Clinical Trials Register

Summary
EudraCT Number:	2011-003407-38
Sponsor's Protocol Code Number:	8669-062
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-11-18
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
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

France - ANSM

A.2

EudraCT number

2011-003407-38

A.3

Full title of the trial

A Phase I Study of Monotherapy Dalotuzumab and
Ridaforolimus-Dalotuzumab Combination Treatment in Pediatric Patients with Advanced Solid Tumors

A.3.1

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

Monotherapy Dalotuzumab and Ridaforolimus-Dalotuzumab Combination Therapy

A.3.2

Name or abbreviated title of the trial where available

Monotherapy Dalotuzumab and Ridaforolimus-Dalotuzumab Combination Therapy

A.4.1

Sponsor's protocol code number

8669-062

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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme Corp., a subsidiary of Merck
B.5.2	Functional name of contact point	Global Clinical Trials Operations
B.5.3	Address:
B.5.3.1	Street Address	One Merck Drive, P.O. Box 100
B.5.3.2	Town/ city	Whitehouse Station
B.5.3.3	Post code	08889-0100
B.5.3.4	Country	United States
B.5.4	Telephone number	12673057094
B.5.5	Fax number	12673051255
B.5.6	E-mail	robert_iannone@merck.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	No
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	Dalotuzumab
D.3.2	Product code	MK-0646
D.3.4	Pharmaceutical form	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	dalotuzumab
D.3.9.1	CAS number	1005389-60-5
D.3.9.2	Current sponsor code	MK-0646
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	No
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/3/05/312
D.3 Description of the IMP
D.3.1	Product name	Ridaforolimus
D.3.2	Product code	MK-8669
D.3.4	Pharmaceutical form	Gastro-resistant tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ridaforolimus
D.3.9.1	CAS number	572924-54-0
D.3.9.2	Current sponsor code	MK-8669
D.3.9.3	Other descriptive name	AP23573, rapa-p-ester, deforolimus (former USAN)
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	10
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

advanced solid tumors including lymphoma and tumors of the central nervous system

E.1.1.1

Medical condition in easily understood language

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	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10065143
E.1.2	Term	Malignant solid tumour
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part 1
• To define the dose limiting toxicities and maximum tolerated dose of dalotuzumab when administered as monotherapy to children from 3 to less than 18 years of age with advanced solid tumors.
• To characterize the pharmacokinetics of dalotuzumab when administered as monotherapy to children from 3 to less than 18 years of age with advanced solid tumors.

Part 2
• To define the dose limiting toxicities and maximum tolerated dose of ridaforolimus and dalotuzumab when administered in combination to children from 6 to less than 18 years of age with advanced solid tumors.
• To characterize the pharmacokinetics of ridaforolimus and dalotuzumab when administered in combination to children from 6 to less than 18 years of age with advanced solid tumors.

Part 3
• To further characterize the safety, tolerability, and pharmacokinetics of ridaforolimus and dalotuzumab when administered in combination to children from 6 to less than 18 years of age with advanced solid tumors.

E.2.2

Secondary objectives of the trial

• To assess for anti-tumor activity of dalotuzumab and ridaforolimus.
• To compare change from baseline pAKT in platelet rich plasma between ridaforolimus monotherapy (historical data) and the ridaforolimus plus dalotuzumab combination at the corresponding ridaforolimus dose levels.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or female age 6 to 17 years (included) on day of signing informed consent are eligible for Parts 1-3 of this study. Additionally, children ages 3 to 5 years are eligible for treatment in the dalotuzumab monotherapy dose escalation cohort (Part 1).
• Histologic or cytologic diagnosis of a malignant solid tumor, including tumors of the central nervous system and lymphoma that have progressed despite standard therapy or for which no effective standard therapy is known.
• Patient must be able to swallow tablets. (Patients to be enrolled into Parts 2 & 3).
• Performance Status: Lansky Play Scale ≥70 for children <10 years of age; Karnofsky score ≥70 for children ≥10 to <16 years; or ECOG Status 0-2 for patients age 16 and older.
• Patient has a Body Surface Area (BSA) that allows evaluation of the current dose level. (For Ridaforolimus-containing Parts 2 and 3 only)
• For females of reproductive potential, a negative pregnancy test must be documented within 72 hours of receiving the first dose of study medication.

E.4

Principal exclusion criteria

• Patients currently receiving any other investigational agents or using any investigational devices.
• Patients with leukemia.
• Patients who have previously received dalotuzumab or other IGF-1R inhibitors (Part 1).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dalotuzumab (Patients to be enrolled into Parts 1-3) or ridaforolimus (Patients to be enrolled into Parts 2-3).
• Patient has persistent acute toxicity from previous therapy ≥ Grade 2 by NCI CTCAE Version 4 (excluding alopecia, neuropathy, or hearing loss).
• Uncontrolled intercurrent illness.
• Pregnancy or females who are breastfeeding.
• Patients to be enrolled into Parts 2-3 only: Patient has a requirement for concurrent treatment with medications that are inducers or inhibitors of cytochrome P450 (CYP3A). Patients should be off these medications for at least 2 weeks prior to the first dose of ridaforolimus.
• Patient has poorly controlled Type 1 or 2 diabetes, defined as a fasting glucose >160 mg/dL.

E.5 End points

E.5.1

Primary end point(s)

• Safety endpoint: DLT rate
• Pharmacokinetics: Mean Day-5 log AUC 0-24 for ridaforolimus. Mean Day-8 pre-dose serum concentration for dalotuzumab.

E.5.1.1

Timepoint(s) of evaluation of this end point

• First 21 days of treatment for safety endpoint
• First days 1-8 for PK endpoints

E.5.2

Secondary end point(s)

• Response rate defined as the proportion of patients whose best response is Partial Response or Complete Response (per RECIST 1.1).
• Summary of change in pAKT between ridaforolimus monotherapy (historical data) and the ridaforolimus plus dalotuzumab combination.

E.5.2.1

Timepoint(s) of evaluation of this end point

• For the duration of study (until discontinuation) for efficacy
• For the duration of study (until discontinuation) for pAKT

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

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

E.7.1.3.1

Other trial type description

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.8.3

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

Canada

France

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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

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	Number of subjects for this age range:	30
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	Yes
F.1.1.5.1	Number of subjects for this age range:	15
F.1.1.6	Adolescents (12-17 years)	Yes
F.1.1.6.1	Number of subjects for this age range:	15
F.1.2	Adults (18-64 years)	No
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	12
F.4.2	For a multinational trial
F.4.2.1	In the EEA	30
F.4.2.2	In the whole clinical trial	60

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

2012-02-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-09-25

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