Safety and Efficacy of Melflufen and Dexamethasone in Relapsed and/or Relapsed-Refractory Multiple Myeloma Patients

• Sponsor: Oncopeptides AB (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01897714
• Collaborator: (none)
• Enrollment: 75
• Locations: 7
• Arms: 6
• Actual Duration (Months): 80
• Patients Per Site: 10.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsed and/or Relapsed-refractory Multiple Myeloma	Drug: Melflufen; Drug: Dexamethasone	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 75 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Dec 1, 2017
• Actual Study Completion Date: Mar 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I: Melflufen 15 mg + Dexamethasone 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.	Drug: Melflufen; Drug: Dexamethasone
Experimental: Phase I: Melflufen 25 mg + Dexamethasone 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.	Drug: Melflufen; Drug: Dexamethasone
Experimental: Phase I: Melflufen 40 mg + Dexamethasone 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.	Drug: Melflufen; Drug: Dexamethasone
Experimental: Phase I: Melflufen 55 mg + Dexamethasone 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.	Drug: Melflufen; Drug: Dexamethasone
Experimental: Phase I + II: Melflufen 40 mg + Dexamethasone 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.	Drug: Melflufen; Drug: Dexamethasone
Experimental: Phase II: Melflufen 40 mg (Single Agent) IV infusion of 40 mg melflufen on Day 1 of each 28-day treatment cycle.	Drug: Melflufen

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Who Achieved Best Overall Disease Response [Baseline (Cycle 1 Day 1) and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   The best overall disease response on treatment including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) or progressive disease (PD) were evaluated. Starting on completion of Cycle 2, response was assessed according to International Myeloma Working Group (IMWG) criteria based on Investigator's assessment for all patients at every cycle during treatment period. PD was defined as increase of ≥25% from lowest response value in any 1 of the following: serum M-component (absolute increase must be ≥0.5 gram/deciliter) and/or urine M-component (absolute increase must be ≥200 mg/24 hr); development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that could be attributed solely to plasma cell proliferative disorder. SD was defined as not meeting criteria for CR, VGPR, PR or PD.

2. Overall Response Rate (ORR) [Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   ORR was defined as percentage of patients with an overall response (OR), defined as first occurrence of confirmed disease response including PR or better (i.e, PR, VGPR, CR or sCR). Starting on completion of Cycle 2, response was assessed according to IMWG criteria based on Investigator's assessment for all patients at every cycle during treatment period. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum plus urine M-protein level <100 mg/24hr and >90% decrease in difference between involved and uninvolved free light chain (FLC) levels (only in FLC diseased patients). CR was defined as negative immunofixation on serum and urine, loss of any soft tissue plasmacytomas, <5% plasma cells in bone marrow and normal FLC ratio of 0.26 to 1.65 (only in FLC diseased patients). sCR was defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or 2 to 4 color flow cytometry.

3. Clinical Benefit Response Rate (CBRR) [Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   The CBRR was defined as the percentage of patients with a clinical benefit response (CBR), defined as the first occurrence of confirmed disease response including MR or better (i.e, MR, PR, VGPR, CR, or sCR). Starting on completion of Cycle 2, response was assessed according to the IMWG criteria based on the Investigator's assessment for all patients at every cycle during the treatment period. MR was defined as ≥25% but <49% reduction of serum M-protein and reduction in 24 hour urine M-protein by 50 to 89%, which still exceeds 200 mg/24 hours. In addition to above; if present at baseline, 25 to 49% reduction in the size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude response). PR was defined as 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥90% or to <200 mg/24 hour.

Secondary Outcome Measures

1. Duration of Disease Response (DOR) [Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   The DOR to treatment was defined as time from first response (PR or better) to disease progression or death, or date of last evaluable disease response assessment for those who had not progressed or died. DOR was estimated using Kaplan-Meier statistics.

2. Time to Disease Response in Patients Who Achieved OR and CBR [Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   Time to first OR was 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 (first of 2 consecutive assessments-confirmed response). Time to first CBR was 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 (first of 2 consecutive assessments-confirmed response). Time to disease response was estimated using Kaplan-Meier statistics.

3. Time to Disease Progression [Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   Time to disease progression was 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. Time to disease progression was estimated using Kaplan-Meier statistics.

4. Median Progression-Free Survival (PFS) [Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   The PFS was defined as the time from the date of the first dose of melflufen (overall reference start date) to the date of the first occurrence of any disease response assessment available for PD or death. The PFS was estimated using Kaplan-Meier statistics.

5. Median Overall Survival (OS) [From baseline until death. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   The OS was defined as the time from the date of the first dose of melflufen (overall reference start date) to death. The OS was estimated using Kaplan-Meier statistics.

6. Time to First Subsequent Treatment [From baseline until start of first subsequent treatment. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   Time to first subsequent treatment start was defined as the time from the date of the actual end of treatment to the date of the first subsequent treatment. Time to first subsequent treatment was estimated using Kaplan-Meier statistics.

7. Number of Patients With Treatment Emergent Adverse Events (TEAEs) [From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months.]

   An adverse event (AE) was any untoward medical occurrence in a study patient administered an investigational product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as any AE, occurring at any dose, that met 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; requires inpatient hospitalization or prolongation of existing hospitalization; or other important medical event. TEAEs were 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 actual EOT date. TESAEs = Treatment emergent serious adverse events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion 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:

4. Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis

5. ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis

6. Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio

7. If no monoclonal protein is detected, then ≥ 30% monoclonal bone marrow plasma cells

8. 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

9. Life expectancy of ≥6 months

10. Patient has an ECOG performance status ≤ 2 (Patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible)

11. Females of childbearing potential must have a negative serum or urine pregnancy test prior to patient registration

12. Female patients of child bearing potential and non-vasectomized male patients agree to practice appropriate methods of birth control

13. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

14. The patient has, or accepts to have, an acceptable infusion device for infusion of melflufen

15. 12 lead ECG with QtcF interval ≤ 470 msec

16. The following laboratory results must be met within 21 days of patient registration:

• Absolute neutrophil count ≥ 1,000 cells/dL (1.0 x 109/L)

• Platelet count ≥ 75,000 cells/dL (75 x 109/L)

• Hemoglobin ≥ 8.0 g/dL

• Total Bilirubin ≤ 1.5 x upper limit of normal

• Renal function: Estimated creatinine clearance ≥ 45 ml/min or serum creatinine ≤ 2.5 mg/dL

• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN

Exclusion Criteria:

1. Patient has evidence of mucosal or internal bleeding and/or is platelet transfusion refractory

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

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 for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to patient registration.

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

10. POEMS syndrome

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 patient registration. Patient has side effects of the previous therapy > grade 1 or previous baseline.

12. Prior peripheral stem cell transplant within 12 weeks of patient registration

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
2	Karmanos Cancer Center	Detroit	Michigan	United States	48201
3	Universtity of North Carolina	Chapel Hill	North Carolina	United States	27514
4	Vejle Hospital	Vejle		Denmark
5	Turin Hospital Myeloma Unit	Turin		Italy
6	Erasmus University Medical Center	Rotterdam		Netherlands
7	Sahlgrenska Hospital	Gothenburg		Sweden

Sponsors and Collaborators

• Oncopeptides AB

Investigators

• Study Director: Paul G Richardson, MD, Dana Farber Cancer Institute, Boston MA, USA
• Study Director: Johan Harmenberg, MD, Oncopeptides AB, Stockholm, Sweden

Study Documents (Full-Text)

• Study Protocol - Nov 2, 2018
• Statistical Analysis Plan - Aug 25, 2017

More Information

Publications

None provided.

• Responsible Party: Oncopeptides AB
• ClinicalTrials.gov Identifier: NCT01897714
• Other Study ID Numbers: O-12-M1
• First Posted: Jul 12, 2013
• Last Update Posted: Oct 23, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone

Study Results

Participant Flow

Recruitment Details	This was an open-label, Phase I/IIa study conducted at 7 study centers in 5 countries in patients with relapsed and/or relapsed-refractory Multiple Myeloma (MM). Overall, 75 patients (23 during Phase I and 52 additional patients during Phase II) were enrolled. The study results are presented until the end of trial (EOT) date of 29 October 2019.
Pre-assignment Detail	The study was conducted in 2 parts: Phase I (dose escalation) and Phase II (maximum tolerated dose [MTD]). During Phase I, the standard 3 + 3 design was followed with 3 to 6 patients tested at each dose level, depending on the dose limiting toxicity (DLT) observed. During Phase II, patients were treated at the MTD determined in Phase I.

Arm/Group Title	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 15 milligram (mg) melflufen as intravenous (IV) infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Period Title: Phase I (Dose Escalation)
STARTED	4	7	6	6	0	0
COMPLETED	1	0	1	0	0	0
NOT COMPLETED	3	7	5	6	0	0
Period Title: Phase I (Dose Escalation)
STARTED	0	0	0	0	45	13
COMPLETED	0	0	0	0	15	2
NOT COMPLETED	0	0	0	0	30	11

Baseline Characteristics

Arm/Group Title	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)	Total
Arm/Group Description	Patients were treated with 15 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Total of all reporting groups
Overall Participants	4	7	6	6	45	13	81
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 25%	3 42.9%	3 50%	2 33.3%	9 20%
>=65 years	3 75%	4 57.1%	3 50%	4 66.7%	14 31.1%
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 500%	8 114.3%	28 466.7%
>=65 years	25 625%	5 71.4%	30 500%
Sex: Female, Male (Count of Participants)
Female	2 50%	4 57.1%	2 33.3%	3 50%	11 24.4%
Male	2 50%	3 42.9%	4 66.7%	3 50%	12 26.7%
Female	15 375%	5 71.4%	20 333.3%
Male	30 750%	8 114.3%	38 633.3%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	1 25%	1 14.3%	0 0%	0 0%	2 4.4%
Caucasian	3 75%	6 85.7%	6 100%	6 100%	21 46.7%
Not collected as per local laws	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 75%	3 42.9%	6 100%
Caucasian	41 1025%	10 142.9%	51 850%
Not collected as per local laws	1 25%	0 0%	1 16.7%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	0 0%	1 14.3%	0 0%	0 0%	1 2.2%
Not Hispanic or Latino	4 100%	6 85.7%	5 83.3%	5 83.3%	20 44.4%
Not collected as per local laws	0 0%	0 0%	1 16.7%	1 16.7%	2 4.4%
Hispanic or Latino	1 25%	0 0%	1 16.7%
Not Hispanic or Latino	37 925%	12 171.4%	49 816.7%
Not collected as per local laws	7 175%	1 14.3%	8 133.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Who Achieved Best Overall Disease Response
Description	The best overall disease response on treatment including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) or progressive disease (PD) were evaluated. Starting on completion of Cycle 2, response was assessed according to International Myeloma Working Group (IMWG) criteria based on Investigator's assessment for all patients at every cycle during treatment period. PD was defined as increase of ≥25% from lowest response value in any 1 of the following: serum M-component (absolute increase must be ≥0.5 gram/deciliter) and/or urine M-component (absolute increase must be ≥200 mg/24 hr); development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that could be attributed solely to plasma cell proliferative disorder. SD was defined as not meeting criteria for CR, VGPR, PR or PD.
Time Frame	Baseline (Cycle 1 Day 1) and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

For Phase I arms: The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug. For Phase II arms: Modified Intent-to-Treat (mITT) Analysis Set included all patients considered to be valid for Safety Analysis Set and who received at least 1 dose of study drug at the MTD as initial dose.

Arm/Group Title	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 15 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	4	7	6	6	45	13
sCR	0.0	0.0	0.0	0.0	0.0	0.0
CR	0.0	0.0	0.0	0.0	0.0	0.0
VGPR	0.0	0.0	16.7	16.7	11.1	0.0
PR	0.0	0.0	50.0	0.0	20.0	7.7
MR	0.0	0.0	0.0	0.0	17.8	15.4
SD	75.0	42.9	16.7	66.7	26.7	69.2
PD	25.0	57.1	16.7	16.7	15.6	7.7
Missing	0.0	0.0	0.0	0.0	8.9	0.0
sCR + CR	0.0	0.0	0.0	0.0	0.0	0.0
sCR + CR + VGPR	0.0	0.0	16.7	16.7	11.1	0.0

2. Primary Outcome

Title	Overall Response Rate (ORR)
Description	ORR was defined as percentage of patients with an overall response (OR), defined as first occurrence of confirmed disease response including PR or better (i.e, PR, VGPR, CR or sCR). Starting on completion of Cycle 2, response was assessed according to IMWG criteria based on Investigator's assessment for all patients at every cycle during treatment period. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum plus urine M-protein level <100 mg/24hr and >90% decrease in difference between involved and uninvolved free light chain (FLC) levels (only in FLC diseased patients). CR was defined as negative immunofixation on serum and urine, loss of any soft tissue plasmacytomas, <5% plasma cells in bone marrow and normal FLC ratio of 0.26 to 1.65 (only in FLC diseased patients). sCR was defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or 2 to 4 color flow cytometry.
Time Frame	Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

For Phase I arms: The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug. For Phase II arms: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose.

Arm/Group Title	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 15 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	4	7	6	6	45	13
Number (95% Confidence Interval) [percentage of patients]	0.0	0.0	66.7	16.7	31.1	7.7

3. Primary Outcome

Title	Clinical Benefit Response Rate (CBRR)
Description	The CBRR was defined as the percentage of patients with a clinical benefit response (CBR), defined as the first occurrence of confirmed disease response including MR or better (i.e, MR, PR, VGPR, CR, or sCR). Starting on completion of Cycle 2, response was assessed according to the IMWG criteria based on the Investigator's assessment for all patients at every cycle during the treatment period. MR was defined as ≥25% but <49% reduction of serum M-protein and reduction in 24 hour urine M-protein by 50 to 89%, which still exceeds 200 mg/24 hours. In addition to above; if present at baseline, 25 to 49% reduction in the size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude response). PR was defined as 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥90% or to <200 mg/24 hour.
Time Frame	Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

For Phase I arms: The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug. For Phase II arms: The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose.

Arm/Group Title	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 15 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	4	7	6	6	45	13
Number (95% Confidence Interval) [percentage of patients]	0.0	0.0	66.7	16.7	48.9	23.1

4. Secondary Outcome

Title	Duration of Disease Response (DOR)
Description	The DOR to treatment was defined as time from first response (PR or better) to disease progression or death, or date of last evaluable disease response assessment for those who had not progressed or died. DOR was estimated using Kaplan-Meier statistics.
Time Frame	Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had achieved at least PR were evaluated.

Arm/Group Title	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	14	1
Median (95% Confidence Interval) [months]	8.4	7.2

5. Secondary Outcome

Title	Time to Disease Response in Patients Who Achieved OR and CBR
Description	Time to first OR was 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 (first of 2 consecutive assessments-confirmed response). Time to first CBR was 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 (first of 2 consecutive assessments-confirmed response). Time to disease response was estimated using Kaplan-Meier statistics.
Time Frame	Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had achieved OR and CBR were evaluated, for each respective time to response parameter.

Arm/Group Title	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	22	3
OR	2.8	6.7
CBR	2.4	2.8

6. Secondary Outcome

Title	Time to Disease Progression
Description	Time to disease progression was 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. Time to disease progression was estimated using Kaplan-Meier statistics.
Time Frame	Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose.

Arm/Group Title	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	45	13
Median (95% Confidence Interval) [months]	6.5	4.4

7. Secondary Outcome

Title	Median Progression-Free Survival (PFS)
Description	The PFS was defined as the time from the date of the first dose of melflufen (overall reference start date) to the date of the first occurrence of any disease response assessment available for PD or death. The PFS was estimated using Kaplan-Meier statistics.
Time Frame	Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about PFS at the time of EOT (29 October 2019) were reported.

Arm/Group Title	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	45	13
Median (95% Confidence Interval) [months]	5.7	4.4

8. Secondary Outcome

Title	Median Overall Survival (OS)
Description	The OS was defined as the time from the date of the first dose of melflufen (overall reference start date) to death. The OS was estimated using Kaplan-Meier statistics.
Time Frame	From baseline until death. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about OS at the time of EOT(29 October 2019) were reported.

Arm/Group Title	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	45	13
Median (95% Confidence Interval) [months]	20.7	15.5

9. Secondary Outcome

Title	Time to First Subsequent Treatment
Description	Time to first subsequent treatment start was defined as the time from the date of the actual end of treatment to the date of the first subsequent treatment. Time to first subsequent treatment was estimated using Kaplan-Meier statistics.
Time Frame	From baseline until start of first subsequent treatment. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about first subsequent treatment at the time of EOT (29 October 2019) were reported.

Arm/Group Title	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	45	13
Median (95% Confidence Interval) [months]	10.5	10.7

10. Secondary Outcome

Title	Number of Patients With Treatment Emergent Adverse Events (TEAEs)
Description	An adverse event (AE) was any untoward medical occurrence in a study patient administered an investigational product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as any AE, occurring at any dose, that met 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; requires inpatient hospitalization or prolongation of existing hospitalization; or other important medical event. TEAEs were 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 actual EOT date. TESAEs = Treatment emergent serious adverse events.
Time Frame	From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug.

Arm/Group Title	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 15 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.	Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
Measure Participants	4	7	6	6	45	13
TEAEs (including both serious and non-serious AEs)	4 100%	7 100%	6 100%	6 100%	45 100%	13 100%
TEAEs leading to death	0 0%	1 14.3%	0 0%	0 0%	3 6.7%	0 0%
TESAEs	3 75%	4 57.1%	2 33.3%	4 66.7%	17 37.8%	9 69.2%
DLT TEAEs	0 0%	0 0%	0 0%	4 66.7%
TEAEs related to melflufen and/or dexamethasone	4 100%	7 100%	6 100%	6 100%	45 100%	13 100%
TESAEs related to melflufen and/or dexamethasone	3 75%	4 57.1%	2 33.3%	4 66.7%	17 37.8%	9 69.2%

Adverse Events

Time Frame	From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Adverse Event Reporting Description	The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug.
Arm/Group Title	Phase I: Melflufen 15 mg + Dexamethasone		Phase I: Melflufen 25 mg + Dexamethasone		Phase I: Melflufen 40 mg + Dexamethasone		Phase I: Melflufen 55 mg + Dexamethasone		Phase I + II: Melflufen 40 mg + Dexamethasone		Phase II: Melflufen 40 mg (Single Agent)
Arm/Group Description	Patients were treated with 15 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.		Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.		Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.		Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.		Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.		Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.
All Cause Mortality
	Phase I: Melflufen 15 mg + Dexamethasone		Phase I: Melflufen 25 mg + Dexamethasone		Phase I: Melflufen 40 mg + Dexamethasone		Phase I: Melflufen 55 mg + Dexamethasone		Phase I + II: Melflufen 40 mg + Dexamethasone		Phase II: Melflufen 40 mg (Single Agent)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		5/7 (71.4%)		2/6 (33.3%)		5/6 (83.3%)		30/45 (66.7%)		10/13 (76.9%)
Serious Adverse Events
	Phase I: Melflufen 15 mg + Dexamethasone		Phase I: Melflufen 25 mg + Dexamethasone		Phase I: Melflufen 40 mg + Dexamethasone		Phase I: Melflufen 55 mg + Dexamethasone		Phase I + II: Melflufen 40 mg + Dexamethasone		Phase II: Melflufen 40 mg (Single Agent)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		4/7 (57.1%)		2/6 (33.3%)		4/6 (66.7%)		17/45 (37.8%)		9/13 (69.2%)
Blood and lymphatic system disorders
Neutropenia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	3/6 (50%)	3	2/45 (4.4%)	2	1/13 (7.7%)	1
Febrile neutropenia	1/4 (25%)	1	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Thrombocytopenia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	2/13 (15.4%)	10
Cardiac disorders
Atrial fibrillation	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Gastrointestinal disorders
Nausea	1/4 (25%)	1	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Vomiting	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/45 (0%)	0	0/13 (0%)	0
Diarrhoea	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	3	0/13 (0%)	0
General disorders
Pyrexia	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	2/45 (4.4%)	2	1/13 (7.7%)	1
Infections and infestations
Pneumonia	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	2/6 (33.3%)	2	5/45 (11.1%)	5	1/13 (7.7%)	1
Bacteraemia	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Cystitis	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Escherichia bacteraemia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/45 (0%)	0	0/13 (0%)	0
Sepsis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/45 (0%)	0	0/13 (0%)	0
Upper respiratory tract infection	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Urinary tract infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/45 (0%)	0	0/13 (0%)	0
Escherichia sepsis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Catheter site infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Parainfluenzae virus infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Pseudomonal sepsis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Spinal compression fracture	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Spinal fracture	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Investigations
White blood cell count decreased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Metabolism and nutrition disorders
Hyperphosphataemia	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Diabetes mellitus	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Hypercalcaemia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	2	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/45 (0%)	0	0/13 (0%)	0
Bone lesion	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Spinal disorder	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasmacytoma	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Nervous system disorders
Spinal cord compression	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Renal and urinary disorders
Renal failure	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Acute kidney injury	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Vascular disorders
Deep vein thrombosis	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	Phase I: Melflufen 15 mg + Dexamethasone		Phase I: Melflufen 25 mg + Dexamethasone		Phase I: Melflufen 40 mg + Dexamethasone		Phase I: Melflufen 55 mg + Dexamethasone		Phase I + II: Melflufen 40 mg + Dexamethasone		Phase II: Melflufen 40 mg (Single Agent)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		7/7 (100%)		6/6 (100%)		6/6 (100%)		45/45 (100%)		12/13 (92.3%)
Blood and lymphatic system disorders
Thrombocytopenia	2/4 (50%)	2	6/7 (85.7%)	9	4/6 (66.7%)	26	5/6 (83.3%)	35	33/45 (73.3%)	154	9/13 (69.2%)	30
Neutropenia	1/4 (25%)	1	3/7 (42.9%)	7	3/6 (50%)	12	6/6 (100%)	26	31/45 (68.9%)	115	9/13 (69.2%)	25
Anaemia	3/4 (75%)	3	4/7 (57.1%)	5	2/6 (33.3%)	4	3/6 (50%)	6	29/45 (64.4%)	96	5/13 (38.5%)	14
Lymphopenia	1/4 (25%)	2	1/7 (14.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	3/45 (6.7%)	3	1/13 (7.7%)	3
Leukopenia	1/4 (25%)	2	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Pancytopenia	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1	1/45 (2.2%)	1	0/13 (0%)	0
Anaemia vitamin B12 deficiency	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Increased tendency to bruise	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/45 (0%)	0	0/13 (0%)	0
Bone marrow failure	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Cardiac disorders
Palpitations	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	2	0/6 (0%)	0	2/45 (4.4%)	3	0/13 (0%)	0
Mitral valve disease mixed	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Sinus tachycardia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Ear and labyrinth disorders
Ear haemorrhage	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Eye disorders
Vision blurred	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/45 (0%)	0	0/13 (0%)	0
Gastrointestinal disorders
Nausea	1/4 (25%)	1	0/7 (0%)	0	4/6 (66.7%)	6	4/6 (66.7%)	5	12/45 (26.7%)	14	2/13 (15.4%)	3
Constipation	2/4 (50%)	2	3/7 (42.9%)	3	1/6 (16.7%)	1	0/6 (0%)	0	7/45 (15.6%)	8	1/13 (7.7%)	1
Diarrhoea	0/4 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	3	4/6 (66.7%)	5	9/45 (20%)	10	2/13 (15.4%)	2
Vomiting	0/4 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	2	2/6 (33.3%)	2	5/45 (11.1%)	5	1/13 (7.7%)	1
Abdominal pain upper	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1	3/45 (6.7%)	5	0/13 (0%)	0
Abdominal pain	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	2/45 (4.4%)	4	0/13 (0%)	0
Dyspepsia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	3/45 (6.7%)	3	0/13 (0%)	0
Gastrointestinal disorder	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Oral pain	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Stomatitis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/45 (6.7%)	3	0/13 (0%)	0
Abdominal distension	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	6	0/13 (0%)	0
Abdominal hernia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Aerophagia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Gastric disorder	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	3	0/13 (0%)	0
General disorders
Fatigue	1/4 (25%)	1	3/7 (42.9%)	5	3/6 (50%)	7	2/6 (33.3%)	2	13/45 (28.9%)	20	4/13 (30.8%)	4
Pyrexia	2/4 (50%)	2	0/7 (0%)	0	2/6 (33.3%)	2	1/6 (16.7%)	1	16/45 (35.6%)	19	0/13 (0%)	0
Mucosal inflammation	0/4 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	1/6 (16.7%)	2	6/45 (13.3%)	8	0/13 (0%)	0
Hyperthermia	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	1/45 (2.2%)	1	0/13 (0%)	0
Asthenia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	3	14/45 (31.1%)	46	0/13 (0%)	0
Chest pain	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Influenza like illness	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	4/45 (8.9%)	4	0/13 (0%)	0
Non-cardiac chest pain	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Oedema peripheral	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	1/13 (7.7%)	1
Pain	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Application site erosion	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Chills	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Feeling cold	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Mucous membrane disorder	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Hepatobiliary disorders
Cholecystitis	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Immune system disorders
Immune system disorder	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Infections and infestations
Bronchitis	0/4 (0%)	0	0/7 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Upper respiratory tract infection	0/4 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	2	0/6 (0%)	0	5/45 (11.1%)	6	0/13 (0%)	0
Candida infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/45 (0%)	0	0/13 (0%)	0
Cystitis	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Enterococcal infection	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Gingivitis	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Influenza	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Mucosal infection	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Nasopharyngitis	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	3/45 (6.7%)	4	0/13 (0%)	0
Oral candidiasis	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Oral fungal infection	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	2	0/13 (0%)	0
Periodontitis	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Pneumonia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/45 (6.7%)	3	1/13 (7.7%)	1
Infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	4/45 (8.9%)	5	0/13 (0%)	0
Oral herpes	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	1/13 (7.7%)	1
Herpes zoster	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Acarodermatitis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Administration site infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Conjunctivitis bacterial	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Eye infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Furuncle	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Gastroenteritis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Gastroenteritis viral	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Herpes virus infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Laryngitis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Lower respiratory tract infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Lung infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Sinusitis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Skin infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	2	0/13 (0%)	0
Vulvovaginal mycotic infection	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Contusion	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/45 (6.7%)	3	0/13 (0%)	0
Spinal compression fracture	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Humerus fracture	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Infusion related reaction	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Joint dislocation	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Thermal burn	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Investigations
Blood creatinine increased	0/4 (0%)	0	3/7 (42.9%)	3	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
White blood cell count decreased	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	4/45 (8.9%)	4	3/13 (23.1%)	3
Aspartate aminotransferase increased	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Blood bilirubin increased	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Blood glucose increased	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Cardiac murmur	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Protein total increased	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
C-reactive protein increased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	4/45 (8.9%)	5	0/13 (0%)	0
CD4 lymphocytes decreased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/45 (6.7%)	3	0/13 (0%)	0
Weight decreased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Blood lactate dehydrogenase increased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Fibrin d dimer increased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
International normalised ratio increased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	4	0/13 (0%)	0
Lymphocyte count decreased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Red blood cell count decreased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Urine output decreased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Vitamin B12 decreased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Weight increased	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/4 (0%)	0	1/7 (14.3%)	1	2/6 (33.3%)	4	1/6 (16.7%)	1	3/45 (6.7%)	5	1/13 (7.7%)	1
Hypoalbuminaemia	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Hypokalaemia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	2/45 (4.4%)	3	0/13 (0%)	0
Hypomagnesaemia	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Hyperglycaemia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	4/45 (8.9%)	13	0/13 (0%)	0
Hypocalcaemia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/45 (6.7%)	4	0/13 (0%)	0
Hyponatraemia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/45 (6.7%)	3	0/13 (0%)	0
Dehydration	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Hyperuricaemia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	1/13 (7.7%)	1
Cachexia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Hypercalcaemia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	2	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/4 (0%)	0	3/7 (42.9%)	3	0/6 (0%)	0	1/6 (16.7%)	1	6/45 (13.3%)	9	2/13 (15.4%)	2
Arthralgia	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	5/45 (11.1%)	5	0/13 (0%)	0
Bone pain	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	6/45 (13.3%)	8	0/13 (0%)	0
Muscle spasms	0/4 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	5/45 (11.1%)	5	0/13 (0%)	0
Bursitis	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Musculoskeletal chest pain	0/4 (0%)	0	1/7 (14.3%)	2	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Myalgia	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Osteoporosis	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Spinal pain	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	4	0/13 (0%)	0
Musculoskeletal pain	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	4	0/13 (0%)	0
Flank pain	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Muscular weakness	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Myopathy	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Neck pain	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Synovial cyst	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasmacytoma	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Nervous system disorders
Dizziness	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	4/45 (8.9%)	4	0/13 (0%)	0
Headache	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	2	6/45 (13.3%)	8	0/13 (0%)	0
Paraesthesia	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Peripheral sensory neuropathy	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Presyncope	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Neuropathy peripheral	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	4/45 (8.9%)	4	0/13 (0%)	0
Ataxia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Somnolence	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Tremor	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Product Issues
Device occlusion	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Psychiatric disorders
Insomnia	1/4 (25%)	1	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	6/45 (13.3%)	8	0/13 (0%)	0
Sleep disorder	0/4 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Anxiety	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Confusional state	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Nervousness	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Mood altered	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	1/13 (7.7%)	1
Depression	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Restlessness	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Renal and urinary disorders
Dysuria	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	1/13 (7.7%)	1
Renal failure	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	1/13 (7.7%)	1
Haematuria	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Reproductive system and breast disorders
Erectile Dysfunction	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/4 (25%)	1	0/7 (0%)	0	2/6 (33.3%)	2	2/6 (33.3%)	2	6/45 (13.3%)	6	1/13 (7.7%)	1
Cough	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	8/45 (17.8%)	11	0/13 (0%)	0
Dyspnoea exertional	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Epistaxis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	6/45 (13.3%)	8	1/13 (7.7%)	1
Dysphonia	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Oropharyngeal pain	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	0/13 (0%)	0
Productive cough	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	1/13 (7.7%)	1
Pleural effusion	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Petechiae	0/4 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Rash	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	3/45 (6.7%)	3	0/13 (0%)	0
Blood blister	0/4 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Erythema	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Hyperhidrosis	0/4 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/45 (2.2%)	1	1/13 (7.7%)	1
Night sweats	1/4 (25%)	1	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Skin lesion	0/4 (0%)	0	1/7 (14.3%)	2	0/6 (0%)	0	0/6 (0%)	0	0/45 (0%)	0	0/13 (0%)	0
Ecchymosis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Vascular disorders
Hypertension	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	3/45 (6.7%)	3	0/13 (0%)	0
Hypotension	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/45 (4.4%)	2	1/13 (7.7%)	1
Flushing	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Haematoma	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Thrombophlebitis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0
Venous thrombosis	0/4 (0%)	0	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/45 (2.2%)	1	0/13 (0%)	0

Limitations/Caveats

Study is terminated and long-term follow-up ended due to Sponsor decision.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.