Clinical Trials Register

Summary
EudraCT Number:	2014-001633-84
Sponsor's Protocol Code Number:	CFZ008
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2015-01-26
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

Spain - AEMPS

A.2

EudraCT number

2014-001633-84

A.3

Full title of the trial

Phase 1b/2 Study of Carfilzomib in Combination with Dexamethasone, Mitoxantrone, PEG-asparaginase, and Vincristine (UK R3 Induction Backbone) in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia

Estudio de fase Ib/II de carfilzomib en combinación con dexametasona, mitoxantrona, PEG-asparaginasa y vincristina (esquema de inducción de UK R3) en niños con leucemia linfoblástica aguda recurrente o resistente

A.3.1

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

A.4.1

Sponsor's protocol code number

CFZ008

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	Dawn Pinchasik, MD
B.5.3	Address:
B.5.3.1	Street Address	249 E. Grand Avenue
B.5.3.2	Town/ city	South San Francisco
B.5.3.3	Post code	94103
B.5.3.4	Country	United States
B.5.4	Telephone number	0034917088600
B.5.5	Fax number	001650266-0387
B.5.6	E-mail	dpinchasik@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	Yes
D.2.1.1.1	Trade name	Kyprolis
D.2.1.1.2	Name of the Marketing Authorisation holder	Onyx Therapeutics Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	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

Leucemia linfoblástica aguda recurrente o resistente

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.

Un grupo de cánceres que normalmente comienzan en la médula ósea y que ocasionan un elevado número de glóbulos blancos anormales

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	18.0
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.

Phase 2
-To estimate the combined rate of bone marrow CR and bone marrow CRp at the end of the Induction Cycle

Fase Ib
- Evaluar la seguridad y tolerabilidad de carfilzomib, solo y en combinación con quimioterapia de inducción, para el tratamiento de niños con leucemia linfoblástica aguda (LLA) recurrente o resistente al tratamiento
- Determinar la dosis máxima tolerada (DMT) de carfilzomib en combinación con quimioterapia de inducción

Fase II
- Estimar la tasa combinada de RC medular y RCp medular al final del ciclo de inducción

E.2.2

Secondary objectives of the trial

Phase 1b
-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
-To estimate the proportion of subjects who achieve MRD status < 10-3 and < 10-4 lymphoblasts at the end of the Induction Cycle
-To assess the safety and tolerability of carfilzomib in combination with induction chemotherapy, for the treatment of children with multiply relapsed ALL
-To characterize the PK of carfilzomib in combination with induction
chemotherapy

Fase Ib
- Caracterizar la farmacocinética (FC) del carfilzomib solo y en combinación con quimioterapia de inducción
- Evaluar la tasa combinada de respuesta completa (RC) medular y de RC medular sin recuperación plaquetaria (RCp) al final del ciclo de inducción
- Estimar la proporción de sujetos que logran un estado de enfermedad residual mínima (ERM) <10 3 y <10 4 linfoblastos al final del ciclo de inducción

Fase II
- Estimar la proporción de sujetos que logran un estado de ERM <10 3 y <10 4 linfoblastos al final del ciclo de inducción
- Evaluar la seguridad y tolerabilidad de carfilzomib en combinación con quimioterapia de inducción para el tratamiento de niños con LLA con múltiples recidivas
- Caracterizar la FC de carfilzomib en combinación con quimioterapia de inducción

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age 18 years or younger at the time of study treatment initiation.
2. Subjects must have a diagnosis of relapsed (Phase 1b and 2) or refractory (Phase 1b only) ALL with ? 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.
?- To be eligible for Phase 1b, 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 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
?- To be eligible for Phase 2, subjects must have had 2 or more prior
therapeutic attempts and have relapsed, but not refractory disease, defined as relapse after achieving a CR following the first or subsequent relapse (i.e., ? 2 relapses)
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.
5. Adequate liver function, defined as both of the following:
? Total bilirubin ? 1.5 × institutional ULN
? AST and ALT ? 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores ? 50 for subjects > 16 years old or ? 16 years old, respectively.

1. Edad de 18 años o menos en el momento del inicio del tratamiento del estudio.
2. Los sujetos deben haber sido diagnosticados de LLA recurrente (fase Ib o II) o resistente al tratamiento (fase Ib solamente) con ?5% de blastos en la médula ósea (enfermedad M2 o M3), con o sin enfermedad extramedular.
- Para ser elegibles para la fase Ib, los sujetos deben haber recibido una o varias iniciativas terapéuticas, lo que se define como:
o Primera recidiva temprana (<36 meses desde el diagnóstico original) después de lograr una RC
O BIEN
o Recidiva después de lograr una RC después de la primera recidiva o una recidiva posterior (esto es, ?2 recidivas)
O BIEN
o Ausencia de RC desde el diagnóstico original después de al menos 1 ciclo de inducción
- Para poder participar en la fase II, los sujetos deben haber recibido 2 o más iniciativas terapéuticas y haber experimentado una recidiva, pero no enfermedad resistente al tratamiento, lo que se define como una recidiva tras lograr una RC después de la primera recidiva o una recidiva posterior (esto es, ?2 recidivas)
3. Los sujetos deben haberse recuperado por completo de los efectos tóxicos agudos de todos los tratamientos quimioterapéuticos, inmunoterapéuticos o radioterapéuticos antes de la inscripción.
4. Los sujetos deben presentar un nivel de creatinina sérica que sea ?1,5 × el límite superior de la normalidad (LSN) del centro según la edad. Si el nivel de creatinina sérica es >1,5 × LSN, el sujeto debe presentar un aclaramiento de la creatinina calculado o una tasa de filtración glomerular (TFG) con radioisótopos ?70 ml/min/1,73 m2.
5. Función hepática adecuada, definida como la que cumple las dos condiciones siguientes:
? Bilirrubina total ?1,5 veces el LSN del centro
? ASAT y ALAT ?5 × LSN del centro
6. Estado funcional: puntuaciones de Karnofsky o Lansky ?50 para los sujetos >16 años o ?16 años respectivamente.

E.4

Principal exclusion criteria

1. Known allergy to any of the drugs used in the study. (Subjects who have had a previous allergy to PEG-asparaginase but can receive
Erwinia are eligible.)
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize
carfilzomib; for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals, Inc. website)
3. Left ventricular fractional shortening < 30%
4. History of pancreatitis; serum amylase > 2 × the institutional ULN
5. Active treatment for graft-versus-host disease
6. Positive culture for bacteria or fungus within 14 days of the initiation of therapy
7. Down Syndrome
8. Prior therapy restrictions:
? -Subjects must have completed therapy with granulocyte-colony stimulating factor (G-CSF) or other myeloid growth factors at least 7 days before enrollment, or at least 14 days before enrollment, if pegylated myeloid growth factors were administered.
? -Subjects must have received the last dose of a non-monoclonal antibody biologic agent at least 7 days before enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be approved by the Onyx study medical monitor.
? -At least 3 antibody half-lives must have elapsed since the last dose of monoclonal antibody (i.e., 66 days for rituximab and 69 days for
epratuzumab) before subjects may enroll in the study.
? -Subjects must have completed any type of active immunotherapy
(e.g., tumor vaccines) at least 42 days before enrollment.
? -Subjects must not have received any other antineoplastic agents within 7 days prior to enrollment.

1. Alergia conocida a alguno de los fármacos utilizados en el estudio.
(Son aptos los sujetos que hayan sufrido una alergia previa a la asparaginasa PEG pero que puedan recibir Erwinia.)
2. Alergia conocida a Captisol (un derivado de la ciclodextrina utilizado para solubilizar carfilzomib; en la página web de Ligand Pharmaceuticals, Inc. se hallará una lista completa de los fármacos con Captisol).
3. Acortamiento fraccional ventricular izquierdo <30%
4. Antecedentes de pancreatitis; amilasa sérica >2 × LSN del centro
5. Tratamiento activo para la enfermedad del injerto contra el huésped
6. Cultivo positivo para bacterias u hongos en los 14 días previos al inicio del tratamiento
7. Síndrome de Down
8. Restricciones de tratamientos previos:
? Los sujetos deben haber finalizado el tratamiento con factores estimulantes de las colonias de granulocitos (G CSF) u otros factores de crecimiento mieloides al menos 7 días antes de la inscripción, o al menos 14 días antes de la inscripción si se administraron factores de crecimiento mieloides pegilados.
? Los sujetos deben haber recibido la última dosis de un fármaco biológico sin anticuerpos monoclonales al menos 7 días antes de la inscripción. Para los fármacos que produzcan acontecimientos adversos conocidos más de 7 días después de la administración, este período debe extenderse hasta después del momento en que se sabe que se producen los acontecimientos adversos. El monitor médico del estudio de Onyx debe aprobar la duración de este intervalo.
? Para que los sujetos puedan inscribirse en el estudio, deben haber transcurrido al menos 3 semividas desde la última dosis de un anticuerpo monoclonal (esto es, 66 días para rituximab y 69 días para epratuzumab).
? Los sujetos deben haber finalizado todo tipo de inmunoterapia activa (p. ej., vacunas tumorales) al menos 42 días antes de la inscripción.
? Los sujetos no deben haber recibido ningún otro antineoplásico en los 7 días previos a la inscripción.

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 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%

Phase 2
? -Combined proportion of subjects who achieve CR or CRp at the end of the Induction Cycle

Fase Ib
- Seguridad y tolerabilidad de carfilzomib solo y en combinación con quimioterapia de inducción, definidas por el tipo, la incidencia, la intensidad y el resultado de los AA; alteraciones con respecto al inicio en los analitos de laboratorio, las constantes vitales y los hallazgos de la exploración física. El tiempo hasta la toxicidad se evaluará para diferenciar carfilzomib en monoterapia de carfilzomib en combinación con quimioterapia de inducción
- Determinación de la DMT como la dosis con la mayor probabilidad posterior de mostrar una tasa de TLD situada dentro del intervalo de toxicidad deseado (20%?33%), mientras que la probabilidad posterior de toxicidad excesiva/inaceptable (>33%?100%) es inferior al 40%

Fase II
- Proporción combinada de sujetos que logran RC o RCp al final del ciclo de inducción

E.5.1.1

Timepoint(s) of evaluation of this end point

End of the Induction Cycle

Final del ciclo de inducción

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
? -Proportion of subjects who achieve MRD status < 10-3 and < 10-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative Ig/TcR PCR
? -Safety and tolerability of carfilzomib in combination with induction
chemotherapy as defined by the type, incidence, severity, and outcome of AEs; changes from baseline in key laboratory analytes, vital signs, and physical findings
? -Pharmacokinetic parameters, principally Cmax and AUC, of carfilzomib in combination with induction chemotherapy derived from levels of carfilzomib assayed in PK samples.

Fase Ib
? Parámetros farmacocinéticos, principalmente la concentración plasmática máxima Cmáx y el área bajo la curva (ABC), de carfilzomib solo o en combinación con quimioterapia de inducción, derivados de los niveles de carfilzomib analizados en las muestras FC
? Proporción combinada de sujetos que logran RC o RCp al final del ciclo de inducción
? Proporción de sujetos que logran un estado de ERM <10 3 y <10 4 de linfoblastos al final del ciclo de inducción evaluada por la reacción en cadena de la polimerasa (RCP) cuantitativa del receptor de inmunoglobulinas/linfocitos T (Ig/TcR).

Fase II
? Proporción de sujetos que logran un estado de ERM <10 3 y <10 4 de linfoblastos al final del ciclo de inducción evaluada por la RCP cuantitativa del Ig/TcR
? Seguridad y tolerabilidad de carfilzomib en combinación con quimioterapia de inducción, definidas por el tipo, la incidencia, la intensidad y el resultado de los AA; alteraciones con respecto al inicio en los analitos de laboratorio, las constantes vitales y los hallazgos de la exploración física.
? Parámetros farmacocinéticos, principalmente la concentración plasmática máxima Cmáx y el ABC, de carfilzomib en combinación con quimioterapia de inducción, derivados de los niveles de carfilzomib analizados en las muestras FC

E.5.2.1

Timepoint(s) of evaluation of this end point

End of the Induction Cycle

Final del ciclo de inducción

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

Australia

Austria

Belgium

Canada

Denmark

France

Germany

Netherlands

Spain

Switzerland

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 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.

El fin del estudio por protocolo se define como, las evaluaciones del fin del estudio deben tener lugar 30 días (± 4 días) después de la última dosis del tratamiento del estudio

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