Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies
Condition: Gastrointestinal Stromal Tumors
MeSH terms: Gastrointestinal Stromal Tumors
Intervention: DCC-2618; Placebo Oral Tablet
Intervention description: Oral KIT/PDGFRA kinase inhibitor; Placebo
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 129.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a 2-arm, randomized, placebo-controlled, double-blind, international, multicenter
      study comparing the efficacy of ripretinib (DCC-2618) to placebo in patients who have
      received treatment with prior anticancer therapies. Prior anticancer therapies must include
      imatinib, sunitinib, and regorafenib (3 prior therapies). Approximately 120 patients were
      randomized in a 2:1 ratio to ripretinib 150 mg QD or placebo
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologic diagnosis of GIST

          2. Patients must have progressed on imatinib, sunitinib, and regorafenib or have
             documented intolerance to any of these treatments.

          3. ECOG PS of 0 to 2 at screening.

          4. Able to provide an archival tumor tissue sample if no anticancer therapy was
             administered since the sample was collected; otherwise, a fresh tumor tissue sample is
             required prior to the first dose of study drug.

          5. Female patients of childbearing potential must have a negative serum beta-human
             chorionic gonadotrophin (β-hCG) pregnancy test at screening and negative urine
             pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug.

          6. Patients of reproductive potential must agree to follow the contraception
             requirements.

          7. The patient is capable of understanding and complying with the protocol and has signed
             the informed consent document. A signed informed consent form must be obtained before
             any study-specific procedures are performed.

          8. At least 1 measurable lesion according to modified RECIST Version 1.1 (non-nodal
             lesions must be ≥1.0 cm in the long axis or ≥double the slide thickness in the long
             axis) within 21 days prior to the first dose of study drug.

          9. Adequate organ function and bone marrow reserve as indicated by the following
             laboratory assessments performed at screening.

               -  Absolute neutrophil count ≥1000/uL

               -  Hemoglobin ≥8 g/dL

               -  Platelet count ≥75,000/uL

               -  Total bilirubin ≤1.5 x the upper limit of normal (ULN)

               -  Aspartate transaminase or alanine transaminase ≤3 x ULN (≤5x ULN in the presence
                  of hepatic metastases)

               -  Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min based on either
                  urine collection or Cockcroft Gault estimation.

               -  Prothrombin time (PT) or international normalized ratio (INR) or partial
                  thromboplastin time ≤1.5 x ULN. Patients on a stable, maintenance regimen of
                  anticoagulant therapy for at least 30 days prior to study drug administration may
                  have PT/INR measurements >1.5 x ULN if, in the opinion of the Investigator, the
                  patient is suitable for the study. An adequate rationale must be provided to the
                  Sponsor prior to randomization.

         10. Resolution of all toxicities from prior therapy to ≤Grade 1 (or baseline) within 1
             week prior to the first dose of study drug (excluding alopecia and ≤Grade 3 clinically
             asymptomatic lipase, amylase, and creatine phosphokinase laboratory abnormalities).

        Exclusion Criteria:

          1. Treatment with anticancer therapy, including investigational therapy, or
             investigational procedures within 14 days or 5 x the half-life (whichever is longer)
             prior to the first dose of study drug. For prior biological therapies, eg, monoclonal
             antibodies with a half-life longer than 3 days, the interval must be at least 28 days
             prior to the first dose of study drug.

          2. Prior treatment with DCC-2618

          3. Prior or concurrent malignancy whose natural history or treatment have the potential
             to interfere with the safety or efficacy assessment of DCC-2618. Patients receiving
             adjuvant cancer treatment are not eligible if those medications are potentially active
             against GIST or excluded per protocol.

          4. Patient has known active central nervous system metastases.

          5. New York Heart Association class II - IV heart disease, active ischemia or any other
             uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac
             arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.

          6. Arterial thrombotic or embolic events such as cerebrovascular accident (including
             ischemic attacks) or hemoptysis within 6 months before the first dose of study drug.

          7. Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg,
             pulmonary embolism) within 3 months before the first dose of study drug. Patients with
             venous thrombotic events ≥3 months before the first dose of study drug on stable
             anticoagulation therapy are eligible.

          8. 12-lead electrocardiogram (ECG) demonstrating QT interval corrected by Fridericia's
             formula >450 ms in males or >470 ms in females at screening or history of long QT
             interval corrected syndrome.

          9. Left ventricular ejection fraction (LVEF) <50% at screening.

         10. Use of proton-pump inhibitors within 4 days prior to the first dose of study drug.
             Other medications that increase gastric pH, ie, histamine H2 receptor antagonists and
             antacids may be taken provided they are not administered within 2 hours before or
             after administration of study drug.

         11. Use of strong or moderate inhibitors and inducers of cytochrome P450 (CYP) 3A4,
             including certain herbal medications (eg, St. John's Wort) and consumption of
             grapefruit or grapefruit juice within 14 days or 5 x the half-life (whichever is
             longer) prior to the first dose of study drug.

         12. Use of known substrates or inhibitors of breast cancer resistance protein (BCRP)
             transporters within 14 days or 5 x the half-life (whichever is longer) prior to the
             first dose of study drug.

         13. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study
             drug. Following major surgeries, >4 weeks prior to the first dose of study drug, all
             surgical wounds must be healed and free of infection or dehiscence.

         14. Any other clinically significant comorbidities, such as uncontrolled pulmonary
             disease, active infection, or any other condition, which in the judgment of the
             Investigator, could compromise compliance with the protocol, interfere with
             interpretation of the study results, or predispose the patient to safety risks.

         15. Known human immunodeficiency virus or hepatitis C infection only if the patient is
             taking medications that are excluded per protocol, active hepatitis B, or active
             hepatitis C infection.

         16. If female, the patient is pregnant or lactating.

         17. Known allergy or hypersensitivity to any component of the investigational drug
             product. Patients with a history of Stevens-Johnson syndrome on a prior TKI are
             excluded.

         18. Gastrointestinal abnormalities including but not limited to:

               -  inability to take oral medication

               -  malabsorption syndromes

               -  requirement for intravenous alimentation

         19. Any active bleeding excluding hemorrhoidal or gum bleeding.