Clinical Trials Register

Summary
EudraCT Number:	2012-004490-10
Sponsor's Protocol Code Number:	2012_32
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-07-09
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2012-004490-10

A.3

Full title of the trial

A Multicenter Open label Phase 2 study of Carfilzomib Weekly plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma.

A.3.1

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

A Multicenter Open label Phase 2 study of Carfilzomib Weekly plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma.

A.4.1

Sponsor's protocol code number

2012_32

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	Ghent University Hospital
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AMGEN
B.4.2	Country	United States
B.4.1	Name of organisation providing support	CHRU Lille
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ghent University Hospital
B.5.2	Functional name of contact point	Bimetra Clinics
B.5.3	Address:
B.5.3.1	Street Address	C. Heymanslaan 10
B.5.3.2	Town/ city	Ghent
B.5.3.3	Post code	9000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3293320500
B.5.5	Fax number	+3293320520
B.5.6	E-mail	Bimetra.Clinics@uzgent.be

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	Yes
D.2.1.1.1	Trade name	Kyprolis
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	France
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/3/08/548
D.3 Description of the IMP
D.3.1	Product name	Carfilzomib (KYPROLIS)
D.3.2	Product code	PR171
D.3.4	Pharmaceutical form	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Carfilzomib
D.3.9.1	CAS number	868540-17-4
D.3.9.2	Current sponsor code	2012_32
D.3.9.3	Other descriptive name	CARFILZOMIB
D.3.9.4	EV Substance Code	SUB32911
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 70
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

A Multicenter Open label Phase 2 study of Carfilzomib Weekly plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma.

E.1.1.1

Medical condition in easily understood language

untreated Symptomatic elderly Multiple Myeloma

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10028228
E.1.2	Term	Multiple myeloma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine MTD of Carfilzomib Weekly based on definition of DLTs

E.2.2

Secondary objectives of the trial

• To determine the VGPR (Very Good Partial Response) + CR (complete response) rate of Carfilzomib weekly at the MTD + MP at the end of the 9 induction cycles
• To determine the safety profile of Carfilzomib weekly +MP for the first 9 cycles and during maintenance.
• To determine the safety profile of Carfilzomib Weekly according to doses in the first part of the study
• To determine the response rate (Partial response and better), the stringent CR rate (sCR) and Immunophenotypic CR (MRD; Will be performed by in Nantes, France) during the first 9 cycles and during maintenance.
• To determine the clinical benefit response rate (CBR, Minor response and better).
• To determine the Progression-free Survival (PFS), Event-free Survival (EFS), and Time to Progression (TTP)
• To determine the Overall Survival
• To determine the Time to response and Response duration

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Must be able to understand and voluntarily sign an informed consent form
2. Must be able to adhere to the study visit schedule and other protocol requirements
3. Age ³ 65 years (at least 65 years of age or older)
4. Life expectancy > 6 months.
5. Patients must have Symptomatic Measurable previously Untreated MM, as defined below:
5.1. Symptomatic MM diagnostic criteria (all 3 required)
• Monoclonal plasma cells in the bone marrow ≥10%
• Monoclonal protein present in the serum and/or urine.
• Myeloma-related organ dysfunction (at least one of the following)1
[C] Calcium elevation in the blood (serum calcium >10.5 mg/dl or upper limit of normal)
[R] Renal insufficiency (serum creatinine >2 mg/dL)
[A] Anemia (hemoglobin <10 g/dL or 2 g < normal)
[B] Lytic bone lesions and/or presence of a biopsy-proven plasmacytoma*
1 A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma-related.
*If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then > 30% plasma cells are required in the bone marrow or proven plasmocytic infiltration in bone marrow biopsy

5.2. AND have measurable disease as defined by the following: Patients must have a clearly detectable and quantifiable monoclonal M-component value in the serum and/or urine.
 IgG (serum M-component > 10g/l)
 IgA (serum M-component > 5g/l)
 IgD (serum M-component > 0.5g/l)
 Light chain (serum M-component >1g/l or Bence Jones > 200mg/24H)
 Serum FLC assay: involved FLC level > 10 mg/dl provided serum FLC ratio is abnormal
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
7. Adequate bone marrow function, documented within 72 hours and without transfusion 5 days prior to the first intake of investigational product (C1J1) nor growth factor support, defined as:
• Absolute neutrophils ≥ 0.75 x109/L,
• Untransfused Platelet count ≥ 75 x109/L
• Hemoglobine ≥8.5 g/L
8. Adequate organ function defined as:
• Serum total bilirubin < 2.0 mg/dL
• Clairance creatinine ≥ 30ml/min
• Serum SGOT/AST or SGPT/ALT < 2.5x upper limit of normal (ULN)
9. Subjects affiliated with an appropriate social security system.
10. Male subjects must:
10.1. Understand the potential teratogenic, and genotoxic risk of Melphalan if engaged in sexual activity with a pregnant female or a female of childbearing potential.
10.2. Understand the potential genotoxic risk of Carfilzomib if engaged in sexual activity with a pregnant female or a female of childbearing potential.
10.3. Practice complete abstinence or understand the need and agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential throughout the entire duration of study treatment, during dose interruptions and until at least 3 months after the end of treatment discontinuation of CMP, even if he has undergone a successful vasectomy. If pregnancy or a positive pregnancy test does occur in the partner of a male study patient during study participation, the investigator must be notified immediately.
10.4. Agree not to donate semen or sperm during study drug therapy and until at least 3 months after the end of treatment discontinuation of CMP.

E.4

Principal exclusion criteria

1. Any other uncontrolled medical condition or comorbidity that might interfere with subject’s participation.
2. Known positive for HIV or active infectious hepatitis, type B or C.
3. Patients with non-secretory MM and non-measurable MM
4. Patient with terminal renal failure that require dialysis and clairance creatinine < 30 ml/min
5. Prior history of malignancies, other than multiple myeloma, unless the patients has been free of the disease for ≥ 5 years. Exceptions include the following:
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix or breast
• Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
6. Prior local irradiation within two weeks before first dose
7. Evidence of central nervous system (CNS) involvement
8. Unable to take corticotherapy at study entry (according to Summary of Cortancyl’s Characteristics)
9. Ongoing active infection
10. Any ongoing adverse event or medical history > grade 2 severity
11. Refusal to participate in the study
12. Persons protected by a legal regime (guardianship, trusteeship)
13. Alkeran’s (Melphalan) contraindication: Hypersensitivity to Melphalan or to any other constituents.
14. Patients with heart failure class 3 and 4 according to the NYHA criteria, or patients with past history of myocardial infarction within the last 6 months or no controlled cardiac conduction abnormalities.
15. Patients with a left ventricular ejection fraction under or equal to 30 % (LVEF ≤ 30%).
16. Female of childbearing potential (Females are defined as not of childbearing potential if documentation of “Natural menopause for at least 24 consecutive months, a hysterectomy, or bilateral oophorectomy”).

E.5 End points

E.5.1

Primary end point(s)

To determine MTD of Carfilzomib Weekly. If dose-limiting toxicities (DLTs) occur in fewer than 3 of these patients per cohort, the next cohort of 6 patients (cohort 2, 3 and 4) will be N+1 up to cohort 4. If at any time during cycle 1 of a dose cohort, > 2 subjects experience a drug-related DLT, the MTD will have been exceeded, additional enrolment within the cohort will cease, and dose escalation will stop. The MTD will be defined as the dose level below which DLT is observed in >33% (i.e. > 2 of 6) subjects in a cohort.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the study when the last patient will have relapsed

E.5.2

Secondary end point(s)

•To determine the VGPR (Very Good Partial Response) + CR (Complete Response) rate of Carfilzomib Weekly at the MTD + MP at the end of the 9 induction cycles using International Myeloma Working Group (IMWG) response criteria
•To determine the Safety profile (type, frequency, severity, and relationship of adverse events to study treatment). Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Events (SAE) and laboratory abnormalities using National Cancer Institute (NCI) common toxicity criteria for the first 9 cycles and during maintenance.
• To determine the safety profile of Carfilzomib Weekly according to doses in the first part of the study
• To determine the Overall Response rate [Partial (PR) and better] using IMWG response criteria and to determine the sCR rate using IMWG response criteria (12) during the first 9 cycles and during maintenance.
• Minor response will be determined using EBMT criteria
• To determine the Progression-free Survival (PFS, from the date of inclusion to the date of the progression); Event-free Survival (EFS, from the date of inclusion to the date of any event, progression, death or any other cause for end of treatment); Time to progression (TTP, from the date of inclusion to the date of the progression or death, whichever occurs first); Overall Survival (OS, from the date of inclusion to the date of the last news);
• To determine the Time to response (TTR, from the date of inclusion to the date of the first observation of response) and Response duration (DOR, time between first documentation of response and disease progression)

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the study when the last patient will have relapsed

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

To determine MTD of Carfilzomib Weekly based on definition of DLTs

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.8.3

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

Patients may continue study until PD develops at which time they will complete a Study Discontinuation visit as outlined in Table 1. In addition, patients who are discontinued from study treatment will be followed for survivals and subsequent MM treatment regimens

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)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Intergroupe Francophone du Myélome (IFM)
G.4.3.4	Network Country	France

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-08-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-18

P. End of Trial
P.	End of Trial Status	Ongoing

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