients (> 1 DLT among 6 patients), escalation stops. 


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The probability of escalating to the next dose for various true underlying rates is given in the 
following table. 
True DLT rate 
0% 
5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 
Probability of dose escalation 
 (i.e. 0/3 or 1/6 with DLT) 
100% 97% 91% 81% 71% 60% 49% 40% 31% 23% 17% 
Probability of MTD 
 (i.e. at most 1/6 with DLT) 
100% 97% 89% 78% 66% 53% 42% 32% 23% 16% 11% 
12.3.2 
Primary Endpoint Analysis Phase IIa  
A true objective response rate of 15% of the patients would be considered promising in this 
population.  The Phase IIa portion of the study originally used a one-stage design to enter 20 
eligible patients for a total of 26 including the 6 patients treated at the MTD.  It was calculated 
that if we saw 4 or more (≥ 15% including MR) responses among 26 evaluable patients, we 
would declare this treatment effective. Subjects are evaluable for response if they complete 
baseline evaluations; receive at least 2 cycles of therapy followed by at least one efficacy 
measurement.  
For patients with more than one post-baseline efficacy assessment, the best response of all 
measurements will be used in the primary endpoint analysis. Patients with incomplete disease 
assessments at baseline will not be admitted into the study.  
Amendment 4 will enroll a cohort of ≥20 efficacy-evaluable patients to single agent melflufen 
to observe the ORR and CBR as an exploratory cohort. These patients will be assessed as part 
of the total efficacy analysis set (55 patients treated at MTD) as well as separately. An ORR rate 
of 15% or higher in the single agent cohort would suggest that melflufen has single agent 
activity. 
12.3.3 
Secondary Endpoint Analysis 
The time to event secondary endpoints are defined as follows:  
• Time to progression: time from first dose of study drug to progression, censored at date 
last known progression-free for those who have not progressed 
• Progression-free survival:  time from first dose of study drug to the disease progression 
or death from any cause, censored at date last known progression-free for those who 
have not progressed or died 
• Duration of response: time from response to disease progression or death, or date last 
known progression-free and alive for those who have not progressed or died  
• Overall survival: time from first dose of study drug to death or date last known alive 
Overall survival, time to progression, progression free survival and the duration of response 
will be estimated using the method of Kaplan-Meier. 
The overall response rate, as well as the different definitions of partial response will be 
presented for all evaluable patients in both absolute numbers and as a proportion with 95 % 
exact confidence interval.  


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Additional exploratory sub-analysis may be conducted to identify sub populations that may 
benefit from therapy or to more clearly define the safety profile and efficacy and/or to correlate 
biomarkers with clinical outcomes. 
12.4 
Sample Size Calculation 
12.4.1 
Phase I 
By using a modified Fibonacci design, cohorts of 3 to 6 evaluable patients will be enrolled in 
the dose-escalation part including at least six patients at the MTD level, as described in Section 
4.  Up to 5 dose levels will be tested. However, in the event the DSMC, upon review of all other 
toxicities noted for the given cohort, determine a reduced dose of dexamethasone (20mg) will 
be implemented for subsequent cohorts then the lower dose of dexamethasone is to be tested 
with the dose level of melflufen, at which the dexamethasone caused the DLT.  In this case up 
to 6 additional patients may be enrolled, for a maximum of 36 patients.  Therefore, for the Phase 
I portion of the study up to 36 patients may be treated in order to determine the MTD. 
12.4.2 
Phase IIa 
Assuming a true response rate of 20 % there is approximately 80 % (exact probability: 79.31 %) 
probability to observe 4 or more responses with 26 evaluable patients.  Amendment 3 increased 
the patient population to 55. Assuming an ORR for melflufen of 50% the study will have 80% 
power to show that the lower limit of a 95 % confidence interval is above 32%. 
Amendment 4 will enroll a cohort of ≥20 efficacy-evaluable patients to single agent melflufen 
as an exploratory cohort. These patients will be assessed as part of the total efficacy analysis 
set (55 patients treated at MTD) as well as separately. An ORR rate of 15% or higher in the 
single agent cohort would suggest that melflufen has single agent activity.  
Dexamethasone alone is not regarded as an effective treatment. If the exploratory cohort shows 
that the main activity of the combination of melflufen and dexamethasone arise from the 
melflufen component, future patients may be treated with melflufen without dexamethasone, 
thus avoiding the well-known dexamethasone side effects. 
 
12.4.3 
Pharmacokinetic methods 
The concentration-time profiles for melflufen and melphalan will be evaluated using non-
compartmental methods and the software WinNonlin Professional Version 5.3 (Pharsight 
Corporation).  
Actual time points for drug administration and plasma sampling will be used.  
The following PK parameters will be assessed where possible: 
• Time of maximum observed concentration (tmax) 
• Maximum observed concentration (Cmax) 
• Area under the concentration versus time curve between 0h and end of drug infusion  
(AUC0-t) 


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• Area under the concentration versus time curve from 0h to infinity (AUCinf) 
• Elimination phase half-life (t½) 
Additional modeling may be performed based on the nature of the data. 
Plasma concentrations reported to be below the limit of quantification (BLQ) will be treated as 
follows: 
• Pre-dose concentrations and samples with BLQ concentrations before the first sampling 
time point with a quantifiable concentration will be set at zero.  
• Concentrations reported as BLQ at time points where samples at both previous and 
subsequent time points show quantifiable concentrations will be estimated using 
interpolation if supported by the pattern of the entire concentration-time profile.  
• Samples reported as BLQ at time points not followed by later time points with 
quantifiable concentrations will not be used for the PK evaluation.  If the estimation of 
the terminal elimination half-life based on quantifiable concentrations indicates that the 
sample taken immediately subsequent to the last quantifiable sample should also have 
shown a quantifiable concentration, the concentration at this first BLQ value will be set 
equal to the LOQ value in the estimation of AUCinf and t½. 
12.4.4 
Statistical methods for PK parameters 
Descriptive statistics including mean, geometric mean, median, minimum, maximum, standard 
deviation (SD), and percent coefficient of variation (CV%) for the obtained PK parameters will 
be calculated using the statistical module in the software WinNonlin.  
Results for estimated PK parameters will be tabulated using 3 significant figures. Exceptions 
are values 1000 or higher where no rounding will be performed. For descriptive statistics mean, 
geometric mean and median values are shown with 4 significant figures, and SD and CV% with 
3 significant figures. In the statistical calculations data will be used as provided by the input 
files and by the PK modeling software, without rounding.   
13 
Ethical Considerations and Administrative Procedures 
13.1 
Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the Investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC/REB must be given to Oncopeptide 
AB (or designated CRO) before study initiation. Prior to study start, the investigator is required 


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to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Oncopeptides AB (or designated 
CRO) monitors, auditors, Clinical Quality Assurance representatives, designated agents of 
Oncopeptides AB, IRBs/IECs/REBs and regulatory authorities as required. 
13.3 
Informed Consent Procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent  
Informed consent must be obtained before conducting any study-specific procedures. The 
process of obtaining informed consent should be documented in the patient source documents. 
The date when a patient’s Informed Consent was actually obtained will be captured in the 
eCRFs. 
Oncopeptides AB (or designated CRO) will provide to investigators, in a separate document, a 
proposed informed consent form (ICF) that is considered appropriate for this study and 
complies with the ICH GCP guideline and regulatory requirements. Any changes to this ICF 
suggested by the investigator must be agreed to by Oncopeptides AB before submission to the 
IRB/IEC/REB, and a copy of the approved version must be provided to the Oncopeptides AB 
(or designated CRO) monitor after IRB/IEC/REB approval. 
13.4 
Discontinuation of the Study 
Oncopeptides AB reserves the right to discontinue this study under the conditions specified in 
the clinical study agreement at a single study center or the study as a whole. Specific conditions 
for terminating the study at any time for reasonable medical or administrative reasons in any 
single center could be but are not limited to: 
• 
Unsatisfactory enrollment with respect to quantity or quality. 
• 
Inaccurate or incomplete data collection. 
• 
Falsification of records. 
• 
Failure to adhere to the study protocol. 
13.5 
Publication of Study Protocol and Results 
Oncopeptides AB assures that the key design elements of this protocol will be posted in a 
publicly accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. Any publication will be 
a joint publication between Oncopeptides AB and the investigators and authorship will be 
determined by mutual agreement. 
13.6 
Study Documentation, Record Keeping and Retention of 
Documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 


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for the protection of confidentiality of patients. As part of participating in an Oncopeptides AB 
sponsored study, each site will permit authorized representatives of the sponsor(s) and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. The study eCRF is the primary data collection instrument for the study. 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported in the eCRFs and all other required reports. Data reported on the eCRF, that are derived 
from source documents, should be consistent with the source documents or the discrepancies 
should be explained. All data requested on the eCRF must be recorded. Any missing data must 
be explained. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
The Investigator must retain the study records for a minimum of 2 years after a marketing 
application for the indication is approved or for 2 years after the IND is withdrawn.  For IND 
studies conducted outside the US, the investigator must retain study records for the time period 
described above or according to local laws or requirements, whichever is longer. 
13.7 
Confidentiality of Study Documents and Patient Records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Oncopeptides AB, their agents or Health Authorities. Signed 
informed consent forms and patient enrollment log must be kept strictly confidential to enable 
patient identification at the site. 
13.8 
Audits and Inspections 
Source data/documents must be available to inspections by Oncopeptides AB or designee or 
Health Authorities. 
13.9 
Financial Disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site prior to study start. 


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14 
Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Oncopeptides 
AB or designated CRO should be notified of this action and the IRB/IEC at the study site should 
be informed according to local regulations. All significant protocol deviations will be recorded 
and reported in the Clinical Study Report. 
14.1 
Amendments to the Protocol 
Any change or addition to the protocol can only be made in a written protocol amendment by 
Oncopeptides AB.  The amendment must be approved by the Health Authorities where required, 
and the IRB/IEC/REB before it may be implemented. Only amendments that are required for 
patient safety may be implemented prior to IRB/IEC/REB approval.  
 
 


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15 
References  
1   Gullbo J, Wickström M, Tullberg M, Ehrsson H, Lewensohn R, Nygren P, Luthman K, Larsson R. 
Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the 
melphalan containing prodrug J1. Journal of Drug Targeting 2003, Jul;11(6): 355-363. 
2  Wickström M, Fryknäs M, Hellman B, Larsson R and Gullbo J. The prodrug J1 is activated by 
aminopeptidase N, which results in high intracellular melphalan concentrations, DNA damage and 
apoptosis. Manuscript: Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, 
Department of Medical Sciences 
3  Chauhan D, Bandi M, Singh A,  Podar K, Richardson P, Nikhil M,  Viktorsson K, Lewensohn R, 
Spira J and Anderson K. Anti-Myeloma Activity Of Enzymatically Activated Melphalan Prodrug 
MELFLUFEN. (poster) ASH 2010. 
4  Kaur G, Hollingshead M, Holbeck S. In vivo cultivation of tumor cells in hollow fibers. Life 
Science, 1995. 57: p. 131-41. 
5  American Cancer Society.  Cancer facts and figures 2005.  Atlanta: American Cancer Society 2005.   
6  Boyle P, Ferlay J.  Cancer incidence and mortality in Europe, 2004.  Ann Oncol 2005; 16: 481–488.   
7  Kumar S., Rajkumar S.V., Dispenzieri A, et al.,  Improved survival in multiple myeloma and the 
impact of novel therapies Blood March 1, 2008 vol. 111 no. 5 2516-2520. 
8  De Barberi, A., Peptichemio: A synthesis of pharmacological, morphological, biochemical and 
biomolecular investigations, in Symposium on Peptichemio. 1972: Milan, Italy. p. 1-46. 
9   Hug, V., Hortobagyi, G.N., Buzdar A.U. et al., A phase II study of Peptichemio in advanced breast 
cancer. Cancer, 1980. 45: p. 2524. 
10 Lawley, P.D. and P. Brookes, Further studies on the alkylation of nucleic acids and their constituent 
nucleotides. Biochem J, 1963. 89: p. 127-38. 
11 Gullbo, J., et al., Structure-activity relationship for alkylating dipeptide nitrogen mustard 
derivatives. Oncol Res, 2003. 14(3): p. 113-32. 
12 Gullbo, J., et al., Antitumor activity of the alkylating oligopeptides J1 (L-melphalanyl-p-L-
fluorophenylalanine ethyl ester) and P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl 
ester): comparison with melphalan. Anticancer Drugs, 2003. 14(8): p. 617-24. 
13 Wickstrom, M., et al., The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo 
and combination analyses in vitro. Invest New Drugs, 2008. 26(3): p. 195-204. 
14 Gullbo, J., et al., Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour 
efficacy of the melphalan containing prodrug J1. J Drug Target, 2003. 11(6): p. 355-63. 
15 Wickström M, The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a 
possible target directed release of melphalan. Biochem Pharmacol, 2010. 79: p. 1281-1290. 
16 Wickström M, J.J., Ponthan F, The novel melphalan prodrug J1 inhibits neuroblastoma growth in 
vitro and in vivo. Mol Cancer Ther, 2007. 6: p. 2409-2417. 
17 Gullbo, J., Preclinical Development of New Alkylating Oligopeptides for Cancer Therapy., in Dept 
of Medical Sciences, Division of Clinical Pharmacology. Uppsala, Uppsala University 2003. 
18 Chauhan D., Anderson  K., Dana Farber Cancer Institute, Harvard Medical School, Boston.   
Unpublished data.   
19 Furner, R.L. and R.K. Brown, L-phenylalanine mustard (L-PAM): the first 25 years. Cancer Treat 
Rep, 1980. 64(4-5): p. 559-74. 
                                                 


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20 Teicher, B.A., Antitumor alkylating agents, in Cancer: Principles & Practise of Oncology (on CD-
ROM), V.T. DeVita, S. Hellman, and S.A. Rosenberg, Editors. 1997, Lippincott-Raven Publishers: 
Philadelphia, Pennsylvania. 
21 Durie et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-
73 
22. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. 
Blood 2011; 117:4691. 
23. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Treatment strategies in relapsed and refractory 
multiple myeloma: A focus on drug sequencing and ‘retreatment’ approaches in the era of novel 
agents. Leukemia, 2012; 26(1), 73–85
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
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20170822 Statistical Analysis Plan version 2.0 
Author: 
 
Version Number: 
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Version Date: 
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Template No: 
 
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Effective Date: 01May2012 
 
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Oncopeptides AB 
STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
Page 1 of 99 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
O-12-M1 
 
AN OPEN-LABEL PHASE I/IIA STUDY OF THE SAFETY AND 
EFFICACY OF MELPHALAN-FLUFENAMIDE (MELFLUFEN) AND 
DEXAMETHASONE COMBINATION FOR PATIENTS WITH 
RELAPSED AND/OR RELAPSED-REFRACTORY MULTIPLE 
MYELOMA 
 
 
 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: V2.0, 25AUG2017 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
Page 4 of 99 
MODIFICATION HISTORY 

Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from Previous 
Authorized Version 
1.0 
09NOV2016 
 
Not Applicable. First Version. 
2.0 
12JUL2017 
 
Updated the definition for the derived 
EOT to take death date into account. 
Refer to “latest output shells” 
throughout document instead of to the 
specific version (except where output 
shells used for DSMC was referenced). 
Updated MedDRA to version 20.0 and 
WHO-DD to version dated 01MAR2017. 
Removed 21-day and 28-day cycle 
length by-group from study drug 
administration section. 
Action taken with melflufen updated 
from “increased” to “other” in text. 
Missing grades or relationships will not 
be indicated and analyzed as “worst 
case”, but will be counted as “missing”. 
Section 9.3 – Added text for 
presentation of major protocol 
deviations as obtained from the CTMS 
report. 
Section 15.2.2 – Histogram for disease 
response rate replaced with swimmers 
plot for time to disease response. 
Section 16.1.9 – added all categories 
displayed in overview TEAE tables. 
Section 16.1.10 – time to onset of grade 
III and/or IV TEAEs limited to 
neutropenia and thrombocytopenia. 
Section 16.2 – Added text to explain that 
counts of Neutropenia and 
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STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
Page 5 of 99 
Thrombocytopenia will be based on 
worst grade per cycle. 
2.0 
22AUG2017 
 
Addition of textbook reference ranges 
for the white blood cell (email 
13Jul2017) differential percentages. 
Incorporate Sponsor comments. 
 
 
 
 
CTMS: Clinical Trials Management System. EOT: End of Treatment. MedDRA: Medical 
Dictionary for Regulatory Activities. TEAE: Treatment-emergent adverse event. WHO-DD: 
World Health Organization-Drug Dictionary. 
 
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Reference: 
 
Effective Date: 01May2012 
 
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Oncopeptides AB 
STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
Page 6 of 99 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION 
14 
2. 
STUDY OBJECTIVES 15 
2.1. 
Primary Objective ..................................................................................................................................... 15 
2.1.1. 
Phase I ...................................................................................................................................................... 15 
2.1.2. 
Phase IIa ................................................................................................................................................... 15 
2.2. 
Secondary Objectives ............................................................................................................................... 15 
2.3. 
Exploratory Objectives ............................................................................................................................. 15 
2.4. 
Safety Objectives ...................................................................................................................................... 16 
3. 
STUDY DESIGN 
17 
3.1. 
General Description .................................................................................................................................. 17 
3.2. 
Schedule of Events ................................................................................................................................... 20 
3.3. 
Changes/Clarifications to Analysis from Protocol and electronic Case Report Form (eCRF) Data Collection
 
………………………………………………………………………………………………………………………………………………………………20 
4. 
PLANNED ANALYSES 
21 
4.1. 
Data Safety Monitoring Committee (DSMC) ............................................................................................. 21 
4.2. 
Interim Analysis........................................................................................................................................ 21 
4.3. 
Final Analysis ............................................................................................................................................ 21 
5. 
ANALYSIS SETS 
22 
5.1. 
All Patients Screened Analysis Set ............................................................................................................ 22 
5.2. 
Safety (SAF) Analysis Set .......................................................................................................................... 22 
5.3. 
Modified Intent-to-Treat (mITT) Analysis Set ........................................................................................... 22 
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Template No: 
 
Reference: 
 
Effective Date: 01May2012 
 
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Page 7 of 99 
5.4. 
Efficacy-evaluable Modified Intent-to-Treat (EEmITT) Analysis Set .......................................................... 22 
5.5. 
Per Protocol (PP) Analysis Set ................................................................................................................... 23 
6. 
GENERAL CONSIDERATIONS 
24 
6.1. 
Reference Start Dates, Reference Stop Dates and Reference Days ........................................................... 24 
6.1.1. 
Derivations ............................................................................................................................................... 25 
6.2. 
Derived Timepoints .................................................................................................................................. 25 
6.2.1. 
Derivations ............................................................................................................................................... 26 
6.3. 
Cycle Length, Cycle Assignment, and Cycle Completion ............................................................................ 26 
6.3.1. 
Derivations ............................................................................................................................................... 26 
6.4. 
Baseline .................................................................................................................................................... 27 
6.5. 
Premature Discontinuation, End of Treatment (EOT) and End of Study (EOS)........................................... 28 
6.6. 
Retests and Unscheduled Visits ................................................................................................................ 28 
6.7. 
Windowing Conventions .......................................................................................................................... 29 
6.8. 
Statistical Output Conventions ................................................................................................................. 29 
6.9. 
Common Calculations ............................................................................................................................... 29 
6.10. 
Software Version .................................................................................................................................. 30 
7. 
STATISTICAL CONSIDERATIONS 31 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ......................................................... 31 
7.2. 
Multisite Studies ...................................................................................................................................... 31 
7.3. 
Missing data ............................................................................................................................................. 31 
7.4. 
Multiple Comparisons/Multiplicity ........................................................................................................... 31 
7.5. 
Examination of Subgroups ........................................................................................................................ 31 
7.5.1. 
Age (Years) ............................................................................................................................................... 31 
7.5.2. 
Baseline International Staging System (ISS) ............................................................................................. 31 
7.5.3. 
Prior Therapies ......................................................................................................................................... 32 
7.5.4. 
Refractory Status ..................................................................................................................................... 32 
7.5.5. 
Baseline Disease Risk Status .................................................................................................................... 33 
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8. 
OUTPUT PRESENTATIONS 34 
9. 
DISPOSITION 
35 
9.1. 
End of Study (EOS) .................................................................................................................................... 35 
9.2. 
End of Treatment (EOT) ............................................................................................................................ 35 
9.3. 
Analysis Sets ............................................................................................................................................. 36 
9.4. 
Visit Dates ................................................................................................................................................ 37 
10. 
DEMOGRAPHIC CHARACTERISTICS 
38 
11. 
MEDICAL AND/OR SURGICAL HISTORY 39 
12. 
DISEASE CHARACTERISTICS OF MULTIPLE MYELOMA 
40 
12.1. 
Disease Characteristics Since/At Initial Diagnosis ................................................................................. 40 
12.1.1. 
Derivations ............................................................................................................................................... 41 
12.2. 
Disease Characteristics At Baseline ....................................................................................................... 41 
12.2.1. 
Derivations ............................................................................................................................................... 43 
12.3. 
Bone Marrow Aspiration at Baseline .................................................................................................... 44 
13. 
THERAPIES, MEDICATIONS AND/OR PROCEDURES 
45 
13.1. 
Prior Therapies ..................................................................................................................................... 45 
13.2. 
Medications/Concomitant Procedures ................................................................................................. 47 
13.2.1. 
Medications ............................................................................................................................................. 47 
13.2.1.1. 
Hematopoietic Growth Factors and Standardized Transfusions ..................................................... 47 
13.2.2. 
Concomitant Procedures ......................................................................................................................... 48 
13.2.3. 
Derivations ............................................................................................................................................... 48 
14. 
STUDY DRUG ADMINISTRATION 49 
14.1. 
Melflufen Administration ..................................................................................................................... 49 
14.1.1. 
Derivations ............................................................................................................................................... 51 
14.2. 
Dexamethasone Administration ........................................................................................................... 51 
14.2.1. 
Derivations ............................................................................................................................................... 53 
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15. 
EFFICACY OUTCOMES 
54 
15.1. 
Multiple Myeloma ................................................................................................................................ 55 
15.1.1. 
Laboratory Assessments .......................................................................................................................... 55 
15.1.2. 
Response Assessment .............................................................................................................................. 55 
15.1.3. 
Data Conventions..................................................................................................................................... 56 
15.1.3.1. 
Central/Local Laboratory Data ......................................................................................................... 56 
15.1.3.2. 
Analyzable Result ............................................................................................................................. 56 
15.1.3.1. 
Evaluable Disease Response Assessment ........................................................................................ 56 
15.1.3.2. 
Best Serum or 24-hour Urine Monoclonal-Protein (M-Protein) or Serum Free Light Chain (SFLC) % 
Change from Baseline (CFB) ................................................................................................................................ 56 
15.2. 
Primary Efficacy .................................................................................................................................... 57 
15.2.1. 
Missing Data Methods for Primary Efficacy Variables ............................................................................. 57 
15.2.2. 
Analysis of Primary Efficacy Variables ..................................................................................................... 57 
15.2.3. 
Sensitivity Analysis of Primary Efficacy Variables .................................................................................... 59 
15.3. 
Secondary Efficacy ................................................................................................................................ 59 
15.3.1. 
Secondary Efficacy Variables and Derivations ......................................................................................... 60 
15.3.1.1. 
Duration of Best Overall Disease Response to Treatment ............................................................... 60 
15.3.1.2. 
Time to Disease Response on Treatment ........................................................................................ 61 
15.3.1.3. 
Time to Disease Progression ............................................................................................................ 62 
15.3.1.4. 
Progression-free Survival (PFS) ........................................................................................................ 62 
15.3.1.5. 
Overall Survival (OS) ........................................................................................................................ 63 
15.3.1.6. 
Time to first subsequent treatment................................................................................................. 63 
15.4. 
Exploratory Efficacy .............................................................................................................................. 64 
15.5. 
Other Efficacy Assessments .................................................................................................................. 64 
15.5.1. 
X-Ray and Imaging Assessments .............................................................................................................. 64 
15.5.2. 
Plasmacytoma Evaluation ........................................................................................................................ 65 
15.5.2.1. 
Derivations ....................................................................................................................................... 66 
16. 
SAFETY OUTCOMES 67 
16.1. 
Adverse Events (AEs) ............................................................................................................................ 67 
16.1.1. 
Severity .................................................................................................................................................... 68 
16.1.2. 
Relationship ............................................................................................................................................. 68 
16.1.3. 
Action Taken with Study Drug ................................................................................................................. 69 
16.1.4. 
Adverse Events (AEs) Leading to Death ................................................................................................... 69 
16.1.5. 
Serious Adverse Events (AEs) ................................................................................................................... 69 
16.1.6. 
Adverse Events (AEs) Leading to Discontinuation of Study Drug ............................................................ 70 
16.1.7. 
Adverse Events (AEs) Leading to Discontinuation of Study ..................................................................... 70 
16.1.8. 
Adverse Events (AEs) Meeting Dose-Limiting Toxicity (DLT) Criteria ...................................................... 70 
16.1.9. 
All Treatment-emergent AEs (TEAEs) ...................................................................................................... 70 
16.1.10. 
Time to Onset of Treatment-emergent AEs (TEAEs) ............................................................................ 71 
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16.1.11. 
Derivations ........................................................................................................................................... 71 
16.2. 
Adverse Events (AEs) of Special Interest ............................................................................................... 72 
16.2.1.1. 
Derivations ....................................................................................................................................... 73 
16.3. 
Laboratory Evaluations ......................................................................................................................... 74 
16.3.1. 
Laboratory Reference Ranges and Clinically significant Criteria .............................................................. 75 
16.3.2. 
Common Terminology Criteria for Adverse Events (CTCAE) Grading for Laboratory Data ..................... 76 
16.4. 
Electrocardiogram (ECG) Evaluations .................................................................................................... 77 
16.4.1. 
Electrocardiogram (ECG) Abnormality as per Specified Criteria .............................................................. 77 
16.5. 
Vital Signs ............................................................................................................................................. 77 
16.5.1. 
Derivations ............................................................................................................................................... 78 
16.6. 
Physical Examination ............................................................................................................................ 78 
16.7. 
Other Safety Assessments .................................................................................................................... 78 
16.7.1. 
Eastern Cooperative Oncology Group (ECOG) Performance ................................................................... 78 
17. 
DATA NOT SUMMARIZED OR PRESENTED 
80 
18. 
REFERENCES 81 
APPENDIX 1. SPECIFIC PROGRAMMING CONVENTIONS FOR OUTPUTS 
82 
 Conventions for Output (Table, listing, figure) ................................................................................ 82 
Dates and Times .................................................................................................................................................. 82 
Spelling Format .................................................................................................................................................... 83 
Presentation of Visits ........................................................................................................................................... 83 
By-patient Data Listings ....................................................................................................................................... 84 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
85 
APPENDIX 3. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE)
 
87 
APPENDIX 4. SPECIFIC MYELOMA CENTRAL LABORATORY EVALUATIONS 
91 
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APPENDIX 5. INTERNATIONAL SYSTEM OF UNITS (SI) 
94 
APPENDIX 6. DISEASE RESPONSE CRITERIA 
98 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
 
 
 
 
AEs 
Adverse events 
ASH 
American Society of Hematology 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below the lower limit of quantification  
CAT/CT 
Computerized axial tomography 
CBRR 
Clinical benefit response rate 
CFB 
Change from Baseline 
CI 
Confidence intervals 
CR 
Complete response 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicities 
DR 
Data review 
DSMC 
Data safety monitoring committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EEmITT 
Efficacy-evaluable Modified Intent-to-Treat 
EHA 
European Hematology Association 
EOS 
End of study 
EOT 
End of Treatment 
FISH 
Fluorescence in situ hybridization 
ICH 
International Conference of Harmonisation 
Ig 
Immunoglobulin 
IMiD 
Immunomodulatory drugs 
IMWG 
International Myeloma Working Group 
ISS 
International Staging System 
IV 
Intravenous 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
M-protein 
Monoclonal protein 
MR 
Minimal response 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
ORR 
Objective response rate 
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STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
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Abbreviation 
Term 
 
 
 
 
OR 
Objective response 
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Proteasome inhibitor 
PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetic 
PO 
Per os 
PP 
Per Protocol 
PR 
Partial response 
PT 
Preferred Term 
QTc 
Corrected QT 
QTcF 
Corrected QT interval using Fridericia’s formula  
SAF 
Safety 
SAP 
Statistical analysis plan 
sCR 
Stringent complete response 
SD 
Standard deviation 
SD 
Stable disease 
SFLC 
Serum free light chain 
SI 
International system of units 
SOC 
System Organ Class 
TEAEs 
Treatment-emergent AEs 
ULQ 
Above the upper limit of quantification 
USA 
United States of America 
VGPR 
Very good partial response 
WHO-DD 
World Health Organization-Drug Dictionary 
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1.INTRODUCTION 
The document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for protocol O-12-M1.  It describes the data to be summarized and analyzed, 
including specifics of the statistical analyses to be performed. 
With reference to the latest version of the data review (DR) plan [1], the statistical analysis plan (SAP) 
also contains definitions of analysis sets and derived variables for the dry run and final analysis. 
 Biostatistics is not responsible for performing the following analyses: 
x
Pharmacokinetic (PK) analyses: To be performed by Oncopeptides AB. 
x
Holter electrocardiogram (ECG) assessments: To be performed by 
. 
x
Data related to correlative studies: To be analyzed by 
. 
The aforementioned are therefore not included in the scope of this SAP. 
The SAP is based on protocol Version 6.0, dated 06JUL2016 including protocol amendments 01 to 05 
[2] and electronic case report form (eCRF) Version 12.0, dated 30AUG2016 [3]. 
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Page 15 of 99 
2.STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
2.1.1. PHASE I 
The primary objective of Phase I of the study is to determine the maximum tolerated dose (MTD), 
after one treatment cycle, of the combination of melflufen and dexamethasone in patients with 
relapsed or relapsed/refractory multiple myeloma. 
Phase I was completed in SEP2014 and the MTD was determined by the data safety monitoring 
committee (DSMC) at the meeting held on 19SEP2014 as 40 mg melflufen. 
2.1.2. PHASE IIA 
The primary objective of Phase IIa of the study is to evaluate the objective response rate (ORR) (partial 
response [PR] or better) and the clinical benefit response rate (CBRR) (minimal response [MR] or 
better) to the combination of melflufen and dexamethasone and melflufen as single-agent at the MTD 
as determined in Phase I. 
2.2. SECONDARY OBJECTIVES 
The secondary objectives of Phase IIa of the study are to evaluate the following in all 
efficacy-evaluable patients: 
x
Duration of disease response. 
x
Time to disease progression. 
x
Progression-free survival (PFS). 
x
Overall survival (OS). 
2.3. EXPLORATORY OBJECTIVES 
The exploratory objectives are to: 
x
Identify mechanisms of response and or resistance to melflufen. 
x
Evaluate pharmacokinetics on patients enrolled at selected sites that are to be trained in the 
process of sample handling (not included in the scope of this SAP). 
x
Review ECG assessments to screen for major effects on the corrected QT (QTc) interval conducted 
at selected sites.  Should a signal be detected further evaluations are to be conducted in future 
studies (not included in the scope of this SAP). 
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2.4. SAFETY OBJECTIVES 
As part of the secondary objectives of the study the safety and tolerability of the combination of 
melflufen and dexamethasone and of melflufen as single-agent are to be evaluated. 
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3.STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is an open-label, Phase I/IIa, multisite study conducted in Europe and the United States of 
America (USA) in patients with relapsed and or relapsed/refractory multiple myeloma.  From this point 
onwards Phase I and Phase II (in lieu of Phase IIa) are used to reference the different phases of the 
study.  Cycles are also used (in lieu of treatment cycles) to reference the relevant treatment period in 
which a patient received study drug.  Phase I followed the standard 3 + 3 modified Fibonacci design 
with 3 to 6 patients, depending on dose limiting toxicity (DLT) observed, tested at each dose level.  Up 
to five dose levels of melflufen (administered as 30-minute infusions on Day 1 at 15 mg, 25 mg, 40 mg, 
55 mg and 70 mg) were to be evaluated during Phase I in combination with a fixed dose of 
dexamethasone (administered as 40 mg intravenous [IV]/per os [PO] on Days 1, 8 and 15 of each 21-
day cycle). 
With reference to Section 2.1.1 Phase I of this SAP, Phase I was completed and the MTD was 
determined as 40 mg melflufen.  At the time of determining MTD only four (15 mg, 25 mg, 40 mg, 
55 mg) of the five dose escalation cohorts had been evaluated. 
An additional 49 patients are to be enrolled and treated at the MTD in Phase II, resulting in a total of 
55 patients treated at the MTD.  This includes the Phase I MTD patients and the Phase II 40 mg dose 
cohort and is referred to as combination regimen (Phase I + Phase II). 
Based on protocol Version 5.0, including protocol amendments 01 to 04 a cohort ŽĨш 20 patients are 
to be enrolled to single-agent melflufen (administered as 40 mg on Day 1 of each 28-day cycle).  All 
study procedures are to remain the same for the single-agent patients except for dexamethasone 
administration that is to be used as an anti-emetic prophylaxis at lower doses only. 
In the event that the risk-benefit balance of single-agent melflufen is determined to be sub optimal, 
the DSMC may at any time and without any further protocol amendment recommend that subsequent 
patients are to be treated with the combination regimen in order to optimize efficacy.  In this case, 
patients are to follow the same dexamethasone dose, schedule and dose modification guidelines as 
previously described in accordance with protocol Version 4.0, dated 27JAN2015 for the combination 
regimen.  Ongoing patients in the single-agent cohort may have weekly dexamethasone doses added 
at the discretion of the investigator. 
For both Phase I and Phase II patients, the planned cycle length was increased from 21 to 28 days 
following a decision by the DSMC on 18MAY2015.  Patients enrolled prior to 18MAY2015 are subject 
to a planned 21-day cycle length, but based on the investigator’s judgment the cycle length for 
ongoing patients may be increased to 28 days.  Patients enrolled after 18MAY2015 are to follow the 
protocol planned 28-day cycle length.  This includes the Phase II single-agent patients.  However, if any 
patient is subject to delayed hematologic recovery, the investigator may decide to increase the cycle 
length beyond the planned 21 or 28 days. 
Patients are to be assessed for disease response after each cycle with confirmation of disease 
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response according to the International Myeloma Working Group (IMWG) response criteria 
(Appendix 6 Disease Response Criteria of this SAP) regardless of dose level treated. 
According to the protocol, melflufen and/or dexamethasone dose modification guidelines are 
provided for patients experiencing toxicity and requiring dose modification. 
Patients are to be assessed at the start of each cycle according to the assessments outlined on Day 1 
of each cycle in Section 8.1 of protocol Version 6.0, including protocol amendments 01 to 05 [2].  To 
initiate a new cycle of study drug the following criteria are to be met: 
x
ďƐŽůƵƚĞŶĞƵƚƌŽƉŚŝůĐŽƵŶƚшϭ͘ϬǆϭϬE9/L. 
x
WůĂƚĞůĞƚĐŽƵŶƚшϱϬ͘ϬǆϭϬE9/L. 
x
All non-ŚĞŵĂƚŽůŽŐŝĐƚŽǆŝĐŝƚŝĞƐŵƵƐƚďĞч'ƌĂĚĞ 1 or returned to baseline (except alopecia). 
x
Absence of any other dose-limiting toxicities (DLTs). 
Patients in both Phase I and Phase II may continue with study drug for up to 8 cycles, until the patient 
experiences unacceptable toxicity, disease progression, withdraws consent, and/or study drug is 
discontinued at the discretion of the investigator.  However, patients who benefit from the treatment 
at the end of 8 cycles may continue treatment at the discretion of the investigator and after approval 
by Oncopeptides AB for each individual case.  Section 8.3 of protocol Version 6.0, including protocol 
amendments 01 to 05 [2] specifies that the End of Treatment (EOT) visit should be performed within 
30 days following study drug discontinuation or prior to initiation of any subsequent treatment 
(whichever occurs first). 
Following disease progression or initiation of subsequent treatment, the post-study follow-up period 
includes documentation of secondary malignancies, subsequent treatment, disease status and 
survival.  Follow-up is to occur every 3 months for up to 2 years.  Patients that discontinue study drug 
for reasons other than disease progression are to continue to have disease response assessments 
performed monthly (for confirmation of disease response/progression) until disease progression or 
initiation of subsequent treatment. 
The study design is schematically displayed below in Figure 1: Phase I and Figure 2: Phase II, 
respectively. 
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Page 19 of 99 
)LJXUH3KDVH,
 
DLT: Dose-limiting toxicity. IV: Intravenous. MTD: Maximum tolerated dose. PO: Per os. 
Dose reductions are not permitted during Cycle 1 of Phase I, unless the patient experiences a dose-limiting toxicity 
(DLT).  Dose reductions are permitted in subsequent cycles of Phase I. 
 
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IV: Intravenous. MTD: Maximum tolerated dose. PO: Per os. 
Dose reductions are permitted during Cycle 1 of Phase II and subsequent cycles of Phase II. 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
Page 20 of 99 
3.2. SCHEDULE OF EVENTS 
Schedule of events is presented in Section 8.1 of protocol Version 6.0, including protocol amendments 
01 to 05 [2]. 
3.3. CHANGES/CLARIFICATIONS TO ANALYSIS FROM PROTOCOL AND ELECTRONIC CASE REPORT 
FORM (ECRF) DATA COLLECTION 
The analysis sets described in the SAP are more comprehensive than those described in protocol 
Version 6.0, including protocol amendments 01 to 05 [2].  The analysis sets of the study are expanded 
to include the following: 
x
Modified Intent-to-Treat (mITT) Analysis Set. 
x
Per Protocol (PP) Analysis Set. 
The modified Intent-to-Treat (mITT) Analysis Set is introduced to allow the inclusion of the 40 mg MTD 
Phase I patients as well as the Phase II patients who have not necessarily completed at least two full 
cycles of study drug (intent-to-treat principle).  Also, as per the International Conference of 
Harmonisation (ICH) guidelines it is recommended to test patients who are more compliant with the 
protocol by looking at the PP Analysis Set.  International Conference of Harmonisation (ICH) 
Chapter 5.2.2 states the following: “The ‘per protocol’ set of subjects, sometimes described as the 
‘valid cases’, the ‘efficacy’ sample or the ‘evaluable subjects’ sample, defines a subset of the subjects 
in the full analysis set who are more compliant with the protocol and is characterised by criteria such 
as the following: 
x
The completion of a certain pre-specified minimal exposure to the treatment regimen. 
x
The availability of measurements of the primary variable(s). 
x
The absence of any major protocol violations including the violation of entry criteria”. 
Within the context of the clinical study report (CSR) transparency with regards such factors is 
important and this aids in producing the relevant table summaries to address the ICH requirements. 
Due to the initial design of the eCRF and the development of the analyses over time, external data in 
EXCEL format, not included in the standard data transfer are to be incorporated in the analysis 
datasets and presented in the output following review and authorization by Oncopeptides AB.  This 
includes: 
x
Appendix 2: Assignment of Patients to Disease Status (Relapsed/Refractory) to Prior Therapy 
(EXCEL spreadsheet), of the DR report. 
x
Appendix 3: Assignment of Patients to a Planned 21-day versus 28-day Cycle (EXCEL spreadsheet), 
of the DR report. 
x
Appendix 4: Hematopoietic growth factors (EXCEL spreadsheet), of the DR report. 
x
Appendix 5: Standardized transfusions (EXCEL spreadsheet), of the DR report. 
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4.PLANNED ANALYSES 
The following formal analyses are to be performed for the study: 
x
Analyses for the conduct of DSMC meetings. 
x
Final analysis. 
4.1. DATA SAFETY MONITORING COMMITTEE (DSMC) 
A DSMC SAP (DSMC_Charter_O-12-M1.doc) and SAP output shells (20150409 O-12-M1 DSMC Outputs 
Draft V5.0.doc) were created as separate documents describing the methodology and presentation of 
results as provided by 
 Biostatistics on several occasions for various DSMC meetings.  
Similar output was requested in preparation for the American Society of Hematology (ASH) poster 
presentations and the European Hematology Association (EHA) meeting. 
4.2. INTERIM ANALYSIS 
No interim analysis is planned for the study. 
4.3. FINAL ANALYSIS 
All final, planned analyses identified in the SAP are to be performed by 
 Biostatistics.  The 
following study documents require Oncopeptides AB’s authorization, unless otherwise specified: 
x
Statistical Analysis Plan (SAP) and latest SAP output shells. 
x
Appendix 1: Assignment of Patients to Analysis Sets and Identification of Major Analysis Set 
Deviations (EXCEL spreadsheet), of the DR report. 
x
Additional EXCEL spreadsheets as detailed in Section 3.3 Changes/Clarifications to Analysis from 
Protocol and electronic Case Report Form (eCRF) Data Collection of this SAP. 
x
 Biostatistics’ and 
 Data Management’s authorization of the final data 
issues log and the data handling report. 
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STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
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5.ANALYSIS SETS 
With reference to the latest authorized version of the DR plan [1] the following analysis sets are 
defined for analysis purposes. 
5.1. ALL PATIENTS SCREENED ANALYSIS SET 
All patients who provided written informed consent prior to performing any specific study-related 
procedures. 
5.2. SAFETY (SAF) ANALYSIS SET 
All patients who received at least one dose, or part thereof, of study drug are to be included in the 
Safety (SAF) Analysis Set.  The first occurrence of either melflufen or dexamethasone is to be 
considered for all patients except for Phase II single-agent patients.  Dexamethasone is to be regarded 
as anti-emetic prophylaxis in the single-agent cohort.  Therefore only the first occurrence of melflufen 
is to be considered for Phase II single-agent patients.  The SAF Analysis Set is regarded as primary for 
the safety analyses. 
5.3. MODIFIED INTENT-TO-TREAT (MITT) ANALYSIS SET 
All patients considered to be valid for the SAF Analysis Set and who received at least one dose of study 
drug at MTD as initial dose.  This includes the 40 mg MTD Phase I patients as well as the Phase II 
patients.  The mITT Analysis Set is regarded as primary for PFS and OS analyses. 
In the event that a deviation in planned versus actual study drug is present, patients are to be 
analyzed according to planned study drug (enrolled dose cohort). 
5.4. EFFICACY-EVALUABLE MODIFIED INTENT-TO-TREAT (EEMITT) ANALYSIS SET 
All patients considered to be valid for the mITT Analysis Set, who have a Baseline efficacy assessment 
(measurable disease assessment) and for whom at least one post-baseline efficacy assessment 
(disease response assessment), following completion of at least two full cycles of study drug, is 
available, are to be included in the Efficacy-evaluable Modified Intent-to-Treat (EEmITT) Analysis Set.  
The EEmITT Analysis Set is regarded as primary for disease response efficacy endpoints including 
response rates, time to response and duration of response analyses as well as disease progression.  
Refer to Table 2: Dose Cohorts of this SAP for the presentation of summaries. 
In the event that a deviation in planned versus actual study drug is present, patients are to be 
analyzed according to actual study drug (actual initial dose of melflufen received as indicated on the 
Melflufen Administration eCRF). 
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5.5. PER PROTOCOL (PP) ANALYSIS SET 
The PP Analysis Set includes all patients who completed the study according to protocol and had no 
major analysis set deviations.  Analysis set deviations are defined as major if they have an influence on 
the efficacy outcome or the effect of the study drug within the patient.  Only patients included in the 
EEmITT Analysis Set are eligible for inclusion in the PP Analysis Set.  Patients who are withdrawn from 
the study due to lack of efficacy or drug-related (relationship to either melflufen or dexamethasone) 
reasons are to be included in the PP Analysis Set if they are otherwise valid.  The PP Analysis Set is 
regarded as confirmation of the primary efficacy results obtained from the EEmITT Analysis Set. 
The PP Analysis Set is further defined by the following valid course criteria: 
x
Compliance with study drug (melflufen and dexamethasone). 
x
Sufficient evidence of the study indication. 
x
Adherence to the visit schedule. 
x
Eligible in accordance with the protocol specified inclusion/exclusion criteria. 
x
Use of prohibited prior/concomitant medication and/or therapy. 
x
No deviation in planned versus actual study drug. 
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6.GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATES, REFERENCE STOP DATES AND REFERENCE DAYS 
7DEOH5HIHUHQFH'DWHV
 
C: Cycle. Dt: Date. EOT: End of Treatment. Ref: Reference. St: Start. Cn: Represents a patient’s last 
cycle. 
Date of first and last dose of study drug is to be based on the earliest (minimum) and the latest 
(maximum) dose date of the two study drugs (melflufen and dexamethasone) in the combination 
regimen, where relevant.  Study drug details are to be obtained as indicated on the Melflufen 
Administration and Dexamethasone Administration eCRFs.  With reference to Table 1: Reference 
Dates, the overall reference start date is defined as the date of first dose of study drug (Cycle 1 Day 1 
is the day of the first dose of study drug).  The first occurrence of either melflufen or dexamethasone 
is to be considered for all patients except for Phase II single-agent patients.  Dexamethasone is 
regarded as anti-emetic prophylaxis in the single-agent cohort.  Therefore only the first occurrence of 
melflufen is to be considered for Phase II single-agent patients.  The overall reference start date is to 
be presented in selected by-patient data listings where an assessment date or event date is presented. 
The last occurrence of either melflufen or dexamethasone (latest [maximum]) is to be considered for 
all patients except for Phase II single-agent patients initially enrolled as per protocol amendment 04.  
Only the last occurrence of melflufen is to be considered for Phase II single-agent patients as the last 
dose date, unless the investigator decides to switch a patient to combination regimen: Phase I + II (per 
protocol amendment 05) for which the last occurrence of either melflufen or dexamethasone (latest 
[maximum]) is to be considered. 
Reference start and stop dates are also defined for each cycle.  The reference start date of Cycle x is 
defined as the date of first dose of study drug on Cycle x Day 1.  The first occurrence of either 
melflufen or dexamethasone is to be identified as described for the overall reference start date.  The 
reference stop date of Cycle x is defined as the day before Day 1 of the subsequent cycle (Cycle [x+1] 
Day 1).  The reference stop date of the last cycle (i.e., the overall reference stop date) is defined as the 
derived EOT date (refer to Section 6.2 Derived Timepoints of this SAP). 
Study days (relative to the overall reference start date) are to be used to indicate the relative day on 
which assessments started/stopped. 
Cycle days (relative to the reference start date of Cycle x) are to be used to indicate the relative day on 
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which assessments started/stopped within an individual cycle.  Cycle days for Screening assessments 
are to be defined relative to the overall reference start date and derived EOT or post-study follow-up 
assessments are to be defined relative to the last melflufen dose date. 
6.1.1. DERIVATIONS 
Study day is to be calculated relative to overall reference start date. 
If the date of the event is on or after the overall reference start date: 
x
Study day = (<Date of event> – <overall reference start date>) + 1. 
If the date of the event is prior to the overall reference start date: 
x
Study day = (<Date of event> – <overall reference start date>). 
Study days are only presented for patients with a least one dose of study drug or part thereof.  Unless 
otherwise specified, if an assessment date is partial or missing, study day, and any corresponding 
durations are to be presented as partial or missing in the by-patient data listings. 
Cycle day is to be calculated relative to reference start date of Cycle x per individual cycle, except for 
Screening assessments to be calculated relative to the overall reference start date and derived EOT or 
post-study follow-up assessments to be calculated relative to the last melflufen dose date. 
If the date of the event of Cycle x is on or after the reference date: 
x
Cycle day = (<Date of event> – <reference date>) + 1. 
If the date of the event of Cycle x is prior to the reference date: 
x
Cycle day = (<Date of event> – <reference date>). 
6.2. DERIVED TIMEPOINTS 
Following data investigation, some patients were identified with the EOT visit occurring after the 
specified 30 days from study drug discontinuation (Section 8.3 of protocol Version 6.0, including 
protocol amendments 01 to 05 [2]).  To ensure inclusion of as much data as possible for the analyses 
and to obtain the actual cycle length of a patient’s last cycle, a reference point (i.e., a derived EOT 
date) was introduced by 
 Biostatistics.  For patients with no actual EOT visit recorded or 
patients with an actual EOT visit occurring within 30 days of the last cycle’s Day 1 melflufen dose date, 
the last study drug date of melflufen + 30-day gap period is to be used as the derived EOT date.  The 
derived EOT date is defined as the latest reference date of either the last melflufen dose date + 30-day 
gap period or the actual EOT visit date, or the death date should it occur first.  If subsequent 
treatment is initiated within the last cycle, derived EOT is calculated as the start date of subsequent 
treatment administration. Please refer to 20170824 EOT derivation.xls EXCEL spreadsheet for 
authorized derived EOT dates based on the above definition and review and authorization from 
Oncopeptides team. 
For patients with no assessments recorded at the actual EOT visit, the last non-missing post-baseline 
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assessment (scheduled or unscheduled) up to and including the derived EOT date is to be carried 
forward to allow change from Baseline (CFB) at EOT calculations.  The last observation carried forward 
(LOCF) data handling convention is to be used to prevent exclusion of data for patients with no 
assessments recorded at the actual EOT visit.  Change from Baseline (CFB) calculations for which the 
LOCF data handling convention is to be applied include plasmacytoma, laboratory (hematology, serum 
chemistry, coagulation, and quantitative urinalysis), 12-lead ECG, and vital signs assessments. 
6.2.1. DERIVATIONS 
x
Derived EOT date = min(max[<Last melflufen dose date> + 30, <actual EOT visit date>], <first 
subsequent treatment date>, <death date>). 
6.3. CYCLE LENGTH, CYCLE ASSIGNMENT, AND CYCLE COMPLETION 
As described in Section 3.1 General Description of this SAP, the planned cycle length was increased 
from 21 to 28 days. 
The actual cycle length (duration) is defined as the difference in days from Day 1 of a patient’s current 
cycle (Cycle x) to the day before Day 1 of the subsequent cycle (Cycle [x + 1] Day 1).  The actual cycle 
length (duration) of a patient’s last cycle is defined as the difference in days from Day 1 of the last 
cycle to the derived EOT date + 1 (refer to Section 6.2 Derived Timepoints of this SAP).  The total 
number of cycles completed (derived sum) is based on patients returning at the start of a subsequent 
cycle who are considered to have completed the previous cycle (refer to Section 6.1 Reference Start 
Dates, Reference Stop Dates and Reference Days of this SAP) plus the addition of the patient’s last 
cycle ending with the derived EOT as reference point. 
6.3.1. DERIVATIONS 
Cycle length (days): Calculated relative to the day before Day 1 of the subsequent cycle: 
x
Cycle x length (days) = ({[Date of Cycle {x + 1} Day 1]} – Date of Cycle x Day 1).  Where x = 1 to n. 
Cycle length (days) of last cycle: Calculated relative to the derived EOT date (refer to Section 6.2 
Derived Timepoints of this SAP): 
x
Cycle n length (days) = (Date of derived EOT – Date of Cycle n Day 1) + 1. 
The number of cycles completed is indicated on the End of Treatment eCRF.  However, the total 
number of cycles completed is to be derived based on the actual administration data as indicated on 
the Melflufen Administration eCRF.  Patients returning at the start of the subsequent cycle (Cycle [x + 
1] Day 1) are to be considered to have completed the previous cycle (Cycle x Day 1).  The patient’s 
derived EOT date is to be used to account for a patient’s last cycle in lieu of the subsequent cycle. 
x
Total number of cycles completed (derived sum) 
 
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Where n represents a patient’s last cycle.  An example below is presented for illustration purposes: 
For n=3, i.e., x=1 to (n-1) 
 
 
 
 
x=1 
Cycle (1 + 1) Day 1 – Cycle 1 Day 1 
ї 
Cycle 2 Day 1 – Cycle 1 Day 1 
= 
1 
x=2 
Cycle (2 + 1) Day 1 – Cycle 2 Day 1 
ї 
Cycle 3 Day 1 – Cycle 2 Day 1 
= 
1 
 
Cycle 3 Day 1 to derived EOT date 
ї 
1 
 
Total number of cycles completed (derived sum) 
= 
3 
EOT: End of Treatment. The derived EOT date is to be used to account for the patient’s last cycle. 
 
The following data are to be assigned to the cycle during which the procedure/medication/event 
started based on cycle reference start and stop dates.  If the procedure/medication/event date is on 
or after the cycle reference start date and on or before the cycle reference stop date, then the 
procedure/medication/event is to be assigned to the relevant cycle. 
x
Concomitant procedures (including standardized transfusions): Cycle occurrence is to be assigned 
based on the date of the procedure. 
x
Concomitant medications (including hematopoietic growth factors): Cycle occurrence is to be 
assigned based on the start date of the medication. 
x
Adverse events (AEs): Cycle occurrence is to be assigned based on the start date of the event. 
x
Neutropenia and thrombocytopenia/events of special interest: Cycle occurrence is to be assigned 
based on the date of laboratory assessment.  Adverse events (AEs), hematopoietic growth factors 
and standardized transfusions are included in the events of special interest and are to be handled 
as described above. 
For the handling of partial dates for AEs, medications, prior therapies, and/or procedures refer to 
Appendix 2 Partial Date Conventions of this SAP. 
6.4. BASELINE 
Baseline is defined as the last non-missing assessment (scheduled or unscheduled up to and including 
Cycle 1 Day 1) prior to the first dose of study drug (overall reference start date).  In the case where the 
last non-missing assessment and the overall reference start date coincide, the assessment is to be 
considered as occurring prior to the start of study drug and is to be used as the Baseline assessment.  
However, AEs and medications commencing on the overall reference start date (Cycle 1 Day 1) are to 
be considered post-baseline, i.e., as treatment-emergent AEs (TEAEs) or concomitant medications. 
For serum free light chain (SFLC) assay differences Baseline is defined as the difference in the last 
non-missing involved SFLC assay and uninvolved SFLC assay where both SFLC assays are obtained from 
the same identified last non-missing SFLC assessment: 
x
Involved kappa: SFLC difference at Baseline = (KappaBaseline - LambdaBaseline). 
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x
Involved lambda: SFLC difference at Baseline = (LambdaBaseline - KappaBaseline). 
Section 15.1.1 Laboratory Assessments of this SAP details the identification of involved and uninvolved 
SFLC assays. 
Post-baseline is defined as any assessment (scheduled or unscheduled) obtained after the first dose of 
study drug (overall reference start date).  For SFLC assay differences, post-baseline is defined as the 
difference in the involved SFLC assay and the uninvolved SFLC assay where both SFLC assays are 
obtained from the same identified post-baseline SFLC assessment: 
x
Involved kappa: SFLC difference at post-baseline = (KappaVisit - LambdaVisit). 
x
Involved lambda: SFLC difference at post-baseline = (LambdaVisit - KappaVisit). 
If one of the components required in the calculation is not available, no SFLC difference is to be 
presented. 
6.5. PREMATURE DISCONTINUATION, END OF TREATMENT (EOT) AND END OF STUDY (EOS) 
At the time patients discontinue study drug, a visit is to be scheduled as soon as possible (within 
30 days following study drug discontinuation or prior to initiation of subsequent treatment [whichever 
occurs first]).  The EOT visit is to be followed by the post-study follow-up assessments. 
At the time patients have completed the post-study follow-up assessments, End of Study (EOS) 
assessments are to be performed.  However, EOS assessments are also to be performed when: 
x
A patient is not willing to participate in the post-study follow-up assessments. 
x
Death occurs during the treatment period or post-study follow-up period. 
End of Treatment (EOT) and EOS assessments are collected as indicated on the eCRF.  Derived EOT 
timepoints are to be presented in the relevant output for which data is presented by visit. 
6.6. RETESTS AND UNSCHEDULED VISITS 
In general, for by-visit summaries, data recorded at nominal visits are to be presented.  Unscheduled 
assessments are not to be included in by-visit summaries, but are to contribute to Baseline, abnormal 
results as per specified criteria or best/worst case results where required (e.g., shift [cross tabulation] 
tables and duration of laboratory assessments). 
For any incidence summaries of laboratory grades, all visits are to be taken into account including 
unscheduled visits.  
In the case of a retest (same sample collection date), the latest available result for that visit is to be 
used for by-visit summaries. 
By-patient data listings are to include scheduled, unscheduled, and retest data (if applicable).  
Unscheduled assessments are also to be included in the by-patient figures. 
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6.7. WINDOWING CONVENTIONS 
No visit windowing is to be performed for the study. 
6.8. STATISTICAL OUTPUT CONVENTIONS 
The default summary statistics for quantitative variables are listed below in the preferred order.  If the 
original data has N decimal places, the default summary statistics are to be presented with the 
following decimal precision (using SAS® function ROUND as the very last step prior to presentation): 
x
Number (n) of patients in each category. 
x
Mean: N + 1. 
x
Standard deviation (SD): N + 2. 
x
Minimum: N. 
x
Median: N + 1. 
x
Maximum: N. 
x
Missing: 0. 
The default summary statistics for qualitative variables are as follows: 
x
Number (n) of patients in each category. 
x
Percentage (%) of patients in each category presented to 1 decimal place (using SAS® function 
ROUND as the very last step prior to presentation) and calculated relative to either one of the 
following, unless otherwise specified: 
o
Total number of patients in the relevant analysis set. 
o
Total number of patients in the relevant analysis set with data available (observed cases). 
The number (n) of patients with missing results for qualitative or quantitative variables is to be 
presented as part of a missing category or missing statistic, where applicable. 
Confidence Intervals (CIs) 
x
Confidence intervals (CIs), 25th and 75th percentiles are to be presented to 1 decimal place. 
x
Presentation of CIs are to be justified so that parentheses displayed on consecutive lines of a table 
“line up”. 
x
Boundary values of CIs are to be separated by a hyphen, i.e., [xx.x-xx.x]. 
6.9. COMMON CALCULATIONS 
For quantitative assessments, CFB is to be calculated as: 
x
CFB = (Test value at visit x – Baseline value). 
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Percentage CFB (% CFB) is to be calculated as: 
x
% CFB = (Test value at visit x – Baseline value)/Baseline value × 100. 
6.10. SOFTWARE VERSION 
All analyses are to be conducted using SAS® Version 9.2 or higher. 
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7.STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES 
Not applicable. 
7.2. MULTISITE STUDIES 
The study is to be conducted by multiple investigators at multiple clinical sites internationally.  The 
following countries are to host selected sites: USA (sites 501, 502 and 503), Denmark (site 601), Italy 
(site 801), Sweden (site 901), and the Netherlands (site 701).  Summaries are to include combined 
data across all sites only.  Individual site data are to be available in by-patient data listings. 
7.3. MISSING DATA 
Missing efficacy data are to be handled as described in Section 15.2.1 Missing Data Methods for 
Primary Efficacy Variables of this SAP.  For the handling of partial dates for AEs, medications, prior 
therapies, and/or procedures refer to Appendix 2 Partial Date Conventions of this SAP. 
7.4. MULTIPLE COMPARISONS/MULTIPLICITY 
Not applicable. 
7.5. EXAMINATION OF SUBGROUPS 
Subgroup analyses are to be conducted as part of the efficacy analysis.  Assignment of patients to the 
subgroup stratification levels is to be included in Appendix 1: Assignment of Patients to Analysis Sets 
and Identification of Major Analysis Set Deviations (EXCEL spreadsheet), of the DR report and 
authorized.  It is to be noted that the study was not designed to detect cohort differences within 
subgroup stratification levels.  With reference to the latest authorized version of the DR plan [1] the 
following subgroups are defined: 
7.5.1. AGE (YEARS) 
Age (years) (calculated relative to Screening) is classified as: 
x
< 65. 
x
шϲϱƚŽчϳϱ͘ 
x
> 75. 
7.5.2. BASELINE INTERNATIONAL STAGING SYSTEM (ISS) 
Baseline International Staging System (ISS) is classified as: 
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x
Stage I: Baseline beta2-microglobulin < 3.5 mg/L and Baseline serum albumin шϯ͘ϱŐͬĚ> (i.e., 
ш 35 g/L). 
x
Stage II: Neither Stage I nor Stage III.  Baseline beta2-microglobulin < 3.5 mg/L and Baseline serum 
albumin < 3.5 g/dL (i.e., < 35 g/L); or Baseline beta2-microglobulin ш3.5 to < 5.5 mg/L irrespective 
of the Baseline serum albumin. 
x
Stage III: Baseline beta2-microglobulin шϱ͘ϱŵg/L. 
x
Unknown: Not categorized as Stage I, II, or III. 
7.5.3. PRIOR THERAPIES 
Number of lines of prior therapy 
The number of lines of prior therapy is classified as: 
x
< 2.  No patients are expected in this subgroup stratification level based on Inclusion Criterion 04. 
x
шϮƚŽчϯ͘ 
x
хϯƚŽчϱ͘ 
x
> 5. 
Type of prior therapy 
The type of prior therapy transplant is classified as follows: 
x
Autologous. 
x
Allogeneic. 
x
Autologous/Allogeneic. 
x
No transplant. 
7.5.4. REFRACTORY STATUS 
Refractory status (refer to Section 13.1 Prior Therapies of this SAP) to lines of prior therapy containing 
any of the below listed medications in a regimen is to be derived (a.) across all lines of prior therapy 
(refractory status to any line) as well as (b.) by last line of prior therapy (refractory status to last line) 
and classified as: 
x
Alkylator (Melphalan, cyclophosphamide, or bendamustine). 
x
Proteasome inhibitor (PI) (Bortezomib, carfilzomib, or ixazomib). 
x
Immunomodulatory drugs (IMiD) (Lenalidomide, thalidomide, or pomalidomide). 
x
Monoclonal antibody (Elotuzumab or daratumumab). 
x
Double refractory (PI and IMiD). 
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x
Double refractory and alkylator (PI and IMiD and alkylator). 
x
Non-refractory (i.e., relapsed) to all of the above. 
7.5.5. BASELINE DISEASE RISK STATUS 
Baseline disease risk status is classified as: 
x
High: Patients with the presence of at least one of del(17p), or t(4;14), or t(14;16), or t(14;20) or 
gain(1q) determined by Baseline fluorescence in situ hybridization (FISH), or nonhyperdiploid 
Baseline karyotype (i.e., hypodiploid), or karyotype del(13). 
x
Standard: Patients with any other cytogenetic abnormality including t(11;14) or t(6;14) determined 
by Baseline FISH and the absence of the high-risk genetics determined by Baseline FISH. 
x
Missing: Patients for whom Baseline disease risk status cannot be categorized as high or standard 
due to missing, indeterminate or other Baseline FISH, karyotype, or ploidy specification. 
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8.OUTPUT PRESENTATIONS 
Appendix 1 Specific Programming Conventions for Outputs of this SAP details the conventions for 
presentation of data.  The latest SAP output shells provided with the SAP describe the presentations 
for the study and therefore the format and content of the summary tables, by-patient data listings and 
figures to be provided by 
 Biostatistics. 
Unless otherwise specified, data are to be presented and summarized for the SAF Analysis Set.  If the 
number (n) of patients in the SAF Analysis Set and mITT differ by more than 10% (i.e., 5 patients) 
summaries are to be repeated for the mITT (i.e., the 40 mg MTD Phase I patients as well as the 
Phase II patients) as specified in the SAP output shells. 
Data that is recorded in free text fields are not to be modified by 
 Biostatistics and are to 
be presented by the text “Specification (eCRF)” as indicated by the investigator on the eCRF.  Selected 
presentations of laboratory data are to contain an assessment identifier indicating the origin of the 
data (i.e., eCRF, local laboratory data, or central laboratory data). 
7DEOH'RVH&RKRUWV
Phase I: Dose Escalation Cohort 
 
Phase II: Dose Cohort MTD 
 
 
MTD: Maximum tolerated dose. N = Total number of patients in the relevant analysis set. The Total 
column is to be derived as the sum of the combination regimen (Phase I + Phase II) and the 
single-agent dose cohorts. 
 
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9.DISPOSITION 
With reference to Section 6 General Considerations and Section 7 Statistical Considerations of this SAP 
summaries are to be provided by the relevant analysis set, phase, and dose cohort (refer to Table 2: 
Dose Cohorts of this SAP) as specified in the latest SAP output shells. There are no statistical 
comparisons planned between the dose cohorts for the study. 
9.1. END OF STUDY (EOS) 
All patients who provided informed consent are to be accounted for in the study.  Data as indicated on 
the End of Study eCRF is to be presented in a by-patient data listing for the All Patients Screened 
Analysis Set.  Accounting for the key study milestones the following are to be presented: 
x
Date of informed consent relative to overall reference start date. 
x
Date of Screening relative to overall reference start date. 
x
Date of first dose (overall reference start date) and last dose (overall reference stop date) of study 
drug. 
x
Study completion/discontinuation and the relevant primary reason for study discontinuation. 
Data are to be summarized for: 
x
Patients who completed the study. 
x
The primary reasons for study discontinuation in the specified order: 
o
Withdrawal of informed consent. 
o
Lost to follow-up. 
o
Death. 
o
Investigator discretion. 
o
Termination of the study by the sponsor. 
o
Other/Specification (eCRF). 
A patient’s study participation status (study completion/study discontinuation) is to be based on the 
End of Study eCRF as indicated by the investigator.  Patients who have completed the 2-year 
post-study follow-up period are considered to have completed the study. 
9.2. END OF TREATMENT (EOT) 
Data as indicated on the End of Treatment eCRF is to be presented. 
x
The total number of cycles completed (to be listed as indicated on the eCRF and to be summarized 
based on the derived sum [refer to Section 6.3.1 Derivations of this SAP]). 
x
The date of last dose of study drug (melflufen and dexamethasone) (to be presented as indicated 
on the eCRF). 
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x
The best overall disease response on treatment (to be presented as indicated on the eCRF). 
x
Study drug discontinuation and the relevant primary reason for discontinuation. 
x
Post-study follow-up participation/Specification (eCRF). 
With reference to Section 6.3 Cycle Length, Cycle Assignment, and Cycle Completion of this SAP 
disease response assessments are based on the investigator’s by-cycle assessments as indicated on 
the Disease Response Assessment eCRF.  The best overall disease response on treatment is based on 
the investigator’s assessment as indicated on the End of Treatment eCRF and is to be used in the 
primary endpoint analysis (refer to Section 15.2.2 Analysis of Primary Efficacy Variables of this SAP). 
Data are to be summarized for: 
x
Patients who discontinued study drug including primary reasons for discontinuation of study drug 
in the specified order: 
o
Disease progression. 
o
Adverse events (AEs). 

As per ICH E3 Structure and Content of Clinical Study Reports and the eCRF design AE 
data as indicated on the Adverse Events/Serious Adverse Events eCRF is not to be 
detailed in the presentation of disposition output. 
o
Requiring other anti-neoplastic therapies. 
o
Protocol deviation. 
o
Withdrawal of informed consent. 
o
Lost to follow-up. 
o
Death. 
o
Pregnancy. 
o
Investigator discretion. 
o
Termination of the study by the sponsor. 
o
Other/Specification (eCRF). 
x
Patients who participated in the post-study follow-up period (as indicated on the End of Treatment 
eCRF). 
9.3. ANALYSIS SETS 
Major analysis set deviations are defined as any factor affecting the efficacy outcome or the treatment 
of the patient and are to be identified and authorized by Oncopeptides AB at the final DR meeting.  
Data are to be summarized for the All Patients Screened Analysis Set: 
x
Number (n) and percentage (%) of patients included or excluded from the hierarchical analysis sets 
and the reason(s) for exclusion.  (Appendix 1: Assignment of Patients to Analysis Sets and 
Identification of Major Analysis Set Deviations [EXCEL spreadsheet], of the DR report).  The 
authorized EXCEL spreadsheet is to be imported into SAS® for use in the analysis datasets and 
presentation in the output. 
Inclusion/exclusion criteria exceptions are defined as criteria with a response of “missing” or “no” to 
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any inclusion criteria or a response of “missing” or “yes” to any exclusion criteria.  The exceptions are 
to be based on the protocol amendment in effect at the time of informed consent provided. 
Major protocol deviations [as obtained from the Clinical Trials Management System (CTMS) report], 
major analysis set deviations, analysis set assignment, and inclusion/exclusion criteria exceptions are 
to be presented in by-patient data listings for the All Patients Screened Analysis Set. 
Screen failures as indicated on the Screen Failure eCRF are to be included in the relevant dose cohorts 
as enrolled and indicated on the Demography eCRF. 
 
 
9.4. VISIT DATES 
With reference to the presentation of visits as tabulated in Appendix 1 Specific Programming 
Conventions for Outputs the following variables are to be presented: 
x
Visits (including date of visit). 
x
Cycle day. 
x
Planned visit window. 
x
Actual cycle length (days). 
x
Patient status of continuing to a subsequent cycle. 
x
Total number of cycles completed (derived) (refer to Section 6.3 Cycle Length, Cycle Assignment, 
and Cycle Completion of this SAP). 
For this presentation the cycle day is to be calculated relative to the reference start date of Cycle x per 
individual cycle.  Visits outside the planned protocol visit window (± 3 days) are to be flagged.  Disease 
response assessments for patients who discontinue study drug for reasons other than disease 
progression are to be flagged.  These patients are to have monthly disease response assessments until 
disease progression or initiation of subsequent treatment.  The initiation of subsequent treatment is 
to be flagged in the by-patient data listing to facilitate identification. 
Following disease progression or initiation of subsequent treatment, post-study follow-up visits are to 
occur every 3 months for up to 2 years after the derived EOT. 
Details of actual cycle length are presented in Section 6.3 Cycle Length, Cycle Assignment, and Cycle 
Completion of this SAP.  Patient status of continuing to a subsequent cycle is to be presented as 
indicated on the Study Status and Study Continuation eCRFs. 
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10. DEMOGRAPHIC CHARACTERISTICS 
Demographic characteristics as indicated on the Demography eCRF are to be presented. 
Data are to be summarized for: 
x
Age (years): Calculated relative to Screening (refer to Section 7.5 Examination of Subgroups of this 
SAP). 
x
Age (years) category: 
o
< 65. 
o
шϲϱƚŽчϳϱ͘ 
o
> 75. 
x
Gender (including childbearing potential for female patients).  Percentage (%) of childbearing 
potential status is to be calculated relative to the total number of female patients with data. 
x
Race. 
o
American Indian or Alaska Native. 
o
Black or African American. 
o
Asian. 
o
Caucasian/White. 
o
Native Hawaiian or other Pacific Islander. 
o
Other/Specification (eCRF). 
x
Ethnicity. 
o
Hispanic or Latino. 
o
Not Hispanic or Latino. 
o
Not collected as per local laws. 
The following are also to be presented in the by-patient data listing: 
x
Date of birth. 
x
Protocol version signed. 
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11. MEDICAL AND/OR SURGICAL HISTORY 
Medical and/or surgical history conditions are defined as any prior significant conditions as indicated 
on the Medical and Surgical History eCRF. 
Patients (n and %) with medical and/or surgical history conditions are to be summarized by System 
Organ Class (SOC), and Preferred Term (PT).  If a medical and/or surgical history condition occurs more 
than once for a patient per level of summarization the patient is only counted once per Medical 
Dictionary for Regulatory Activities (MedDRA) SOC or PT.  System Organ Classes (SOCs) are to be 
sorted by total decreasing frequency.  Preferred Terms (PTs) are to be sorted by total decreasing 
frequency within each SOC.  If SOCs or PTs have the same total frequency they are to be sorted 
alphabetically. 
Partial dates are not to be imputed and as such study day is to be presented as missing.  Uncoded 
medical and/or surgical history conditions (i.e., conditions with no dictionary coding information 
available) are only to be presented if applicable using the investigator’s Verbatim Term (eCRF) 
presented as PT within the text “UNCODED” as SOC. 
Medical and/or surgical history conditions are coded using MedDRA Version 20.0. 
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12. DISEASE CHARACTERISTICS OF MULTIPLE MYELOMA 
12.1. DISEASE CHARACTERISTICS SINCE/AT INITIAL DIAGNOSIS 
Disease characteristics at initial diagnosis as indicated on the History of Multiple Myeloma eCRF are to 
be summarized for: 
x
Time since initial diagnosis (years): Calculated relative to overall reference start date. 
x
Age at initial diagnosis (years): Calculated relative to date of initial diagnosis. 
x
Stage at initial diagnosis. 
o
Durie-Salmon. 

IA; IB. 

IIA; IIB. 

IIIA; IIIB. 

Unknown. 
o
International Staging System (ISS). 

I. 

II. 

III. 

Unknown. 
x
Disease type at initial diagnosis. 
o
Immunoglobulin (Ig) (A, D, E, G, M). 
o
Other/Specification (eCRF). 
x
Light chain type at initial diagnosis. 
o
Kappa. 
o
Lambda. 
o
Unknown. 
x
Evidence of lytic bone disease at initial diagnosis. 
o
Yes. 
o
No. 
o
Unknown. 
x
Evidence of extramedullary disease at initial diagnosis. 
o
Yes. 
o
No. 
o
Unknown. 
x
Conventional karyotype at initial diagnosis. 
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o
Not detected. 
o
Unknown. 
o
Not done. 
o
Abnormal karyotype/Specification (eCRF). 
x
Fluorescence in situ hybridization (FISH) at initial diagnosis. 
o
Unknown. 
o
Not done. 
o
Del17p13. 
o
T(4;14)(p16.3;q32.3). 
o
T(14;16)(q32.3;q23). 
o
+1q21;Amp1q21. 
o
Del(13);13q14.3. 
o
Other/Specification (eCRF). 
x
Ploidy at initial diagnosis. 
o
Unknown. 
o
Not done. 
o
Hyperdiploid. 
o
Hypodiploid. 
Multiple categories for disease type, light chain type and FISH results may be selected resulting in 
percentages not necessarily adding up to 100%. 
12.1.1.DERIVATIONS 
Time since initial diagnosis (years): Calculated relative to overall reference start date using the 
following SAS® code: 
x
Time since initial diagnosis (years) = int((intck(“month”, <date of initial diagnosis>, <date of first 
dose of study drug>) - (day(<date of first dose of study drug>) < day(<date of initial 
diagnosis>)))/12). 
Age (years): Calculated relative to date of initial diagnosis using the following SAS® code: 
x
Age (years) = int((intck(“month”, <date of birth>, <date of initial diagnosis>) - (day(<date of initial 
diagnosis>) < day(<date of birth>)))/12). 
For the handling of partial initial diagnosis dates refer to Appendix 2 Partial Date Conventions of this 
SAP. 
12.2. DISEASE CHARACTERISTICS AT BASELINE 
Both local and central laboratory results are to be obtained regarding the evaluation of multiple 
myeloma.  Refer to Section 15.1.3.1 Central/Local Laboratory Data of this SAP for the handling of 
local/central laboratory assessments in view of Baseline derivations. 
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Disease characteristics at Baseline are only to be presented for the SAF Analysis Set.  Unless the 
relevant eCRF is specified as assessment identifier, results are to be obtained from central laboratory 
when available and local laboratory otherwise.  Disease characteristics at Baseline (refer to Section 6.4 
Baseline of this SAP) are to be summarized for: 
x
Baseline ISS category (refer to Section 7.5.2 Baseline International Staging System (ISS) of this SAP). 
o
I. 
o
II. 
o
III. 
o
Unknown. 
x
Current disease status category (as indicated by the investigator on the History of Multiple 
Myeloma eCRF). 
o
Relapsed. 
o
Relapsed/Refractory. 
o
Primary refractory. 
o
Unknown. 
x
Eastern Cooperative Oncology Group (ECOG) (as indicated by the investigator on the ECOG 
Performance Status eCRF). 
o
Performance status: 

Grade 0: Normal activity, fully active, able to carry on all pre-disease performance 
without restriction. 

Grade 1: Symptoms, but fully ambulatory, restricted in physically strenuous but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 

Grade 2: Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 

Grade 3: Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 

Grade 4: Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 

Grade 5: Dead. 
x
Serum chemistry (as indicated on the Local Laboratory/Serum Chemistry eCRF, but converted to 
international system of units [SI], where required). 
o
Creatinine (μmol/L). 
o
Creatinine clearance (mL/min) (eCRF). 
o
Corrected calcium (mmol/L) (derived) (refer to Section 12.2.1 Derivations of this SAP). 
o
Albumin (g/L). 
x
Special chemistry. 
o
Serum beta2-microglobullin (mg/L). 
x
Serum electrophoresis. 
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o
Monoclonal protein (M-protein) abs (g/L).  Multiple assessments are to be presented in the 
by-patient data listing, if applicable. 

The sum of the measurable results is to be used as analyzable result when multiple 
assessments of the same test are available at the same visit.  Refer to Appendix 4 
Specific Myeloma Central Laboratory Evaluations of this SAP for mapping of laboratory 
panels to the correct laboratory system/variable for the analysis. 
x
Urine electrophoresis. 
o
Monoclonal protein (M-protein) (mg/24h).  Multiple assessments are to be presented in the 
by-patient data listing, if applicable. 

The sum of the measurable results is to be handled in the same manner as described for 
serum electrophoresis. 
x
Serum immunology. 
o
Immunoglobulin (Ig) (A, D, E, G, M). 
x
Serum chemistry. 
o
Protein total (g/L). 
o
Serum free light chain (SFLC) assay kappa (mg/L). 
o
Serum free light chain (SFLC) assay lambda (mg/L). 

The involved SFLC assay (refer to Section 15.1.1 Laboratory Assessments of this SAP) is 
to be flagged in the by-patient data listing to enable the correct subtraction of kappa 
and lambda results to calculate the CFB and % CFB. 
o
Serum free light chain (SFLC) kappa/lambda ratio. 

Normal. 

Abnormal. 
x
Urine chemistry. 
o
Protein urine (mg/24h). 
x
Serum interpretation (as per central laboratory data). 
o
Monoclonal Ig (A, D, E, G, M) kappa or lambda. 
x
Urine interpretation (as per central laboratory data). 
o
Free light chain kappa or lambda. 
x
Bone marrow aspirate. 
o
Plasma cells (%). 
12.2.1.DERIVATIONS 
Corrected calcium (mmol/L) calculated using the following formula [5] [7]: 
x
Corrected calcium (mmol/L) = Serum calcium (mmol/L) + 0.02 × [40 (g/L) - serum albumin (g/L)]. 
Refer to Section 6.4 Baseline of this SAP for the Baseline and post-baseline definitions for SFLC assays. 
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Page 44 of 99 
12.3. BONE MARROW ASPIRATION AT BASELINE 
Bone marrow aspiration at Baseline as indicated on the Local Lab/Bone Marrow Aspiration eCRF is to 
be presented.  Bone marrow aspiration at Baseline is to be summarized for: 
x
Cytogenetics. 
o
Indeterminate/Inadequate specimen. 
o
None detected. 
o
Abnormal karyotype. 
x
Fluorescence in situ hybridization (FISH). 
o
Indeterminate/Inadequate specimen. 
o
Del17p13. 
o
T(4;14)(p16.3;q32.3). 
o
T(14;16)(q32.3;q23). 
o
+1q21;Amp1q21. 
o
Del(13);13q14.3. 
o
Other/Specification (eCRF). 
x
Baseline disease risk status category (derived) (refer to Section 7.5.5 Baseline Disease Risk Status 
of this SAP). 
o
High. 
o
Standard. 
o
Missing. 
x
Ploidy. 
o
Indeterminate. 
o
Hyperdiploid. 
o
Hypodiploid. 
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13. THERAPIES, MEDICATIONS AND/OR PROCEDURES 
13.1. PRIOR THERAPIES 
Based on protocol Version 6.0, including protocol amendments 01 to 05 [2] a line of prior therapy 
consists of at least one or more cycles of a planned treatment regimen (including single-agent or 
combination therapy or a sequence of treatments administered in a planned manner).  A new line of 
prior therapy starts when a planned course is modified as a result of disease progression, relapse or 
toxicity or when a planned period of observation is interrupted by the need for additional treatment 
of the disease.  As per the eCRF design, radiation therapy forms part of the options for a line of prior 
therapy, although as advised by Oncopeptides AB, radiation therapy is not to be considered as a line 
of prior therapy. 
According to the IMWG Consensus panel 1 on uniform reporting criteria in clinical studies [4] the 
following definitions are relevant to the classification per medication within each line of prior therapy: 
x
Relapsed status: Defined as a patient with a disease response of MR or better to the medication 
within each line of prior therapy and who progressed later than 60 days after the last dose of the 
stop date of the individual medication. 
x
Refractory status: Defined as a patient who has never achieved a disease response of MR or better 
the medication within each line of prior therapy. 
x
Relapsed/Refractory status: Defined as a patient with a disease response of MR or better the 
medication within each line of prior therapy and who progressed while on prior therapy or within 
60 days of the last dose of the stop date of the individual medication. 
In addition to the classification per medication within each line of prior therapy, a patient can also 
have an overall status of relapsed, relapsed/refractory or primary refractory.  The following definitions 
to derive the overall status to the classification of prior therapy are: 
x
Overall relapsed status: Defined as a patient who never progressed while on prior therapy or 
within 60 days of last dose of prior therapy. 
x
Overall primary refractory status: Defined as a patient who never responded to any line of prior 
therapy. 
x
Overall relapsed/refractory status: Defined as a patient who might be refractory to one specific 
line of prior therapy, but responded to other lines of prior therapy. 
The subcategories relapsed, refractory, or relapsed/refractory status to any line of prior therapy, to 
last line of prior therapy as well as overall status are to be derived per individual medication in 
regimen.  Prior therapy derivations (Appendix 2: Assignment of Patients to Disease Status 
[Relapsed/Refractory] to Prior Therapy [EXCEL spreadsheet], of the DR report), are to be authorized by 
Oncopeptides AB at the final DR meeting.  The overall status as indicated by the investigator on the 
History of Multiple Myeloma eCRF is to be compared with the derived overall status (derived by 
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 Biostatistics) to ensure results are comparable, but the derived results are to be 
summarized. 
Prior therapies as indicated on the Prior Therapy eCRF are to be summarized as follows: 
x
Number of lines of prior therapy (including a summary of number of lines of prior therapy 
category). 
o
Total number of lines of prior therapy that a patient received based on the maximum result of 
the raw.PT.PTPRG variable. 
x
Type of prior therapy (transplant category) (refer to Section 7.5.3 Prior Therapies of this SAP). 
x
Best disease response to last line of prior therapy (as indicated by the investigator on the Prior 
Therapy eCRF). 
x
Status of (a.) any line of prior therapy and (b.) last line of prior therapy, regardless of regimen. 
x
Patients with (a.) any line of prior therapy and (b.) last line of prior therapy including regimen 
containing: 
o
Alkylator (Melphalan, cyclophosphamide, bendamustine). 
o
Proteasome inhibitor (PI) (Bortezomib, carfilzomib or ixazomib). 
o
Immunomodulatory drug (IMiD) (Lenalidomide, thalidomide, or pomalidomide). 
o
Monoclonal antibody (Elotuzumab, or daratumumab). 
o
Double refractory, defined as PI and IMiD. 
o
Double refractory and alkylator, defined as PI and IMiD and alkylator. 
The number (n) of patients with (a.) any line of prior therapy including regimen containing at least one 
of the specified medications of interest is to be used as denominator for the calculation of relapsed, 
refractory, and relapsed/refractory status to any line of prior therapy across stratification levels.  
Similarly, the number (n) of patients with (b.) the last line of prior therapy including regimen 
containing at least one of the specified medications of interest is to be used as denominator for the 
calculation of relapsed, refractory, and relapsed/refractory status to last line of prior therapy across 
stratification levels. 
x
The derived subcategories are to be repeated for: 
o
Relapsed, refractory, or relapsed/refractory status to any line of prior therapy to regimen 
containing an alkylator, PI, IMiD, monoclonal antibody, PI and IMiD, PI and IMiD and alkylator. 
o
Relapsed, refractory, or relapsed/refractory status to last line of prior therapy to regimen 
containing an alkylator, PI, IMiD, monoclonal antibody, PI and IMiD, PI and IMiD and alkylator. 
Medications of interest are to be selected based on code.  Prior therapies are to be coded using the 
World Health Organization-Drug Dictionary (WHO-DD)01MAR2017.  Refer to Appendix 2 Partial Date 
Conventions of this SAP for the handling of partial dates for prior therapies.  Instead of handling 
missing disease progression dates as a worst-case scenario through imputation, the prior therapy stop 
date of the line of prior therapy containing a missing disease progression date is to be compared to 
the subsequent line of prior therapy’s start date, to determine if the subsequent line’s start date is 
within 60 days of the line containing the missing disease progression date. 
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Radiation therapy as indicated on the Prior Radiation Therapy eCRF is to be presented in a by-patient 
data listing.  Radiation therapy is not considered a line of prior therapy and is not to be included in the 
prior therapy summaries.  Any line of prior therapy containing radiation therapy mentions amongst 
other individual medications in a regimen is to be modified by 
 Biostatistics by omitting 
the radiation therapy from the line of prior therapy.  These lines of prior therapy are not to form part 
of the number of lines of prior therapy. 
13.2. MEDICATIONS/CONCOMITANT PROCEDURES 
Medications as indicated on the Concomitant Medications eCRF are to be coded using the WHO-
DD01MAR2017.  However, the Anatomical Therapeutic Chemical (ATC) classification system is not 
included in the scope of coding.  Concomitant procedures as indicated on the Concomitant Procedures 
eCRF are not to be coded. 
Refer to Appendix 2 Partial Date Conventions of this SAP, for the handling of partial dates for 
medications and/or concomitant procedures.  Medications and concomitant procedures are to be 
classified by cycle occurrence based on the start date of the medication or concomitant procedure 
(refer to Section 6.3 Cycle Length, Cycle Assignment, and Cycle Completion of this SAP). 
13.2.1.MEDICATIONS 
Medications are to be presented as: 
x
Prior medications (PM): Defined as medications which started and stopped prior to the first dose 
of the study drug (overall reference start date). 
x
Concomitant medications (CM): Defined as medications which are taken on or after the first dose 
of the study drug (overall reference start date) up to and including derived EOT or which are 
ongoing. 
x
Follow-up medications (FM): Defined as medications which are taken after derived EOT or which 
are ongoing. 
Concomitant medications and follow-up medications are not mutually exclusive and a medication can 
therefore be classified as both CM/FM. 
13.2.1.1. HEMATOPOIETIC GROWTH FACTORS AND STANDARDIZED TRANSFUSIONS 
Hematopoietic growth factors as indicated on the Concomitant Medications eCRF and standardized 
transfusions as indicated on the Concomitant Procedures eCRF are to be identified and classified by 
the 
 medical advisor and authorized by Oncopeptides AB at the final DR meeting. 
Patients who have received hematopoietic growth factors and/or standardized transfusions during the 
course of the study are to be summarized and the output is to be repeated for the following by-group 
variable: 
x
Overall. 
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STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
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x
Melflufen dose reduced. 
o
For this by-group variable, the total number of patients in the relevant analysis set (N) presents 
a subset of the number of patients in the Safety Analysis Set, i.e., the number (n) of patients 
with at least one melflufen dose reduction in at least one or more cycles. 
The number (n) of patients treated in each cycle or overall is to be used as denominator for the 
percentage (%) calculation of patients who received hematopoietic growth factors and/or 
standardized transfusions during the course of the study. 
13.2.2.CONCOMITANT PROCEDURES 
Standardized transfusions are to be identified as noted in Section 13.2.1.1 Hematopoietic Growth 
Factors and Standardized Transfusions of this SAP. 
The time (days) from a platelet transfusion to the subsequent melflufen dose is to be derived (refer to 
Section 13.2.3 Derivations of this SAP).  In addition, the number of cycles in which platelet 
transfusions were administered within 1 week of subsequent melflufen dose (refer to Section 13.2.3 
Derivations of this SAP) is to be classified as follows: 
x
< 2 cycles. 
x
ш 2 to ч 3 cycles. 
x
ш 4 cycles. 
o
The number (n) of patients who received at least one platelet transfusion within 1 week of 
subsequent melflufen dose is to be used as denominator for the aforementioned category 
percentage (%) calculation. 
13.2.3.DERIVATIONS 
Time to subsequent melflufen dose (days) is to be derived using the following formula: 
x
Time to subsequent melflufen dose (days) = abs(<Date of platelet transfusion> - <date of 
subsequent melflufen dose>). 
x
Number of cycles in which platelet transfusions were administered within 1 week of subsequent 
melflufen dose 
 
 
Where n represents a patient’s last cycle (i.e., in this case the last Day 1 melflufen dose). 
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14. STUDY DRUG ADMINISTRATION 
Patients are to be treated with melflufen on Day 1 of each cycle.  Patients following a 21-day cycle are 
to be treated with a maximum of 40 mg dexamethasone on Days 1, 8, 15.  Similarly, patients following 
a 28-day cycle are to be treated with a maximum of 40 mg dexamethasone on Days 1, 8, 15, 22 and 
single-agent patients are to be treated with a maximum of 24 mg dexamethasone on Days 1, 2 
(Days 3, 4 are optional for dexamethasone treatment) for anti-emetic purposes as per protocol 
amendment 04.  Single-agent patients switching from protocol amendment 04 (as initially enrolled) to 
protocol amendment 05 may receive the combination regimen of melflufen and 40 mg 
dexamethasone. 
Percentage (%) of patients with action(s) taken with melflufen/dexamethasone and patients with 
reason(s) for modification of melflufen/dexamethasone is to be calculated relative to the total 
number of patients treated in an individual cycle or overall.  Multiple categories for action taken and 
reason(s) for modification are allowed resulting in percentages not necessarily adding up to 100%. 
14.1. MELFLUFEN ADMINISTRATION 
Study drug administration data as indicated on the Melflufen Administration eCRF are to be 
presented. 
The following variables are to be presented in a by-patient data listing: 
x
Visit (containing cycles). 
x
Actual cycle length (days) (refer to Section 6.3 Cycle Length, Cycle Assignment, and Cycle 
Completion of this SAP). 
x
Date of study drug administration. 
x
Infusion data. 
o
Type of device used. 

Implanted port. 

Peripherally inserted central catheter (PICC) line. 

Central venous catheter. 
o
Planned and actual dose per individual cycle. 
o
Infusion preparation start time. 
o
Infusion start time, stop time and duration, and volume infused. 
x
New cycle initiation criteria (refer to Section 3.1 General Description of this SAP) including action 
taken with study drug and reason(s) for dose modification. 
x
Relative dose data. 
x
Administration of anti-emetics. 
The planned melflufen dose per individual cycle for patients enrolled in Phase I comprises 15 mg, 
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25 mg, 40 mg, or 55 mg and for patients enrolled in Phase II the planned melflufen dose per individual 
cycle comprises 40 mg.  The actual dose per individual cycle is to be obtained as indicated on the 
Melflufen Administration eCRF, and is to be used in conjunction with the number of vials used for 
study drug administration.  Vials to be used for melflufen preparation include: 
x
15 mg Melflufen: (1 × 15 mg vial) or (1 × 20 mg vial). 
x
25 mg Melflufen: (1 × 25 mg vial) or (2 × 20 mg vials). 
x
40 mg Melflufen: (1 × 15 mg vial + 1 × 25 mg vial) or (2 × 20 mg vials). 
x
55 mg Melflufen: 2 × 15 mg vials + 1 × 25 mg vial. 
The 30-minute melflufen IV infusions are to be administered within 30 minutes from the start of the 
infusion preparation. 
Relative dose data are to include planned cumulative dose (mg), actual cumulative dose (mg), 
percentage (%) relative dose and relative dose category: 
x
ч 50%. 
x
> 50% to ч 80%. 
x
> 80% to ч 100%. 
x
> 100%. 
Planned cumulative dose (mg) is defined as the planned dose per individual cycle multiplied by the 
total number of melflufen IV infusions received.  Actual cumulative dose (mg) is defined as the sum of 
the actual study drug doses across all cycles.  Refer to Section 14.1.1 Derivations of this SAP. 
Data to be summarized include: 
x
(*)Total number of cycles completed (based on the actual administration data as indicated on the 
Melflufen Administration eCRF).  Refer to Section 6.3 Cycle Length, Cycle Assignment, and Cycle 
Completion of this SAP. 
x
(*)Total number of cycles with at least one melflufen dose reduction.  This is defined as the sum of 
all cycles during which any patient experienced at least one melflufen dose reduction.  Dose 
reduction is based on the action taken with melflufen. 
x
(*)Total number of cycles with at least one melflufen dose interruption.  This is defined as the sum 
of all cycles during which any patient experienced at least one melflufen dose interruption.  Dose 
interruption is based on the action taken with melflufen. 
x
(*)Number (n) of patients treated at least once. 
x
Number (n) of patients treated in cycle. 
x
Patients with action(s) taken with melflufen. 
o
Interrupted. 
o
Reduced. 
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o
Delayed. 
o
Held. 
o
Other. 
o
Permanently discontinued. 
x
Reason(s) for modification of melflufen. 
o
Adverse event (AE). 
o
Other.  As indicated by the investigator on the Melflufen Administration eCRF. 
x
(*)Actual cumulative dose (mg). 
x
(*)Relative dose (%). 
x
(*)Relative dose (%) category. 
x
Actual cycle length (days).  Refer to Section 6.3 Cycle Length, Cycle Assignment, and Cycle 
Completion of this SAP. 
Variables are to be summarized for each individual cycle, but variables marked with an asterisk (*) are 
to be summarized across all cycles only (i.e., Visit = “OVERALL”). 
14.1.1.DERIVATIONS 
x
Melflufen IV infusion duration (min) = <Infusion stop time> - <infusion start time>. 
x
Time from melflufen preparation to infusion (min) = <Infusion start time> - <preparation start 
time>. 
o
The result is to be presented as a binary Yes/No response to the required 30 minutes allowed 
from infusion preparation to administration. 
x
Planned cumulative dose (mg) = (Planned dose × total number of melflufen IV infusions). 
x
Actual cumulative dose (mg) 
x
 
 
Where n represents a patient’s last cycle (i.e., in this case the last Day 1 melflufen dose). 
x
Relative dose (%) = (Actual cumulative dose/planned cumulative dose) × 100. 
14.2. DEXAMETHASONE ADMINISTRATION 
Study drug data as indicated on the Dexamethasone Administration and Dexamethasone 
Administration for Day 1 to Day 4 eCRFs are to be presented. 
The following variables are to be presented in a by-patient data listing: 
x
Visit (containing cycles and cycle days). 
x
Actual cycle length (days) (refer to Section 6.3 Cycle Length, Cycle Assignment, and Cycle 
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Completion of this SAP). 
x
Date of study drug administration. 
x
Study drug route. 
x
Action taken with study drug and reason(s) for dose modification. 
x
Continuation to the subsequent cycle (as indicated on the Study Status and Study Continuation 
eCRFs). 
x
Total number of cycles completed (derived sum). 
x
Actual cumulative dose (mg) per individual cycle and overall 
Actual cumulative dose (mg) per individual cycle is defined as the sum of the actual study drug doses 
per individual cycle.  Overall actual cumulative dose (mg) is defined as the sum of the actual study 
drug doses across all cycles.  Refer to Section 14.2.1 Derivations of this SAP. 
Data to be summarized include: 
x
(*)Total number of cycles completed (based on the actual administration data as indicated on the 
Melflufen Administration eCRF).  Refer to Section 6.3 Cycle Length, Cycle Assignment, and Cycle 
Completion of this SAP. 
x
(*)Total number of cycles with at least one dexamethasone dose reduction.  This is defined as the 
sum of all cycles during which any patient experienced at least one dexamethasone dose 
reduction.  Dose reduction is based on the action taken with dexamethasone. 
x
(*)Total number of cycles with at least one dexamethasone dose held. .  This is defined as the sum 
of all cycles during which any patient experienced at least one dexamethasone dose held.  Dose 
held is based on the action taken with dexamethasone. 
x
(*)Number (n) of patients treated at least once. 
x
Number (n) of patients treated in cycle. 
x
Patients with action(s) taken with dexamethasone. 
o
Reduced. 
o
Delayed. 
o
Held. 
o
Permanently discontinued. 
x
Reason(s) for modification of dexamethasone. 
o
Adverse event (AE). 
o
Other.  As indicated by the investigator on the Dexamethasone Administration and 
Dexamethasone Administration for Day 1 to Day 4 eCRFs. 
x
Actual cumulative dose (mg).  Includes summary across all cycles. 
Variables are to be summarized for each individual cycle, but variables marked with an asterisk (*) are 
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to be summarized across all cycles only (i.e., Visit = “OVERALL”). 
14.2.1.DERIVATIONS 
x
Actual cumulative dose per individual cycle (mg) 
x
 
 
Where x represents an individual cycle and n represents Day 1, 8, and 15 for patients following a 
21-day cycle and Day 1, 8, 15, and 22 for patients following a 28-day cycle. 
x
Overall actual cumulative dose (mg) 
 
 
Where n represents a patient’s last cycle and m represents Day 1, 8, and 15 for patients following a 
21-day cycle and Day 1, 8, 15, and 22 for patients following a 28-day cycle. 
 
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15. EFFICACY OUTCOMES 
The EEmITT Analysis Set is regarded as primary for disease response efficacy endpoints including 
disease response rates, time to disease response and duration of disease response analyses as well as 
disease progression.  The mITT Analysis Set is regarded as primary for PFS, OS and time to first 
subsequent treatment analyses.  Unless otherwise specified, all efficacy outputs are to be summarized 
for each of the subgroups as defined in Section 7.5 Examination of Subgroups of this SAP and all 
figures are to be presented for the EEmITT Analysis Set.  The following list provides a comprehensive 
overview of the primary and secondary endpoints of the study: 
The primary endpoints of the study are to evaluate the following in all evaluable patients: 
x
Best overall disease response on treatment defined as the best overall disease response on 
treatment including progressive disease (PD), stable disease (SD), MR, PR, very good partial 
response (VGPR), complete response (CR), or stringent complete response (sCR). 
x
Objective response (OR) defined as the first occurrence of disease response including PR or better 
(i.e., PR, VGPR, CR, or sCR). 
x
Clinical benefit response (CBR) defined as the first occurrence of disease response including MR or 
better (i.e., MR, PR, VGPR, CR, or sCR). 
x
Objective response rate (ORR). 
x
Clinical benefit response rate (CBRR). 
The secondary endpoints of the study are to evaluate the following in all evaluable patients: 
x
Duration of best overall disease response to treatment (months). 
o
Per disease response hierarchy (including SD or better). 
o
Duration of OR. 
o
Duration of CBR. 
x
Time to disease response on treatment (months). 
o
Time to first OR. 
o
Time to first CBR. 
o
Time to best overall disease response on treatment (only included in a figure and a by-patient 
data listing). 
x
Time to disease progression (months). 
x
Progression-free survival (PFS) (months). 
o
Overall. 
o
Per disease response hierarchy. 
x
Overall survival (OS) (months). 
x
Time to first subsequent treatment (months). 
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15.1. MULTIPLE MYELOMA 
15.1.1.LABORATORY ASSESSMENTS 
Appendix 4 Specific Myeloma Central Laboratory Evaluations of this SAP provides the complete list of 
laboratory assessments obtained from the local and central laboratories.  Quantitative safety 
laboratory assessments are to be compared with the relevant laboratory reference ranges in SI units 
and are to be classified as: 
x
Low (L): Below the lower limit of the laboratory reference range. 
x
Normal: Within the laboratory reference range (upper and lower limit included). 
x
High (H): Above the upper limit of the laboratory reference range. 
The kappa/lambda ratio is to be classified as normal or abnormal based on the laboratory specific 
reference range. 
Patients with a kappa/lambda SFLC ratio below the lower reference range are defined as having 
monoclonal lambda SFLC and patients with a kappa/lambda SFLC ratio above the upper reference 
range are defined as having a monoclonal kappa SFLC.  If the SFLC ratio is above the upper reference 
range, kappa is considered to be the “involved” SFLC and lambda the “uninvolved” SFLC, and vice 
versa if the ratio is below the lower reference range.  Involved SFLC assay results are to be flagged in 
the by-patient data listing to enable the correct subtraction of kappa and lambda results to calculate 
the CFB.  Refer to Section 6.4 Baseline of this SAP for the Baseline and post-baseline definitions for 
SFLC assays. 
The following figures are to be presented: 
x
The best serum or 24-hour urine M-protein or SFLC % CFB.  The waterfall plot is to present the best 
% CFB for each patient, sorted by descending % CFB. 
x
Serum and urine M-protein and involved SFLC results are to be presented over time for individual 
patients.  For the by-patient figure, the involved SFLC (kappa or lambda [mg/L]) results are to be 
converted to g/L to plot the involved SFLC assay together with the serum M-protein results on the 
same axis.  The kappa/lambda ratio is not to be included in the figure presentation. 
15.1.2.RESPONSE ASSESSMENT 
The investigator is to assess disease response at every cycle starting on completion of Cycle 2 in 
accordance with the IMWG response criteria (refer to Appendix 6 Disease Response Criteria of this 
SAP).  An assessment of a patient’s disease response to study drug is based on the multiple myeloma 
laboratory assessments together with the investigator’s clinical expertise and the confirmation of two 
consecutive disease response assessments can therefore not be performed on a data analysis level. 
 Biostatistics is to derive a by-cycle disease response assessment based on the laboratory 
data to evaluate derived outcome in comparison to the investigator’s by-cycle disease response 
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assessments as indicated on the Disease Response Assessment eCRF.  In addition, 
 
Biostatistics is to derive a best overall disease response on treatment based on derived by-cycle 
disease response assessments to evaluate derived outcome in comparison to the investigator’s 
assessment as indicated on the EOT eCRF.  However, despite any potential differences, analysis of 
disease response assessments is to be based on the investigator’s by-cycle assessments or EOT 
assessment, as specified.  The disease response hierarchy from best to worst includes sCR, CR, VGPR, 
PR, MR, SD, and PD. 
15.1.3.DATA CONVENTIONS 
15.1.3.1. CENTRAL/LOCAL LABORATORY DATA 
For the current study laboratory results related to disease response evaluations of multiple myeloma 
are obtained from both local and central laboratories.  From a scientific standpoint it is preferable to 
have only one source of laboratory assessments.  The database is to contain both sets of results such 
that local and central laboratory assessments are to be used interchangeably for analysis purposes [6]. 
However, preference is to be given to central laboratory assessments when available, otherwise local 
laboratory assessments are to be used.  In the by-patient data listings the assessment identifier of the 
data (i.e., eCRF, central laboratory data or local laboratory data) is to be presented. 
15.1.3.2. ANALYZABLE RESULT 
Based on the current data, entries exist such that some patients have multiple results for M-protein 
assessments at one or more visit(s).  The sum of the measurable results is to be used as analyzable 
result when multiple assessments of the same test are available at the same visit. 
15.1.3.1. EVALUABLE DISEASE RESPONSE ASSESSMENT 
Disease response assessments recorded prior to the initiation of subsequent treatment are to be 
defined as evaluable disease response assessments for efficacy outputs.  This is to ensure exclusion of 
disease response assessments subject to subsequent treatment administration. 
15.1.3.2. BEST SERUM OR 24-HOUR URINE MONOCLONAL-PROTEIN (M-PROTEIN) OR SERUM FREE LIGHT 
CHAIN (SFLC) % CHANGE FROM BASELINE (CFB) 
The best % CFB is defined as the CFB to the minimum (lowest) analyzable serum or 24-hour urine 
M-protein or SFLC result post-baseline up to and including derived EOT (LOCF assessment). 
For patients with measurable serum M-protein at Baseline, it is the best % CFB based on analyzable 
post-baseline serum M-protein results up to and including derived EOT.  For patients with 
non-measurable serum M-protein, but measurable 24-hour urine M-protein, it is the best % CFB based 
on analyzable post-baseline 24-hour urine M-protein results up to and including derived EOT.  For 
patients with non-measurable serum M-protein and non-measurable 24-hour urine M-protein, it is 
the best % CFB based on analyzable post-baseline SFLC results up to and including derived EOT.  The 
best SFLC % CFB is to be based on the minimum (lowest) involved kappa/lambda analyzable result 
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post-baseline, where both kappa and lambda are obtained from the same identified post-baseline 
SFLC assessment. 
The CFB and % CFB are to be presented for all test results available per the analyzable flags in the 
listing and the best % CFB (CFB to minimum [lowest] analyzable result post-baseline based on serum 
or 24-hour urine M-protein or SFLC results up to and including derived EOT [LOCF assessment]) is to 
be flagged to facilitate identification of the same result in the corresponding figure. 
Refer to Section 6.1 Reference Start Dates, Reference Stop Dates and Reference Days of this SAP for 
Baseline and post-baseline SFLC assessment. 
15.2. PRIMARY EFFICACY 
The primary objectives described in the SAP are more comprehensive than those described in protocol 
Version 6.0, including protocol amendments 01 to 05 [2] and in view of the protocol specified Phase II 
objectives, the following efficacy endpoints are: 
x
Best overall disease response on treatment defined as the best overall disease response on 
treatment including PD, SD, MR, PR, VGPR, CR, or sCR. 
x
Objective response (OR) defined as the first occurrence of disease response including PR or better 
(i.e., PR, VGPR, CR, or sCR). 
x
Clinical benefit response (CBR) defined as the first occurrence of disease response including MR or 
better (i.e., MR, PR, VGPR, CR, or sCR). 
x
Objective response rate (ORR). 
x
Clinical benefit response rate (CBRR). 
The aforementioned is to be evaluated in the combination regimen and the single-agent dose cohorts.  
Following the approval of protocol Version 6.0, ongoing patients in the single-agent cohort may have 
weekly dexamethasone doses added at the discretion of the investigator.  The addition of the weekly 
dexamethasone can influence the effect of study drug, but with the “Total” column in the SAP output 
shells, all cycles from the single-agent patients are to be included for analysis purposes. 
15.2.1.MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLES 
Missing primary efficacy variables are not to be imputed.  The EEmITT Analysis Set is to be used as 
primary for the efficacy endpoints.  Per definition the EEmITT Analysis Set is not to include patients 
with no Baseline efficacy assessment (measurable disease assessment) and no post-baseline efficacy 
assessment (disease response assessment), following completion of at least two full cycles of study 
drug. 
15.2.2.ANALYSIS OF PRIMARY EFFICACY VARIABLES 
The best overall disease response on treatment based on the investigator’s assessment as indicated 
on the End of Treatment eCRF is to be summarized per the individual disease responses within the 
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hierarchy as well as for the following disease response combinations: 
x
Stringent complete response (sCR) + CR. 
x
Stringent complete response (sCR) + CR + VGPR. 
x
Objective response rate (ORR): sCR + CR + VGPR + PR. 
x
Clinical benefit response rate (CBRR): sCR + CR + VGPR + PR + MR. 
The primary objective of Phase II is to test the null hypothesis (H0) that the ORR of melflufen and 
dexamethasone combination is below the specified response rate: 
x
H0: ORR < 15%. 
The alternative hypothesis (HA) is that the ORR of melflufen and dexamethasone combination is equal 
to or greater than the specified response rate: 
x
HA: ORR ш 15%. 
The ORR is considered to be the more conservative endpoint when assessing ORR and CBR given that 
ORR is obtained based on the first occurrence of PR or better.  The outcome of disease response 
assessments are related to the binomial distribution, because a patient either experiences a given 
response or not.  The Clopper-Pearson method is to be used to calculate a 95% confidence interval (CI) 
for the binomial proportion.  The following SAS® code is to be used: 
proc freq data=dd; 
 
by treatment; 
 
tables response / nocum norow binomial alpha=0.05; 
 
exact binomial; 
run; 
Notes: 
x
The treatment variable refers to the relevant dose cohorts. 
x
The FREQUENCY procedure computes the CI for the lowest level of the response variable, unless 
specified otherwise. 
An ORR ш 15% may indicate that melflufen in combination with dexamethasone is considered 
promising for the treatment of multiple myeloma.  Similarly, an ORR ш 15% for melflufen as 
single-agent at the MTD may indicate that melflufen is considered to have single activity for the 
treatment of multiple myeloma. 
The following figure is to be presented: 
x
Swimlane plot of disease response (PR or better) based on the investigator’s by-cycle assessments 
as indicated on the Disease Response Assessment eCRF is to be presented in a swimmers plot. 
x
Swimlane plot of disease response (SD or MR) based on the investigator’s by-cycle assessments as 
indicated on the Disease Response Assessment eCRF is to be presented in a swimmers plot. 
 
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In the disease response assessment by-patient data listing the following are to be presented: 
x
First dose of study drug (overall reference start date). 
x
Visit (containing cycles and cycle days). 
x
Date and method of the disease response assessment. 
x
Investigator’s by-cycle disease response assessment. 
x
Best overall disease response assessment on treatment. 
x
First occurrence of an OR, CBR or PD. 
15.2.3.SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLES 
The PP Analysis Set is characterized by specific criteria and it defines a subset of patients in the EEmITT 
Analysis Set who are more compliant with the protocol and who represent the scientific model.  
Within the context of the CSR transparency with regards to these factors is important and this aids in 
producing the relevant table summaries to address the ICH requirements.  If the EEmITT Analysis Set 
and the PP Analysis Set therefore differ by more than 10% (i.e., 5 patients) then the output is to be 
repeated for the PP Analysis Set to confirm the results obtained from the EEmITT Analysis Set.  This 
applies to all efficacy output with the exception of OS, time to first subsequent treatment, and shift 
presentations of X-ray and imaging assessments and plasmacytoma evaluations. 
If the mITT Analysis Set and the EEmITT Analysis Set differ by more than 10% (i.e., 5 patients) then the 
PFS output is to be repeated for the EEmITT Analysis Set to confirm the results obtained from the mITT 
Analysis Set. 
15.3. SECONDARY EFFICACY 
The secondary objectives of the study are expanded to include: 
x
Duration of best overall disease response to treatment (months). 
o
Per disease response hierarchy (including SD or better). 
o
Duration of OR. 
o
Duration of CBR. 
x
Time to disease response on treatment (months). 
o
Time to first OR. 
o
Time to first CBR. 
x
Time to disease progression (months). 
x
Progression-free survival (PFS) (months). 
o
Overall. 
o
Per disease response hierarchy. 
x
Overall survival (OS) (months). 
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x
Time to first subsequent treatment. 
15.3.1.SECONDARY EFFICACY VARIABLES AND DERIVATIONS 
Survival analysis (duration of time until the occurrence of a specified event) estimates the underlying 
distribution of the survival time variable and assesses the dependence of the survival time variable on 
the independent variables.  Analysis of survival data must take censoring into account and correctly 
use both the censored observations and the uncensored observations.  The overall reference start 
date is referenced as the date of first dose of study drug in the time to event calculations. 
The LIFETEST procedure in SAS® is a nonparametric procedure for analyzing survival data to compute 
the Kaplan-Meier curve, which is a nonparametric maximum likelihood estimate of the survival 
function.  From the Kaplan-Meier statistics the following are to be presented based on the relevant 
time to specified event: 
x
25th percentile. 
x
Median (including 95% CI). 
x
75th percentile. 
This is calculated using the following SAS® code: 
proc lifetest data=dd outsurv=dd1 method=KM alpha=0.05 alphaqt=0.05 conftype=linear 
plots=(survival(strata=individual)); 
 
 
time <survival time> * <censoring indicator>; 
 
 
by treatment; 
run; 
With the following indicators for the censoring of patients: 
x
1 = Patients that have an event. 
x
0 = Patients that do not have an event, i.e., censored patients. 
Note: 
x
The treatment variable refers to the relevant dose cohorts. 
15.3.1.1. DURATION OF BEST OVERALL DISEASE RESPONSE TO TREATMENT 
Duration of best overall disease response to treatment (months) is to be summarized per disease 
response hierarchy (including SD or better).  Duration of best overall disease response to treatment 
(months) is defined as the time from the date of the first occurrence of the best overall disease 
response on treatment to the date of the first occurrence of evaluable PD or death.  For patients who 
do not experience evaluable PD or death the date of the last evaluable disease response assessment 
(i.e., SD or better) is to be used (censored). 
Duration of best overall disease response to treatment (months) per disease response hierarchy: 
x
Patients with an event: Formula = (<date of first occurrence of evaluable PD or death> - <date of 
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first occurrence of best overall disease response to treatment>)/365.25 × 12. 
x
Patients with no event: Censored formula = (<date of the last evaluable disease response 
assessment (i.e., SD or better)> - <date of first occurrence of best overall disease response on 
treatment>)/365.25 × 12. 
Duration of OR (months): 
x
Patients with an event: Formula = (<date of first occurrence of evaluable PD or death> - <date of 
first occurrence of PR or better>)/365.25 × 12. 
x
Patients with no event: Censored formula = (<date of the last evaluable disease response 
assessment (i.e., SD or better)> - <date of first occurrence of PR or better>)/365.25 × 12. 
Duration of CBR (months): 
x
Patients with an event: Formula = (<date of first occurrence of evaluable PD or death>) - <date of 
first occurrence of MR or better>)/365.25 × 12. 
x
Patients with no event: Censored formula = (<date of the last evaluable disease response 
assessment (i.e., SD or better)>) - <date of first occurrence of MR or better>)/365.25 × 12. 
15.3.1.2. TIME TO DISEASE RESPONSE ON TREATMENT 
Time to first OR (months) is defined as the time from the date of the first dose of study drug (overall 
reference start date) to the date of the first occurrence of PR or better.  For patients who do not 
experience an OR the date of the last available disease response assessment (i.e., MR or SD or PD) on 
treatment is to be used (censored). 
Time to first CBR (months) is defined as the time from the date of the first dose of study drug (overall 
reference start date) to the date of the first occurrence of MR or better.  For patients who do not 
experience a CBR the date of the last available disease response assessment (i.e., SD or PD) on 
treatment is to be used (censored). 
Time to first OR (months): 
x
Patients with an event: Formula = (<date of first occurrence of PR or better> - <date of first dose of 
study drug>)/365.25 × 12. 
x
Patients with no event: Censored formula = (<date of the last available disease response 
assessment (i.e., MR or SD or PD) on treatment > - <date of first dose of study drug>)/365.25 × 12. 
Time to first CBR (months): 
x
Patients with an event: Formula = (<date of first occurrence of MR or better> - <date of first dose 
of study drug>)/365.25 × 12. 
x
Patients with no event: Censored formula = (<date of the last available disease response 
assessment (i.e., SD or PD) on treatment> - <date of first dose of study drug>)/365.25 × 12. 
The following figures (Kaplan-Meier plots) are to be presented for the EEmITT Analysis Set: 
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x
Time to first OR. 
x
Time to first CBR. 
x
Time to best overall disease response on treatment. 
15.3.1.3. TIME TO DISEASE PROGRESSION 
Time to disease progression (months) is defined as the time from the date of the first dose of study 
drug (overall reference start date) to the date of the first occurrence of evaluable PD.  For patients 
who do not experience evaluable PD the date of the last evaluable disease response assessment (i.e., 
SD or better) is to be used (censored). 
Time to disease progression (months): 
x
Patients with an event: Formula = (<date of first occurrence of evaluable PD> - <date of first dose 
of study drug>)/365.25 × 12. 
x
Patients with no event: Censored formula = (<date of the last evaluable disease response 
assessment (i.e., SD or better)> - <date of first dose of study drug>)/365.25 × 12. 
The time to disease progression is to be presented in a figure (Kaplan-Meier plot).  The following 
variables are to be presented in the by-patient data listing: 
x
Date of first dose of study drug (overall reference start date). 
x
Date of disease progression. 
x
Date of death. 
x
Date of last evaluable disease response (SD or better). 
x
Time to disease progression (months) and PFS (months). 
15.3.1.4. PROGRESSION-FREE SURVIVAL (PFS) 
Progression-free survival (PFS) (months) is defined as the time from the date of the first dose of study 
drug (overall reference start date) to the date of the first occurrence of evaluable PD or death.  For 
patients who do not experience evaluable PD or death, but who started non-protocol anticancer 
treatment before documentation of PD or death, who are lost to follow-up or who are alive without 
documentation of PD or death at the date of last contact, the date of the last evaluable disease 
response assessment (i.e., SD or better) is to be used (censored). 
Progression-free survival (PFS) (months): 
x
Patients with an event: Formula = (day(<date of first occurrence of evaluable PD or death> - <date 
of first dose of study drug>)/365.25 × 12. 
x
Patients with no event: Censored formula = (<date of the last evaluable disease response 
assessment (i.e., SD or better)> - <date of first dose of study drug>)/365.25 × 12. 
Progression-free survival (PFS) is to be presented in a figure (Kaplan-Meier plot) for the mITT Analysis 
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Set.  Summarized PFS output and the PFS figure are to be repeated per disease response hierarchy. 
15.3.1.5. OVERALL SURVIVAL (OS) 
Overall survival (OS) data is to be presented as indicated on the Survival Follow Up eCRF.  Overall 
survival (OS) (months) is defined as the time from the date of the first dose of study drug (overall 
reference start date) to death.  For patients who do not experience death the last date that a patient 
is known to be alive or the date of last contact (whichever is latest) is to be used (censored). 
Overall survival (OS) (months): 
x
Patients with an event: Formula = (<date of death> - <date of first dose of study drug>)/365.25 × 
12. 
x
Patients with no event: Censored formula = (<maximum of date last known to be alive and date of 
last contact> - <date of first dose of study drug>)/365.25 × 12. 
Overall survival (OS) is to be presented in a figure (Kaplan-Meier plot) for the mITT Analysis Set.  The 
following variables are to be presented in the by-patient data listing: 
x
Date of first dose of study drug (overall reference start date). 
x
Date and method of contact. 
x
Date of death (including primary reason for death and autopsy information). 
x
Date of last contact. 
x
Anti-cancer status (including type of, start date of and time to subsequent treatment). 
x
Secondary malignancy (including type and date). 
x
Date last known to be alive. 
x
Overall survival (OS) (months). 
15.3.1.6. TIME TO FIRST SUBSEQUENT TREATMENT 
The use of subsequent treatments are indicated on the Survival Follow Up eCRF.  Presentation of time 
to first subsequent treatment is not to be repeated for any subgroups.  Time to first subsequent 
treatment (months) start is defined as the time from the date of the derived EOT to the date of the 
first subsequent treatment.  For patients who are not receiving subsequent treatment the date of last 
contact is to be used (censored). 
Time to first subsequent treatment (months): 
x
Patients with an event: Formula = (<date of first subsequent treatment> - <date of derived 
EOT>)/365.25 × 12. 
x
Patients with no event: Censored formula = (<date of last contact> - <date of derived 
EOT>)/365.25 × 12. 
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15.4. EXPLORATORY EFFICACY 
Not applicable. 
15.5. OTHER EFFICACY ASSESSMENTS 
Presentation of OS, time to first subsequent treatment, and shift presentations of X-ray and imaging 
assessments and plasmacytoma evaluations are not to be repeated for any subgroups. 
15.5.1.X-RAY AND IMAGING ASSESSMENTS 
X-ray and imaging assessments as indicated on the Chest X-ray, Imaging Assessment, Screening and 
Imaging Assessment eCRFs are to be presented in a by-patient data listing for the SAF Analysis Set.  
The following variables are to be presented: 
x
Visit (containing cycles and cycle days). 
x
Date and category of the imaging assessment. 
x
Presence of lytic bone lesions or plasmacytomas. 
x
Anatomical site. 
x
Procedure type. 
x
Result as indicated by the investigator on the Chest X-ray, Imaging Assessment, Screening and 
Imaging Assessment eCRFs: 
o
Normal. 
o
Abnormal, not clinically significant (ANCS). 
o
Abnormal, clinically significant (ACS). 
x
Reason for assessment and change since previous assessment are to be presented. 
Imaging assessments are classified as: 
x
Chest X-ray. 
o
Chest radiography. 
x
Imaging. 
o
Skeletal survey. 
o
Computerized axial tomography (CAT or CT)/positron emission tomography (PET) scan. 
o
Other imaging procedure. 
Chest X-rays are scheduled to be performed at Screening and EOT.  Only selected variables (visit, date 
of assessment, category/assessment, and result/specification) as indicated on the Chest X-ray eCRF 
are to be presented for the chest X-ray category amongst other imaging variables. 
A shift table is to summarize the data based on the Baseline and derived EOT result for the mITT 
Analysis Set.  The results are to be presented as judged by the investigator as follows: 
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x
Normal. 
x
Abnormal, not clinically significant (ANCS). 
x
Abnormal, clinically significant (ACS). 
For summary purposes, the imaging procedure type (e.g., bone scan, magnetic resonance imaging 
[MRI], skeletal survey etc.) is to be the same for Baseline and derived EOT.  Percentage (%) of patients 
in each category is to be calculated relative to the total number of patients in the relevant analysis set, 
with assessments available at Baseline and the relevant post-baseline assessment. 
15.5.2.PLASMACYTOMA EVALUATION 
Plasmacytoma evaluation as indicated on the Plasmacytoma Evaluation Screening and Plasmacytoma 
Measurement eCRFs is to be presented in a by-patient data listing.  The following variables are to be 
presented: 
x
Visit (containing cycles and cycle days). 
x
Date of assessment. 
x
Plasmacytoma number and category. 
x
Anatomical site. 
x
Procedure. 
x
Lesion measurement and result. 
x
Change since the previous assessment. 
Plasmacytomas are classified as: 
x
Soft tissue. 
x
Lytic bone. 
x
Other. 
Soft tissue and lytic bone plasmacytomas are to be included in the presentation of total plasmacytoma 
size, but other plasmacytoma site codes are only to be presented in the by-patient data listing. 
Soft tissue plasmacytomas total size is to include liver (visceral), lung (visceral), node or soft tissue all 
plasmacytomas as indicated on the Plasmacytoma Evaluation Screening and Plasmacytoma 
Measurement eCRFs.  Lytic bone plasmacytomas total size is to include lytic bone plasmacytomas as 
indicated on the Plasmacytoma Evaluation Screening and Plasmacytoma Measurement eCRFs. 
A total plasmacytoma size is to be calculated by adding the lesion measurements (mm2) within the 
plasmacytoma categories (i.e., soft tissue or lytic bone). 
A by-visit presentation (at Baseline and derived EOT) for the mITT Analysis Set is to summarize the 
observed and CFB results in derived total plasmacytomas size by plasmacytoma category. 
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15.5.2.1. DERIVATIONS 
x
Plasmacytoma total size = 
 
Where n represents the total number of plasmacytomas reported for a patient within the 
plasmacytoma categories (i.e., soft tissue or lytic bone). 
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16. SAFETY OUTCOMES 
The Safety Analysis Set is to be regarded as primary for the safety analyses. 
16.1. ADVERSE EVENTS (AES) 
Adverse events (AEs) are to be presented as indicated on the Adverse Events/Serious Adverse Events 
eCRF.  Progression of malignancy is not to be reported as an AE. 
For the purpose of the analysis, AEs are to be assigned to a cycle as detailed in Section 6.3 Cycle 
Length, Cycle Assignment, and Cycle Completion of this SAP.  Refer to Appendix 2 Partial Date 
Conventions of this SAP for the handling of partial dates for AEs. 
Analysis flags are to be derived to indicate if the AE is a DLT AE (D), a prior AE (P), a TEAE (T) or a 
follow-up AE (FU) based on the following definitions: 
x
Dose-limiting toxicity AEs (D): As indicated on the Adverse Events/Serious Adverse Events eCRF 
and is only to be assessed for Phase I patients. 
x
Prior AEs (P): Defined as AEs that started before the first dose of study drug (overall reference start 
date). 
x
Treatment-emergent AEs (T): Defined as AEs that started or worsened on or after the first dose of 
study drug (overall reference start date) up to and including the derived EOT date. 
x
Follow-up AEs (FU): Defined as AEs that started or worsened after the derived EOT date. 
Adverse events (AEs) are to be coded using the MedDRA central coding dictionary, Version 20.0. 
Incidence of TEAEs are to be presented by SOC and PT.  Uncoded AEs (i.e., AEs with no dictionary 
coding information available) are only to be presented if applicable using the investigator’s Verbatim 
Term (eCRF) as PT within the text “UNCODED” as SOC.  System Organ Classes (SOCs) are to be sorted 
by total decreasing frequency.  Preferred Terms (PTs) are to be sorted by total decreasing frequency 
within each SOC.  If SOCs or PTs have the same total frequency they are to be sorted alphabetically. 
For presentation and derivation purposes, the following statistics are defined: 
x
n: Defined as the number of patients with at least one TEAE in each category.  Patients with 
multiple TEAEs in each category are counted only once in each category. 
x
m: Defined as the number of mentions (events) in each category, i.e., the actual unique number of 
events. 
x
N: Defined as the total number of patients in the relevant analysis set. 
x
%: Defined as the percentage of patients with at least one TEAE in each category calculated 
relative to the total number of patients in the relevant analysis set. 
By-patient data listings are to include all AEs (i.e., TEAEs and non-TEAEs [AEs that did not start within 
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the defined treatment period of evaluation]) for the All Patients Screened Analysis set.  However, for 
the by-patient data listing of AEs leading to discontinuation of study drug (melflufen or 
dexamethasone or both) the output is to be limited to the SAF Analysis Set. 
16.1.1.SEVERITY 
The severity of AEs is to be described using the Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.03. Treatment-emergent AEs (TEAEs) starting after the first dose of study drug 
(overall reference start date) with a missing severity are to be analyzed as a missing category. For AEs 
not adequately addressed in the CTCAE, Table 3: Toxicity Scale is to be used for grading the severity. 
7DEOH7R[LFLW\6FDOH
Severity 
Description 
Grade I - Mild 
Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
Grade II - 
Moderate 
Mild to moderate limitation in activity - some assistance may be needed; no or 
minimal medical intervention/therapy required 
Grade III - 
Severe 
Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 
Grade IV - Life-
threatening 
Extreme limitation in activity, significant assistance required; life-threatening 
(immediate risk of death); significant medical intervention/therapy required, 
hospitalization or hospice care probable 
Grade V - Fatal 
Death 
16.1.2.RELATIONSHIP 
The relationship to study drug, as indicated by the investigator, is classified as: 
x
Not related. 
x
Possibly related. 
x
Definitely related. 
A related TEAE is defined as a TEAE for which relationship to melflufen is indicated as possibly related 
or definitely related.  TEAEs starting after the first dose of study drug (overall reference start date) 
with a missing relationship are to be analyzed as a missing category. 
In addition the following relationships will also be summarized and defined as follows: 
x
A TEAE related to dexamethasone is defined as a TEAE for which the relationship to 
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dexamethasone is indicated as possible related or definitely related. 
x
A TEAE related to melflufen and/or dexamethasone is defined as a TEAE for which the 
relationship to melflufen is indicated as possible related or definitely related and/or 
relationship to dexamethasone is indicated as possible related or definitely related. 
16.1.3.ACTION TAKEN WITH STUDY DRUG 
The action taken with study drug, as indicated by the investigator, is classified as: 
x
Dose interrupted. 
x
Dose reduced. 
x
Dose delayed. 
x
Dose held. 
x
Other. 
Action taken classified as drug permanently discontinued (melflufen) or dose permanently 
discontinued (dexamethasone) is to be used to identify and select all AEs leading to discontinuation of 
study drug. 
A summary of treatment-related TEAEs by action taken with melflufen as well as action taken with 
dexamethasone is also to be presented with a by-group specification indicating the cycle occurrence 
(refer to Section 6.3 Cycle Length, Cycle Assignment, and Cycle Completion of this SAP). 
16.1.4.ADVERSE EVENTS (AES) LEADING TO DEATH 
Adverse events (AEs) leading to death are selected as all AEs with an outcome recorded as “Fatal”. 
16.1.5.SERIOUS ADVERSE EVENTS (AES) 
Serious AEs are events judged as “Serious” by the investigator.  Serious criteria include the following 
events: 
x
Death. 
o
Date of death. 
o
Primary cause of death. 
o
Date of autopsy (if performed). 
o
Death certificate (if available). 
x
Life-threatening. 
x
Hospitalization or prolongation of existing hospitalization. 
o
Date of admission. 
o
Date of discharge. 
Duration of hospitalization is to be calculated as follows: 
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o
Hospitalization duration (days) = (<Date of hospital discharge> – <date of hospital admission>) + 
1.  Only if date of hospital discharge is not missing (i.e., ongoing). 
x
Persistent or significant disability/incapacity. 
x
Congenital abnormality/birth defect. 
x
Medically significant. 
x
Other/Specification (eCRF). 
16.1.6.ADVERSE EVENTS (AES) LEADING TO DISCONTINUATION OF STUDY DRUG 
Adverse events (AEs) leading to permanent discontinuation of study drug are to be identified and 
selected based on the action taken with melflufen being drug permanently discontinued and/or the 
action taken with dexamethasone being dose permanently discontinued.  The incidence of TEAEs 
leading to discontinuation of study drug is to be presented by: 
x
Melflufen (IV). 
x
Dexamethasone. 
x
Melflufen (IV) and Dexamethasone, i.e., patient discontinued both study drugs. 
16.1.7.ADVERSE EVENTS (AES) LEADING TO DISCONTINUATION OF STUDY 
Adverse events (AEs) leading to discontinuation of study are to be identified based on the response to 
the question “Did the AE cause the subject to discontinue from the study?” 
16.1.8.ADVERSE EVENTS (AES) MEETING DOSE-LIMITING TOXICITY (DLT) CRITERIA 
Adverse events (AEs) meeting DLT criteria are only to be assessed for Phase I patients during Cycle 1.  
Dose-limiting toxicity AEs are to be identified and selected based on the response to the question “Is 
this adverse event a DLT?” 
16.1.9.ALL TREATMENT-EMERGENT AES (TEAES) 
Based on the aforementioned definitions, three overview summaries are to be provided including 
TEAEs, treatment-related (melflufen) TEAEs and TEAEs of special interest.  The following are to be 
presented for the overview summaries: 
x
Any TEAE. 
x
Treatment-emergent AEs leading to death. 
x
Serious TEAEs. 
x
Treatment-emergent AEs leading to discontinuation of melflufen and/or dexamethasone. 
x
Treatment-emergent AEs leading to discontinuation of study. 
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x
Treatment-emergent AEs leading to dose reduction of melflufen and/or dexamethasone. 
x
Dose-limiting toxicity TEAEs. 
x
Treatment-emergent AEs by relationship to melflufen. 
x
Grade ш III treatment-emergent AEs by relationship to melflufen. 
x
Serious treatment-emergent AEs by relationship to melflufen. 
x
Treatment-emergent AEs by relationship to dexamethasone. 
x
Grade ш III treatment-emergent AEs by relationship to dexamethasone. 
x
Serious treatment-emergent AEs by relationship to dexamethasone. 
x
Treatment-emergent AEs by relationship to melflufen and/or dexamethasone. 
x
Grade ш III treatment-emergent AEs by relationship to melflufen and/or dexamethasone. 
x
Serious treatment-emergent AEs by relationship to melflufen and/or dexamethasone. 
x
Treatment-emergent AEs by severity. 
x
Treatment-emergent AEs by worst severity. 
x
Treatment-emergent AEs of special interest.  Refer to Section 16.2 Adverse Events (AEs) of Special 
Interest of this SAP. 
x
Treatment-emergent AEs by action taken. 
x
Treatment-emergent AEs leading to action taken with melflufen. 
x
Treatment-emergent AEs leading to action taken with dexamethasone. 
16.1.10.
TIME TO ONSET OF TREATMENT-EMERGENT AES (TEAES) 
The median time to onset (including 25th and 75th percentiles) of Grade III (severe) and/or Grade IV 
(life-threatening) neutropenia and thrombocytopenia TEAEs is to be calculated using the Kaplan-Meier 
statistics.  Similar code as described in Section 15.3.1 Secondary Efficacy Variables and Derivations of 
this SAP is to be applied.  Patients with no Grade III or Grade IV neutropenia and thrombocytopenia 
TEAEs are to be censored at the time of the derived EOT date.  
16.1.11.
DERIVATIONS 
Time to onset of Grade III (severe) and/or Grade IV (life-threatening) TEAEs (per patient per event) is 
to be calculated using the following formula: 
x
Time to onset of Grade III or Grade IV TEAEs (months) [per event] = (<date of first Grade III or 
Grade IV TEAE [per event]> - <date of first dose of study drug>)/365.25 × 12. 
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o
Only to be presented for the SAF Analysis Set.  The overall reference start date is referenced as 
the date of first dose of study drug in the time to onset calculation for Grade III or Grade IV 
TEAEs up to and including the derived EOT date. 
16.2. ADVERSE EVENTS (AES) OF SPECIAL INTEREST 
Adverse events (AEs) of special interest include neutropenia and thrombocytopenia events based 
respectively on PT Code [10029354] and [10043554] and are to be presented for the All Patients 
Screened Analysis Set in the by-patient data listing. 
In addition to the incidence of TEAEs of special interest an overview of TEAEs of special interest in 
combination with neutrophil and platelet laboratory data as well as hematopoietic growth factor and 
standardized transfusion administration is to be presented.  With reference to Section 6.3 Cycle 
Length, Cycle Assignment, and Cycle Completion of this SAP, the combined presentation by cycle 
occurrence is to include: 
x
The number (n) of patients treated in a cycle. 
x
The number (n) of patients with at least one TEAE/Neutropenia. 
o
Grade 1 to Grade 4 (based on worst grade per cycle). 

Including the number of mentions in each category (events). 
o
Duration (days) per grade. 

Based on the actual number of mentions per grade. 
x
The number (n) of patients with at least one TEAE/Thrombocytopenia. 
o
Grade 1 to Grade 4 (based on worst grade per cycle). 

Including the number of mentions in each category (events). 
o
Duration (days) per grade. 

Based on the actual number of mentions per grade. 
x
The number (n) of patients with at least one laboratory/hematology assessment: 
o
Neutrophils abs (decreased). 

Common Terminology Criteria for Adverse Events (CTCAE) Grade 0 to Grade 4, and 
ш Grade 3. 
o
Platelets abs (decreased). 

Common Terminology Criteria for Adverse Events (CTCAE) Grade 0 to Grade 4, and 
ш Grade 3. 
o
The number (n) of patients with at least one hematopoietic growth factor. 

Filgrastim. 

Neupogen. 

… 
o
The number (n) of patients with at least one standardized transfusion type. 

Platelet transfusion. 

Red blood cell transfusion. 
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… 
Percentage (%) calculations are as follows: 
x
For the number (n) of patients with at least one TEAE, percentage (%) is to be calculated relative to 
the total number of patients treated per individual cycle. 
x
For the number (n) of patients with at least one laboratory/hematology assessment, percentage 
(%) is to be calculated relative to the total number of patients treated per individual cycle with at 
least one assessment following study drug administration on Cycle x Day 1. 
x
For the number (n) of patients with at least one hematopoietic growth factor or standardized 
transfusion, percentage (%) is to be calculated relative to the total number of patients treated per 
individual cycle with at least one administration following melflufen administration on Cycle x 
Day 1. 
Patients with a normal result (i.e., a result not complying with the CTCAE grade for the 
laboratory/hematology assessments) are to be assigned a Grade 0 severity.  The summarized output is 
to be repeated for the following by-group variable: 
x
Overall. 
x
Melflufen dose reduced. 
x
Melflufen dose reduction. 
o
For this by-group variable, the total number of patients in the relevant analysis set (N) is to 
present a subset of the number of patients in the Safety Analysis Set, i.e., the number of 
patients with at least one melflufen dose reduction across all cycles.  Dose reduction is based on 
the action taken with melflufen. 
x
Melflufen dose interrupted. 
o
Similarly this by-group variable is to present a subset of the number of patients in the Safety 
Analysis Set, i.e., the number of patients with at least one melflufen dose interruption across all 
cycles.  Dose interruption is based on the action taken with melflufen. 
The laboratory/hematology assessments of special interest, hematopoietic growth factors, and 
standardized transfusions are to be presented in a by-patient figure for the SAF Analysis Set.  
Melflufen administration and potential dose modifications are also to be included in this figure.  
Neutrophils abs (decreased) and platelets abs (decreased) of CTCAE Grade 3 and/or 4 are to be 
highlighted in the presentation. 
16.2.1.1. DERIVATIONS 
Treatment-emergent AE duration (days) is calculated as follows: 
x
Treatment-emergent AE duration (days) = (<Stop date> - <start date of the event>) + 1. 
Patients experiencing an ongoing TEAE (i.e., no stop date is available) are to be censored at the 
timepoint of the subsequent laboratory assessment that adheres to the cycle initiation criteria 
(Section 3.1 General Description of this SAP) or EOT.  Default summary statistics to be presented for 
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TEAE duration per grade include all mentions (events) at that particular grade. 
16.3. LABORATORY EVALUATIONS 
Safety laboratory data as captured on the Local Laboratory/Complete Blood Count, Local 
Laboratory/Serum Chemistry, Local Laboratory/Coagulation, and Local Laboratory/Urinalysis eCRFs 
are to be presented.  Complete blood count (i.e., hematology), serum chemistry, coagulation, and 
urinalysis (pH being the only quantitative urinalysis variable) data are only to be obtained from local 
laboratories.  Laboratory system/category, variable and SI are presented in Appendix 5 International 
System of Units (SI) of this SAP. 
With reference to Appendix 5 International System of Units (SI) of this SAP, a derived “Neutrophils 
abs” variable is to be created based on the two Local Laboratory/Complete Blood Count eCRF 
variables “Neutrophils” and “Absolute Neutrophil Count”.  Depending on which of the two eCRF 
variables contain data (or the most accurate data pertaining to decimal precision), 
 
Biostatistics is to create a derived variable for purposes of the analysis and presentation of output. 
The following variables are to be presented for all quantitative laboratory assessments in by-patient 
data listings: 
x
Visit (containing cycles and cycle days). 
x
Date of assessment. 
x
Result. 
x
Common Terminology Criteria for Adverse Events (CTCAE) grade. 
x
Reference range. 
x
Investigator’s judgment as indicated on the eCRF. 
With the exception of CTCAE grade and reference range, the above variables are also to be presented 
for qualitative urinalysis assessments.  Pregnancy assessments as indicated on the Local 
Laboratory/Pregnancy Test eCRF are also to be presented in a by-patient data listing.  Refer to 
Section 6.2 Derived Timepoints and Section 6.4 Baseline of this SAP for the definitions of Baseline and 
derived EOT, respectively. 
A change in the following serum chemistry variables based on the shift from Baseline CTCAE grade to 
the worst post-baseline CTCAE grade (LOCF assessment up to and including the derived EOT date) 
(refer to Section 16.3.2 Common Terminology Criteria for Adverse Events (CTCAE) Grading for 
Laboratory Data of this SAP) is to be presented: 
x
Glucose (mmol/L).  No CTCAE for non-fasting glucose levels. 
x
Corrected calcium (mmol/L).  Common Terminology Criteria for Adverse Events (CTCAE) includes 
hypercalcemia and hypocalcemia. 
x
Alkaline phosphatase (IU/L). 
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x
Alanine aminotransferase (IU/L). 
x
Aspartate aminotransferase (IU/L). 
x
Total bilirubin (μmol/L).  Blood bilirubin as per CTCAE terminology. 
x
Creatinine (μmol/L). 
x
Creatinine clearance (mL/min). 
Percentage (%) of patients in each category is calculated relative to the total number of patients in the 
relevant analysis set, with assessments available at Baseline and at least one post-baseline assessment 
up to and including the derived EOT date (LOCF assessment up to and including the derived EOT date).  
If more than one disorder exists per the CTCAE criteria, the relevant disorder is presented as a 
by-variable (e.g., Glucose (mmol/L)/Hyperglycemia).  The available CTCAE criteria are detailed in 
Appendix 3 Common Terminology Criteria for Adverse Events (CTCAE) of this SAP for the relevant 
variables. 
For quantitative laboratory assessments, default summary statistics are to be presented for: 
x
Observed result at visit (Baseline and derived EOT [LOCF]). 
x
Change from Baseline (CFB) at derived EOT (LOCF) (refer to Section 6.9 Common Calculations of 
this SAP). 
All assessments (scheduled or unscheduled) are to be presented in the by-patient data listings. 
16.3.1.LABORATORY REFERENCE RANGES AND CLINICALLY SIGNIFICANT CRITERIA 
Quantitative laboratory assessments are to be compared with the relevant laboratory reference range 
in SI units and classified as: 
x
Low (L): Below the lower limit of the laboratory reference range. 
x
Normal: Within the laboratory reference range (upper and lower limit included). 
x
High (H): Above the upper limit of the laboratory reference range. 
Quantitative laboratory results reported as “< x”, i.e., below the lower limit of quantification (BLQ), or 
“> x”, i.e., above the upper limit of quantification (ULQ), are to be converted to x for the purpose of 
quantitative summaries, but are to be presented as recorded, i.e., as “< x” or “> x” in the by-patient 
data listings. 
In addition to the high and low quantitative laboratory assignments (as identified by means of the 
laboratory reference ranges), laboratory assessments are also to be assessed as judged by the 
investigator as follows: 
x
Normal. 
x
Abnormal, not clinically significant (ANCS). 
x
Abnormal, clinically significant (ACS). 
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16.3.2.COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) GRADING FOR LABORATORY 
DATA 
The laboratory results are to be graded using the CTCAE, Version 4.03.  The worst CTCAE post-baseline 
result (highest grade) up to and including derived EOT (LOCF) is to be flagged for each patient per 
relevant laboratory variable as judged by the investigator is to be classified as: 
x
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
x
(*)Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL). 
x
(**)Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
x
Grade 4: Life-threatening consequences; urgent intervention indicated. 
x
Grade 5: Death related to AE. 
(*) Instrumental ADL: Preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
(**) Self-care ADL: Bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
Patients with a result not complying with the CTCAE grades for a given laboratory assessment are to 
be assigned with a Grade 0 severity. 
In addition, box plots are to be presented for platelets abs, neutrophils abs, and hemoglobin over time 
for the SAF Analysis Set. 
16.3.3.
TEXTBOOK RANGES FOR LABORATORY DATA 
The laboratory results are to be xxx as indicated in Table 5: Standardization of Temperature. 
7DEOH7H[WERRN5HIHUHQFH5DQJHV
White blood cell differential 
Percentage reference range 
Basophils 
0% to 2% 
Eosinophils 
0% to 4% 
Lymphocytes 
20% to 44% 
Monocytes 
2% to 9% 
Neutrophils 
50% to 70% 
Neutrophil-Individual Bands 
2% to 6% 
Source: Harmening, DM 2009, Clinical Hematology and Fundamentals of Hemostasis, 5th Edition. 
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16.4. ELECTROCARDIOGRAM (ECG) EVALUATIONS 
The corrected QT interval using Fridericia’s formula (QTcF) (msec), as indicated on the 12-lead ECG 
eCRF, is the only 12-lead ECG parameter that is to be reported for the study. 
The QTcF interval (msec) as judged by the investigator is to be classified as: 
x
Normal. 
x
Abnormal, not clinically significant (ANCS). 
x
Abnormal, clinically significant (ACS). 
Default summary statistics are to be presented for the QTcF variable: 
x
Observed result at visit (Baseline and derived EOT [LOCF]). 
x
Change from Baseline (CFB) at derived EOT (LOCF). 
All assessments (scheduled or unscheduled) are to be presented in the by-patient data listing. 
16.4.1.ELECTROCARDIOGRAM (ECG) ABNORMALITY AS PER SPECIFIED CRITERIA 
Abnormal QTcF intervals (msec) are to be identified in accordance with the following predefined 
abnormal criteria for inclusion in the by-patient data listing: 
x
Absolute values for QTcF are to be classified as: 
o
> 450 msec. 
o
> 470 msec. 
o
> 480 msec. 
o
> 500 msec. 
The aforementioned categories are not mutually exclusive and a result can therefore fall into more 
than one category simultaneously. 
x
Change from Baseline (CFB) for QTcF is to be classified as: 
o
> 30 msec increase from Baseline. 
o
> 60 msec increase from Baseline. 
If one of the timepoints required for the calculation is not available, no CFB is to be presented. 
16.5. VITAL SIGNS 
From Cycle 1 Day 1 onwards vital signs assessments are to be performed pre- and post-melflufen 
infusion.  Default summary statistics are to be presented for vital signs assessments for: 
x
Observed result at visit (Baseline and derived EOT [LOCF]). 
x
Change from Baseline (CFB) at derived EOT (LOCF). 
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All assessments (scheduled or unscheduled) are to be presented in the by-patient data listing.  The 
following vital signs variables are to be presented: 
x
Systolic blood pressure (mmHg). 
x
Diastolic blood pressure (mmHg). 
x
Pulse rate (bpm). 
x
Respiratory rate (breaths/min). 
x
Standardized body temperature (°C). 
x
Weight (kg). 
x
Height (cm).  Only recorded at Screening.  Not to be included in the summaries, but only to be 
presented in the by-patient data listing. 
16.5.1.DERIVATIONS 
Body temperature is to be standardized to oral body temperature as indicated in Table 5: 
Standardization of Temperature. 
 
7DEOH6WDQGDUGL]DWLRQRI7HPSHUDWXUH
Temperature method 
Standardized to oral body temperature 
Oral 
No adjustment 
Rectal 
-(0.3°C to 0.6°C) 
Axillary (arm pit) 
+(0.3°C to 0.6°C) 
Tympanic (ear) 
-(0.3°C to 0.6°C) 
Standardized intervals based on current research. 
16.6. PHYSICAL EXAMINATION 
Any abnormal physical examination finding is to be presented in a by-patient data listing.  Clinical 
significance as judged by the investigator and as indicated on the Physical Examination, Screening, 
Physical Examination, or Symptom Directed Physical Examination eCRFs is to be presented. 
16.7. OTHER SAFETY ASSESSMENTS 
16.7.1.EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
Eastern Cooperative Oncology Group (ECOG) Performance data as indicated on the ECOG 
Performance Status eCRF is to be presented in a by-patient data listing.  The ECOG grades comprise 
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Grade 1 (normal) to Grade 5 (death). 
The worst post-baseline performance grade (highest grade) up to and including derived EOT (LOCF) is 
to be flagged for each patient. 
A change in the performance grade based on the shift from Baseline CTCAE grade to the worst 
post-baseline CTCAE grade up to and including derived EOT (LOCF) is to be presented. 
Percentage (%) of patients in each category is calculated relative to the total number of patients in the 
relevant analysis set, with assessments available at Baseline and at least one post-baseline assessment 
up to and including derived EOT (LOCF). 
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17. DATA NOT SUMMARIZED OR PRESENTED 
Not applicable. 
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Oncopeptides AB 
STATISTICAL ANALYSIS PLAN: PROTOCOL O-12-M1 
Page 81 of 99 
18. REFERENCES 
1. 20161025dd O-12-M1 Data Review Plan Version 2.0. 
2. Clinical Development Protocol No.O-12-M1; Phase I/IIa Amendment 5, dated 06JUL2016. 
3. Electronic Case Report Form (eCRF) – Annotated Study Book for Study Design O-12-M1 
Version 12.0, dated 30AUG2016. 
4. Rajkumar S.V., Harousseau J.L., Durie B, Anderson K.C., Dimopoulos M, Kyle R, Blade J, 
Richardson P, Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, Palumbo A, 
Zonder J, Ludwig H, Vesole D, Sezer O, Munshi N.C., Miguel J.S. and on behalf of the 
International Myeloma Workshop Consensus Panel 1. (2011 MAY). Consensus recommendations 
for the uniform reporting of clinical trials: Report of the International Myeloma Workshop 
Consensus Panel 1. BLOOD, 117(18): 4691-4695. 
5. Parent X, Spielmann C, Hanser AM. (2009 July-August). “Corrected” calcium: calcium status 
underestimation in non-hypoalbuminemic patients and in hypercalcemic patients. NCBI; 67(4): 
411-8. 
6. Addona et al. (2009 July). Multi-site assessment of the precision and reproducibility of multiple 
reaction monitoring–based measurements of proteins in plasma. Nat Biotechnol, 27(7): 633-
641. doi:10.1038/nbt.1546. 
7. Bruns DE, Burtis CA. Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, sixth 
edition. 
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