Clinical Trials Register

Summary
EudraCT Number:	2019-002184-97
Sponsor's Protocol Code Number:	CABOCOL-01
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:	2019-10-18
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

France - ANSM

A.2

EudraCT number

2019-002184-97

A.3

Full title of the trial

A phase II study assessing safety and efficacy of Cabozantinib for advanced or metastatic cervical carcinoma after platinum treatment failure

Etude de phase II évaluant l’efficacité et la tolérance du Cabozantinib dans le traitement du cancer du col avancé ou métastatique après échec d’un traitement par sel de platine

A.3.1

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

A phase II study assessing safety and efficacy of Cabozantinib for advanced or metastatic cervical carcinoma after platinum treatment failure

Etude de phase II évaluant l’efficacité et la tolérance du Cabozantinib dans le traitement du cancer du col avancé ou métastatique après échec d’un traitement par sel de platine

A.3.2

Name or abbreviated title of the trial where available

CABOCOL-01

A.4.1

Sponsor's protocol code number

CABOCOL-01

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	Centre François Baclesse
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	IPSEN Laboratories
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Centre François Baclesse
B.5.2	Functional name of contact point	Chef de Projet/recherche clinique
B.5.3	Address:
B.5.3.1	Street Address	3 Avenue du Général Harris
B.5.3.2	Town/ city	CAEN
B.5.3.3	Post code	14076
B.5.3.4	Country	France
B.5.4	Telephone number	332314550505384
B.5.5	Fax number	33231455158
B.5.6	E-mail	a.leconte@baclesse.unicancer.fr

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	CABOZANTINIB
D.2.1.1.2	Name of the Marketing Authorisation holder	IPSEN PHARMA
D.2.1.2	Country which granted the Marketing Authorisation	France
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	CABOMETYX
D.3.4	Pharmaceutical form	Coated 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	CABOZANTINIB
D.3.9.1	CAS number	849217-68-1
D.3.9.4	EV Substance Code	SUB93452
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 60
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

Recurrent unresectable or metastatic cervix carcinoma

Cancer du col avancé ou métastatique après échec d’un traitement par sel de platine

E.1.1.1

Medical condition in easily understood language

Recurrent unresectable or metastatic cervix carcinoma

Cancer du col avancé ou métastatique après échec d’un traitement par sel de platine

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10008344
E.1.2	Term	Cervix carcinoma recurrent
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

To assess efficacy and safety of cabozantinib in monotherapy in advanced/metastatic cervical cancer (CC) after failure of platinum-based regimen treatment.

L’objectif principal sera basé sur les critères principaux d’efficacité et de sécurité proposés dans la conception de Bryant-and-Day

E.2.2

Secondary objectives of the trial

- The safety profile of cabozantinib
- The objective response (RECIST v1.1 criteria)
- The progression-free and overall survival
- The health-related quality-of-life (QoL) of patients
To constitute biological collections (blood, tumoral tissue) for further biological explorations

- Le profil de tolérance du cabozantinib
- La réponse objective (critères RECIST v1.1)
- La survie sans progression et globale
- La qualité de vie des patients

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Female 18 years of age or older
- Histologically confirmed recurrent unresectable or metastatic cervix carcinoma
- Patient may have received at least one prior chemotherapy regimen of platinum-based chemotherapy for recurrence or metastatic disease. Cisplatin given in combination with radiation for a localized disease does not count as a prior chemotherapy. Prior treatment for advanced/metastatic disease with bevacizumab is allowed. Prior treatments with immune checkpoint inhibitors are allowed.
- ECOG performance status 0-2
- Measurable disease per RECIST 1.1
- The subject must have recovered to baseline or CTCAE v.5.04.0 (Common Terminology Criteria for Adverse Events, version 54.0) ≤ Grade 1 from clinical toxicities related to any prior treatments, i.e chemotherapy or pelvis radiation unless AE(s) are clinically non-significant (for example alopecia)
- Adequate organ and marrow function, defined as follows, based upon laboratory tests performed within 7 days before randomizationinclusion:
o Absolute neutrophil count (ANC) ≥ 1000/mm3 (≥ 1.0 GI/L)
o Platelets ≥ 100,000/mm3 (≥ 100 GI/L)
o Hemoglobin ≥ 10 g/dL (≥ 100 g/L) (red blood cell transfusion is allowed)
o Total bilirubin ≤ 1.5 fold the upper limit of normal (for subjects with Gilbert’s disease, ≤ 3 mg/dL or ≤ 51.3 µmol/L)
o Serum albumin ≥ 2.8 g/dL (≥ 28 g/L)
o Calculated creatinine clearance ≥ 50 mL/min by the Cockcroft –Gault method
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 x the upper limit of normal
o Urine protein/creatinine ratio (UPCR) ≤ 1 (≤ 113.17 mg/mmol creatinine)
o Serum potassium ≥ lower limit of normal
o Serum calcium ≥ lower limit of normal
o Serum magnesium ≥ lower limit of normal
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 450 msec
- Left-ventricular ejection fraction ≥ 50%
- Subjects affiliated to an appropriate social security system
- Female subjects of childbearing potential must not be pregnant at screening and during treatment by Cabozantinib. Effective methods of contraception should be used throughout the course of treatment and for at least 4 months after the end of treatment. Sexually active fertile subjects and their partners must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the study and 4 months after the last dose of study treatment, even if oral contraceptives are also used.
- Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.

E.4

Principal exclusion criteria

- Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding and/or fistula/perforation including, but not limited to: Active peptic ulcer disease, inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
- Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: malabsorption syndrome, major resection of the stomach or small bowel.
- History of any one or more of the following cardiovascular conditions within the past 6 months: Cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).
- Uncontrolled hypertension defined as systolic blood pressure (SBP) of > 140 mmHg or diastolic blood pressure (DBP) of > 90 mmHg despite an optimal treatment.
- History of cerebrovascular accident including transient ischemic attack (TIA), symptomatic pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT or asymptomatic pulmonary embolism who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.
- Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer.
- Evidence of active bleeding or pathologic conditions that carry high risk of bleeding such as known bleeding disorders, coagulopathy or tumor involving major vessels.
- Any external radiation therapy within 4 weeks before randomization.
- Presence of brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before randomization. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of randomization.
- Concomitant use of known strong CYP3A4 inhibitors or inducers.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- Patients with second primary cancer, except adequately treated non-melanoma skin cancer, or other solid tumors curatively treated with no evidence of disease for ≥ 3 years
- Concurrent participation in any therapeutic clinical trial
- Patient deprived of liberty or placed under the authority of a tutor

E.5 End points

E.5.1

Primary end point(s)

The main objective will be based on joint primary endpoints of efficacy and safety as proposed by the Bryant-and-Day design:
• Efficacy: assessed by the proportion of patients with disease control rate 3 months after cabozantinib treatment initiation.
• Safety assessed by the proportion of patients with fistula

Le critère principal repose sur l’évaluation conjointe de l’efficacité et de la tolérance, par un design de Bryant-and-Day.
- l’efficacité sera mesurée par le taux de contrôle de la maladie à 3 mois après le début du traitement
- la tolérance sera mesurée par la proportion de patientes présentant une fistule

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months after cabozantinib treatment initiation

3 mois après le début du traitement

E.5.2

Secondary end point(s)

The secondary endpoints are :
o Progression-free survival, defined as the time between initiation of cabozantinib treatment and progression (RECIST 1.1 criteria) or death of any cause whichever occurs first.
o Overall survival, defined as the time between initiation of cabozantinib treatment and death of whatever cause.
o Toxicities evaluated according to NCI CTCAE v5.04.03 criteria, in terms of kind, grade, time of onset, reversibility
o Significant toxicities responsible for interruption or dose reduction of cabozantinib treatment
o Proportion of patients requiring cabozantinib dose reduction or treatment stopping for toxicity
o Objective response rate defined as the percentage of patients who have achieved complete response or partial response with RECIST 1.1 criteria.
o Scores of Quality-of-life according to self-administered questionnaire: EORTC QLQ-C30 and its additional cervix cancer module (QLQ–CX24)

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of study

A la fin de l'étude

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

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)

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)

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)

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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.8.9.1

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

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:

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

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-10-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-08

P. End of Trial
P.	End of Trial Status	Completed

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