Clinical Trials Register

Summary
EudraCT Number:	2022-002169-14
Sponsor's Protocol Code Number:	TAK-573-2001
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2022-12-20
Trial 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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2022-002169-14

A.3

Full title of the trial

A Phase 1/2a Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Modakafusp Alfa in Combination With Daratumumab Subcutaneous in Patients With Relapsed or Refractory Multiple Myeloma

A.3.1

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

A Study of Modakafusp Alfa in Combination With Daratumumab Subcutaneous in Patients With Relapsed/Refractory Multiple Myeloma

A.4.1

Sponsor's protocol code number

TAK-573-2001

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	Takeda Development Center Americas, Inc.
B.1.3.4	Country	United States
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	Takeda Development Center Americas, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Takeda Development Center Americas, Inc.
B.5.2	Functional name of contact point	Lam Calderon
B.5.3	Address:
B.5.3.1	Street Address	95 Hayden Avenue
B.5.3.2	Town/ city	Lexington
B.5.3.3	Post code	MA 02421
B.5.3.4	Country	United States
B.5.4	Telephone number	847.736.1497
B.5.6	E-mail	Lam.Calderon@Takeda.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Modakafusp Alfa
D.3.2	Product code	TAK-573
D.3.4	Pharmaceutical form	Powder for concentrate 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	Modakafusp alfa
D.3.9.2	Current sponsor code	TAK-573
D.3.9.4	EV Substance Code	SUB198192
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Darzalex 1800 mg solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	EU/3/13/1153
D.3 Description of the IMP
D.3.1	Product name	Darzalex
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Daratumumab
D.3.9.1	CAS number	945721-28-8
D.3.9.4	EV Substance Code	SUB175772
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	1800
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Multiple Myeloma

E.1.1.1

Medical condition in easily understood language

Relapsed or Refractory Multiple Myeloma

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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

Phase 1 Dose Escalation
- To determine the safety and tolerability of modakafusp alfa in combination with daratumumab subcutaneous (SC).

Phase 2a Dose Finding
- To inform the recommended phase 2 dose (RP2D) of modakafusp alfa in combination with daratumumab SC.
- To provide a preliminary evaluation of the clinical efficacy of modakafusp alfa in combination with daratumumab SC as measured by overall response rate (ORR).

E.2.2

Secondary objectives of the trial

Phase 1 Dose Escalation
- To characterize the PK profile of modakafusp alfa and daratumumab in the combination setting.
- To characterize antimyeloma activity as measured by ORR, DOR, PFS, and OS.
- To characterize the immunogenicity of modakafusp alfa in combination with daratumumab SC.
- To characterize measurable (minimal) residual disease (MRD) negativity and duration of MRD negativity.

Phase 2a Dose Finding
- To determine DOR, CBR, DCB, DCR, duration of disease control, time to progression, TTR, TTNT, PFS, and OS.
- To further characterize safety and tolerability of modakafusp alfa in combination with daratumumab SC.
- To collect PK data for modakafusp alfa to support population PK and E-R analysis.
- To collect PK data for daratumumab SC to assess any potential impact of immunogenicity on daratumumab PK.
- To further characterize the immunogenicity of modakafusp alfa in combination with daratumumab SC.
- To characterize MRD negativity and duration of MRD negativity.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Each patient must meet all the following criteria to be enrolled in the study:
1. Patients aged 18 years or older.
2. Documented multiple myeloma (MM) diagnosis per International Myeloma Working Group (IMWG) criteria.
3. Measurable disease, defined as at least 1 of the following:
a. Serum M protein ≥0.5 g/dL (≥5 g/L) on serum protein electrophoresis (SPEP).
b. Urine M protein ≥200 mg/24 hours on urine protein electrophoresis (UPEP).
c. Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal.
4. For patients in the phase 1 dose escalation only:
Must have received at least 3 prior lines of therapy, including at least 1 PI, 1 IMiD, and 1 anti-CD38 mAb drug; or who are triple refractory to a PI, an IMiD, and an anti-CD38 mAb drug, regardless of the number of prior line(s) or therapy.
5. For patients in phase 2a dose finding only:
a. Received 1 to 3 prior line(s) of antimyeloma therapy.
b. Must be refractory to prior lenalidomide treatment.
c. Patients must be sensitive (nonrefractory) or naïve to prior anti-CD38 mAb treatment.
d. Documented progressive disease on or after the last regimen.
e. Patients must have PR or better to at least 1 line of prior therapy...

Please see Protocol Section 7.1 for full inclusion criteria

E.4

Principal exclusion criteria

Patients meeting any of the following criteria are not to be enrolled in the study:
1. Prior exposure to modakafusp alfa.
2. Patient has POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, plasma cell leukemia, or lymphoplasmacytic lymphoma.
3. Patient has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE, Version 5 Grade ≤1 or baseline, except for alopecia.
4. Previous allogeneic stem cell transplant at any time or ASCT within 12 weeks of planned start of dosing...

Please see Protocol Section 7.2 for full exclusion criteria.

E.5 End points

E.5.1

Primary end point(s)

Phase 1 Dose Escalation
- dose-limiting toxicity (DLT) incidences.
- Frequency and severity of treatment-emergent adverse event (TEAEs) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.

Phase 2a Dose Finding
- overall response rate (ORR), defined as the proportion of patients who achieved a confirmed response of partial response (PR) or better during the study as assessed by the investigator.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 60 months

E.5.2

Secondary end point(s)

Phase 1 Dose Escalation
- Summary statistics by dose level and cycle day for the following PK parameters for modakafusp alfa for Cycles 1 and 2:
– Single-dose maximum observed serum concentration (Cmax).
– Time of first occurrence of Cmax (tmax).
– Area under the serum concentration-time curve from time 0 to infinity (AUC∞).
– Area under the serum concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast).
– Apparent serum modakafusp alfa terminal disposition rate constant.
– Apparent serum modakafusp alfa terminal disposition phase half-life.
– Clearance.
– Volume of distribution at steady state after intravenous (IV) administration.
- Summary statistics by dose level and cycle day for the following PK parameters for daratumumab for Cycles 1 and 2:
– Single-dose Cmax.
– tmax.
– Single-dose and multiple-dose observed concentration at the end of a dosing interval (Ctrough).
– AUC∞.
– AUClast.
- ORR by the investigator.
- DOR by the investigator.
- PFS by the investigator.
- OS.
- ADA incidence and characteristics (eg, titer and specificity) and neutralizing antibody (NAb).
- Rate of MRD[-] CR, at a threshold of 10-5, with CR assessed by the investigator.
- Rate of MRD[-], at a threshold of 10-5.
- Duration of MRD negativity, at a threshold of 10-5.

Phase 2a Dose Finding
- DOR by investigator.
- CBR response of sCR, CR, very good partial response (VGPR), PR, or minimal responses by investigator.
- DCB by investigator.
- DCR (CBR + stable disease [SD]) by investigator.
- Duration of disease control by investigator.
- TTP by investigator.
- TTR by investigator.
- TTNT.
- PFS by investigator.
- OS.
- Frequency and severity of TEAEs according to the NCI CTCAE, Version 5.0.
- ADA incidence and characteristics (eg, titer and specificity) and NAb.
- Rate of MRD[-] CR, at threshold of 10-5, with CR assessed by the investigator.
- Rate of MRD[-], at a threshold of 10-5.
- Duration of MRD negativity, at a threshold of 10-5.

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 60 months

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability, Immunogenicity

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

China

Korea, Republic of

United States

France

Spain

Czechia

Germany

Hungary

United Kingdom

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

The final analysis for the clinical study report will be conducted after all patients enrolled in the study have completed all study assessments as outlined in the Schedules of Event (SOEs) or have withdrawn from the study.

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)

At the end or termination of the study, ongoing patients who continue benefiting from modakafusp alfa in combination with daratumumab SC, have no locally available comparable or satisfactory alternative therapeutic option, and would be negatively affected without continued access to modakafusp alfa, in the opinion of the investigator and confirmed by the sponsor, may continue to receive modakafusp alfa through the posttrial access (PTA) program (where permitted by local regulations).

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

2023-03-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-02-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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