Clinical Trials Register

Summary
EudraCT Number:	2015-001174-18
Sponsor's Protocol Code Number:	CLO21800205
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2015-05-18
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2015-001174-18

A.3

Full title of the trial

A Phase I/II Dose-Escalation Study of Clofarabine in Combination with Etoposide and Cyclophosphamide in Pediatric Patients with Refractory or Relapsed Acute Leukemias

A.3.1

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

A Study of Clofarabine in Combination With Etoposide and Cyclophosphamide in Children With Acute Leukemias

A.4.1

Sponsor's protocol code number

CLO21800205

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00315705

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	Genzyme Corporation
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	Genzyme Corporation
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	Genzyme, a Sanofi Company
B.5.2	Functional name of contact point	Trial Transparency Team
B.5.3	Address:
B.5.3.1	Street Address	-
B.5.3.2	Town/ city	-
B.5.3.4	Country	United States
B.5.6	E-mail	Contact-US@sanofi.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.2.5	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	Clofarabine
D.3.4	Pharmaceutical form	Concentrate 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	CLOFARABINE
D.3.9.1	CAS number	123318-82-1
D.3.9.3	Other descriptive name	CLOFARABINE
D.3.9.4	EV Substance Code	SUB21902
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.IMP: 2
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.2.5	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	etoposide
D.3.4	Pharmaceutical form	Concentrate 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	ETOPOSIDE
D.3.9.3	Other descriptive name	ETOPOSIDE
D.3.9.4	EV Substance Code	SUB07337MIG
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	20
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: 3
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.2.5	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	cyclophosphamide
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	CYCLOPHOSPHAMIDE MONOHYDRATE
D.3.9.1	CAS number	6055-19-2
D.3.9.3	Other descriptive name	CYCLOPHOSPHAMIDE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB16414MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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

Acute Lymphoblastic Leukemia

E.1.1.1

Medical condition in easily understood language

Acute Lymphoblastic Leukemia

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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	10000845
E.1.2	Term	Acute lymphoblastic leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective for the Phase I portion of the study is to determine the maximum tolerated dose
(MTD), dose limiting toxicities (DLTs), and the recommended Phase II dose (RP2D) of clofarabine when
used in combination with etoposide and cyclophosphamide and to assess the feasibility and safety of this
combination regimen to treat children with refractory or relapsed acute lymphocytic leukemia (ALL) or acute
myelogenous leukemia (AML).
Note: Only the Phase I portion of the study is open to both ALL and AML patients.

E.2.2

Secondary objectives of the trial

Phase I portion of the study : to determine the safety and tolerability of clofarabine when used in combination with etoposide (Ep) and cyclophosphamide (Cyp) and to determine the duration, seriousness, and relationship of adverse events that occurred during the treatment and follow-up periods;
•To determine the overall remission (OR) rate (complete remission [CR ]+ CR without
platelet recovery [CRp]) of clofarabine plus Ep and Cyp in pediatric patients with
refractory or relapsed ALL at the established clofarabine RP2D in combination with Ep and Cyp;
• To document the rate of partial remission (PR[s]) in the study population;
• To document time-to-event parameters, including duration of remission, event free survival (EFS),
4-month EFS, and overall survival (OS);and
• To characterize the pharmacodynamics of intracellular clofarabine triphosphate in combination with
etoposide and cyclophosphamide in a subset of patients treated at institutions with sample-processing
expertise.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•NOTE: the following eligibility criteria were applicable to acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study).
•ALL with > 25% blasts in bone marrow; AML with ≥ 5% blasts in bone marrow; ALL and AML patients may have extramedullary disease
•Karnofsky Performance Status ≥ 50 for patients > 10 years old; Lansky Performance Status ≥ 50 for patients ≤ 10 years old
•Prior therapy: AML: 1-2 prior induction regimens and ≤ 1 hematopoietic stem cell transplant (HSCT); ALL: 1-3 prior induction regimens
•Adequate liver, renal, pancreatic, and cardiac function
•Have received no prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)

E.4

Principal exclusion criteria

•NOTE: the following eligibility criteria were applicable to ALL and AML patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study).
•Burkitt's leukemia
•Previous treatment with clofarabine
•Uncontrolled systemic fungal, bacterial or other infection and 48 hrs negative blood cultures required for patients with a history of fever within 3 days of enrollment
•Active CNS involvement (i.e., should be CNS1 or CNS2)
•Inadequate time since last therapy: ≤ 14 days since last cytotoxic chemotherapy; ≤ 7 days since last biologic therapy; ≤ 14 days since last monoclonal antibody therapy
•Have received prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)
•Pregnant or lactating
•Have tested positive for hepatitis B or hepatitis C infection or history of cirrhosis

E.5 End points

E.5.1

Primary end point(s)

- Maximum Tolerated Dose (MTD) in Phase 1
- Participants With Dose Limiting Toxicity in Phase 1
- Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2

E.5.1.1

Timepoint(s) of evaluation of this end point

- Maximum Tolerated Dose (MTD) in Phase 1: Up to Day 42 (Phase 1 portion of study)
- Participants With Dose Limiting Toxicity in Phase 1: Up to Day 42 (Phase 1 portion of study)
- Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2: Approximately 28-56 days (Phase 2 portion of study)

E.5.2

Secondary end point(s)

1- Summary of Participants With Adverse Events (AEs) in Phase 1
2- Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1
3- Time to Remission for Participants Who Had a Response in Phase 1
4- Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1
5- Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1
6- Number of Participants With 4-month Event Free Survival in Phase 1
7- Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1
8- Summary of Participants With Adverse Events (AEs) in Phase 2
9- Time to Remission for Participants Who Had a Response in Phase 2
10- Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2
11- Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2
12- Number of Participants With 4-month Event Free Survival in Phase 2
13- Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2

E.5.2.1

Timepoint(s) of evaluation of this end point

1- Up to 9.5 months (Phase 1 portion of study)
2- Approximately 2 months
3- Up to 8 weeks (Phase 1 portion of study)
4- Up to 2 years (Phase 1 portion of study)
5- Up to 2 years (Phase 1 portion of study)
6- 4 months (Phase I portion of study)
7- Up to 2 years (Phase 1 portion of study)
8- Up to 9.5 months (Phase 2 portion of study)
9- Up to 8 weeks (Phase 2 portion of study)
10- Up to 2 years (Phase 2 portion of study)
11- Up to 2 years (Phase 2 portion of study)
12- 4 months (Phase 2 portion of study)
13- Up to 2 years (Phase 2 portion of study)

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

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)

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

A Phase I/II Dose-Escalation Study of Clofarabine in Combination with Etoposide and Cyclophosphamide

E.7.2

Therapeutic exploratory (Phase II)

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

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.8.9.2

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

Number of subjects for this age range:

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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