Clinical Trials Register

Summary
EudraCT Number:	2014-001633-84
Sponsor's Protocol Code Number:	20140106
National Competent Authority:	Romania - National Agency for Medicines and Medical Devices
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-04-19
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

Romania - National Agency for Medicines and Medical Devices

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 Romania SRL
B.5.2	Functional name of contact point	Departamentul medical
B.5.3	Address:
B.5.3.1	Street Address	Bucharest Business Park, 1A Bucuresti-Ploiesti Road, Building A2, 2nd floor
B.5.3.2	Town/ city	Bucharest
B.5.3.3	Post code	013681
B.5.3.4	Country	Romania
B.5.4	Telephone number	0040215273000
B.5.6	E-mail	medinfo-romania@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 the 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

Phase 1b:
1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation.
2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5 % blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.
• To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as:
o Early first relapse (≤ 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following the original diagnosis after achieving a CR (T-ALL) OR
o First refractory bone marrow relapse occurring any time after original diagnosis after achieving a CR (ie, ≥ 1 failed attempt to induce a second remission) OR
o Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses) OR
o Failing to achieve a CR from original diagnosis after at least 1 induction attempt
3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit of normal (ULN) according to age. If serum creatinine level is ≥ 1.5 × ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2, or for children ≤ 2 years of age, ≥ 50mL/min/1.73 m2.
5. Adequate liver function, defined as both of the following:
o Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert Syndrome
o Alanine aminotransferase (ALT) ≤ 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively.

see protocol for additional phase 1b inclusion criteria

Phase 2:

1. 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.
2. Age ≥ 1 month to ≤ 21 years. Subjects ≥ 18 years must have had their original diagnosis at < 18 years of age
3. Subjects must be diagnosed with relapsed or refractory relapsed ALL
4. Subjects must have a documented first remission, ≤ 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.
5. T-cell ALL with bone marrow relapse (defined as ≥ 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 ≥5% leukemia blasts in bone marrow) after having received a targeted B-cell immune therapy as treatment for a prior relapse (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without extramedullary disease. Subjects that received blinatumomab for treatment of MRD positive disease during first remission or for primary induction failure to achieve a first remission do not qualify.

see protocol for additional Phase 2 inclusion criteria

E.4

Principal exclusion criteria

phase 1b:

1. Known allergy to any of the drugs used in the study. (Subjects who have had a previous allergy to PEG-asparaginase are eligible and if able, may receive receive Erwinia asparaginase at the investigator’s discretion)
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
3. Left ventricular fractional shortening ≤30%
4. History of ≥ Grade 2 pancreatitis
5. Active graft versus host disease requiring systemic treatment
6. Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment
7. Down Syndrome
8. Prior therapy restrictions:
o Subjects must have completed therapy with granulocyte colony stimulating factor (G CSF) or other myeloid growth factors at least 7 days before study treatment initiation, or at least 14 days before study treatment initiation, if pegylated myeloid growth factors were administered.
o Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
o At least 3 antibody half lives must have elapsed since the last dose of monoclonal antibody (e.g., 66 days for rituximab, 69 days for epratuzumab and 36 days for inotuzumab) before subjects may initiate study treatment.
o Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
o Subjects must not have received other antineoplastic agents with therapeutic intent, excluding hydroxyurea and antimetabolites administered as part of maintenance chemotherapy, within 7 days prior to study treatment initiation
9. Hepatitis B infection with positive hepatitis B DNA

see protocol for addition phase 1b exclusion criteria

Phase 2:

1. Prior treatment with carfilzomib.
2. Prior treatment with a proteasome inhibitor (other than carfilzomib) within < 3 months of enrollment or to which a subject did not respond (response is defined as bone marrow with < 5% blasts).
3. Treatment with a chemotherapy regimen including a vinca alkaloid, steroid, L asparaginase, and anthracycline combination with or without other chemotherapy agents within 2 months of enrollment (eg VXLD, VPLD, R3).
4. Intolerance, hypersensitivity, or inability to receive any of the chemotherapy components of the VXLD regimen (or acceptable substitutes as listed in the protocol). An exception is allowed for allergy to asparaginase products if Erwinia Asparaginase is unable to be administered.
5. Autologous HSCT within 6 weeks prior to start of study treatment.
6. Allogeneic HSCT within 3 months prior to start of study treatment.

Please see protocol for additional phase 2 exclusion criteria

E.5 End points

E.5.1

Primary end point(s)

Phase 1b:
• Safety and tolerability of carfilzomib alone and in combination with induction
chemotherapy as defined by the type, incidence, severity, and outcome of adverse events (AEs); changes from baseline in key laboratory analytes, vital signs, and physical findings. Time to toxicity will be evaluated to differentiate single-agent carfilzomib from carfilzomib in combination with induction chemotherapy
• Determination of the MTD as the dose that has the highest posterior probability of having a DLT rate within the target toxicity interval (20% – 33%), while the posterior probability of excessive/unacceptable toxicity (> 33% – 100%) is less than 40% (per BLRM algorithm), or the stopping rules as specified in Section 5.2, and per CSRC recommendation.

Phase 2:
• CR after induction therapy between days 29 and 45 or initiation of next therapy, whichever comes first for subjects ≥ 12 months of age at screening
• CR after induction therapy between days 36 and 50 or initiation of next therapy, whichever comes first for subjects < 12 months of age at screening

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase 1 : End of the Induction Cycle

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

E.5.2

Secondary end point(s)

Phase 1b:
•Pharmacokinetic parameters, principally maximum plasma concentration (Cmax) and area under the curve (AUC), alone and in combination with induction
chemotherapy, derived from levels of carfilzomib assayed in PK samples
• Combined proportion of subjects who achieve CR or CRp at the end of the
Induction Cycle
• Proportion of subjects who achieve MRD status ≤ 10-3 and ≤ 10-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative immunoglobulin/T-cell receptor (Ig/TcR) polymerase chain reaction (PCR)

Phase 2:

• 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 level using NGS < 10-4 after induction therapy in subjects achieving CR
• MRD level using NGS < 10-3 and < 10 4 by NGS in subjects achieving CR, CRp, CRh, or CRi after induction and consolidation therapy
• Occurrence of a stem cell transplant or CAR-T, without an intervening relapse after the end of protocol specified therapy
• 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 after consolidation therapy between days 29 and 45 or initiation of next therapy, whichever comes first, for subjects ≥ 12 months of age at screening
• CR, CRp, CRh, and CRi after consolidation therapy between days 36 and 50 or initiation of next therapy, whichever comes first, for subjects < 12 months of age at screening
• 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

Russian Federation

Singapore

Taiwan

Turkey

United States

Austria

Denmark

France

Germany

Greece

Italy

Poland

Portugal

Bulgaria

Netherlands

Romania

Spain

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1