Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)
Condition: Gastrointestinal Stromal Tumors
MeSH terms: Gastrointestinal Stromal Tumors
Intervention: Regorafenib (Stivarga, BAY73-4506); Placebo; Best supportive care
Intervention description: 160 mg po once daily (od), 3 weeks on/1 week off. Route of administration: oral; once daily (od), 3 weeks on/1 week off. Route of administration: oral; Best supportive care includes any method to preserve the comfort and dignity of the patients, and excludes any disease-specific anti-neoplastic therapy such as any kinase inhibitor, chemotherapy, radiation therapy, or surgical intervention.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 199.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Gastrointestinal stromal cancer; GIST; multikinase inhibitor

Summary:

      A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best
      supportive care versus placebo plus best supportive care for subjects with metastatic and/or
      unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite
      prior treatment with at least imatinib and sunitinib.

      The study is composed of 3 periods: A Screening Period, a Treatment Period, and a Survival
      Follow up Period.

      Subjects randomized to be treated with regorafenib will receive 160 mg po od for 3 weeks of
      every 4 week (28 day) cycle (ie, 3 weeks on/1 week off). In addition subjects will receive
      best supportive care which excludes any disease specific anti cancer therapy such as any
      kinase inhibitor, chemotherapy, radiation therapy, or surgery.

      Tumor assessment will be every 4 weeks for the first 3 months, every 6 weeks for the next 3
      months (through month 6), and every 8 weeks until the end of treatment, or more frequently if
      clinically indicated. Tumor assessments include CT or MRI and will be performed until tumor
      progression is seen in a central radiology review.

      Subjects receiving placebo who experience disease progression may be offered active
      treatment.

      Subjects who experience progression during regorafenib treatment may continue open label
      treatment.

      All subjects will enter the Survival Follow-up Period upon discontinuation of randomized
      study treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female subjects 18 years of age.

          -  Subjects with histologically confirmed metastatic and/or unresectable GIST.

          -  At least imatinib and sunitinib as prior treatment regimens, with objective disease
             progression or intolerance to imatinib, as well as disease progression while on
             sunitinib therapy. Additionally, disease progression or intolerance to other systemic
             therapies, as well as investigational new agents, is allowed, except prior treatment
             with any other vascular endothelial growth factor receptor (VEGFR) inhibitor.

          -  Subjects must have at least one measurable lesion according to Response Evaluation
             Criteria in Solid Tumors (RECIST), version 1.1. A lesion in a previously irradiated
             area is eligible to be considered as measurable disease as long as there is objective
             evidence of progression of the lesion prior to study enrollment.

        Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

          -  Adequate bone marrow, liver, and renal function as assessed by laboratory parameters.

        Recovery to NCI-CTCAE v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior
        treatment from any previous drug/procedure-related toxicity (except alopecia and anemia).

        Exclusion Criteria:

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             before start of study medication.

          -  Congestive heart failure New York Heart Association (NYHA) class 2.

          -  Unstable angina (angina symptoms at rest, new-onset angina, ie, within the last 3
             months) or myocardial infarction (MI) within the past 6 months before start of study
             medication.

          -  Uncontrolled hypertension (systolic blood pressure 140 mmHg or diastolic pressure 90
             mmHg despite optimal medical management).

        Arterial thrombotic or embolic events such as cerebrovascular accident (including transient
        ischemic attacks), or pulmonary embolism within the 6 months before start of study drug or
        venous thrombotic events such as deep vein thrombosis within the 3 months before start of
        study drug.

          -  Ongoing infection grade 2 National Cancer Institute-Common Terminology Criteria for
             Adverse Events (NCI CTCAE) version 4.0.

        Symptomatic metastatic brain or meningeal tumors.

          -  Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding
             event NCI-CTCAE version 4.0 grade 3 or higher within 4 weeks prior to the start of
             study drug.

        Non-healing wound, ulcer, or bone fracture.

          -  Persistent proteinuria of NCI-CTCAE version 4.0 grade 3 or higher (3.5 g/24 hrs,
             measured by urine protein:creatinine ratio on a random urine sample).