Clinical Trials Register

Summary
EudraCT Number:	2008-002320-29
Sponsor's Protocol Code Number:	XL184-301
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2009-07-21
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

Portugal - INFARMED

A.2

EudraCT number

2008-002320-29

A.3

Full title of the trial

An International, Randomized, Double-Blinded, Phase 3 Efficacy Study of XL184 versus Placebo in Subjects with Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer

A.3.1

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

An International clinical trial in patients with thyroid cancer investigating XL184

A.4.1

Sponsor's protocol code number

XL184-301

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	Exelixis, 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	Exelixis 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	Exelixis, Inc.
B.5.2	Functional name of contact point	Exelixis Medical Affairs
B.5.3	Address:
B.5.3.1	Street Address	1851 Harbor Bay Parkway
B.5.3.2	Town/ city	Alameda, CA
B.5.3.3	Post code	94502
B.5.3.4	Country	United States
B.5.4	Telephone number	18883935494
B.5.6	E-mail	druginfo@exelixis.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	XL184
D.3.2	Product code	XL184
D.3.4	Pharmaceutical form	Capsule, hard
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.3.9.2	Current sponsor code	XL184
D.3.9.3	Other descriptive name	XL184
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	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: 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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	XL184
D.3.2	Product code	XL184
D.3.4	Pharmaceutical form	Capsule, hard
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.3.9.2	Current sponsor code	XL184
D.3.9.3	Other descriptive name	XL184
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	80
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Medullary thyroid carcinoma (MTC)

E.1.1.1

Medical condition in easily understood language

Cancer (thyroid)

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10055107
E.1.2	Term	Thyroid cancer metastatic
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate progression free survival (PFS) with XL184 treatment as compared with placebo in subjects with unresectable, locally advanced or metastatic medullary thyroid carcinoma (MTC).

E.2.2

Secondary objectives of the trial

• To evaluate overall survival (OS) with XL184 treatment as compared with placebo
• To evaluate the objective response rate (ORR) and duration of response in subjects with measurable disease with XL184 treatment as compared with placebo, as per modified Response Evaluation Criteria In Solid Tumors (mRECIST)
• To evaluate changes in serum levels of calcitonin and CEA as prognostic biomarkers for XL184 treatment benefit as compared with placebo
• To assess the potential relationship between RET germline and/or tumor DNA sequence alteration and the efficacy of XL184
• To assess the pharmacodynamic effects of XL184
• To evaluate the safety and tolerability of XL184 treatment
• To assess the pharmacokinetics (PK) of XL184

The exploratory objective of this study is to evaluate subject self-assessment parameters and symptom burden with XL184 treatment as compared with placebo, as per the MD Anderson Symptom Inventory (MDASI) Thyroid Module.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. The subject has a histologically confirmed diagnosis of MTC that is unresectable, locally advanced, or metastatic, and disease that is measurable or non-measurable per mRECIST.
2. The subject is at least 18 years old.
3. The subject has an ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2.
4. The subject has documented progressive disease (PD) on computerized tomography (CT), magnetic resonance imaging (MRI), bone scan, or X-ray (determined by the investigator) per mRECIST at screening compared with a previous image done within 14 months of screening.
5. The subject has recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grade less than or equal to 1 from clinically significant adverse events (AEs) due to antineoplastic agents, investigational drugs, or other medications that were administered prior to randomization.
6. The subject has organ and marrow function as follows: absolute
neutrophil count greater than or equal to 1500/mm3, platelets greater than or equal to 100,000/mm3, hemoglobin greater than or equal to 9 g/dl, bilirubin less than or equal to 1.5 times the upper limit of normal (does not apply to subjects with Gilbert’s syndrome), serum creatinine less than or equal to 1.5 mg/dl, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equaly to 2.5 times the upper limit of normal.
7. Sexually active subjects must agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study treatments (excluding women who are not of child bearing potential and men who have been sterilized).
8. The subject has no other diagnosis of malignancy (unless non-melanoma skin cancer, carcinoma in situ of the cervix, or a malignancy diagnosed greater than or equal to 2 years previously) and currently has no evidence of malignancy (unless non-melanoma skin cancer or carcinoma in situ of the cervix).
9. Female subjects of childbearing potential must have a negative pregnancy test at screening. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression.

E.4

Principal exclusion criteria

1. The subject has received prior systemic anti-tumor therapy (e.g. chemotherapy, biologic modifiers or anti-angiogenic therapy) within 4 weeks of randomization (6 weeks for nitrosoureas or mitomycin C).
2. The subject has received radiation to greater than or equal to 25 % of bone marrow.
3. The subject has received treatment with other investigational agents within 4 weeks of randomization.
4. The subject has received treatment with XL184.
5. The subject has brain metastases or spinal cord compression, unless completed radiation therapy greater than or equal to 4 weeks prior to randomization and stable without steroid and without anti-convulsant treatment for greater than or equal to 10 days.
6. The subject has a history of clinically significant hematemesis or a recent history of hemoptysis of greater than 2.5 ml of red blood or other signs indicative of pulmonary hemorrhage or evidence of endobronchial lesion(s).
7. The subject has a urine protein/creatinine ratio of greater than or equal to 1 (reported in grams of protein over grams of creatinine).
8. The subject has serious intercurrent illness, such as hypertension (two or more blood pressure readings performed at screening of greater than 140 mmHg systolic or greater than 90 mmHg diastolic) despite optimal treatment, unhealed wounds from recent surgery, or cardiac arrhythmias; or a recent history of serious disease such as either symptomatic congestive heart failure or unstable angina pectoris within the past 3 months, or myocardial infarction, stroke or transient ischemic attack within the past 6 months.
9. The subject is pregnant or breastfeeding.
10. The subject has an active infection requiring systemic treatment.
11. The subject has a known allergy or hypersensitivity to any of the components of the XL184 or placebo formulations.
12. The subject is incapable of understanding and complying with the protocol or unable to provide informed consent.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is duration of PFS.

E.5.1.1

Timepoint(s) of evaluation of this end point

Duration of PFS (every 12 weeks)

E.5.2

Secondary end point(s)

The key secondary efficacy endpoints for this study are duration of OS and ORR.

E.5.2.1

Timepoint(s) of evaluation of this end point

For subjects who are alive at the time of data cutoff or are permanently lost to follow-up, duration of OS will be right censored at the date the subject was last known to be alive.

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

E.6.10

Pharmacogenetic

Yes

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)

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)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

Austria

Belgium

Brazil

Canada

Chile

Denmark

France

Germany

Greece

India

Israel

Italy

Korea, Republic of

Netherlands

Poland

Portugal

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

To observe at least 217 deaths to evaluate overall survival (OS) as a key secondary endpoint.

A total of 217 deaths are required to provide 80% power to detect a 50% improvement in OS (HR = 0.667) using the log-rank test and a 2-sided significance level of 4%.

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

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)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

250

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

250

F.4.2.2

In the whole clinical trial

315

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)

Patients will be treated by standard of care at the physician's discretion.

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

2009-08-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-12-04

P. End of Trial
P.	End of Trial Status	Ongoing

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