Clinical Trials Register

Summary
EudraCT Number:	2018-000627-13
Sponsor's Protocol Code Number:	C201
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-04-05
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

Czechia - SUKL

A.2

EudraCT number

2018-000627-13

A.3

Full title of the trial

OPEN, NON CONTROLLED, PARALLEL COHORTS, MULTICENTER, PHASE 2A STUDY FOR THE EVALUATION OF THE ANTITUMOR ACTIVITY OF GM102 SINGLE AGENT AND IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC COLORECTAL CANCER

Otevřená, nekontrolovaná, s dvěma paralelními kohortami, multicentrická studie fáze IIA pro hodnocení protinádorové aktivity samotného GM102 a v kombinaci s chemoterapií u pacientů s pokročilým nebo metastatickým kolorektálním karcinomem.

A.3.1

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

This is an exploratory study (phase 2a) assessing the antitumor activity (capability to control or reduce the tumor itself and/or metastases) of GM102, a monoclonal antibody, administered alone or in combination with a chemotherapy in patients with previously treated colorectal cancer. The open study means that the medical staff, the patient and the sponsor or its delegates know exactly the study treatment given to the patient.

A.4.1

Sponsor's protocol code number

C201

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	GAMAMABS Pharma
B.1.3.4	Country	France
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	GAMAMABS Pharma
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	ICTA PM
B.5.2	Functional name of contact point	Prune ROCHE
B.5.3	Address:
B.5.3.1	Street Address	Société ICTA PM, 11 rue du Bocage
B.5.3.2	Town/ city	Fontaine Les Dijon
B.5.3.3	Post code	21121
B.5.3.4	Country	France
B.5.4	Telephone number	33380534059
B.5.5	Fax number	33380571022
B.5.6	E-mail	c201@icta.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	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	GM102
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.3.9.2	Current sponsor code	GM102
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	10
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	Yes
D.2.1.1.1	Trade name	Lonsurf
D.2.1.1.2	Name of the Marketing Authorisation holder	Les Laboratoires Servier
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Film-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	trifluridine-tipiracil
D.3.9.1	CAS number	733030-01-8
D.3.9.3	Other descriptive name	TIPIRACIL HYDROCHLORIDE MIXTURE WITH TRIFLURIDINE
D.3.9.4	EV Substance Code	SUB78359
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	15/6,14
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	trifluridine-tipiracil
D.3.9.1	CAS number	733030-01-8
D.3.9.3	Other descriptive name	TIPIRACIL HYDROCHLORIDE MIXTURE WITH TRIFLURIDINE
D.3.9.4	EV Substance Code	SUB78359
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	20/8,19
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

Patients with locally advanced or metastatic colorectal cancer (CRC), having received at least two lines of therapy for the locally advanced or metastatic CRC disease.

E.1.1.1

Medical condition in easily understood language

Patients with locally advanced CRC (grown out the organ started but not yet spread to body distant parts) or metastatic CRC (spread to other body parts), having received at least 2 treatment lines.

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	10010030
E.1.2	Term	Colorectal cancer recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10010034
E.1.2	Term	Colorectal cancer stage III
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10010035
E.1.2	Term	Colorectal cancer stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10052358
E.1.2	Term	Colorectal 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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the anti-tumor activity of GM102 single agent and in combination with trifluridine/tipiracil in locally advanced and metastatic colorectal cancers (CRC).

E.2.2

Secondary objectives of the trial

- To further evaluate the anti-tumor activity of GM102 single agent and in combination with trifluridine/tipiracil with other efficacy parameters.
- To document the PD immunological effect of GM102 on the tumor and its microenvironment.
- To assess and document AMHRII expression at baseline and under GM102 treatment in the CRC indication.
- To confirm GM102 single agent safety profile in the population of patients with advanced and metastatic CRC and to characterize GM102 safety profile in combination with trifluridine/tipiracil.
- To characterize the systemic exposure of male and female patients with CRC to GM102 single agent and in combination with trifluridine/tipiracil.
- To assess the potential immunogenicity of GM102.

Exploratory objectives:
- To document potential PD effect of GM102 in immune circulating cells.
- To assess the ISH assay under development for AMHRII detection.
- To identify any other biomarkers predictive of tumor response to GM102 (Biobank).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria
All patients
1. Histologically-confirmed metastatic or locally advanced colorectal adenocarcinoma.
2. Having failed the previous line of treatment for locally advanced or metastatic disease and having received at least two systemic chemotherapy regimens for metastatic colorectal cancer; adjuvant regimen can be considered as one chemotherapy regimen for metastatic disease if the participant had disease recurrence within 6 months of completion.
3. At least one of the tumor sites amenable to core needle biopsy (may not be the site of disease for measuring antitumor response). Patient must agree to this pre-treatment biopsy and on the principle of a second biopsy under treatment; however, if eventually the second biopsy cannot be performed, patients will continue on the study and will be considered evaluable for efficacy.
4. At least one measurable lesion (≥ 1.0 cm longest diameter or ≥ 1.5 cm in short axis for malignant lymph nodes) based on RECIST 1.1 on the screening CT-scan.
5. Written Informed Consent forms signed.
6. Willing and able to comply with the trial requirements.
7. Covered by healthcare insurance in accordance with local requirements.

Specific to each cohort:
8. Cohort I (single agent GM102): refractory patients, having exhausted all therapeutic options.
Cohort II (combination with trifluridine/tipiracil): patients eligible for trifluridine/tipiracil who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents. Patients must have received at least 2 prior lines of standard chemotherapy for mCRC.

E.4

Principal exclusion criteria

1. Age < 18 years old.
2. ECOG performance status ≥ 2.
3. Life expectancy < 12 weeks.
4. Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or anticipation of needing such procedure while receiving study treatment.
5. Known or symptomatic brain metastasis (other than totally resected or previously irradiated and non-progressive/relapsing) or lepto-meningeal carcinomatosis.
6. Concurrent treatment with any other anticancer therapy (or investigational agent) or received any anticancer therapy (or investigational agent) within 4 weeks prior to first treatment.
7. Known severe anaphylactic or other hypersensitivity reactions to IMP and/or its excipients.
8. Unresolved toxicity ≥ grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 attributed to any prior therapies (excluding anemia, alopecia, skin pigmentation, and platinum induced neurotoxicity).
9. Serious concomitant illness, e.g. active infection requiring systemic antibiotic, antifungal or antiviral drug, or physical examination or laboratory abnormalities, that, in the opinion of the Investigator, would compromise protocol objectives.
10. Poor bone marrow reserve as defined by WBC < 3.0 x 109/L, neutrophils < 1.5 x 109/L or haemoglobin < 9.0 g/dL or platelet count < 100 x 109/L.
11. Poor organ function as defined by any one of the following:
- Serum creatinine > 1.5 x ULN
- Total bilirubin > 1.5 x ULN or > 2.5 x ULN if due to Gilbert’s syndrome
- AST, ALT > 2.5 x ULN in the absence of liver metastasis or > 5 x ULN in case of documented liver metastasis.
12. Pregnancy or breastfeeding.
13. Patient with reproductive potential who does not agree to use an accepted highly effective method of contraception – per investigator’s judgment - during the study period and for at least 6 months following completion of study treatment.
14. Patient deprived of liberty by a judicial or administrative decision, patient admitted to a hospital, social institution or who is under a measure of legal protection, patient hospitalized without consent or who is in an emergency situation.

E.5 End points

E.5.1

Primary end point(s)

The primeary endpoint is Overall Tumor Response Rate (ORR) defined as the proportion of patients who achieve partial or complete response (RECIST criteria version 1.1) from the end of cycle 2 and subsequently confirmed at least 4 weeks after.

E.5.1.1

Timepoint(s) of evaluation of this end point

From the end of cycle 2

E.5.2

Secondary end point(s)

- ORR will also be assessed according to iRECIST criteria from the end of cycle 2.
- Clinical benefit rate (CBR) at 8 and 16 weeks (number and % of non-progressors, i.e. CR+PR+SD) using RECIST and iRECIST criteria.
- Tumor Growth Rate (TGR) before and under treatment.
- Progression free survival (PFS).
- Overall Survival (OS).
- PD evaluation: Tumor Immune Environment analysis and evolution:
• Quantity and quality of immune cells, including macrophages (M1 and M2 and phenotype changes), total and subpopulations of T cells.
• Localization of the immune cells inside and around the tumor in the TME.
• Other relevant biomarkers, assessed on biopsy materials.
- AMHRII expression in tumor biopsies at baseline and under GM102 treatment (after 2 cycles of treatment), by immunostaining (IHC).
- Incidence of SAE and TEAE experienced throughout the study period using NCI-CTCAE version 4.03.
- Exposure to GM102 as a single agent and in combination with trifluridine/tipiracil will be assessed through PK parameters analysis by nonlinear mixed effect modelling.
- Exposure of patients to trifluridine in cohort II will be assessed through description of trifluridine plasma concentrations in PK samples.
- Evidence of anti-GM102 antibodies (ADA) at screening, at the beginning of every even cycle (pre-dose), and at the end of treatment visit.

Exploratory Endpoints:
- Evolution of quantification and qualification of circulating immune cells, including T cells and monocytes characteristics and activation under GM102.
- Comparison on AMHRII detection findings between the IHC assay and the assay under development (ISH) in patient biopsy samples (baseline and under treatment).
- Other circulating or tumor-based biomarkers predictive of sensitivity to GM102 may be assessed (Biobank).

E.5.2.1

Timepoint(s) of evaluation of this end point

- ORR: from the end of cycle 2
- CBR: at 8 and 16 weeks
- TGR: at 8 weeks
- PFS and OS: throughout the study period
- PD evaluation: at baseline and by the end of cycle 2
- AMHRII expression: at baseline and by the end of cycle 2
- Incidence of SAE and TEAE: throughout the study period
- Exposure to GM102 and in combination with trifluridine/tipiracil: at D1 and D15 of cycle 1 and 2; and End of Treatment (EoT) visit
- Evidence of ADA: at screening, at D1 of each even cycle, and at the EoT visit.
Exploratory Endpoints:
- Evolution of quantification and qualification of circulating immune cells: at baseline and by the end of cycle 2
- Comparison on AMHRII detection findings: at baseline and by the end of cycle 2
- Biobanking: at baseline and D1 of each even cycle

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

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

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)

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

The study completion is defined as last patient last visit (LPLV).

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

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

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

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)

Patients will continue the study treatment until confirmed disease progression, unacceptable toxicity, death or withdrawal of consent (for any reason), non-compliance to the protocol or if the investigator considers it is no longer in the patient’s best interest to continue IMP(s) treatment.

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

2018-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-02-10

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