Clinical Trials Register

Summary
EudraCT Number:	2020-005771-12
Sponsor's Protocol Code Number:	AIO-KRK-0420
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2022-02-04
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

Germany - PEI

A.2

EudraCT number

2020-005771-12

A.3

Full title of the trial

Neoadjuvant encorafenib, binimetinib and cetuximab for patients with BRAF V600E mutated/pMMR localized colorectal cancer

A.3.1

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

Treatment with encorafenib, binimetinib, and cetuximab prior to surgery in patients with BRAF V600E mutated/pMMR localized colorectal cancer

A.3.2

Name or abbreviated title of the trial where available

NeoBRAF

A.4.1

Sponsor's protocol code number

AIO-KRK-0420

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	AIO-Studien-gGmbH
B.1.3.4	Country	Germany
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	Pierre Fabre Pharma GmbH
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Merck KGaA
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AIO-Studien-gGmbH
B.5.2	Functional name of contact point	AIO-Studien-gGmbH
B.5.3	Address:
B.5.3.1	Street Address	Kuno-Fischer-Str. 8
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	14057
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049030814534458
B.5.5	Fax number	0049030322932926
B.5.6	E-mail	aio.regulatory@aio-studien-ggmbh.de

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	Erbitux (cetuximab)
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck KGaA
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	Erbitux (cetuximab)
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.3.8	INN - Proposed INN	Cetuximab
D.3.9.1	CAS number	205923-56-4
D.3.9.4	EV Substance Code	SUB01178MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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	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	Yes
D.2.1.1.1	Trade name	Braftovi (Encorafenib)
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Pharma
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.3.9.1	CAS number	1269440-17-6
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	range
D.3.10.3	Concentration number	50 to 75
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	additional label “intended for clinical trial”
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Pharma
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	Binimetinib
D.3.4	Pharmaceutical form
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	Binimetinib
D.3.9.1	CAS number	606143-89-9
D.3.9.4	EV Substance Code	SUB179942
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	45
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 unresected BRAFV600E mutated/pMMR localized colorectal cancer

E.1.1.1

Medical condition in easily understood language

Patients with not resected, mutated/mismatch repairable colon cancer

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	10009944
E.1.2	Term	Colon cancer
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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10061451
E.1.2	Term	Colorectal cancer
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	10001167
E.1.2	Term	Adenocarcinoma of colon
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	22.0
E.1.2	Level	PT
E.1.2	Classification code	10075676
E.1.2	Term	BRAF V600E mutation positive
E.1.2	System Organ Class	10022891 - Investigations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine the clinical efficacy of the targeted triplet combination of encorafenib, binimetinib and cetuximab in BRAF V600E mutant/pMMR localized colorectal cancer patients in terms of tumor regression (TRG2-4).

E.2.2

Secondary objectives of the trial

Determine safety, tolerability, and feasibility of the regimen in the neoadjuvant setting. Determine the efficacy of the experimental regimen in terms of overall response rate and disease-free survival.

Translational data will inform about molecular mechanisms of response/resistance to triplet combination and the potential utility of liquid biopsy monitoring during treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Biopsy-confirmed adenocarcinoma of the colon or upper rectum if too high for radiotherapy.
2. Radiologically (CT/MRI) staged disease as: T3-4 (as invasion of surrounding tissue structures or organs) and/or nodal positive (N+ defined as regional lymph node(s) without fat hilus and short axis diameter of ≥1 cm), M0.
3. BRAF V600E mutation and pMMR or MSS (as determined by a validated test, preferably PCR or NGS).
4. ECOG performance status ≤ 1.
5. Age ≥ 18 years.
6. Adequate hematologic function at screening as follows: ANC 1.5 x 109/L, platelets 100 x109/L, hemoglobin ≥ 9.0 g/dL.
7. Adequate liver function at screening as measured by serum transaminases (AST & ALT) 2.5 x ULN and total bilirubin 1.5 x ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
8. Adequate renal function at screening: serum creatinine  1.5 x ULN.
9. Adequate serum electrolytes at screening defined as serum potassium and magnesium levels within institutional normal limits (Note: replacement treatment to achieve adequate electrolytes will be allowed.
10. Adequate cardiac function at screening characterized by left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO and QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤ 480 msec.
11. Negative serum pregnancy test at screening for women of childbearing potential.
12. Highly effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the trial drugs on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use highly effective contraception, defined as methods with a failure rate of less than 1 % per year, containing at least 1 form of non-hormonal contraception. Highly effective contraception is required at least 28 days prior, throughout and for at least 6 months after interventional study treatment (encorafenib, binimetinib and cetuximab).
13. Signed and dated written informed consent.
14. Ability to take oral medication.
15. Ability to comply with the protocol for the duration of the study, including hospital/office visits for treatment and scheduled follow-up visits and examinations.

E.4

Principal exclusion criteria

1. Any prior systemic therapy, surgery or radiotherapy of the colorectal cancer disease.
2. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
3. Malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
4. Known severe hypersensitivity reactions to monoclonal antibodies or BRAF-/MEK-inhibitors (grade ≥ 3 NCI-CTCAE v 5), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
5. Pregnancy or lactation.
6. Known alcohol or drug abuse.
7. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (≤ 6 months prior to enrolment); myocardial infarction (≤ 6 months prior to enrolment), acute coronary syndromes [including unstable angina, coronary artery bypass graft (CABG), coronary angioplasty or stenting) ≤ 6 months prior to enrolment]; congestive heart failure (≥ New York Heart Association Classification Class II); or history or current evidence of clinically significant arrhythmia and/or conduction abnormality (≤ 6 months prior to enrolment), except rate controlled atrial fibrillation and paroxysmal supraventricular tachycardia.
8. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
9. Pre-existing interstitial lung disease.
10. Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).
11. History of thromboembolic or cerebrovascular events ≤ 6 months prior to enrolment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli.
12. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
13. Known human immunodeficiency virus (HIV) infection or active hepatitis B or C infection.
14. All other significant diseases, which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment.
15. Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
16. Any approved anticancer therapy, including chemotherapy, hormonal therapy or radiotherapy, within 5 half-lives or 4 weeks (the longer period applies) prior to initiation of study treatment.
17. Current treatment with a non-topical medication or current intake of herbal preparations / supplements / foods known to be a strong inhibitor of CYP3A4. However, patients who either discontinue such treatment/intake or switch to another medication at least 7 days prior to starting study treatment are eligible.
18. Concomitant use of St. John’s Wort (hypericum perforatum).

E.5 End points

E.5.1

Primary end point(s)

Tumor regression grade (TRG)

E.5.1.1

Timepoint(s) of evaluation of this end point

after 36 months

E.5.2

Secondary end point(s)

• Safety and tolerability (acc. to NCI CTC AE v5.0) incl. vital signs, clinical parameters and overall feasibility of the regimen
• Perioperative morbidity and mortality
• R0-resection rate
• Overall response rate (according to RECIST v1.1)
• Disease free survival
• Overall survival
• Correlation of quantitative BRAF V600E levels (measured by ddPCR) with TRG
• Evaluation of mechanism of relative resistance in patients with less response (evaluated by tumor and liquid biopsy NGS profiling at baseline and after treatment)
• Comparison of ctDNA clearance and TRG with a BRAF mutant/pMMR cohort from the planned neoadjuvant PROTECTOR study receiving neoadjuvant chemotherapy

E.5.2.1

Timepoint(s) of evaluation of this end point

after 36 months

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

after first patient has completed max. 48 months Follow-Up

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 months

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.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 continued at the treating physicians 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

2022-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-04-25

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2024-02-09

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