Phase Ib Study of SUnitinib Alternating With REgorafenib in Patients With Metastatic and/or Unresectable GIST

A Non-randomized, Open-label Phase Ib Study of SUnitinib Alternating With REgorafenib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) Progressing After Prior Therapy With Tyrosine Kinase Inhibitors

The purpose of this research study is to determine the safety and tolerability of sunitinib alternating with regorafenib in participants with advanced gastrointestinal stromal tumor GIST, if the standard approved therapies (imatinib, sunitinib and regorafenib) have failed to control the disease. Additionally, this study seeks to determine the highest dose that can be given safely for this combination of drugs.

This is a non-randomized, open label, single-center, single-arm, phase Ib study to evaluate the safety and the preliminary efficacy of short cycles of sunitinib alternated with regorafenib in participants with metastatic and/or unresectable gastrointestinal stromal tumor GISTs with prior failure of tyrosine kinase inhibitors (TKI). The study consists of two cohorts: a dose-escalation, dose-finding cohort, and dose-expansion cohort. Between 6 to 15 patients are expected to be included in the escalation cohort. A total of 20 eligible and evaluable patients will be included in the expansion cohort to further assess toxicity and evaluate preliminary efficacy.

Each treatment cycle lasts 28 days (4 weeks), during which time you will be taking the study drug, sunitinib, for the first 3 days of the week, followed by the study drug, regorafenib, for the last 4 days of the week. The study drugs will be taken continuously for 4 weeks each cycle, unless the study team instructs you otherwise. Each participant will receive a study diary. The diary will also include special instructions for taking the study drugs.

Inclusion Criteria:

• At least 18 years of age at the time of study entry.
• Histologically confirmed metastatic and/or unresectable GIST. Patients must demonstrate prior failure to at least imatinib, sunitinib and regorafenib (4th line and beyond). Any number of previous therapies for GIST is allowed.
• Measurable disease per modified RECIST 1.1. A lesion in a previously irradiated area is ineligible to be considered as measurable disease unless there is objective evidence of progression of the lesion prior to study enrollment.
• ECOG performance status 0 or 1 (see Appendix A).
• Participants must have adequate organ and marrow function as outlined in the protocol.
• Patients must be able to swallow oral medication.
• Willingness to use effective means of birth control throughout the duration of clinical study and for at least 3 months after completion of study drug.
• Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of study drug administration.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Use of any approved tyrosine kinase inhibitors or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is shorter, prior to receiving study drugs.
• Patients with intolerance to sunitinib and/or regorafenib.
• Participants who have had radiotherapy within 4 weeks prior to study entry.
• Major surgery, or significant traumatic injury within 4 weeks prior to study entry.
• Presence of symptomatic or uncontrolled brain or central nervous system metastases.
• Known or suspected allergy to the investigational agent or any agent given in association with this trial.
• Individuals with a history of a different malignancy, other than cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, are ineligible, except if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy OR other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Clinically significant cardiac arrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Patients with controlled atrial fibrillation are not excluded.
• History of clinically significant cardiac disease or congestive heart failure > NYHA class 2 (See Appendix C). Patients must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months.
• Hypertension as defined by systolic blood pressure >140 mmHg or diastolic blood pressure > 90 mmH despite optimal medical management.
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than 1 month before the start of study medication).
• Patients with evidence or history of any bleeding diathesis, irrespective of severity.
• Ongoing infection ≥ Grade 2.
• Patients with any seizure disorder requiring medication.
• Non-healing wound, ulcer, or bone fracture.
• Persistent proteinuria Grade 2 or higher measured by urine protein:creatinine ratio on a urine sample or during 24-hour assessment.
• HIV-positive individuals on combination antiretroviral therapy.
• Patients with active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
• Uncontrolled intercurrent illness.
• Pregnant or lactating females.
• Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol.
• Strong CYP3A4 inhibitors within 28 days or 5 drug half-lives, whichever is longer, before start of study drug.