Clinical Trials Register

Summary
EudraCT Number:	2019-004819-31
Sponsor's Protocol Code Number:	IN-CRC-001
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-03-19
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

Bulgarian Drug Agency

A.2

EudraCT number

2019-004819-31

A.3

Full title of the trial

A Phase I/II, multi-centre, open-label, adaptive design, umbrella study assessing the safety, tolerability, immunogenicity and efficacy of IN01 in combination with small-molecule inhibitors in two cohort of patients with either constitutively RAS or BRAF mutated unresectable metastatic colorectal cancer eligible for second line treatment.

A.3.1

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

First in human study assessing the safety, immunogenicity and efficacy of the cancer vaccine IN01 as second line of treatment in RAS and BRAF mutated metastatic colorectal cancer patients

A.3.2

Name or abbreviated title of the trial where available

CRAcIm 1

A.4.1

Sponsor's protocol code number

IN-CRC-001

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	IN3BIO
B.1.3.4	Country	United Kingdom
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	IN3BIO
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IN3BIO
B.5.2	Functional name of contact point	Head of Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	Cornell road
B.5.3.2	Town/ city	Aberdeen
B.5.3.3	Post code	AB25 2ZP
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	33695181107
B.5.6	E-mail	thomas@in3bio.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.3.2	Product code	IN01
D.3.4	Pharmaceutical form	Emulsion and suspension for emulsion for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IN01
D.3.9.3	Other descriptive name	IN01
D.3.9.4	EV Substance Code	SUB223389
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	1
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)	Yes
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	MEKINIST
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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.3.1	Product name	trametinib
D.3.4	Pharmaceutical form	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	TRAMETINIB
D.3.9.3	Other descriptive name	trametinib
D.3.9.4	EV Substance Code	SUB119776
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	2
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: 3
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	BRAFTOVI
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Médicament
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.3.1	Product name	encorafenib
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.3.8	INN - Proposed INN	ENCORAFENIB
D.3.9.3	Other descriptive name	encorafenib
D.3.9.4	EV Substance Code	SUB177218
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	50
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

colorectal cancer at a metastatic stage, eligible for a second line treatment and presenting with a constitutive BRAF or RAS mutation

E.1.1.1

Medical condition in easily understood language

patients with a colorectal cancer with distant metastasis and laboratory identified BRAF or RAS constitutive tumour mutations eligible to receive a second line treatment

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	21.0
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

Phase I:
Characterize the safety, tolerability and immunogenicity of IN01 in combination with a small molecule inhibitor to confirm the recommended Phase II treatment dose and schedule

Phase II:
Further assess the efficacy in the different selected mCRC genotypes based on tumour response, biomarkers and survival. Some biomarker collection and/or analysis may be limited to selected sites and patients

E.2.2

Secondary objectives of the trial

Phase I:
Assess the pharmacodynamic and efficacy (proof-of-concept) on biomarkers, tumour response and survival in different selected mCRC genotypes. Some biomarker collection and/or analysis may be limited to selected sites and patients

Phase II:
• Confirm the safety profile
• Confirm the immunogenicity profile
• Assess the patient reported outcomes (PROs) including solicited adverse reactions and quality of life

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

Patients presenting with liver metastases will have the possibility to consent to liver metastasis biopsies in order to assess their tumour EGF/EGFR pathway activation status at two time points during the study treatment

E.3

Principal inclusion criteria

1. Male and female patients, 18 years of age or older
2. With unresectable metastatic (stage IV) histologically or cytologically confirmed adenocarcinoma of the colon or the rectum
3. With at least one constitutive mutation in K or N RAS exon 2 codon 12 or 13, exon 3 codon 59 or 61, or exon 4 codon 117 or 146, or with a constitutive BRAFv600E. mutation (The mutation must have been identified on a tissue biopsy obtained before the first-line treatment or at the first-line treatment starts.)
4. Whose disease progresses after first line cancer treatment regimen
5. Able to take oral medication
6. With eastern cooperative oncology group (ECOG) performance status of ≤ 1 and at least 3 months of expected survival
7. With a baseline lymphocyte count ≥ 1 G/L (1,000/mm3)
8. Who agree to take appropriate precautions to avoid pregnancy/fathering a child from screening to 4 weeks after end of study treatment (males and females alike; except for postmenopausal women for at least 1 year [i.e., spontaneous amenorrhea at least 1 year prior to first IMP administration and confirmed follicle stimulating hormone [FSH] level >40 IU/L], or surgically sterile patients for at least 6 weeks; See 4.2 for more details).
9. Who consented to participate by signing and dating the written informed consent form prior to any study-specific procedures

E.4

Principal exclusion criteria

1. No baseline measurable lesion (as defined by RECIST 1.1 criteria)
2. Constitutive MSI-high patients (status determined on a tissue biopsy obtained before the first-line treatment or at the first-line treatment start)
3. Still under first line oncological treatment regimen
4. Any contraindication to intra-muscular injection as estimated by the investigator including but not limited to concomitant treatment with an anticoagulant which cannot be temporarily discontinued for allowing safe IN01 injections, as per recommended specific anticoagulant management.
5. Any contraindication (absolute or relative) to the monotherapy treatment with the planned concomitant small inhibitor molecule (trametinib for cohort A or encorafenib for cohort B) according to its approved summary of product characteristics
6. History of other cancer, unless in complete remission and off all chemotherapy and/or radiotherapy for that disease for a minimum of 5 years
7. Use of immunosuppressant drugs such as azathioprine, tacrolimus, cyclosporine, etc. Immunosuppressants are not permitted within 1 month before first IMP administration
8. Administration of any other vaccines with the exception of the influenza and COVID-19 vaccines, within 28 days before first IMP administration
9. Known history of any autoimmune disease
10. Any known primary or secondary immunodeficiencies (e.g. documented Human Immunodeficiency Virus [HIV]) not resolved at least 2 months before IMP administration
11. Treatment with oral, intramuscular or intravenous corticosteroids. Use is not permitted within 7 days before first IMP administration. Inhaled corticosteroids to treat respiratory insufficiency (e.g. chronic obstructive pulmonary disease [COPD]), or topical steroids are permitted
12. History of splenectomy
13. Known incompatibility to both CT scan and MRI
14. Female patients who are pregnant or lactating
15. Any evidence that the patient is unlikely to comply with study treatment, procedures, restrictions or requirements, including uncontrolled systemic or psychiatric diseases (e.g. active infection, uncontrolled hypertension, unstable heart, liver, kidney or metabolic disease) which may compromise the patient’s safety or ability to participate in the study
16. Patients who have received any investigational treatment agent within 28 days before first IMP administration
17. Known allergies, hypersensitivity, or intolerance to the IMP, its excipients or any other vaccine

E.5 End points

E.5.1

Primary end point(s)

Phase I:
• Proportion of patients achieving an anti-EGF antibody immune response
• Dose limiting toxicity rates

Phase II:
Objective response rate (ORR: complete and partial responses) according to RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I:
every 2 weeks for 6 weeks after treatment start

Phase II:
every 8 weeks from treatment start untill end of study

E.5.2

Secondary end point(s)

Phase I:
• Treatment emergent Adverse-event (TEAE) per System Organ Class (SOC) and Preferred Terms (PT) and laboratory toxicity rates per CTCAE grade
• Anti-EGF antibody kinetic profile
• Absolute and relative changes in circulating EGF level over time

Phase II:
• Median duration of response according to RECIST 1.1
• Treatment emergent Adverse-event (TEAE) and per SOC and PT and laboratory toxicity rates per CTCAE grade
• Absolute and relative changes in circulating EGF level over time
• Anti-EGF antibody kinetic profile
• Tumour shrinkage rate (at least 15% shrinkage of tumour diameter defined as relation of the smallest sum of tumour diameter to baseline)
• median depth of response (maximum relative shrinkage of target lesions defined as relation of the smallest sum of tumour diameter to baseline)
• Median progression free survival (PFS: time to PD or death due to any cause)
• Progression-free survival rates at 3, 6 and 12 months
• Median overall survival (OS: time to death due to any cause)
• Overall survival rates at 3, 6, 12 and 18 months

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase I and Phase II:
Every 2 weeks for the first 8 weeks and every 8 weeks after

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)

Yes

E.7.1.1

First administration to humans

Yes

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)

E.8.2.2

Placebo

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

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

when all enrolled patients have a recorded death event or 1 year have elapsed since the date the last patient discontinued treatment, or the trial is prematurely closed by the competent authorities or by the Sponsor for any reason

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)

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

2021-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-07

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

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