Clinical Trials Register

Summary
EudraCT Number:	2020-000876-40
Sponsor's Protocol Code Number:	IJB-REGINA-2020
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-11-23
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2020-000876-40

A.3

Full title of the trial

A phase II trial of neoadjuvant REGorafenib in combination with nIvolumab and short-course radiotherapy iN stage II-III rectAl cancer

A.3.1

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

A phase II trial of neoadjuvant REGorafenib in combination with nIvolumab and short-course radiotherapy iN stage II-III rectAl cancer

A.3.2

Name or abbreviated title of the trial where available

REGINA

A.4.1

Sponsor's protocol code number

IJB-REGINA-2020

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	Institut Jules Bordet
B.1.3.4	Country	Belgium
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	Bayer HealthCare Pharmaceuticals
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	Institut Jules Bordet
B.5.2	Functional name of contact point	CTSU
B.5.3	Address:
B.5.3.1	Street Address	Rue Meylemeersch, 90
B.5.3.2	Town/ city	Anderlecht
B.5.3.3	Post code	1070
B.5.3.4	Country	Belgium
B.5.6	E-mail	ctsu.trials@bordet.be

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	stivarga
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer AG
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	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.3.9.1	CAS number	755037-03-7
D.3.9.3	Other descriptive name	REGORAFENIB
D.3.9.4	EV Substance Code	SUB73090
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	40
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	nivolumab
D.3.4	Pharmaceutical form	Concentrate for 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.3.9.3	Other descriptive name	NIVOLUMAB
D.3.9.4	EV Substance Code	SUB122750
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	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	No
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	regorafenib_IJB
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.3.9.1	CAS number	755037-03-7
D.3.9.2	Current sponsor code	regorafenib_IJB
D.3.9.4	EV Substance Code	SUB73090
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	30
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

rectal cancer

E.1.1.1

Medical condition in easily understood language

rectal 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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10038049
E.1.2	Term	Rectal cancer stage II
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	10038050
E.1.2	Term	Rectal cancer stage III
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 demonstrate that administering combination treatment with nivolumab plus regorafenib before and after standard, pre-operative SCRT is associated with a promising complete response (CR) rate in subjects with pMMR/MSS tumours.

E.2.2

Secondary objectives of the trial

To assess the safety of the investigational treatment in terms of toxicity during and after completion of pre-operative therapy and intra-/post-operative complications
- To assess the feasibility of combining regorafenib with nivolumab in the setting of locally-advanced rectal cancer as demonstrated by subject compliance with the investigational strategy, SCRT and surgery (if performed)
- To assess other efficacy outcome measures including R0 resection rate, pathological tumour regression grade, tumour downstaging/downsizing, disease-free survival, progression-free survival and overall survival
- To assess the immune activation induced by the investigational treatment regorafenib with nivolumab as shown by the increase in inflammatory infiltrate in post-treatment tumour tissue samples

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following criteria in order to be eligible for this study:
1) Female or Male
2) Age ≥ 18 years old
3) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
4) Histologically or cytologically verified adenocarcinoma of the rectum
5) Tumour with distal border below the peritoneal reflection and within 15 cm from the anal verge
6) Stage cT3/T4a and Nany or cT1-2 and N+ as documented by baseline pelvic MRI
7) Absence of distant metastases as shown by baseline computed tomography (CT) of the thorax-abdomen or CT scan of the thorax and MRI of the abdomen
8) Adequate haematological function as defined by absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and haemoglobin ≥9 g/dL
9) Adequate hepatic function as defined by a total bilirubin level ≤1.5 × the upper limit of normal (ULN) range (excluding subjects with known Gilbert’s syndrome), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN
10) Adequate renal function as defined by an estimated creatinine clearance ≥30 mL/min according to the Cockcroft-Gault or Wright formula
11) Negative serum pregnancy test at screening (up to 7 days before treatment start) for women of childbearing potential
12) Women of childbearing potential must agree to use of one highly effective method of contraception (cfr protocol section 6.7.) prior study entry, during the course of the study and at least 7 months after the last administration of study treatment.
13) Men with childbearing potential partner must agree to use condom during the course of this study and for at least 5 months after the last administration of the study treatment.
14) Absence of 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
15) Absence of clinical conditions that, in the opinion of the investigator, would contraindicate neoadjuvant therapy and/or surgery
16) Life expectancy of at least 3 months
17) Completion of all necessary screening procedures within 28 days prior to enrolment.
18) Signed Informed Consent form (ICF) obtained prior to any study related procedure.

E.4

Principal exclusion criteria

Subjects meeting one of the following criteria are not eligible for this study:
1) Any prior or concurrent surgery, chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for rectal cancer. Concurrent use of hormones for noncancer-related conditions (i.e., insulin for diabetes and hormone replacement therapy) is acceptable.
2) Any contraindication to pelvic irradiation as evaluated by the investigator
3) Prior organ transplantation, including allogeneic stem cell transplantation
4) Clinically significant acute or chronic infections including, among others:
- known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- known history of testing positive for hepatitis B virus (HBV) surface antigen or anti-hepatitis C virus (HCV) antibody and confirmatory HCV ribonucleic acid (RNA) test
5) Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent (subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible)
6) Systemic corticosteroids administered as hormone replacement or as immunosuppressants at doses exceeding 10 mg/day of prednisone or equivalent. Other immunosuppressive medications including, but not limited to methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the management of treatment-related AEs or in subjects with contrast allergies is acceptable. A temporary period of steroids is allowed for different indications, at the discretion of the investigator (i.e., chronic obstructive pulmonary disease, radiation, nausea, etc.). Administration of steroids through a route known to result in a minimal systemic exposure [topical, intranasal, intro-ocular, or inhalation] is acceptable.
7) Known severe hypersensitivity reactions to the investigational treatments, or any excipients or non-investigational medicinal products or concomitant medications
8) Pregnant and/or lactating women
9) Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure, uncontrolled arterial hypertension, or serious cardiac arrhythmia requiring medication
10) Prior myocarditis
11) Known history of immune colitis, immune pneumonitis, pulmonary fibrosis or other medical conditions (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment
12) Vaccination within 28 days of the first dose of study treatment and while on trial (except for administration of inactivated vaccines)
13) Other invasive malignancy within 2 years except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured. Anti-neoplastic treatment received in the past for malignancies cured 2 or more years before enrolment are permitted.
14) Any investigational anti-cancer therapy other than the protocol specified therapies.
15) Strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole), strong UGT1A9 inhibitors (e.g. mefenamic acid, diflunisal, and niflumic acid), and strong inducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital and St. John’s wort) from 28 days before study enrolment up to the end of study treatment.

E.5 End points

E.5.1

Primary end point(s)

Complete response (CR) rate (including either pathological [pCR] or clinical complete response [cCR]) in subjects with pMMR/MSS tumours.

E.5.1.1

Timepoint(s) of evaluation of this end point

end of trial

E.5.2

Secondary end point(s)

- Toxicity
- Compliance to treatment
- R0 resection rate; Pathological tumour regression grade (pTRG) ; Local recurrence rate; Distant recurrence rate; Event-free survival (EFS); Overall survival (OS)
- CD3 and CD8 T-cells infiltrate increase in post-treatment tumour tissue samples

E.5.2.1

Timepoint(s) of evaluation of this end point

end of trial

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

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.8.2.4

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

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

The end of trial is declared when all the following criteria have been met:
- After last visit of the last subject
- The trial is mature for the analysis of all the endpoints as defined in the protocol, if the trial reaches its endpoints
- The database has been fully cleaned and frozen/lock for the final analysis

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:

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)

At the discretion of the physician according to the local standard of care

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

2021-03-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-03-09

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

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