Clinical Trials Register

Summary
EudraCT Number:	2012-000128-16
Sponsor's Protocol Code Number:	2011-003
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-08-09
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Greece - EOF

A.2

EudraCT number

2012-000128-16

A.3

Full title of the trial

A Randomized, Open-label, Phase 3 Study of Carfilzomib Plus Dexamethasone vs Bortezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma

A.3.1

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

Phase 3 study with carfilzomib and dexamethasone versus velcade and dexamethasone for relapsed multiple myeloma patients

A.4.1

Sponsor's protocol code number

2011-003

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	Onyx Therapeutics, 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	Onyx Therapeutics, 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	Onyx Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Heidi Gillenwater, Clinical Science
B.5.3	Address:
B.5.3.1	Street Address	249 East Grand Avenue
B.5.3.2	Town/ city	South San Francisco
B.5.3.3	Post code	CA 94080
B.5.3.4	Country	United States
B.5.4	Telephone number	0014349781494
B.5.6	E-mail	hgillenwater@onyx.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	EU/3/08/548
D.3 Description of the IMP
D.3.1	Product name	Carfilzomib
D.3.2	Product code	PR-171
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	Carfilzomib
D.3.9.1	CAS number	868540-17-4
D.3.9.2	Current sponsor code	PR-171
D.3.9.3	Other descriptive name	FP-101; 506160
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	2
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	Comparator
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	Velcade
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	Belgium
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	Velcade
D.3.4	Pharmaceutical form	Powder for solution for injection
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	BORTEZOMIB
D.3.9.1	CAS number	179324-69-7
D.3.9.4	EV Substance Code	SUB20020
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	1
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

Multiple myeloma

E.1.1.1

Medical condition in easily understood language

Bone marrow cancer

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10028228
E.1.2	Term	Multiple myeloma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 compare progression-free survival (PFS) in patients with multiple myeloma relapsed after 1 to 3 prior therapies treated with either carfilzomib plus dexamethasone (Cd) or bortezomib (Velcade®) plus dexamethasone (Vd).

E.2.2

Secondary objectives of the trial

To compare the following between the treatment groups:
- Overall Survival (OS)
- Overall Response Rate (ORR) [defined as the proportion of best
overall response of stringent Complete Response (sCR), Complete
Response (CR), Very Good Partial Response (VGPR), and Partial
Response (PR)]
- Duration of Response (DOR)
- Neuropathy Events (defined from Grade 2 or higher peripheral
neuropathy incidence, and FACT/GOG-NTx [version 4; "Additional Concerns" questionnaire] score)
- Health-related quality of life (HR-QOL) (measured by European
Organization for Research and Treatment of Cancer [EORTC] Core
Module [QLQ-C30] and Multiple Myeloma Module [QLQ-MY20)]
questionnaires)
- Safety and Tolerability

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacokinetic sub-study (will not be conducted in Greece):
Blood samples will be collected from approximately 100 patients in the Cd arm for measurement of plasma carfilzomib concentrations and subsequent estimation of a number of pharmacokinetic parameters.

Pharmacodynamics and Biomarkers sub-study (will no be conducted in Greece):
Pharmacodynamics in the form of proteasome inhibition will be measured in whole blood and isolated peripheral blood mononuclear cells collected from at least 15 patients per treatment arm. Analysis of biomarkers predictive of response to proteasome inhibitors will also be performed on these samples, as will genomic and proteomic analyses in an attempt to determine biomarkers that predict for response metrics and safety signals.

ECHO sub-study (will not be conducted in Greece):
A transthoracic ECHO to assess LVEF will be conducted on all patients at screening, within 21 days prior to randomization. A subset of patients from both arms (a minimum of 100 patients and a maximum of 300 patients total; 50 to 150 patients per treatment arm, depending on input from the data monitoring committee [DMC]) will be assessed for LVEF with transthoracic ECHO every 12 weeks and at end of treatment
Pharmacogenetic sub-study (will be conducted in Greece): Bone marrow sample will be collected from consenting patients at screening/baseline visit for future DNA and protein analysis

E.3

Principal inclusion criteria

1.Multiple myeloma with relapsing or progressing disease at study entry.
2.Patients must have evaluable multiple myeloma with, at least one of the following (assessed within 21 days prior to randomization):
•Serum M-protein ≥ 0.5 g/dL, or
•Urine M-protein ≥ 200 mg/24 hour, or
•In patients without detectable serum or urine M-protein, serum free light chain (FLC) > 100 mg/L (involved light chain) and an abnormal / ratio (>4:1 or <2:1), or
•For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL).
3.Patients must have documented at least PR to at least 1 line of prior therapy. PR documentation can be based on Investigator assessment.
4. Received at least 1, but no more than 3 prior treatment regimens or lines of therapy for
multiple myeloma. (Induction therapy followed by stem cell transplant and
consolidation/maintenance therapy will be considered as one line of therapy).
5. Prior therapy with Velcade is allowed as long as the patient had at least a PR to prior
Velcade therapy, was not removed from Velcade therapy due to toxicity, and will have at
least a 6 month Velcade treatment-free interval from last dose received until first study
treatment. (Patients may receive maintenance therapy with drugs that are not in the
proteasome inhibitor class during this 6 month Velcade treatment-free interval).
6. Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to prior carfilzomib therapy, was not removed from carfilzomib therapy due to toxicity, and had at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not in the proteasome inhibitor class during this 6 month carfilzomib treatment-free interval). The exception to this are patients randomized or previously randomized in any other Onyx-Sponsored Ph 3 trial
7.Males and females ≥ 18 years of age.
8. ECOG Performance Status of 0 to 2.
9. Adequate hepatic function within 21 days prior to randomization, with bilirubin
< 1.5 times the ULN, and AST and ALT < 3 times the ULN.
10. LVEF ≥ 40%. 2-D transthoracic ECHO is the preferred method of evaluation. MUGA is acceptable if ECHO is not available.
11. ANC ≥ 1000/mm3 within 21 days prior to randomization. Screening ANC should be independent of growth factor support for ≥ 1 week.
12. Hemoglobin ≥ 8.0 g/dL within 21 days prior to randomization. Use of erythropoietic stimulating factors and RBC transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.
13. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow is > 50%) within 21 days prior to randomization. Patients should not have received
platelet transfusions for at least 1 week prior to obtaining the screening platelet count.
14. Calculated or measured CrCl of ≥ 15 mL/min within 21 days prior to randomization. Calculation should be based on standard formula such as the Cockcroft and Gault: [(140 – Age)  Mass (kg) / (72  Creatinine mg/dL)]; multiply result by 0.85 if female.
15. Written informed consent in accordance with federal, local, and institutional guidelines.
16. FCBP must have a negative serum pregnancy test within 21 days prior to randomization and agree to use an effective method of contraception during and for 3 months following
last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations). Postmenopausal females (> 45 years old and without menses for > 1 year)
and surgically sterilized females are exempt from a pregnancy test.
17. Male patients must agree to use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.

E.4

Principal exclusion criteria

1. Multiple myeloma of IgM subtype.
2. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days prior to randomization.
3. POEMS syndrome.
4. Plasma cell leukemia or circulating plasma cells ≥ 2 × 109/L.
5. Waldenstrom’s Macroglobulinemia.
6. Patients with known amyloidosis.
7. Chemotherapy with approved or investigational anticancer therapeutics within 21 days prior to randomization.
8. Patients randomized or previously randomized in any other Onyx-sponsored Phase 3 trial.
9. Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to randomization (i.e., prior radiation must have been to less than 30% of the bone marrow).
10. Immunotherapy within 21 days prior to randomization.
11. Major surgery (except kyphoplasty) within 28 days prior to randomization.
12. Active congestive heart failure (NYHA Class III to IV; refer to Appendix H), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior to randomization.
13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to randomization.
14. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B SAg or core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed).
15. Patients with known cirrhosis.
16. Second malignancy within the past 3 years except:
- adequately treated basal cell or squamous cell skin cancer
- carcinoma in situ of the cervix
- prostate cancer < Gleason Score 6 with stable PSA over the past 12 months
- breast carcinoma in situ with full surgical resection
- treated medullary or papillary thyroid cancer
17. Patients with myelodysplastic syndrome.
18. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days prior to randomization.
19. Female patients who are pregnant or lactating.
20. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
21. Patients with hypersensitivity to carfilzomib, Velcade, boron, or mannitol.
22. Patients with contraindication to dexamethasone.
23. Contraindication to any of the required concomitant drugs or supportive treatments,including hypersensitivity to antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
24. Ongoing graft-vs-host disease.
25. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization.
26. Any other clinically significant medical disease or psychiatric condition that, in the Investigator’s opinion, may interfere with protocol adherence or a patient’s ability to give informed consent.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is PFS by Independent Review Committee (IRC)

E.5.1.1

Timepoint(s) of evaluation of this end point

Study is expected to have required number of PFS events approximately 8 months after enrollment is complete

E.5.2

Secondary end point(s)

The secondary endpoints are:
•Overall survival
•Overall Response Rate (defined as the proportion of best overall response of sCR, CR, VGPR, and PR); by IRC
•Duration of Response; by Independent Review Committee
•Neuropathy Events (defined from Grade 2 or higher peripheral neuropathy incidence, and FACT/GOG-NTx [version 4; "Additional Concerns" questionnaire] score)
•HR-QOL (assessed by EORTC QLQ-C30 and QLQ-MY20 questionnaires)
•Safety and Tolerability

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary end points are to be evaluated at the time of the final OS analysis when the required number of events have been reached, estimated at approximately 78 months after the enrollment start.

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

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

Yes

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)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

Austria

Belgium

Brazil

Bulgaria

Canada

Czech Republic

France

Germany

Greece

Hungary

India

Israel

Italy

Korea, Republic of

New Zealand

Poland

Romania

Russian Federation

Slovakia

Taiwan

Ukraine

United Kingdom

United States

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

End of the study defined as when the final OS analysis takes place

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:

592

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

296

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

340

F.4.2.2

In the whole clinical trial

888

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)

Not applicable

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

2012-07-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-02-05

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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