Clinical Trials Register

Summary
EudraCT Number:	2018-000478-31
Sponsor's Protocol Code Number:	OP-107
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-05-04
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2018-000478-31

A.3

Full title of the trial

A Study of the Pharmacokinetics of Melphalan During Treatment with Melflufen and Dexamethasone in Patients with Relapsed Refractory Multiple Myeloma and Impaired Renal Function

Klinická studie farmakokinetiky melfalanu během léčby melflufenem a dexametazonem u pacientů s relabujícím refrakterním mnohočetným myelomem a narušenou funkcí ledvin

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Multicenter study to assess Pharmacokinetics of Melphalan During Treatment with Melflufen and Dexamethasone

A.3.2

Name or abbreviated title of the trial where available

BRIDGE study

A.4.1

Sponsor's protocol code number

OP-107

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Oncopeptides AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Oncopeptides AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Oncopeptides AB
B.5.2	Functional name of contact point	Clinical Trials Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Västra Trädgårdsgatan 15
B.5.3.2	Town/ city	Stockholm
B.5.3.3	Post code	SE-111 53
B.5.3.4	Country	Sweden
B.5.6	E-mail	trials@oncopeptides.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/293/14
D.3 Description of the IMP
D.3.1	Product name	Melflufen
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	melphalan fulfenamide hydrochloride
D.3.9.1	CAS number	380449-54-7
D.3.9.4	EV Substance Code	SUB22033
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Dexamethason 4 mg, JENAPHARM
D.2.1.1.2	Name of the Marketing Authorisation holder	mibe GmbH Arzneimittel
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Dexamethasone
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DEXAMETHASONE
D.3.9.1	CAS number	50-02-2
D.3.9.4	EV Substance Code	SUB07017MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with Relapsed Refractory Multiple and Impaired Renal Function

E.1.1.1

Medical condition in easily understood language

Patients with Multiple Myeloma and moderate to severe renal impairment

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	HLT
E.1.2	Classification code	10028229
E.1.2	Term	Multiple myelomas
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

- To evaluate the relationship between renal function and the PK parameters for melphalan during treatment with melflufen
- To assess the safety and tolerability of melflufen in patients with moderate (cohort 1a and 1b) and severe (cohort 2) renal impairment

E.2.2

Secondary objectives of the trial

- To assess the best tumor response as well as overall response rate (ORR)
- To assess the PFS
- To assess duration of response (DOR) in patients with ≥ PR (stringent complete response (sCR), CR, VGPR, PR) as best response
- To assess clinical benefit rate (CBR) and duration of clinical benefit (i.e., proportion of patients with ≥ MR) as best response
- To assess time to response (TTR) in patients with a PR or better and time to CB for patients with MR or better.
- Overall Survival (OS)

All tumor response and progression-depended objectives are assessed by investigators according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) (Rajkumar et al. 2011) unless otherwise specified.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, age 18 years or older, at the time of signing the informed consent;
2. A prior diagnosis of MM with documented disease progression in need of treatment at time of screening;
3. Received 2- 4 prior lines of therapy.
4. Measurable disease defined as any of the following:
a. Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
b. ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP)
c. SFLC ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio;
5. Life expectancy of ≥ 6 months;
6. ECOG performance status ≤ 2. (Patients with lower performance status based solely on bone pain secondary to MM may be eligible following consultation and approval of the medical monitor);
7. Patient is a female of childbearing potential (FCBP)* with a negative serum or urine pregnancy test prior to initiation of therapy and agrees to practice appropriate methods of birth control, or the patient is male and agrees to practice appropriate methods of birth control (Section 7.1);
8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent;
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec ;
10. Renal function: Estimated GFR by CKD-EPI formula on 2 consecutive screening evaluations. Patients meeting criteria for Screening 1, must also meet criteria for Screening 2 following optimal hydration (as determined by the investigator). Screening 2 must be on or as close as possible to treatment start date (preferably < 24-48 hours) but cannot exceed 72 hours.
Cohort 1 (a and b):
Screening 1: eGFR between ≥25mL/min to <45 mL/min
Screening 2: eGFR between ≥30 mL/min to <45 mL/min.
Cohort 2 will only be enrolled following approval from the
DSMC.
Cohort 2:
Screening 1: eGFR between ≥ 15 mL/min to < 25 mL/min.
Screening 2: eGFR between ≥15 mL/min to < 30 mL/min.
Patients meeting Cohort 2, Screening 1 criteria that improve following hydration and meet Cohort 1, Screening 2 criteria may enroll in Cohort 1
Patients with fluctuating values of eGFR may be eligible following consideration of additional assessments in consultation with the medical monitor.
11. The following laboratory results must be met during screening (within 21 days) and immediately before study drug 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 therapy)
• Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without required 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), or higher in patients diagnosed with Gilbert’s syndrome, that have been reviewed and approved by the medical monitor
• Aspartate transaminase / Serum glutamic oxaloacetic transaminase (AST /SGOT) and alanine transaminase / Serum glutamic pyruvic transaminase (ALT/ SGPT) ≤ 3.0 x ULN;
12. Must have, or be willing to have, an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC] line, or central venous catheter);

E.4

Principal exclusion criteria

1. Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy);
2. Evidence of mucosal or internal bleeding and/or are platelet transfusion refraktory (platelet count fails to increase by > 10,000 cells/mm3 [10.0 x 109/L] after 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 conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months);
4. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of therapy;
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. Known human immunodeficiency virus or active hepatitis B or C viral infection;
9. Concurrent symptomatic amyloidosis or plasma cell leukemia;
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);
11. Previous cytotoxic therapies, including cytotoxic investigational agents, for 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 (mAb) within 4 weeks of initiation of therapy. Prednisone up to but no more than 10 mg orally once daily (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;
12. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 2 without pain are permitted);
13. Prior peripheral stem cell transplant within 12 weeks of initiation of therapy;
14. Prior allogeneic stem cell transplantation with active graft-versus-host- disease;
15. Prior major surgical procedure or radiation therapy within 4 weeks of initiation of study therapy this does not include limited course of radiation used for management of bone pain to be completed within 7 days of initiation of study therapy. Plasmapheresis is not permitted within 14 days of initiation of therapy;
16. Known intolerance to steroid therapy;
17. Prior renal transplant;
18. Currently in need of renal dialysis.

E.5 End points

E.5.1

Primary end point(s)

- PK parameters of melphalan
- Frequency and grade of AE’s.

E.5.1.1

Timepoint(s) of evaluation of this end point

During the course of the study

E.5.2

Secondary end point(s)

ORR: Proportion of patients with ≥ PR (sCR, CR, VGPR and PR) as best response
CBR: Proportion of patients with ≥ MR (sCR, CR, VGPR, PR and MR) as best response
PFS: defined as time (months) from date of initiation of therapy to the earlier of confirmed disease progression or death due to any cause.
DOR: defined as the time from the first evidence of confirmed assessment of sCR, CR, VGPR, or PR to first confirmed disease progression, or to death due to any cause. DOR is defined only for patients with a confirmed PR or better. Duration of clinical benefit, for patients with a confirmed MR, or better will also be evaluated.
TTR: Time from first dose or therapy to first documented confirmed response.
Best response during the study (sCR, CR, VGPR, PR, MR, SD or PD).
OS: defined as time (months) from date of initiation of therapy to death due to any cause.
Patients still alive at end of study, or lost to follow up, will be censored at last day known alive.

E.5.2.1

Timepoint(s) of evaluation of this end point

During the course of the study.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard of Care.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-06-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-12-22

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