Clinical Trials Register

Summary
EudraCT Number:	2015-001298-42
Sponsor's Protocol Code Number:	1321
National Competent Authority:	Norway - NOMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-09-21
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

Norway - NOMA

A.2

EudraCT number

2015-001298-42

A.3

Full title of the trial

A randomised phase II trial of imatinib alternating with
regorafenib compared to imatinib alone for the first line
treatment of advanced gastrointestinal stromal tumour (GIST)

A.3.1

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

A randomised phase II trial of imatinib alternating with
regorafenib compared to imatinib alone for the first line
treatment of advanced gastrointestinal stromal tumour (GIST)

A.3.2

Name or abbreviated title of the trial where available

ALT GIST

A.4.1

Sponsor's protocol code number

1321

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02365441

A.5.4

Other Identifiers

Name:	NHMRC CTC Protocol number	Number:	CTC 0122/AGITG AG1013GST
Name:	SSG	Number:	ALT-GIST/SSG XXIII

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	European Organisation for Research and Treatment of Cancer
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
B.4.2	Country	United States
B.4.1	Name of organisation providing support	AGITG
B.4.2	Country	Australia
B.4.1	Name of organisation providing support	EORTC
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	EORTC
B.5.2	Functional name of contact point	Head of Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	Avenue E. Mounier 83/11
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3227741035
B.5.5	Fax number	+3227741030
B.5.6	E-mail	regulatory@eortc.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.2.5	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	Imatinib
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	IMATINIB MESILATE
D.3.9.1	CAS number	220127-57-1
D.3.9.4	EV Substance Code	SUB12517MIG
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	400
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.2.1.1.1	Trade name	Stivarga
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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	Regorafenib
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	Regorafenib
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.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

unresectable metastatic GIST

E.1.1.1

Medical condition in easily understood language

gastrointestinal stromal tumour (GIST -, a cancer of the stomach and bowel) that has spread and cannot be surgically removed

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10062427
E.1.2	Term	Gastrointestinal stromal tumor
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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10051066
E.1.2	Term	Gastrointestinal stromal tumour
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	18.0
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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 determine if an alternating regimen of imatinib and
regorafenib has sufficient activity and safety to warrant further
evaluation as a first line treatment for metastatic GIST.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adults (over 18 yrs) with histologically confirmed GIST. In CD‐117‐negative cases DOG‐1 must be positive or a KIT/PDGFRA mutation must be present.
2. Unresectable, metastatic disease.
3. No prior TKI for metastatic disease, with the exception of those patients who have had up to 21 days of uninterrupted treatment on 400mg daily of imatinib.
4. Imatinib therapy given as an adjuvant treatment and completed at least 3 months prior to entry into this trial is permitted. Patients who have progression of GIST while on adjuvant therapy are not eligible for this trial.
5. ECOG performance status 0‐2
6. Measurable disease by RECIST version 1.1. (Note: Participants with only peritoneal disease will be eligible only if they have lesions measurable in two dimensions and have at least 1 lesion
which is ≥ 2 cm in size).
7. Adequate bone marrow function (Haemoglobin ≥ 9.0g/dL, platelet count ≥ 100 x 109/L, and absolute neutrophil count ≥ 1.5 x 109/L).
8. Adequate liver function (Serum total bilirubin ≤1.5 x ULN, INR ≤ 1.5, and ALT, AST, ALP ≤2.5 x ULN (≤ 5 x ULN for participants with liver metastases). Lipase level must be ≤ 1.5 x ULN.
9. Adequate renal function (Creatinine clearance > 50ml/min) based on either the Cockcroft Gault formula, 24 hour urine or Glomerular Filtration Rate (GFR scan); and serum creatinine ≤ 1.5 x ULN.
10. Tumour tissue available for central review.
11. Willing and able to comply with all study requirements, including treatment timing and/or nature of required assessments.
12. Study treatment both planned and able to start within 14 days of randomisation.
13. Signed, written informed consent.

E.4

Principal exclusion criteria

1. Concurrent GI illness which may prevent absorption of imatinib or regorafenib – please note that prior gastrectomy or bowel resection does not exclude patients from this study.
2. Use of other investigational drugs within 4 weeks prior to enrolment.
3. Known sensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
4. Participants receiving therapeutic doses of warfarin.
5. Presence of brain metastases.
6. The presence of PDGFR D842V mutation or other mutation known to cause imatinib resistance.
7. Inability to swallow tablets.
8. Arterial thrombotic or ischaemic events, such as cerebrovascular accident or pulmonary embolism within 6 months prior to randomisation; or major venous thrombotic events requiring use of an anticoagulant such as warfarin within 6 months prior to randomisation.
9. Poorly controlled hypertension (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
10. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation, or non healing wound, ulcer or fracture.
11. Congestive cardiac failure (NYHA ≥ grade 2), unstable angina or new onset angina within the previous 3 months, or AMI within the previous 6 months. Cardiac arrhythmias requiring antiarrhythmic
therapy (beta blockers or digoxin are permitted).
12. Haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v4.0 within 4 weeks prior to randomisation.
13. Ongoing infection of > Grade 2 according to CTCAE v4.0.
14. Active hepatitis B or C or HIV, or chronic hepatitis B or C requiring treatment with antiviral therapy. Testing for these is not mandatory unless clinically indicated.
15. Interstitial lung disease with ongoing signs and symptoms.
16. Persistent proteinuria of ≥ Grade 3 (>3.5g/24 hours) according to CTCAE v4.0
17. Other significant medical or psychiatric condition judged by the investigator to interfere with protocol requirements.
18. Use of biological response modifiers such as granulocyte colony stimulating factor (G‐CSF), within 3 weeks prior to randomisation.
19. Patients taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinovir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg carbamazepine, phenobarbitol, phenytoin, rifampicin, St John’s wort).
20. History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated carcinoma‐in‐situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible.
Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment.
21. Pregnancy, lactation, or inadequate contraception. Women must be post menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a
negative pregnancy test done within 7 days prior to registration. Women of childbearing potential and men must agree to use adequate contraception before entering the trial until at
least 8 weeks after the last study drug administration.

E.5 End points

E.5.1

Primary end point(s)

Progression free survival

E.5.1.1

Timepoint(s) of evaluation of this end point

Progression free survival will be assessed 8 weekly for the first 12 months of treatment and thereafter 12 weekly until 24 months of treatment.

E.5.2

Secondary end point(s)

- Objective tumour response rate at 2 cycles after randomisation
- Clinical benefit rate (SD + PR + CR) following 2 cycles of treatment
- Complete response rate
- Time to treatment failure
- Safety/toxicity/tolerability
- Overall survival

E.5.2.1

Timepoint(s) of evaluation of this end point

Objective tumour response rate and clinical benefit rate will assessed every 8 weeks until 16 weeks from randomization.
Time to treatment failure, overall survival, complete response rate and safety will be assessed 8 weekly for the first 12 months of treatment and thereafter 12 weekly until 24 months of treatment.

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

Yes

E.6.13.1

Other scope of the trial description

Translational research

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

Yes

E.8.1.1

Randomised

Yes

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)

Yes

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

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

Denmark

Finland

France

Hong Kong

Italy

Netherlands

Norway

Singapore

Slovakia

Spain

Sweden

United Kingdom

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

Study End occurs when all of the following criteria have been satisfied:
1. thirty days have elapsed after all patients have stopped Protocol treatment
2. the trial is ready for the analysis of the primary endpoint as defined in the Protocol
3. the database has been fully cleaned and frozen for this analysis.
There are no study specific procedures foreseen after the end of trial but patients may continue visits to their treating physician in the frame of standard of care.

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)

F.1.2.1

Number of subjects for this age range:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

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

210

F.4.2.2

In the whole clinical trial

240

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)

Treatment after discontinuation of study treatment is at the discretion of the patient's clinician.
In addition, Bayer will provide regorafenib to study participants for as long as they receive benefit from the treatment until local reimbursement after the completion of the study.

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

2015-11-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-05-08

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