Clinical Trials Register

Summary
EudraCT Number:	2014-001633-84
Sponsor's Protocol Code Number:	20140106
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-02-12
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2014-001633-84

A.3

Full title of the trial

Phase 1b/2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia

A.3.1

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

Phase 1b/2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia

A.4.1

Sponsor's protocol code number

20140106

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02303821

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/016/2021

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Onyx Therapeutics, Inc., an Amgen Inc. subsidiary
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., an Amgen Inc. subsidiary
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 Biotechnologia Sp. z o.o.
B.5.2	Functional name of contact point	Medical Information
B.5.3	Address:
B.5.3.1	Street Address	ul. Pulawska 145
B.5.3.2	Town/ city	Warszawa
B.5.3.3	Post code	02-715
B.5.3.4	Country	Poland
B.5.4	Telephone number	+4822581 30 00
B.5.5	Fax number	+4822581 30 01
B.5.6	E-mail	medinfo-pol@amgen.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	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.3.1	Product name	Carfilzomib Lyophilisate for Solution for Injection
D.3.2	Product code	PR-171
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 Acute Lymphoblastic Leukemia

E.1.1.1

Medical condition in easily understood language

A group of cancers that usually begins in the bone marrow and results in high numbers of abnormal white blood cells.

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	10025230
E.1.2	Term	Lymphatic leukemia
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

Phase 1b:
- To assess the safety and tolerability of carfilzomib, alone and in combination with induction chemotherapy, for the treatment of children with relapsed or refractory acute lymphoblastic leukemia (ALL)
-To determine the maximum tolerated dose (MTD) of carfilzomib in combination with induction chemotherapy and to recommend a phase 2 dose of carfilzomib in combination with induction chemotherapy

Phase 2:
- Compare the rate of CR of CFZ-VXLD at the end of induction therapy to an appropriate external control.

E.2.2

Secondary objectives of the trial

Phase 1:
-To characterize the pharmacokinetics (PK) of carfilzomib alone and in combination with induction chemotherapy
-To evaluate the combined rate of bone marrow complete response (CR) and bone marrow CR without platelet recovery (CRp) at the end of the Induction Cycle
-To estimate the proportion of subjects who achieve minimal residual disease (MRD) status ≤ 10-3 and ≤ 10-4 lymphoblasts at the end of the Induction Cycle

Phase 2:
-Compare the rate of CR, CRp, CRh, and CRi of CFZ-VXLD at the end of induction therapy relative to an appropriate external control
-Compare EFS for CFZ VXLD to an appropriate external control
-Compare OS for CFZ-VXLD relative to an appropriate external control
-Estimate DOR for CFZ-VXLD relative to an appropriate external control
-Estimate the rate of MRD[-] at the end of induction in subjects receiving CFZ-VXLD

refer to protocol for additional secondary objectives

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

110 Subject's legally acceptable representative has provided informed
consent when the subject is legally too young to provide informed
consent and the subject has provided written assent based on local
regulations and/or guidelines prior to any study-specific
activities/procedures being initiated, except for standard of care local
testing as permitted per Section 21.3.
111 Age greater than or equal to 1 month to less than 21 years. Subjects
greater than or equal to 18 years must have had their original diagnosis
at less than 18 years of age.
112 Subjects must be diagnosed with relapsed or refractory relapsed
ALL.
113 Subjects must have a documented first remission, less than 5%
blasts in the bone marrow (M1 bone marrow) and no evidence of
extramedullary disease.
114 T-cell ALL with bone marrow relapse (defined as greater than or
equal to 5% leukemia blasts in bone marrow) or refractory relapse with
or without extramedullary disease.
OR
B-cell ALL with bone marrow relapse or refractory relapse (defined as
greater than or equal to 5% leukemia blasts in bone marrow) after
having received a targeted B-cell immune therapy (eg, blinatumomab,
inotuzumab, or a CAR-T therapy) with or without extramedullary
disease.
115 Adequate liver function: bilirubin less than or equal to 1.5 x upper
limit of normal (ULN), alanine aminotransferase (ALT) less than or equal
to 5 x ULN.
116 Adequate renal function: serum creatinine less than or equal to 1.5 x
ULN or glomerular filtration rate (GFR) greater than or equal to 70
mL/min/1.73 m2; or for children less than 2 years of age, greater than
or equal to 50 mL/min/1.73 m2.
117 Adequate cardiac function: shortening fraction greater than or equal
to 30% or ejection fraction greater than or equal to 50%.
118 Karnofsky (subjects greater than or equal to 16 years of age) or
Lansky (subjects 12 months to less than 16 years of age) performance
status greater than or equal to 50%.
119 Subjects must have fully recovered from the acute toxic effects of all
previous chemotherapy, immunotherapy, or radiotherapy treatment
before enrolment (for example: recovery from gastrointestinal toxicity
may occur more rapidly than less reversible organ toxicities such as
sinusoidal obstruction syndrome or non-infectious pneumonitis, for
serious prior toxicities recommend discussion with Amgen medical
monitor).
120 Life expectancy of greater than 6 weeks per investigator`s
judgment at time of screening

E.4

Principal exclusion criteria

211 Prior treatment with carfilzomib.
214 Intolerance, hypersensitivity, or inability to receive any of the
chemotherapy components of the VXLD regimen. An exception is allowed
for allergy to asparaginase products if Erwinia asparaginase is unable to
be administered.
215 Autologous HSCT within 6 weeks prior to start of study treatment.
216 Allogeneic HSCT within 3 months prior to start of study treatment.
217 Active GVHD requiring systemic immune suppression.
218 < 30 days from discontinuation of immune suppressive therapy
administered for the treatment of acute or chronic GVHD.
219 Isolated extramedullary relapse.
220 Positive bacterial or fungal infection within 14 days of enrolment
(except for documented line infection, line has been removed, and blood
culture after line removal is negative for 5 days prior to first dose of
induction therapy). Antibiotics may be administered for prophylaxis as
per institutional standards up to and after enrollment.
221 Subjects with < 3 antibody half-lives since the last dose of
monoclonal antibody, prior to first dose of investigational product must
be discussed with the Amgen medical monitor and may be allowed to
enroll based on extent of disease or evidence of rapidly rising peripheral
or bone marrow blast counts.
222 Cell-based immunotherapy within 42 days prior to first dose of
investigational product. If the Amgen medical monitor agrees, an
exception may be granted to the 42-day requirement for subjects with
rapidly rising peripheral or bone marrow blast counts.
223 Down's syndrome.
224 Presence of another active cancer.
225 History of grade greater than or equal to 2 pancreatitis within 6
months to screening
226 Unresolved toxicities from prior anticancer therapy, defined as not
having resolved to CTCAE version 4.03 grade 1 or to levels dictated in
the eligibility criteria apart from alopecia or toxicities from prior
anticancer therapy that are considered irreversible and do not trigger
another exclusion criterion (defined as having been present and stable
for greater than 4 weeks)
227 Antitumor therapy within 7 days of day 1 of induction. Exception:
hydroxyurea to control peripheral blood leukemic cell counts is allowed
until start of investigational product.
228 Active viral infection, including but not limited to CMV, Hepatitis B
with positive serum hepatitis surface antigen or hepatitis B DNA, HIV,
Hepatitis C with detectable hepatitis C RNA. Subjects who have
previously received a stem cell transplant must be screened for CMV
infection, unless both subject and donor are known to be CMV negative.
229 Currently receiving treatment in another investigational device or
product study, or less than 14 days since ending treatment on another
investigational device or product study.
230 Uncontrolled arrhythmias or screening ECG with corrected QTc >
470 msec.
231 History or evidence of any other clinically significant disorder,
condition or disease that, in the opinion of the investigator or Amgen
physician, if consulted, would pose a risk to subject safety or interfere
with the study evaluation, procedures or completion.
232 Female subject is pregnant/breastfeeding or planning to become
pregnant/breastfeed during treatment and for an additional 6 months
after the last dose of any study treatment or for 12 months after last
dose of cyclophosphamide if administered during optional consolidation
cycle.
233 Female subjects of childbearing potential unwilling to use 1 highly
effective method of contraception during treatment and for an additional
6 months after the last dose of any study treatment or for 12 months
after last dose of cyclophosphamide if administered during optional
consolidation cycle.
234 Female subjects of childbearing potential with a positive pregnancy
test assessed at Screening by a serum or urine pregnancy test.
235 Male subjects with a female partner of childbearing potential who
are unwilling to practice sexual abstinence or use a condom with
spermicide during treatment and for an additional 6 months after the
last dose of any study treatment, even if they have undergone a successful vasectomy.
236 Male subjects with a pregnant partner who are unwilling to practice
abstinence or use a condom with spermicide during treatment, for
duration of pregnancy, and for an additional 6 months after the last dose
of any study treatment.
237 Male subjects unwilling to abstain from donating semen or sperm
during treatment and for an additional 6 months after the last dose of
any study treatment.
238 Known allergy to captisol.

E.5 End points

E.5.1

Primary end point(s)

CR after induction therapy

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase 2: The OR for the PoCR for CFZ-VXLD versus external control.

E.5.2

Secondary end point(s)

•Treatment-emergent and treatment-related adverse events and severe
adverse events and laboratory abnormalities during the induction
therapy and consolidation therapy
•CR, CRp, CRh, and CRi at the end of induction therapy
•EFS, defined as time from initiation of therapy until treatment failure
(defined as failure to reach at least a CRi after consolidation or after
induction in subjects that do not receive consolidation), relapse, or
death from any cause
•OS defined as time from initiation of therapy until death from any cause
•DOR, defined as time from earliest of CR, CRp, CRh, or CRi to relapse or
death from any cause
•MRD status using NGS less than 10-3 and less than 10-4 by NGS in
subjects achieving CR, CRp, CRh, or CRi after induction and consolidation
therapy
•MRD status using NGS >10^-4 after induction therapy in subjects
achieving CR
•Occurrence of a stem cell transplant or CAR-T, without an intervening
relapse after the end of protocol specified therapy
•CR, CRp, CRh, and CRi after consolidation therapy
•Carfilzomib pharmacokinetic parameters, including AUC, Cmax and if
feasible t1/2

E.5.2.1

Timepoint(s) of evaluation of this end point

End of the Induction Cycle

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

Yes

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

dose-escalation study

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)

Information not present in EudraCT

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

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

Argentina

Australia

Brazil

Canada

Hong Kong

Israel

Korea, Republic of

Mexico

Singapore

Taiwan

United States

Austria

France

Poland

Bulgaria

Netherlands

Romania

Spain

Germany

Greece

Italy

Denmark

Portugal

Russian Federation

Turkey

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 study per protocol is defined as, the end of study assessments must be completed 30 days (± 4 days) following the last dose of study treatment.

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

Yes

F.1.1