A Randomised Trial of Imatinib Alternating With Regorafenib Compared to Imatinib Alone for the First Line Treatment of Advanced Gastrointestinal Stromal Tumour (GIST)

NCT02365441 | Unknown Phase 2 DMC

• 2 other identifiers: AG1013GSTACTRN12614000950662
• Study Type: interventional
• Target: 78
• Locations: 10 countries
• Sites: 25

Brief Summary

An open label randomised trial for adults with histologically confirmed measurable metastatic GIST who have received no other treatment for metastatic disease. The study aims to determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety in comparison to imatinib alone to warrant further evaluation as a first line treatment for metastatic GIST.

Conditions

Gastrointestinal Stromal Tumour

Keywords

GIST; Advanced

Outcome Measures

Primary Outcomes (1)

• Objective tumour response (complete or partial response) as determined by RECIST v1.1

  The objective tumour response rate (OTRR) will be calculated by summing the number of participants assessed as having a complete or partial response within the first 9 months from the time from either (i) randomization (if patients have not yet commenced treatment) or (ii) commencement of therapy (if patients are randomized during the first cycle of imatinib), and dividing this by the total number of participants evaluable for response. For patients who undergo surgery, the best response is determined in the time period that precedes the date of surgery. The responses are confirmed at the time of the next scheduled imaging, usually done 8 weeks after the first detection of response, provided that imaging of the target lesions is not indicated sooner than this for other reasons. Both the numbers and the proportions of confirmed and unconfirmed responses will be reported. The minimum duration of SD is defined as 8 weeks.

  At or before 9 months from the time from either (i) randomization (if patients have not yet commenced treatment) or (ii) commencement of therapy (if patients are randomized during the first cycle of imatinib)

Secondary Outcomes (5)

• Progression free survival at 24 months (disease progression or death)

  24 Months

• Clinical benefit rate at 24 weeks

  24 weeks

• Time to treatment failure

  5 years

• Adverse Events

  5 years

• Overall survival

  5 years

Other Outcomes (6)

• Macroscopically complete removal of all residual disease by surgery

  5 years

• Change in PET imaging during washout period of regorafenib and imatinib in those taking part in the PET substudy

  3 years

• Imatinib plasma levels 4 and 12 weeks after commencement of treatment in both arms. Arm B: Imatinib plasma levels at 3 and 11 weeks after commencement of treatment and regorafenib plasma levels 7 and 15 weeks after commencement of treatment.

  3 years

Study Arms (2)

Arm A

ACTIVE COMPARATOR

imatinib 400mg orally daily continuously

Drug: imatinib

Arm B

EXPERIMENTAL

alternating 28-day periods of imatinib 400mg orally daily for 21 to 25 days followed by a washout (drug free) period of 3 to 7 days, then regorafenib 160mg orally daily for 3 weeks followed by a 7 day washout (drug free) period.

Drug: Regorafenib; Drug: imatinib

Interventions

Regorafenib DRUG

Arm B

imatinib DRUG

Also known as: Glevec

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Unresectable, metastatic disease.
• 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.
• 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.
• ECOG performance status 0-2
• 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).
• Adequate bone marrow function (Haemoglobin ≥ 9.0g/dL, platelet count ≥ 100 x 109/L, and absolute neutrophil count ≥ 1.5 x 109/L).
• 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.
• 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.
• Tumour tissue available for central review.
• Willing and able to comply with all study requirements, including treatment timing and/or nature of required assessments.
• Study treatment both planned and able to start within 14 days of randomisation.
• Signed, written informed consent.

You may not qualify if:

• 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.
• Use of other investigational drugs within 4 weeks prior to enrolment.
• Known sensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
• Participants receiving therapeutic doses of warfarin.
• Presence of brain metastases.
• The presence of PDGFR D842V mutation or other mutation known to cause imatinib resistance.
• Inability to swallow tablets.
• 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.
• Poorly controlled hypertension (systolic blood pressure \> 140 mmHg or diastolic pressure \> 90 mmHg despite optimal medical management).
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation, or non healing wound, ulcer or fracture.
• 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 anti-arrhythmic therapy (beta blockers or digoxin are permitted).
• Haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v4.0 within 4 weeks prior to randomisation.
• Ongoing infection of \> Grade 2 according to CTCAE v4.0.
• 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.
• Interstitial lung disease with ongoing signs and symptoms.

Sponsors & Collaborators

• Australasian Gastro-Intestinal Trials Group: lead
• European Organisation for Research and Treatment of Cancer - EORTC: collaborator
• Scandinavian Sarcoma Group: collaborator

Study Sites (25)

Canberra Hospital

Canberra, Australian Capital Territory, 2606, Australia

Location

Calvary Mater Newcastle Hospital

Newcastle, New South Wales, 2310, Australia

Location

Prince of Wales Hospital

Sydney, New South Wales, 2031, Australia

Location

Princess Alexandra Hospital

Brisbane, Queensland, 4120, Australia

Location

Ashford Cancer Centre Research

Adelaide, South Australia, 5037, Australia

Location

Flinders Medical Centre

Adelaide, South Australia, 5042, Australia

Location

Royal Hobart Hospital

Hobart, Tasmania, 7001, Australia

Location

Peninsula & South Eastern Haematology and Oncology Group

Frankston, Victoria, 3199, Australia

Location

Border Medical Oncology

Wodonga, Victoria, 3690, Australia

Location

Sir Charles Gairdner

Perth, Western Australia, 6009, Australia

Location

Helsinki University Hospital

Helsinki, Finland

Location

Institut Bergonie

Bordeaux, 2050, France

Location

Centre Georges-Francois Leclerc

Dijon, France

Location

Centre Leon Berard

Léon, France

Location

Institut Gustave Roussy

Paris, 2050, France

Location

Netherlands Cancer Institute -Antoni Van Leeuwenhoek

Amsterdam, Netherlands

Location

Haukeland University Hospital

Bergen, Norway

Location

The Norwegian Radium Hospital

Oslo, Norway

Location

National Cancer Centre Singapore

Singapore, 169610, Singapore

Location

National Cancer Institute

Bratislava, NSW, 2050, Slovakia

Location

ICO L'Hospitalet - Hospital Duran i Reynals

Barcelona, Spain

Location

Lund University Hospital

Lund, Sweden

Location

University Hospital Birmingham - Queen Elizabeth Hospital

Birmingham, United Kingdom

Location

Royal Marsden Hospital

London, United Kingdom

Location

Nottingham University Hospitals NHS Trust - Nottingham City Hospital

Nottingham, United Kingdom

Location

Related Publications (1)

• Yip D, Zalcberg J, Blay JY, Eriksson M, Espinoza D, Price T, Marreaud S, Italiano A, Steeghs N, Boye K, Underhill C, Gebski V, Simes J, Gelderblom H, Joensuu H. Imatinib alternating with regorafenib compared to imatinib alone for the first-line treatment of advanced gastrointestinal stromal tumor: The AGITG ALT-GIST intergroup randomized phase II trial. Br J Cancer. 2025 Jun;132(10):897-904. doi: 10.1038/s41416-025-02983-w. Epub 2025 Mar 25.

  PMID: 40133509 DERIVED

MeSH Terms

Conditions

Gastrointestinal Stromal Tumors

Interventions

regorafenib; Imatinib Mesylate

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Heikki Joensuu, Professor

  SSG

  STUDY CHAIR

• Desmond Yip, A/Professor

  AGITG

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 4, 2014
• First Posted: February 19, 2015
• Study Start: June 30, 2015
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: July 7, 2023

Record last verified: 2023-07

Locations

AU (10); FI (1); GB (3); SG (1); SL (1); ES (1); FR (4); NL (1); NO (2); SE (1)