Phase Ib Study of SUnitinib Alternating With REgorafenib in Patients With Metastatic and/or Unresectable GIST
Condition: Gastrointestinal Stromal Tumor
MeSH terms: Gastrointestinal Stromal Tumors
Intervention: Sunitinib; Regorafenib
Intervention description: Intervention Description: 3 days of once daily sunitinib alternating with 4 days of once daily regorafenib throughout each 28 day cycle. The starting dose level (level 1) is sunitinib 37.5 mg/d and regorafenib 120 mg/d, and doses will be escalated in subsequent cohorts following a classical 3+3 design up to sunitinib 50 mg/d and regorafenib 160 mg/d or until maximum tolerable dosage (MTD) and recommended phase II dose (RP2D) is determined. Number of Cycles: until progression or unacceptable toxicity develops.; Intervention Description: 3 days of once daily sunitinib alternating with 4 days of once daily regorafenib throughout each 28 day cycle. The starting dose level (level 1) is sunitinib 37.5 mg/d and regorafenib 120 mg/d, and doses will be escalated in subsequent cohorts following a classical 3+3 design up to sunitinib 50 mg/d and regorafenib 160 mg/d or until maximum tolerable dosage (MTD) and recommended phase II dose (RP2D) is determined. Number of Cycles: until progression or unacceptable toxicity develops.
Intervention MeSH terms: Sunitinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Gastrointestinal Stromal Tumor

Summary:

      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.
    

Eligibility criteria:

        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.