A randomised phase II trial of imatinib alternating withregorafenib compared to imatinib alone for the first linetreatment of advanced gastrointestinal stromal tumour (GIST)
- Conditions
- unresectable metastatic GISTMedDRA version: 20.0Level: LLTClassification code 10062427Term: Gastrointestinal stromal tumorSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.1Level: PTClassification code 10051066Term: Gastrointestinal stromal tumourSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: SOCClassification code 10029104Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps)System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2015-001298-42-SK
- Lead Sponsor
- European Organisation for Research and Treatment of Cancer
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 76
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 and including 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 38
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 38
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 known PDGFRA 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 v4.03 within 4 weeks prior to randomisation.
13. Ongoing infection of > Grade 2 according to CTCAE v4.03.
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 v4.03
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.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To determine if an alternating regimen of imatinib and<br>regorafenib has sufficient activity and safety to warrant further<br>evaluation as a first line treatment for metastatic GIST.;Secondary Objective: Not applicable;Primary end point(s): Objective tumour response (complete or partial<br>response) as determined by RECIST v1.1 at or before 9<br>months from the time from either (i) randomization (if<br>patients have not yet commenced treatment) or (ii)<br>commencement of therapy (if patients are randomized<br>during the first cycle of imatinib).;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.
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Progression free survival<br>Clinical benefit rate (SD + PR + CR) following 3 cycles (24 weeks) of treatment<br>Time to treatment failure<br>Safety/toxicity/tolerability<br>Overall survival;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.<br>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.