Clinical Trials Register

Summary
EudraCT Number:	2010-020121-41
Sponsor's Protocol Code Number:	BAY 73-4506/11728
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-12-16
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2010-020121-41

A.3

Full title of the trial

An uncontrolled, open-label, phase II study in subjects with metastatic adenocarcinoma of the colon or rectum who are receiving first line chemotherapy with mFOLFOX6 (oxaliplatin/ folinic acid/5-fluorouracil [5-FU]) in combination with regorafenib

A.3.1

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

First Line chemotherapy treatment with the chemotherapeutic regimen FOLFOX6 in combination with regorafenib of patients with bowel cancer

A.4.1

Sponsor's protocol code number

BAY 73-4506/11728

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	Bayer HealthCare AG
B.1.3.4	Country	Germany
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	Bayer HealthCare AG
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	Bayer HealthCare AG
B.5.2	Functional name of contact point	Bayer Clinical Trials Contact
B.5.3	Address:
B.5.3.1	Street Address	CTP Team / Ref: „EU CTR" / S102 – Room 156,
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13342
B.5.3.4	Country	Germany
B.5.6	E-mail	clinical-trials-contact@bayerhealthcare.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.3.1	Product name	Regorafenib
D.3.2	Product code	Bay 73-4506
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	Regorafenib
D.3.9.1	CAS number	755037-03-7
D.3.9.2	Current sponsor code	Bay 73-4506
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.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

Metastatic adenocarcinoma of the colon or rectum (metastatic CRC)

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

•Objective tumor response rate (ORR), centrally assessed

E.2.2

Secondary objectives of the trial

•Overall survival (OS)
•Progression-free survival (PFS), centrally assessed
•Disease control rate (DCR), centrally assessed
•Duration of response (DOR) and stable disease (SD), centrally assessed

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Male or female subjects aged ≥ 18 years
•Histological or cytological documentation of adenocarcinoma of the colon or rectum
•Suitable to receive mFOLFOX6 regimen as first line metastatic treatment
•At least 1 measurable lesion as per RECIST version 1.1
•Unresectable or unlikely becoming resectable metastatic disease
•Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
•Life expectancy of at least 3 months
•Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to first dose of study treatment
•Total bilirubin ≤ 1.5 x the upper limit of normal (ULN)
•Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer)
• Lipase ≤ 1.5 x the ULN
•Serum creatinine ≤ 1.5 x the ULN
•Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 according to the modified diet in renal disease (MDRD) abbreviated formula
•International normalized ratio (INR)/partial thromboplastin time (PTT) ≤ 1.5 x ULN. (Subjects who are being therapeutically anticoagulated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in this parameter exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is predose as defined by the local standard of care.)
•Platelet count ≥ 100000/mm3, hemoglobin (Hb) ≥ 9 g/dl, absolute neutrophil count (ANC) ≥ 1500/mm3
•Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer
•Persistent proteinuria of CTC Grade 3 or higher (> 3,5 g/24 hrs, measured by urine protein: creatinine ration on a random urine sample)
•Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment.
•Women of childbearing potential and men must agree to use adequate contraception (eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method) since signing of the informed consent form until at least 6 months after the last study treatment administration. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control.
•Signed informed consent must be obtained before any study specific procedure. Subjects must be able to understand and willing to sign the written informed consent.

E.4

Principal exclusion criteria

•Previous assignment to treatment during this study. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study.
•Prior systemic anticancer therapy for metastatic CRC. Adjuvant chemotherapy for CRC (Stage I, II, III) is permitted, if the adjuvant therapy ended > 6 months before screening and recurrent disease was documented.
•Prior treatment with antivascular endothelial growth factor (anti-VEGF) agents and any signal transduction inhibitors (STIs)
•Previous or concurrent cancer that is distinct in primary site or histology from CRC within 5 years prior to screening, EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [Non invasive tumor], Tis [Carcinoma in situ] and T1 [Tumor invades lamina propria]).
•Pregnant or breastfeeding subjects. Women of childbearing potential not employing adequate contraception or < 2 years from last menstruation.
•Congestive heart failure ≥ New York Heart Association (NYHA) class II
•Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of study treatment.
•Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
•Uncontrolled hypertension (systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg despite optimal medical management)
•Subjects with phaeochromocytoma
•Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study treatment
•Ongoing infection > Grade 2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
•Known history of human immunodeficiency virus (HIV) infection
•Active or chronic hepatitis B or C infection with a need for antiviral treatment
•Subjects with symptoms, signs, or history of brain metastases (in the case of suspected brain metastases, a cranial CT/MRI is required to exclude brain metastases)
•History of organ allograft
•Subjects with evidence or history of bleeding diathesis.
•Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study treatment
•Nonhealing wound, ulcer, or bone fracture
•Renal failure requiring hemo-or peritoneal dialysis
•Dehydration ≥ CTCAE Grade 1
•Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results
•Known hypersensitivity to any drug of study treatment, study drug classes, or excipients in the formulation
•Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study
•Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
•Subjects unable to swallow oral medications
•Any malabsorption condition
•Close affiliation with the investigational site (eg, a close relative of the investigator, dependent person [eg, employee or student of the investigational site])
•Known dihydropyrimidine dehydrogenase deficiency
•Sensory neuropathy (> CTCAE Grade 1), unresolved toxicity > CTCAE Grade 1 attributed to any prior therapy/procedure excluding alopecia
•Use of any herbal remedy (eg, St. John's wort [Hypericum perforatum])
•Pernicious anemia or other anemias due to vitamin B12 deficiency
•Subjects with seizure disorder requiring medications
•Major surgery, open biopsy, or significant traumatic injury within 4 weeks prior to first dose of study treatment. Minor surgery within 2 weeks prior to first dose of study treatment. Subjects must have recovered from all surgery-related toxicities
•Radiotherapy within 4 weeks prior to first dose. Subjects must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease (PD) if this is the only site of disease.
•Investigational drug treatment within 4 weeks prior to study entry

E.5 End points

E.5.1

Primary end point(s)

Objective tumor response rate (ORR) based on blinded central radiological review of all tumor evaluations is the primary end point of the study.
The study is planned according to the fixed-sample design for proving efficacy. The aim is to show that therapy with mFOLFOX6 for colorectal cancer in combination with regorafenib improves the response rate observed for the standard therapy alone. The response rate for the standard therapy is assumed to be 40%.
The design specifications are as follows:
one-sided type I error level = 10% ,
power = 90% (type II error rate = 10%), and
"response rate for standard therapy" p0= 0.40 (null hypothesis),
where the one-sided type I error level is the probability of rejecting the null hypothesis if the true response rate is less than or equal to 40% and 1-power is the probability of rejecting the alternative hypothesis if the true response rate is greater 40%.
For the power calculation it is assumed, that under the alternative hypothesis the expected response rate for combination therapy may be 60%, ie, p1 = 0.6.
These specifications result in the total sample size of 41 patients.

The final analysis of efficacy will be performed after the last subject included into the
treatment phase has been treated for at least 6 months. If this last subject discontinues from
the study, for any reason, before being treated for 6 months then the preceding subject will be
treated and followed for 6 months before the final analysis of efficacy will be performed.

E.5.1.1

Timepoint(s) of evaluation of this end point

if at least 41 subjects who have been treated for at least 6 months are valid for the per protocol analysis OR

E.5.2

Secondary end point(s)

overall survival, progression-free-survival, disease control rate, duration of response and stable disease

E.5.2.1

Timepoint(s) of evaluation of this end point

after the last patient included into the treatment phase has been treated for at least 6 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

Yes

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

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

Information not present in EudraCT

E.8.4

The trial involves multiple sites in the Member State concerned

Information not present in EudraCT

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

United States

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

For each participating European Union (EU) country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last subject for all centers in the respective country has occurred.

The primary completion date for this study according to the FDA Amendment Act is specified in a separate document (not part of this protocol).

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

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)

not applicable

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

2011-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-03-17

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

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