IRB Study Number 23-678
Status Recruiting
Institute Taussig Cancer Institute
Description
6.1.1. Primary Objective
• To compare the efficacy of ripretinib vs sunitinib as measured by PFS based on IRR
6.1.2. Key Secondary Objectives
• To compare the ORR by IRR of ripretinib vs sunitinib using mRECIST
• To compare the OS of ripretinib vs sunitinib
6.1.3. Other Secondary Objectives
• To compare QoL during treatment as measured by the EORTC-QLQ-C30, select items from the NCI-PRO-CTCAE, and the EQ-5D-5L of ripretinib vs sunitinib
• To compare DCR, TTP by IRR, PFS based on Investigator assessment, DOR, and TTR of ripretinib vs sunitinib
• To assess the safety profiles of ripretinib vs sunitinib
6.1.4. Exploratory Objectives
• To assess the PK of ripretinib in participants with prior imatinib treatment
• To assess PFS2 and second PFS
• To assess healthcare utilization
• To investigate baseline levels and effects of ripretinib on select biomarkers
• To explore association of genetic variants with differences in PK, pharmacodynamics, efficacy, tolerability, and/or safety
Inclusion Criteria
Male or female ≥18 years of age.
Histologic diagnosis of GIST with co-occurring KIT exons 11+17/18 mutations confirmed by ctDNA sample analyzed by the central laboratory at pre-screening according to requirements outlined in Section 11.2.
Participants must have advanced GIST and radiologic progression on imatinib treatment. Imatinib treatment must have been discontinued at least 10 days prior to the first dose of study drug. All prior imatinib treatment will count as 1 line of therapy (eg, adjuvant imatinib and dose escalation of imatinib).
ECOG PS of ≤2 at screening.
Female participants of childbearing potential must have a negative serum beta-human chorionic gonadotrophin pregnancy test at screening and a negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug.
Participants of reproductive potential must agree to follow contraception requirements outlined in Section 8.4.
Participants must have at least 1 measurable lesion according to mRECIST v1.1 (nonmodal lesions must be ≥1.0 cm in the long axis or ≥double the slice thickness in the long axis) within 21 days prior to the first dose of study drug. Bone lesions and lymph nodes are not allowed as target lesions.
Adequate organ function and bone marrow reserve as indicated by the following central laboratory assessments performed at screening:
a. ANC ≥1000/μL
b. Hemoglobin ≥8 g/dL
c. Platelet count ≥75,000/μL
d. Total bilirubin ≤1.5×ULN
e. AST and ALT ≤3×ULN (≤5×ULN in the presence of hepatic metastases)
f. Creatinine clearance ≥50 mL/min based on the CKD-EPI estimation
g. PT, INR, and PTT ≤1.5×ULN. Participants on a stable regimen of anticoagulant therapy for at least 1 month prior to the first dose of study drug may have PT/INR measurements >1.5×ULN if, in the opinion of the Investigator, the participant is suitable for the study. An adequate rationale must be provided to the Sponsor prior to randomization.
Resolution of all toxicities from prior therapy to Grade ≤1 (or participant baseline) within 1 week prior to the first dose of study drug (excluding alopecia).
The participant is capable of understanding and complying with the protocol and the participant has signed the informed consent document. Signed ICF must be obtained before any study-specific procedures are performed.
Exclusion Criteria
Presence of co-occurring KIT exons 11+17 and/or 18 mutations that cannot be confirmed by central laboratory testing of ctDNA.
History of KIT exon 9 mutation or detection of KIT exon 9, 13, or 14 mutation in a ctDNA sample by the central laboratory at pre-screening.
Treatment with any other line of therapy in addition to imatinib for advanced GIST. Imatinib-containing combination therapy in the first-line setting is not allowed.
A prior or concurrent malignancy whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical study are not eligible. For example, participants receiving adjuvant cancer treatment are not eligible if those medications are potentially active against GIST or excluded per protocol. NOTE: Participants with a history of breast cancer, requiring continued hormonal treatment (eg, anti-estrogen or an aromatase inhibitor) may continue treatment. Participants with a history of prostate cancer, requiring continued support with luteinizing hormone-releasing hormone agonists, with or without androgens, may continue treatment.
Has known active central nervous system metastases.
New York Heart Association Class II-IV heart disease, myocardial infarction within 6 months of Cycle 1 Day 1, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, or congestive heart failure.
LVEF <50% at screening.
Arterial thrombotic or embolic events such as cerebrovascular accident (including ischemic attacks) or hemoptysis within 6 months prior to the first dose of study drug.
Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg, pulmonary embolism) within 1 month prior to the first dose of study drug. Participants on stable anticoagulation therapy for at least 1 month are eligible.
12-lead ECG demonstrating QTcF >470 ms in both males and females at screening or history of long QT syndrome.
Use of strong or moderate inhibitors or inducers of CYP3A, including certain herbal medications (eg, St. John’s Wort) within 14 days or 5× the half-life (whichever is longer) prior to the first dose of study drug, and consumption of grapefruit or grapefruit juice within 14 days prior to the first dose of study drug.
Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study drug. All major surgical wounds must be healed and free of infection or dehiscence prior to the first dose of study drug.
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 participant to safety risks.
Known human immunodeficiency virus or hepatitis C infection only if the participant is taking medications that are excluded per protocol, acute or chronic hepatitis B, or acute or chronic hepatitis C infection.
If female, the participant is pregnant or breastfeeding.
Known allergy or hypersensitivity to any component of the study drug. Participants with history of Stevens-Johnson syndrome on a prior TKI are excluded.
Gastrointestinal abnormalities including, but not limited to:
a. inability to take oral medication
b. malabsorption syndromes
c. requirement for intravenous alimentation
Any active bleeding excluding hemorrhoidal or gum bleeding.
Ongoing participation in a non-GIST interventional study or prior participation within 30 days of screening. Ongoing participation in a noninterventional study (including observational studies) is permitted.
