Protocol Title

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)

Aim

The aim of this study is to determine whether an alternating regimen of Imatinib and Regorafenib improves disease control in patients with metastatic GIST. The primary objective for the study is progression free survival at 24 months. Secondary objectives include objective tumour response rate, clinical benefit rate, complete response rate, time-to-treatment failure, safety/toxicity/tolerability and overall survival.

Background

ALT GIST is a randomised Phase II designed to determine whether an alternating Imatinib and Regorafenib treatment plan will be effective in stopping drug resistance in patients with advanced GIST.

Currently, the standard first line treatment for unresectable GIST is continuous treatment with Imatinib. However, in almost all cases the cancer will develop resistance to the drug. One possible cellular mechanism behind this resistance is that after continual exposure to the drug, GIST cells develop changes in their growth pathways that allow them to eventually become unaffected by the medication. The purpose of ALT GIST is to alternate Imatinib with a second drug called Regorafenib, which has been found to display efficacy in delaying the progression of cancer. Using an alternating regimen of Imatinib and Regorafenib, with brief drug-free intervals, may allow tumour stem cells to re-enter the cell cycle and become susceptible once more to drug therapy. Regorafenib, a multi-targeted tyrosine kinase inhibitor (TKI) with activity against angiogenic, stromal and oncogenic receptor tyrosine kinases, has demonstrated activity in the treatment of GIST and is FDA approved for third line therapy of advanced GIST.

If the alternating treatment is found to be beneficial and tolerable, it would be further studied in a Phase III trial.

Clinical Trial Design

ALT GIST is a randomised Phase II trial designed to investigate effectiveness and activity by alternating the medications: Imatinib and Regorafenib.

Participants will be randomly allocated to one of two groups. Participants will either be treated continuously with Imatinib (control group) or receive alternating treatment with Imatinib and Regorafenib.

For a single cycle of study treatment in the experimental arm, an Imatinib (400mg) tablet will be taken orally for 21 to 25 days followed by a 3 to 7-day gap when there will be no medication. In total, the days taking Imatinib plus the period without medication must be 28 days. This is followed by 21 days of Regorafenib (40mg), which will be taken as 4 tablets daily, and a 7-day gap without medication.

The control group will be given a regimen of continuous Imatinib in a 56-day cycle.  For both groups treatment will continue until progressive disease or unacceptable toxicity. A drug administration diary will be provided to all participants to record their intake and progress.

For the first 12 months, CT scans every 8 weeks will evaluate the effectiveness of the treatment. After the initial 12 months of the trial, the CT scans will be performed every 12 weeks and continue until there is cancer progression.

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.

Key Eligibility Criteria

Please note that the information below contains only the most important inclusion and exclusion criteria and is not a comprehensive list.

Key inclusion criteria:

• Adults (18 years or over) with histologically confirmed, measurable metastatic GIST, who have received no prior treatment for metastatic disease. (Patients who are currently taking, and have had up to 21 days of uninterrupted treatment with 400mg daily of Imatinib are eligible to participate.)
• Metastatic GIST that cannot be treated with surgery
• Adequate liver, renal and bone marrow function
• Willing to follow all study requirements, including treatment, timing and/or nature of required assessments and follow-up.

Key exclusion criteria:

• Existing gastrointestinal illness that will prevent absorption of Imatinib or Regorafenib
• Already taking warfarin
• Inability to swallow tablets
• Use of other investigational drugs within 28 days prior to enrolment
• Patients who have had major surgery, open biopsy or major traumatic injury within the 28 days prior to randomisation
• Presence of brain metastases
• Patients with significant active infection, which includes chronic active hepatitis B, C or HIV
• Poorly controlled hypertension (blood pressure)

Visit ANZTCR for more detailed information on inclusion/exclusion criteria and eligibility.

Contact Email

Principal Investigator

Professor Desmond Yip (The Canberra Hospital, Woden ACT)

More Information

Available online at the Australian New Zealand Clinical Trial Registry (ANZCTR) here.

Funding

Bayer Global