Clinical Trials Register

Summary
EudraCT Number:	2018-000665-36
Sponsor's Protocol Code Number:	20180015
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-06-08
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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2018-000665-36

A.3

Full title of the trial

A Randomized, Open-label, Phase 3 Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination with Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (A.R.R.O.W.2)

Randomizované, otvorené klinické skúšanie fázy 3, ktoré porovnáva užívanie karfilzomibu raz týždenne verzus dvakrát týždenne, v kombinácii s lenalidomidom a dexametazónom, u pacientov s relabujúcim alebo refraktérnym mnohopočetným myelómom (A.R.R.O.W.2)

A.3.1

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

A Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination with Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

A.3.2

Name or abbreviated title of the trial where available

A.R.R.O.W.2

A.4.1

Sponsor's protocol code number

20180015

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	Amgen 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	Amgen 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	Amgen Slovakia s.r.o.
B.5.2	Functional name of contact point	Medicínske informačné centrum
B.5.3	Address:
B.5.3.1	Street Address	Digital park, Einsteinova 23
B.5.3.2	Town/ city	Bratislava
B.5.3.3	Post code	85101
B.5.3.4	Country	Slovakia
B.5.4	Telephone number	+421232111449
B.5.6	E-mail	euskmedinfo@amgen.sk

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	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/3/08/548
D.3 Description of the IMP
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	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	CARFILZOMIB
D.3.9.4	EV Substance Code	SUB32911
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.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

Relapsed or Refractory 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	21.0
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

compare efficacy of
56 mg/m2 carfilzomib administered
once-weekly in combination with
lenalidomide and dexamethasone
(KRd 56 mg/m2) to
27 mg/m2 carfilzomib administered
twice-weekly in combination with
lenalidomide and dexamethasone
(KRd 27 mg/m2) in subjects with
RRMM with 1 to 3 prior lines of
therapy

E.2.2

Secondary objectives of the trial

*compare progression-free survival
(PFS) between treatment arms
*compare patient-reported
convenience with carfilzomib-dosing
schedule between treatment arms

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

*Subject has provided informed consent prior to initiation of any study-specific
activities or procedures or subject’s legally acceptable representative has
provided informed consent prior to any study-specific activities/procedures being
initiated when the subject has any kind of condition that, in the opinion of the
Investigator, may compromise the ability of the subject to give written informed
consent.
*Males or females ≥ 18 years of age.
*Documented relapse or progressive multiple myeloma after last treatment
(Subjects refractory to the most recent line of therapy are eligible, unless last
treatment contained PI or lenalidomide and dexamethasone).
*Subjects must have at least PR to at least 1 line of prior therapy.
*Subjects must have received at least 1 but not more than 3 prior lines of therapy
for multiple myeloma (induction therapy followed by stem cell transplant and
consolidation maintenance therapy will be considered as 1 line of therapy). See
Section 12.8 for guidelines for documenting prior treatment.
* Prior therapy with a PI or the combination of lenalidomide and dexamethasone
are allowed if,
• the patient had at least a PR to the most recent therapy with a PI or lenalidomide
and dexamethasone,
• neither PI or lenalidomide and dexamethasone in combination were ceased
due to toxicity, (unless at the time of enrollment that toxicity was neuropathy not exceeding grade
2 which has either resolved or if ongoing is ≤ grade 1),
• the patient has not received a PI and has not received lenalidomide and
dexamethasone in combination in the 6 months prior to first study
treatment. (Patients are permitted to have received single agent
lenalidomide as maintenance therapy during the 6-months prior to first study
treatment).
*Previous treatment with a lenalidomide and dexamethasone containing regimen
is allowed, as long as the subject did not progress during the first 3 months after
initiating lenalidomide and dexamethasone containing therapy.
Measurable disease with at least 1 of the following assessed within 28 days prior
to randomization:
• IgG multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL
• IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL
• urine M-protein ≥ 200 mg per 24 hours
• in subjects without measurable serum or urine M-protein, serum-free light
chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum
kappa lambda ratio
*Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0  2
(see Section 12.9).

E.4

Principal exclusion criteria

Disease-related
*Waldenström macroglobulinemia.
*Multiple myeloma of IgM subtype.
*POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal
protein, and skin changes).
*Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard
differential).
*Primary amyloidosis (patients with multiple myeloma with asymptomatic
deposition of amyloid plaques found on biopsy would be eligible if all other
criteria are met).
*Myelodysplastic syndrome.
Other Medical Conditions
*History of other malignancy within the past 5 years, with the following exceptions:
• Malignancy treated with curative intent and with no known active disease
present for ≥ 3 years before enrollment and felt to be at low risk for
recurrence by the treating physician
• Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Adequately treated breast ductal carcinoma in situ without evidence of
disease
• Prostatic intraepithelial neoplasia without evidence of prostate cancer
• Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in
situ
• Treated medullary or papillary thyroid cancer
• Similar neoplastic conditions with an expectation of > 95% 5-year
disease-free survival
* Known HIV infection, hepatitis C infection (subjects with hepatitis C that achieve
a sustained virologic response after antiviral therapy are allowed), or hepatitis B
infection (subjects with hepatitis B surface antigen or core antibody that achieve
sustained virologic response with antiviral therapy are permitted with a
requirement for regular monitoring for reactivation for the duration of
treatment on the study).
*Ongoing graft-vs-host disease.
*Acute active infection requiring systemic antibiotics, antifungal, antiviral (except
antiviral therapy directed at hepatitis B) agents within 14 days prior to
randomization.
*Known cirrhosis.
*Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior
to randomization.
*Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to randomization.
Cardiopulmonary Conditions
* Uncontrolled hypertension, defined as subject whose blood pressure exceeds
≥ 160 mmHg - systolic or ≥ 100 mmHg diastolic when taken in accordance with the European Society of Hypertension/European Society of Cardiology 2018 guidelines. (Section 12.10; Williams et al, 2018).
*Active congestive heart failure (New York Heart Association Class III to IV),
symptomatic ischemia, uncontrolled arrhythmias, screening ECG with corrected
QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction
within 4 months prior to randomization.
*Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
*History of interstitial lung disease or ongoing interstitial lung disease.
Prior/Concomitant Therapy
*Immunotherapy within 28 days prior to randomization.
*Monoclonal antibody therapy within 28 days prior to randomization.
*Chemotherapy with approved anticancer therapeutic within 28 days prior to
randomization.
*Glucocorticoid therapy within 14 days prior to randomization that exceeds a
cumulative dose of 160 mg of dexamethasone or equivalent dose of other
corticosteroids.
*Focal radiation therapy within 7 days prior to randomization. Radiation therapy to
an extended field involving a significant volume of bone marrow within 28 days
prior to randomization (ie, prior radiation must have been to < 30% of the bone
marrow).
*Major surgery (except kyphoplasty) within 28 days prior to randomization.
*Autologous or allogeneic stem cell transplant within 90 days prior to
randomization.
*Contraindication or intolerance to lenalidomide, dexamethasone, or carfilzomib.
*Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize
carfilzomib).
*Subject has known hypersensitivity to any of the products or components to be
administered during dosing, including hypersensitivity to antiviral drugs.
Prior/Concurrent Clinical Study Experience
*Currently receiving treatment in another investigational device or drug study, or
< 28 days since ending treatment on another investigational device or drug
study(ies).
Organ Function Assessments
* Hepatic dysfunction within 28 days prior to randomization:
• direct bilirubin ≥ 1.5x the upper limit of normal (ULN)
• aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
≥ 2.5 x ULN
*Left ventricular ejection fraction < 40% assessed by transthoracic
echocardiogram (ECHO).
*Absolute neutrophil count (ANC) < 1 x 109/L within 28 days prior to
randomization. Screening ANC should be independent of growth factor support
for ≥ 1 week.

E.5 End points

E.5.1

Primary end point(s)

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] per
International Myeloma Working Group
Uniform Response Criteria [IMWG-URC]) over the duration of the study

E.5.1.1

Timepoint(s) of evaluation of this end point

Over the duration of the study

E.5.2

Secondary end point(s)

* PFS over the duration of the study
*convenience as measured by the
Patient-reported Convenience With
Carfilzomib-dosing Schedule Question
after cycle 4 of treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

*1-year PFS
*convenience as measured by the
Patient-reported Convenience With
Carfilzomib-dosing Schedule Question
after cycle 4 of treatment

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

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)

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

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

115

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

Austria

Bulgaria

Canada

Czechia

Finland

France

Germany

Greece

Japan

Lithuania

Netherlands

Romania

Russian Federation

Slovakia

Spain

Sweden

Turkey

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

LVLS

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:

230

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

230

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

254

F.4.2.2

In the whole clinical trial

460

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-09-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-21

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

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