PORT: A PK, Safety and Tolerability Study of Peripheral and Central Infusion of Melflufen in RRMM Patients

• Sponsor: Oncopeptides AB (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04412707
• Collaborator: (none)
• Enrollment: 27
• Locations: 10
• Arms: 2
• Actual Duration (Months): 17.2
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy.

Condition or Disease	Intervention/Treatment	Phase
RRMM	Drug: Melphalan-flufenamide; Drug: Dexamethasone	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Two-period, Cross-over, Phase 2 Study, Comparing Pharmacokinetics, and Assessing Safety and Tolerability of Peripheral and Central i.v. Administration of Melphalan Flufenamide (Melflufen) in RRMM Patients
• Actual Study Start Date: Aug 4, 2020
• Actual Primary Completion Date: Jun 2, 2021
• Actual Study Completion Date: Jan 10, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if > 75 years of age 20 mg. Cycle 1 will be administered via a Peripheral Venous Catheter (PVC) and cycle 2 and onwards melflufen will be administered via a Central Venous Catheter (CVC).	Drug: Melphalan-flufenamide; Peripheral versus central administration; Other Names: melflufen ; Drug: Dexamethasone; Oral tablets
Active Comparator: Arm B Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if > 75 years of age 20 mg. Cycle 1 will be administered via a Central Venous Catheter (CVC) and cycle 2 will be administered via a Peripheral Venous Catheter (PVC). From cycle 3 and onwards melflufen will be administered via CVC.	Drug: Melphalan-flufenamide; Peripheral versus central administration; Other Names: melflufen ; Drug: Dexamethasone; Oral tablets

Outcome Measures

Primary Outcome Measures

1. Peak Plasma Concentration for Melphalan [Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.]

   To evaluate and compare the pharmacokinetic (PK) variable Cmax of melphalan after central and peripheral intravenous infusion of melflufen.

2. Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan [Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.]

   To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melphalan after central and peripheral intravenous infusion of melflufen.

3. Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan [Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.]

   To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melphalan after central and peripheral intravenous infusion of melflufen

4. Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration [15 minutes and 4 hours after peripheral intravenous administration, pre- and post-infusion on Day 1 and Day 8]

   Assessment of the local tolerability of peripheral intravenous administration of melflufen using the Visual Infusion Phlebitis (VIP) scale. The VIP scale provides a score from 0 to 5, noting an ascending order of severity of inflammation. A score of 0 is the lowest possible score, meaning no inflammation detected, and 5 is the highest score, indicating the most severe reaction.

Secondary Outcome Measures

1. Peak Plasma Concentration for Melflufen and Desethyl-melflufen [Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)]

   To evaluate and compare the pharmacokinetic (PK) variable Cmax of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen.

2. Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen [Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)]

   To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen

3. Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen [Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)]

   To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen

4. Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen [Cycle 1 Day 1 and Cycle 2 Day 1 - 13 measurements during and post infusion (28 days cycle)]

   To evaluate elimination half-life (t½) for melflufen, melphalan and desethyl-melflufen after central and peripheral intravenous infusion of melflufen.

5. Frequency and Grade of Treatment Emergent Adverse Events (TEAEs) [From screening to 30 days after last dose]

   To assess safety and general tolerability of melflufen by collecting Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first.

6. Best Response (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) [From initiation of therapy until disease progression. For an average patient this is achieved within 6 months.]

   To assess best response during the study with the following criteria: immunofixation negative in serum and urine, disappearance of any soft tissue plasmacytomas, < 5% plasma cells in bone marrow, normal Free Light Chain (FLC) ratio, and absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry. In patients with only FLC disease, a normal FLC ratio of 0.26-1.65 was required.

7. ORR [From initiation of therapy until disease progression. For an average patient this is achieved within 6 months.]

   To assess the best tumor response as well as overall response rate (ORR)

8. CBR [During treatment, for an average patient this is approximately 6 months.]

   To assess clinical benefit rate (CBR) i.e., proportion of patients that achieve a confirmed minimal response or better (sCR, CR, VGPR, PR and MR).

9. DOR [From confirmed response until disease progression. For an average patient this last for approximately 8-9 months.]

   To assess duration of response (DOR) in patients with ≥ PR (stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR) as best response.

10. DOCB [From first evidence of confirmed assessment of sCR, CR, VGPR, PR or MR to first confirmed disease progression, or to death due to any cause, assessed up to 2 years. .]

    To assess duration of clinical benefit (DOCB) in patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR, or MR.

11. TTR [From initiation of therapy until documented disease response. For an average patient this is achieved within 6 months.]

    To assess time to response (TTR) in patients with PR or better.

12. TTP [From date of randomization until documented disease progression. For an average patient this is achieved within 6 months.]

    To assess time to progression(TTP).

13. TTNT [From randomization to the date of next anti-myeloma treatment. For an average patient this is achieved within 9 months.]

    To assess time to next treatment (TTNT)

14. PFS [From initiation of therapy until documented disease progression or initiation of new therapy. For average this is reached after 6 months,]

    To assess progression free survival (PFS)

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. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol;

3. A prior diagnosis of multiple myeloma (MM) with documented disease progression in need of treatment at time of screening;

4. Measurable disease defined as any of the following:

• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)

• ≥ 200 mg/24hr of monoclonal protein in the 24hour urine collection by electrophoresis (UPEP)

• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain (FLC) ratio

1. Received at least 2 prior lines of therapy and is refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI). The definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles of therapy, see Appendix 10 and Appendix 8.

2. Adequate peripheral arm veins for repeated intravenous infusions

3. Life expectancy of ≥ 6 months;

4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, see Appendix 6. Patients with ECOG performance status > 2 solely based on bone pain secondary to MM may be eligible following consultation and approval of medical monitor;

5. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec, see Appendix 11;

6. Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study treatment administration on Cycle 1 Day 1:

• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm³ (1.0 x 10⁹/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of study treatment)

• Platelet count ≥ 75,000 cells/ mm³ (75 x 10⁹/L) (without transfusions during the 10 days prior to initiation of therapy)

• Hemoglobin ≥ 8.0 g/dL (Red blood cell [RBC] transfusions are permitted)

• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except patients diagnosed with Gilbert's syndrome that have been reviewed and approved by the Medical Monitor

• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) ≤ 3.0 x ULN

• Renal function: Estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula of ≥ 45 mL/min, see Appendix

2. Must have or be willing to have an acceptable central catheter (Port a Cath, peripherally inserted central catheter [PICC] line, or central venous catheter [CVC]) and a PVC;

3. 1. Male patients: A male patient is eligible if he agrees to use contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 3 months after the last dose of study treatment and refrains from donating sperm during this period b) Female patients: A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 or II. A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and for at least 28 days after the last dose of study treatment

Exclusion Criteria:

1. Primary refractory disease (i.e. never responded with at least minimal response [MR] to any prior therapy);

2. Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet count fails to increase by > 10,000 cells/mm³ after a transfusion of an appropriate dose of platelets);

3. 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 cardiac conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months);

4. Known active infection that is uncontrolled or has required intravenous systemic therapy within 14 days of randomization. Patients that have required oral anti-infective treatment within 14 days of randomization should be discussed with the Medical Monitor;

5. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance;

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. Human immunodeficiency virus (HIV) or active hepatitis B or C viral infection;

9. Concurrent known or suspected amyloidosis or plasma cell leukemia;

10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);

11. Known central nervous system (CNS) or meningeal involvement of myeloma

12. Any of the following treatments, within the specified timeframe

• Previous cytotoxic therapies, including cytotoxic investigational agents, for MM within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy.

• The use of live vaccines within 30 days before initiation of therapy.

• IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy.

• Other investigational therapies and monoclonal antibodies within 4 weeks of initiation of therapy.

• Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to initiation of therapy.

Other washout times may be considered following consultation with the medical monitor.

1. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 1 without pain are permitted);

2. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy;

3. Prior allogeneic stem cell transplantation with active graft-versus-host-disease;

4. Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy);

5. Known intolerance to the required dose and schedule of steroid therapy, as determined by the investigator;

6. Known hypersensitivity reaction to melphalan, melflufen or its excipients

7. Prior treatment with melflufen

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Oncology Institute of Hope & Innovation - Glendale	Glendale	California	United States	91204
2	Specialized Hospital for Active Treatment of Hematological Diseases, Sofia	Sofia		Bulgaria
3	Multiprofile Hospital for Active Treatment "Sveta Marina", Varna	Varna		Bulgaria
4	University Hospital Brno, Clinic of Internal Medicine - Hematology and Oncology	Brno		Czechia	62500
5	University Hospital Olomouc, Clinic of Hemato-Oncology	Olomouc		Czechia	77900
6	Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation	Budapest		Hungary
7	Semmelweis University, 3rd Department of Internal Medicine	Budapest		Hungary
8	Public Non-Profit Enterprise "City Clinical Hospital #4" under Dnipro City Council, Regional Hematology Center	Dnipro		Ukraine
9	Public Non-Profit Enterprise "Kyiv City Clinical Hospital #9" under the Executive Body of Kyiv City Council, Hematology Department #1	Kyiv		Ukraine
10	Institute of Blood Pathology and Transfusion Medicine, Department of Hematology with Laboratory Group	Lviv		Ukraine

Sponsors and Collaborators

• Oncopeptides AB

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 10, 2021
• Statistical Analysis Plan - Jan 24, 2022

More Information

Publications

None provided.

• Responsible Party: Oncopeptides AB
• ClinicalTrials.gov Identifier: NCT04412707
• Other Study ID Numbers: OP-109
• First Posted: Jun 2, 2020
• Last Update Posted: Aug 16, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Oncopeptides AB: central intravenous administration; peripheral intravenous administration; central venous catheter (CVC); peripheral venous catheter (PVC)
• Additional relevant MeSH terms: Dexamethasone; Melphalan

Study Results

Participant Flow

Arm/Group Title	Arm A	Arm B
Arm/Group Description	Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. Melphalan-flufenamide: Peripheral versus central administration Dexamethasone: Oral tablets	Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration Dexamethasone: Oral tablets
Period Title: Cycle 1
STARTED	14	13
Discontinued	1	5
COMPLETED	13	8
NOT COMPLETED	1	5
Period Title: Cycle 1
STARTED	13	8
Discontinued	3	1
COMPLETED	10	7
NOT COMPLETED	3	1
Period Title: Cycle 1
STARTED	10	7
Ongoing in Study at Data Cut	0	0
Discontinued Study in Cycle 3 or Later	10	7
COMPLETED	0	0
NOT COMPLETED	10	7

Baseline Characteristics

Arm/Group Title	Arm A	Arm B	Total
Arm/Group Description	Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. Melphalan-flufenamide: Peripheral versus central administration Dexamethasone: Oral tablets	Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration Dexamethasone: Oral tablets	Total of all reporting groups
Overall Participants	14	13	27
Age, Customized (Count of Participants)
<65 years	8 57.1%	4 30.8%	12 44.4%
>=65 - 75 years	5 35.7%	5 38.5%	10 37%
> 75 years	1 7.1%	4 30.8%	5 18.5%
Sex: Female, Male (Count of Participants)
Female	7 50%	7 53.8%	14 51.9%
Male	7 50%	6 46.2%	13 48.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	13 92.9%	13 100%	26 96.3%
Unknown or Not Reported	1 7.1%	0 0%	1 3.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	14 100%	13 100%	27 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Hungary	1 7.1%	3 23.1%	4 14.8%
Czechia	4 28.6%	7 53.8%	11 40.7%
Ukraine	3 21.4%	2 15.4%	5 18.5%
Bulgaria	6 42.9%	1 7.7%	7 25.9%
Baseline fertility status (Count of Participants)
Potentially able to bear children	1 7.1%	0 0%	1 3.7%
Not able to bear children	6 42.9%	7 53.8%	13 48.1%

Outcome Measures

1. Primary Outcome

Title	Peak Plasma Concentration for Melphalan
Description	To evaluate and compare the pharmacokinetic (PK) variable Cmax of melphalan after central and peripheral intravenous infusion of melflufen.
Time Frame	Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK.

Arm/Group Title	Peripheral Venous Catheter (PVC)	Central Venous Catheter (CVC)
Arm/Group Description	Combined treatment ARM for all PVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration. Dexamethasone: Oral tablets.	Combined treatment ARM for all CVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration. Dexamethasone: Oral tablets.
Measure Participants	21	21
Cycle 1	486.1 (21.34)	530.1 (25.23)
Cycle 2	546.3 (31.83)	449.2 (40.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Peripheral Venous Catheter (PVC), Central Venous Catheter (CVC)
	Comments	Based on a geometric mean ratio (GMR) peripheral vs. central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.
	Type of Statistical Test	Equivalence
	Comments	The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (GMR)
	Estimated Value	0.946
	Confidence Interval	(2-Sided) 90%; 0.849 to 1.053
	Parameter Dispersion	Type: Value:
	Estimation Comments	CVC vs. PVC, where CVC is numerator and PVC is denominator. Linear Mixed Effect Model included terms for period, sequence and administration route (PVC or CVC) as fixed effects and subject nested within sequence as a random effect.

2. Primary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan
Description	To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melphalan after central and peripheral intravenous infusion of melflufen.
Time Frame	Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Set

Arm/Group Title	Peripheral Venous Catheter (PVC)	Central Venous Catheter (CVC)
Arm/Group Description	Combined treatment ARM for all PVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration. Dexamethasone: Oral tablets.	Combined treatment ARM for all CVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration. Dexamethasone: Oral tablets.
Measure Participants	21	21
Cycle 1	49518.36 (23.710)	59543.20 (17.698)
Cycle 2	60273.95 (30.037)	46173.13 (43.336)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Peripheral Venous Catheter (PVC), Central Venous Catheter (CVC)
	Comments	Based on a geometric mean ratio (GMR) peripheral vs. central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.
	Type of Statistical Test	Equivalence
	Comments	The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (GMR)
	Estimated Value	0.952
	Confidence Interval	(2-Sided) 90%; 0.861 to 1.053
	Parameter Dispersion	Type: Value:
	Estimation Comments	CVC vs. PVC, where CVC is numerator and PVC is denominator. Linear Mixed Effect Model included terms for period, sequence and administration route (PVC or CVC) as fixed effects and subject nested within sequence as a random effect.

3. Primary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan
Description	To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melphalan after central and peripheral intravenous infusion of melflufen
Time Frame	Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Set

Arm/Group Title	Peripheral Venous Catheter (PVC)	Central Venous Catheter (CVC)
Arm/Group Description	Combined treatment ARM for all PVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration. Dexamethasone: Oral tablets.	Combined treatment ARM for all CVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration. Dexamethasone: Oral tablets.
Measure Participants	21	21
Cycle 1	54216.70 (23.794)	66835.47 (18.171)
Cycle 2	67403.07 (30.149)	50835.59 (44.728)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Peripheral Venous Catheter (PVC), Central Venous Catheter (CVC)
	Comments	Based on a geometric mean ratio (GMR) peripheral vs. central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients.
	Type of Statistical Test	Equivalence
	Comments	The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio (GMR)
	Estimated Value	0.955
	Confidence Interval	(2-Sided) 90%; 0.863 to 1.058
	Parameter Dispersion	Type: Value:
	Estimation Comments	CVC vs. PVC, where CVC is numerator and PVC is denominator. Linear Mixed Effect Model included terms for period, sequence and administration route (PVC or CVC) as fixed effects and subject nested within sequence as a random effect.

4. Primary Outcome

Title	Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration
Description	Assessment of the local tolerability of peripheral intravenous administration of melflufen using the Visual Infusion Phlebitis (VIP) scale. The VIP scale provides a score from 0 to 5, noting an ascending order of severity of inflammation. A score of 0 is the lowest possible score, meaning no inflammation detected, and 5 is the highest score, indicating the most severe reaction.
Time Frame	15 minutes and 4 hours after peripheral intravenous administration, pre- and post-infusion on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Peripheral Venous Catheter (PVC)
Arm/Group Description	Combined treatment ARM for all PVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration. Dexamethasone: Oral tablets.
Measure Participants	27
VIP score = 0	13 92.9%
VIP score = 1	0 0%
VIP score = 2	0 0%
VIP score = 3	0 0%
VIP score = 4	0 0%
VIP score = 5	0 0%
VIP score = 0	13 92.9%
VIP score = 1	0 0%
VIP score = 2	0 0%
VIP score = 3	0 0%
VIP score = 4	0 0%
VIP score = 5	0 0%
VIP score = 0	10 71.4%
VIP score = 1	0 0%
VIP score = 2	0 0%
VIP score = 3	0 0%
VIP score = 4	0 0%
VIP score = 5	0 0%
VIP score = 0	8 57.1%
VIP score = 1	0 0%
VIP score = 2	0 0%
VIP score = 3	0 0%
VIP score = 4	0 0%
VIP score = 5	0 0%

5. Secondary Outcome

Title	Peak Plasma Concentration for Melflufen and Desethyl-melflufen
Description	To evaluate and compare the pharmacokinetic (PK) variable Cmax of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen.
Time Frame	Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen
Description	To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen
Time Frame	Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen
Description	To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen
Time Frame	Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen
Description	To evaluate elimination half-life (t½) for melflufen, melphalan and desethyl-melflufen after central and peripheral intravenous infusion of melflufen.
Time Frame	Cycle 1 Day 1 and Cycle 2 Day 1 - 13 measurements during and post infusion (28 days cycle)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Frequency and Grade of Treatment Emergent Adverse Events (TEAEs)
Description	To assess safety and general tolerability of melflufen by collecting Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first.
Time Frame	From screening to 30 days after last dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Best Response (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)
Description	To assess best response during the study with the following criteria: immunofixation negative in serum and urine, disappearance of any soft tissue plasmacytomas, < 5% plasma cells in bone marrow, normal Free Light Chain (FLC) ratio, and absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry. In patients with only FLC disease, a normal FLC ratio of 0.26-1.65 was required.
Time Frame	From initiation of therapy until disease progression. For an average patient this is achieved within 6 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	ORR
Description	To assess the best tumor response as well as overall response rate (ORR)
Time Frame	From initiation of therapy until disease progression. For an average patient this is achieved within 6 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	CBR
Description	To assess clinical benefit rate (CBR) i.e., proportion of patients that achieve a confirmed minimal response or better (sCR, CR, VGPR, PR and MR).
Time Frame	During treatment, for an average patient this is approximately 6 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	DOR
Description	To assess duration of response (DOR) in patients with ≥ PR (stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR) as best response.
Time Frame	From confirmed response until disease progression. For an average patient this last for approximately 8-9 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	DOCB
Description	To assess duration of clinical benefit (DOCB) in patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR, or MR.
Time Frame	From first evidence of confirmed assessment of sCR, CR, VGPR, PR or MR to first confirmed disease progression, or to death due to any cause, assessed up to 2 years. .

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	TTR
Description	To assess time to response (TTR) in patients with PR or better.
Time Frame	From initiation of therapy until documented disease response. For an average patient this is achieved within 6 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	TTP
Description	To assess time to progression(TTP).
Time Frame	From date of randomization until documented disease progression. For an average patient this is achieved within 6 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Secondary Outcome

Title	TTNT
Description	To assess time to next treatment (TTNT)
Time Frame	From randomization to the date of next anti-myeloma treatment. For an average patient this is achieved within 9 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

Title	PFS
Description	To assess progression free survival (PFS)
Time Frame	From initiation of therapy until documented disease progression or initiation of new therapy. For average this is reached after 6 months,

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	SAEs were collected from signing of the ICF until 30 days after last dose of study treatment or initiation of subsequent therapy, whichever occurred first. Non-serious AEs were collected from the start of study treatment until 30 days after the last dose of any study drug or initiation of subsequent therapy, whichever occurred first. Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. The AE reporting period is estimated to be similar.
Adverse Event Reporting Description	Adverse events cannot be compared for Arm A versus Arm B. Because of the crossover design of the study, all patients had a different route of administration in Cycle 2 than Cycle 1, and later AEs could be due to a cumulative effect of multiple treatment cycles. Thus, AEs occurring in Cycle 2 and beyond cannot be attributed to only 1 route of administration.
Arm/Group Title	Arm A		Arm B
Arm/Group Description	Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. Melphalan-flufenamide: Peripheral versus central administration Dexamethasone: Oral tablets		Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melphalan-flufenamide: Peripheral versus central administration Dexamethasone: Oral tablets
All Cause Mortality
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)		8/13 (61.5%)
Serious Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/14 (35.7%)		9/13 (69.2%)
Blood and lymphatic system disorders
Febrile neutropenia	1/14 (7.1%)	1	1/13 (7.7%)	1
Gastrointestinal disorders
Ileus	1/14 (7.1%)	1	0/13 (0%)	0
General disorders
Death	0/14 (0%)	0	1/13 (7.7%)	1
General physical health deterioration	0/14 (0%)	0	2/13 (15.4%)	2
Infections and infestations
Asymptomatic COVID-19	1/14 (7.1%)	1	0/13 (0%)	0
COVID-19 pneumonia	0/14 (0%)	0	3/13 (23.1%)	4
Pneumonia	2/14 (14.3%)	2	2/13 (15.4%)	2
Sepsis	1/14 (7.1%)	1	0/13 (0%)	0
Injury, poisoning and procedural complications
Femoral neck fracture	0/14 (0%)	0	1/13 (7.7%)	1
Femur fracture	0/14 (0%)	0	1/13 (7.7%)	1
Nervous system disorders
Ischaemic stroke	1/14 (7.1%)	1	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/14 (92.9%)		13/13 (100%)
Blood and lymphatic system disorders
Anaemia	9/14 (64.3%)	16	7/13 (53.8%)	12
Leukopenia	2/14 (14.3%)	7	1/13 (7.7%)	2
Lymphopenia	1/14 (7.1%)	2	1/13 (7.7%)	3
Neutropenia	9/14 (64.3%)	36	9/13 (69.2%)	33
Thrombocytopenia	10/14 (71.4%)	34	10/13 (76.9%)	23
Ear and labyrinth disorders
Vertigo	0/14 (0%)	0	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal discomfort	1/14 (7.1%)	1	0/13 (0%)	0
Abdominal pain upper	1/14 (7.1%)	1	0/13 (0%)	0
Diarrhoea	1/14 (7.1%)	1	1/13 (7.7%)	1
Dyspepsia	0/14 (0%)	0	1/13 (7.7%)	1
Dysphagia	0/14 (0%)	0	1/13 (7.7%)	1
Nausea	1/14 (7.1%)	1	0/13 (0%)	0
Stomatitis	0/14 (0%)	0	1/13 (7.7%)	1
General disorders
Asthenia	1/14 (7.1%)	1	1/13 (7.7%)	1
Fatigue	1/14 (7.1%)	2	2/13 (15.4%)	2
General physical health deterioration	0/14 (0%)	0	1/13 (7.7%)	1
Oedema peripheral	1/14 (7.1%)	1	0/13 (0%)	0
Pyrexia	2/14 (14.3%)	2	3/13 (23.1%)	3
Infections and infestations
COVID-19	1/14 (7.1%)	1	1/13 (7.7%)	2
Infection	1/14 (7.1%)	2	0/13 (0%)	0
Pharyngitis	1/14 (7.1%)	1	0/13 (0%)	0
Pneumonia	1/14 (7.1%)	2	0/13 (0%)	0
Respiratory tract infection	2/14 (14.3%)	3	0/13 (0%)	0
Rhinitis	1/14 (7.1%)	1	0/13 (0%)	0
Upper respiratory tract infection	1/14 (7.1%)	1	1/13 (7.7%)	1
Urinary tract infection	1/14 (7.1%)	1	0/13 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	0/14 (0%)	0	1/13 (7.7%)	1
Investigations
Body temperature increased	1/14 (7.1%)	1	0/13 (0%)	0
C-reactive protein increased	2/14 (14.3%)	3	0/13 (0%)	0
SARS-CoV-2 test positive	2/14 (14.3%)	2	4/13 (30.8%)	4
Metabolism and nutrition disorders
Decreased appetite	0/14 (0%)	0	1/13 (7.7%)	1
Type 2 diabetes mellitus	1/14 (7.1%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/14 (7.1%)	1	2/13 (15.4%)	2
Back pain	2/14 (14.3%)	2	1/13 (7.7%)	1
Bone pain	2/14 (14.3%)	2	0/13 (0%)	0
Muscular weakness	0/14 (0%)	0	1/13 (7.7%)	1
Musculoskeletal chest pain	0/14 (0%)	0	1/13 (7.7%)	1
Nervous system disorders
Aphasia	0/14 (0%)	0	1/13 (7.7%)	1
Cognitive disorder	0/14 (0%)	0	1/13 (7.7%)	1
Renal and urinary disorders
Renal impairment	0/14 (0%)	0	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/14 (7.1%)	1	1/13 (7.7%)	1
Rhinorrhoea	0/14 (0%)	0	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Rash	2/14 (14.3%)	2	0/13 (0%)	0
Vascular disorders
Hypertension	0/14 (0%)	0	1/13 (7.7%)	1
Vascular pain	1/14 (7.1%)	1	0/13 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.