CompletedPhase 2ACTRN12614000950662

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 phase II 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.

Sponsor

Australasian Gastro-Intestinal Trials Group (AGITG)

Enrollment

76 participants

Start Date

Jun 30, 2015

Study Type

Interventional

Conditions

Metastatic gastrointestinal stromal tumour (GIST)

Summary

The aim of this study is to determine whether an alternating regime of imatinib and regorafenib improves disease control in patients with metastatic gastrointestinal stromal tumours (GIST). Who is it for? You may be eligible to join this study if you aged 18 years or more and have a confirmed diagnosis of metastatic GIST. Study details Participants in this study will be randomly (by chance) allocated to one of two groups. Participants in one group will receive an alternating regime of treatment with the drugs imatinib and regorafenib (administered orally by tablet). One treatment cycle lasts for 8 weeks. Participants in the other group will receive treatment with daily imatinib tablets only. Imatinib is currently used as the initial treatment for incurable GIST. Although many people with metastatic disease initially respond to imatinib, the cancer usually becomes resistant to this drug and starts to grow. The cancer drug called regorafenib works in a similar way to imatinib and has been shown to be effective against GIST after other treatments have stopped working. Participants will be regularly monitored for a minimum of 24 months follow-up in order to determine whether the alternating treatment approach improves disease control. If it is found to have benefit and be tolerable, this alternating approach will be further evaluated in a larger study.

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria13

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 greater than or equal to 2 cm in size).
Adequate bone marrow function (Haemoglobin greater than or equal to 9.0g/dL, platelet count greater than or equal to 100 x 109/L, and absolute neutrophil count greater than or equal to 1.5 x 109/L).
Adequate liver function (Serum total bilirubin less than or equal to 1.5 x ULN, INR less than or equal to 1.5, and ALT, AST, ALP less than or equal to 2.5 x ULN (less than or equal to 5 x ULN for participants with liver metastases). Lipase level must be less than or equal to 1.5 x ULN.
Adequate renal function (Creatinine clearance greater than 50ml/min) based on either the Cockcroft Gault formula, 24 hour urine or Glomerular Filtration Rate (GFR scan); and serum creatinine less than or equal to 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.

Exclusion Criteria21

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 greater than 140 mmHg or diastolic pressure greater than 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 greater than or equal to 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 greater than or equal to Grade 3 according to CTCAE v4.0 within 4 weeks prior to randomisation.
Ongoing infection of greater than 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.
Persistent proteinuria of greater than or equal to Grade 3 (greater than 3.5g/24 hours) according to CTCAE v4.0
Other significant medical or psychiatric condition judged by the investigator to interfere with protocol requirements.
Use of biological response modifiers such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
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).
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.
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.

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Interventions

Those randomised to the experimental alternating arm will receive: Imatinib 400mg (1 x 400mg tablet) orally daily for 21 to 25 days (washout period determined by treating investigator), then a 3 - 7

Those randomised to the experimental alternating arm will receive: Imatinib 400mg (1 x 400mg tablet) orally daily for 21 to 25 days (washout period determined by treating investigator), then a 3 - 7 day washout period (no drug). In total, the days taking imatinib plus the washout period must be 28 days. This is followed by regorafenib 160 mg (4 x 40mg tablets) orally daily for 21 days, then a 7 day washout period. This combination of imatinib, regorafenib and intervening washout periods will constitute 1 cycle of study treatment (imatinib plus washout period 28 days in total; regorafenib 3 weeks on, 1 week off; cycle duration 8 weeks in total). Treatment will continue until progressive disease or unacceptable toxicity. A drug administration diary will be provided to patients.