Clinical Trials Register

Summary
EudraCT Number:	2008-005806-38
Sponsor's Protocol Code Number:	NO21884
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:	2009-08-06
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

2008-005806-38

A.3

Full title of the trial

A multiple ascending dose study to evaluate the safety, tolerability and effect on tumor response of the mTOR inhibitor (RAD001) in combination with the IGF-1R antagonist (R1507) in patients with advanced solid tumors

A.4.1

Sponsor's protocol code number

NO21884

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	F.Hoffmann-La Roche Ltd.
B.1.3.4	Country	Switzerland
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
B.5.2	Functional name of contact point

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	huMab IGF1-R
D.3.2	Product code	RO4858696/F05
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	RO4858696
D.3.9.3	Other descriptive name	R1507 (CHO)
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	125
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	R1507 is a fully human monoclonal IgG1 antibody with specificity for human IGF-1R
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.2.1.1.1	Trade name	AFINITOR
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma Stein AG
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/449
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Everolimus
D.3.9.2	Current sponsor code	3745429.013
D.3.9.3	Other descriptive name	RAD001
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	5
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

PIb: solid malignancy that is metastatic or unresectable
PII: C 1: Advanced metastatic renal cell carcinoma
C 2: Advanced low- to intermediate grade metastatic or unresectable locoregional pancreatic neuroendocrine tumors + carcinoid tumors

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10050076
E.1.2	Term	Metastatic renal carcinoma

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10065147
E.1.2	Term	Malignant solid tumor

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10052399
E.1.2	Term	Neuroendocrine tumour

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10026664
E.1.2	Term	Malignant pancreatic islet neoplasm

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

P Ib:
• To characterize the safety and tolerability of R1507 administered every 3 weeks in combination with daily RAD001 and to determine the maximum-tolerated dose (MTD) of RAD001 administered orally daily, in combination with R1507 administered intravenously every 3 weeks in patients with advanced solid malignancies, and to determine the recommended dose of RAD001 for the phase II study of the combined regimen.
P II:
• To assess the clinical activity of combination R1507 and RAD001 in two cohorts of patients, defined by:
• PFS rate at 24 weeks, in a cohort of patients with advanced stage renal cell carcinoma [RCC cohort],
• PFS rate at 24 weeks, in a cohort of patients with advanced low to intermediate grade metastatic or unresectable locoregional pancreatic neuroendocrine tumors (pNET) and carcinoid tumors, [NET cohort].
• NOTE: the NET cohort will be comprised of equal numbers of patients of 2 tumor subgroups, (pancreatic islet cell tumors and carcinoid tumors)

E.2.2

Secondary objectives of the trial

Phase Ib:
• To describe the tolerability and adverse event profile of the combination of R1507 and RAD001 in patients with advanced solid tumors.
• To describe pharmacokinetics (PK) of the combination of RAD001 and R1507 using a population PK approach
• To evaluate preliminary anti-tumor activity of the combination.

Phase II:
• To determine the overall objective response rate, response duration, progression-free survival and overall survival in two cohorts of patients 1) patients with advanced stage renal cell carcinoma (RCC) cohort, and 2) patients with advanced low- to intermediate grade metastatic or unresectable locoregional neuroendocrine tumors (NET) cohort.
• To determine the tolerability and adverse event profile of combination R1507 and RAD001 in patients with advanced solid tumors.
• To describe pharmacokinetics (PK) of the combination of RAD001 and R1507 using a population PK approach.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Roche Clinical Repository (RCR):
Exploratory Objectives Specimens stored in the RCR will be used for research purposes with the aim of identifying
• Dynamic biomarkers that are predictive of response to R1507 and RAD001 treatment (in terms of dose, safety and tolerability);
• Gene expression profiles of genes known to be involved in cancer pathogenesis, or genes differentially expressed relative to response or dose response;
• Genetic and pharmacogenomic analysis aimed at identifying genes associated with treatment response, toxicity or disease risk.

E.3

Principal inclusion criteria

1. [Phase Ib] Patients must have histologically confirmed recurrent or refractory advanced solid malignancy with no known standard of care according to the judgment of the investigator (including Hodgkin’s and non-Hodgkin’s lymphoma)

[Phase II] Patients must have histologically confirmed:
• Advanced metastatic renal cell carcinoma (RCC) with evidence of progressive disease despite prior VEGFr- TKI therapy.
• Advanced low- to intermediate grade metastatic or unresectable locoregional pancreatic neuroendocrine tumors (pNET) and carcinoid tumors who have failed standard therapy and have evidence of progressive disease. Patients with either carcinoid or islet cell tumors
will be included in this cohort.

2. Measurable disease according to RECIST in Phase II

3. Male and female patients, ≥ 18 years age

5. Patients with treated, asymptomatic, stable CNS metastases are eligible for enrollment only if:
• Patient has received prior treatment to the site(s) of CNS metastatic disease at least 4 weeks prior to treatment
• Patient has no requirement for glucocorticoids (discontinued at least 3 weeks prior to treatment)
• Patient is not taking anticonvulsants (discontinued at least 3 weeks prior to treatment)
• Patient has no overt evidence of neurological deficit

6. ECOG performance status 0-2

7. Patients must have adequate organ and marrow function

8. Negative pregnancy test (serum β-HCG) within 7 days of startingStudy treatment in women of childbearing potential (both premenopausal women and women < 2 years after the onset of menopause).

10. HbA1c ≤ 7% at screening.

E.4

Principal exclusion criteria

1. Prior treatment with agents that act via inhibition of the IGF-1R
pathway.

2. Prior treatment with agents that act via mTOR inhibition (e.g. sirolimus, temsirolimus, everolimus) for the phase II portion only.

3. Patients with untreated CNS metastases.

5. Previous or current anti cancer therapy: Patients who are currently receiving any anti cancer therapy (other than those administered on this study) or who have received:
• Radiotherapy ≤ 4 weeks prior to enrollment
• Chemotherapy (including biologic therapy) ≤ 4 weeks prior to enrollment
• Patients who have received therapy more than 4 weeks prior to enrollment who have not recovered adverse events to ≤ grade 1, (excluding alopecia)

7. History of allogeneic bone marrow transplantation or organ transplantation.

11. Patients who are pregnant or breastfeeding.

12. Fertile men and women of childbearing potential not employing an effective method of birth control throughout the trial and for 3 months after last study drug administration in both sexes. Women of childbearing potential must have a negative pregnancy test (serum β- HCG) within the 7 days prior to study drug administration.

13. Known hypersensitivity to R1507 or its excipients or to RAD001 or compounds of similar chemical or biologic composition to RAD001.

14. Any known severe and/or uncontrolled medical conditions

E.5 End points

E.5.1

Primary end point(s)

The primary endpoints are defined according to the cohort in which a patient is entered into the study:
– Progression-free survival rate at 24 weeks after start of therapy in the advanced renal cell carcinoma cohort
– Progression-free survival rate at 24 weeks in the advanced NET cohort.

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

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability, biomarkers research

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 finding

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

Information not present in EudraCT

E.8.1.2

Open

Information not present in EudraCT

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Information not present in EudraCT

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

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Information not present in EudraCT

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

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

see protocol section 3.1.5 page 66:
Each patient may remain in the study until the development of progressive disease, intolerable toxicity or any other criteria for removal as set forth in the protocol.
For analysis purposes, the study will be considered “complete” when all patients have completed the tumor evaluationsand enough information on PFS has been gathered, (30 weeks for patients with RCC and 12 months for patients with neuroendocrine tumors).

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	No
F.1.1.1	In Utero	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
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	50
F.4.2	For a multinational trial
F.4.2.1	In the EEA	94
F.4.2.2	In the whole clinical trial	134

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

2009-10-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-06-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-06-06

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