(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors

A Phase 3 Randomized, Open-Label, Multicenter Clinical Study of CGT9486+Sunitinib vs. Sunitinib in Subjects With Locally Advanced, Unresectable, or Metastatic Gastrointestinal Stromal Tumors

This is a Phase 3, open-label, international, multicenter study of CGT9486 in combination with sunitinib. This is a multi-part study that will enroll approximately 482 patients. Part 1 consists of two evaluations: 1) confirming the dose of an updated formulation of CGT9486 to be used in subsequent parts in approximately 20 patients who have received at least one prior line of therapy for GIST and 2) evaluating the potential for drug-drug interactions between CGT9486 and sunitinib in approximately 18 patients who have received at least two prior tyrosine kinase inhibitors (TKIs) for GISTs. The second part of the study will enroll approximately 388 patients who are intolerant to, or who failed prior treatment with imatinib only and will compare the efficacy of CGT9486 plus sunitinib to sunitinib alone with patients being randomized in a 1:1 manner. This study also contains two substudies: 1) a drug-drug interactions substudy will investigate the potential for CGT9486 to be a CYP3A4 inducer in approximately 16 patients who have received at least one prior line of therapy for GIST and 2) a substudy intended to test the efficacy of bezuclastinib and sunitinib as first-line treatment of GIST in approximately 40 participants with KIT exon 9 mutations and no prior systemic therapy (with the exception of up to 10 subjects with ongoing imatinib therapy of ≤4 weeks).

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Cancer; Advanced Gastrointestinal Stromal Tumors
• Intervention / Treatment: Drug: CGT9486 plus sunitinib; Drug: Sunitinib; Drug: Sunitinib; Drug: CGT9486; Drug: CGT9486 plus sunitinib; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Estimated): 482
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1426ANZ
    • Instituto Alexander Fleming
  • Córdoba, Argentina, X5000HWE
    • Instituto Oncologico de Cordoba (IONC)
• Australia
  • Bankstown, Australia, 2200
    • Bankstown-Lidcombe Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Brazil
  • Campinas, Brazil, 130.83-888
    • Hospital das Clinicas da Universidade Estadual de Campinas (UNICAMP)
  • Rio de Janeiro, Brazil, 20.230-130
    • lnstituto Nacional de Cancer - INCA
  • São Paulo, Brazil, 09060-650
    • CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia
• Canada
  • Calgary, Canada, T2N 4N2
    • Tom Baker Cancer Center
  • Montreal, Canada, HIT 2M4
    • Universite de Montreal - Hopital Maisonneuve-Rosemont (HMR)
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Alberta Health Services Cross Cancer Institute
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
• Chile
  • Santiago, Chile, 7500921
    • Instituto Oncologico FALP
  • Santiago, Chile, 7560908
    • Centro de Oncologia de Precision, Universidad Mayor
• Czechia
  • Brno, Czechia, 65653
    • Masarykuv onkologicky ustav
  • Olomouc, Czechia, 77900
    • Fakultni nemocnice Olomouc - Oncology clinic
• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital
• France
  • Bordeaux, France, 33076
    • Institut Bergonié
  • Lille, France, 59000
    • Centre Oscar Lambret
  • Lyon, France, 69008
    • Centre Leon Berard
  • Marseille, France, 13005
    • AP-HM - Hôpital de la Timone
  • Rennes, France, 35042
    • Centre Eugène Marquis
  • Saint-Herblain, France, 44800
    • ICO St-Herblain
  • Toulouse, France, 31400
    • CHU de Toulouse - Hospital Rangueil
  • Villejuif, France, 94805
    • Gustave Roussy
• Germany
  • Bad Saarow, Germany, 15526
    • Helios Klinikum Bad Saarow
  • Berlin, Germany, 13125
    • Helios Klinikum Berlin-Buch
  • Essen, Germany, 45147
    • Universitaetsklinikum Essen
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
  • Hanover, Germany, 30625
    • Medizinische Hochschule Hannover- Urology Oncology
  • Mannheim, Germany, 68167
    • UniversitaetsMedizin Mannheim
• Hong Kong
  • Jordon, Hong Kong
    • Hong Kong United Oncology Centre
  • Shatin, Hong Kong
    • Prince of Wales Hospital
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem, Klinikai Központ, Onkológiai Klinika
• Italy
  • Aviano, Italy, 33081
    • Centro Riferimento Oncologico - Aviano
  • Bologna, Italy, 40138
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant'Orsola
  • Brescia, Italy, 25123
    • ASST degli Spedali Civili di Brescia
  • Florence, Italy, 50134
    • Azienda Ospedaliero-Universitaria Careggi
  • Meldola, Italy, 47014
    • Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Milan, Italy, 20141
    • Istituto Europeo di Oncologia
  • Palermo, Italy, 90127
    • Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone
  • Roma, Italy, 00128
    • Policlinico Universitario Campus Bio-Medico
  • Rozzano, Italy, 20089
    • Istituto Clinico Humanitas
  • Verona, Italy, 31726
    • Azienda Ospedaliera Universitaria Integrata Verona-Ospedale Borgo Trento
• Mexico
  • Monterrey, Mexico, 64710
    • I Can Oncology Center SA De CV
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Nederlands Kanker Instituut - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL)
  • Groningen, Netherlands, 9713 GZ
    • UMC Groningen
  • Nijmegen, Netherlands, 6525 GA
    • Stichting Radboud Universitair Medisch Centrum
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
• Norway
  • Bergen, Norway, 5021
    • Haukeland University Hospital - Bergen
  • Oslo, Norway, 0310
    • Oslo University Hospital
• Poland
  • Brzozów, Poland, 36-200
    • Szpital Specjalistyczny w Brzozowie
  • Gliwice, Poland, 44-102
    • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy, Oddzial w Gliwicach, Oddzial Chemioterapii Dziennej
  • Warsaw, Poland, 02-781
    • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy, Klinika Nowotworow Tkanek Miekkich, Kosci i Czerniakow
• South Korea
  • Seoul, South Korea, 05505
    • Asan Medical Center
  • Seoul, South Korea, 06351
    • Samsung Medical Center
  • Seoul, South Korea, 08308
    • Korea University Guro Hospital
  • Seoul, South Korea, 03080
    • Seoul National University Hosptial
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08908
    • Institut Catala d'Oncologia - L'Hospitalet
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain, 28040
    • Hospital Fundación Jimenez Diaz
  • Santiago de Compostela, Spain, 15706
    • Hospital Clinico Universitario de Santiago de Compostela
  • Seville, Spain, 41013
    • Hospital Universitario Virgen del Rocío
• Sweden
  • Lund, Sweden, 22185
    • Skane University Hospital Lund
  • Solna, Sweden, 171 76
    • Karolinska university Hospital
• Taiwan
  • Kaohsiung City, Taiwan, 83301
    • Chang Gung Memorial Hospital - Kaohsiung Branch
  • New Taipei City, Taiwan, 10002
    • National Taiwan University Hospital
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital (VGHTP)
  • Taoyuan, Taiwan, 33305
    • Chang Gung Memorial Hospital - Linkou Branch (CGMHLK)
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge Addenbrooke's Hospital
  • London, United Kingdom, NW1 2PG
    • University College London Hospital
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden Hospital - Surrey
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Sheffield, United Kingdom, S10 2SJ
    • Sheffield Teaching Hospitals NHS Foundation Trust
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
    • Tucson, Arizona, United States, 85719
      • University of Arizona- Cancer Center
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90404
      • University of California, Los Angeles (UCLA)
    • San Diego, California, United States, 92093
      • University of California, San Diego (UCSD)
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
  • Colorado
    • Denver, Colorado, United States, 80204
      • University of Colorado Denver
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Medstar Washington Hospital Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami - Sylvester Comprehensive Cancer Center
    • Orlando, Florida, United States, 32806
      • Orlando Health Cancer Institute
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospital and Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63130
      • Washington University
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
  • New York
    • Buffalo, New York, United States, 14203
      • Roswell Park Comprehensive Cancer Center
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University (OHSU)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center - Hillman Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030-4009
      • The University of Texas MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin - Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Histologically confirmed locally advanced, metastatic, and/or unresectable GIST. Molecular pathology report must be available for Part 2; if molecular pathology report is unavailable or inadequate, an archival or fresh tumor tissue sample will be required to evaluate mutational status prior to randomization. (GIST 1L Substudy: must have documented mutation in KIT Exon 9 with an available molecular pathology report; archival or fresh tumor tissue sample will be required)
2. Documented disease progression on or intolerance to imatinib (Part 1a, Part 1b, Part 2, DDI Substudy)

3. Subjects must have received the following treatment:

   • DDI Substudy/Part 1a: Treatment with ≥1 prior lines of therapy for GIST
   • Part 1b: Treatment with ≥2 prior TKI for GISTs
   • Part 2: Prior treatment with imatinib only
   • GIST 1L Substudy: No prior systemic therapy for GIST including adjuvant therapy. Exception: up to 10 subjects with ongoing imatinib therapy of ≤4 weeks
4. Have at least 1 measurable lesion according to mRECIST v1.1 (Part1a, Part 1b, Part 2, GIST 1L Substudy)

5. ECOG

   • 0 to 2 (Part 1a, Part 1b, Part 2, DDI Substudy)
   • 0 to 1 (GIST 1L Substudy)
6. Have clinically acceptable local laboratory screening results (clinical chemistry and hematology) within certain limits

Key Exclusion Criteria:

1. Known PDGFR driving mutations or known succinate dehydrogenase deficiency (Part 1a, Part 1b, Part 2, DDI Substudy)
2. Clinically significant cardiac disease
3. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study drug (Part 1a, Part 1b, Part 2, DDI Substudy)
4. Gastrointestinal abnormalities including, but not limited to, significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption
5. Any active bleeding excluding hemorrhoidal or gum bleeding
6. Seropositive for HIV 1 or 2, or positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody.
7. Active, uncontrolled, systemic bacterial, fungal, or viral infections at Screening
8. Received strong CYP3A4 inhibitors or inducers (Part 1a, Part 1b, Part 2, DDI Substudy)
9. Received sunitinib within 3 weeks (Part 1a, Part 1b, DDI Substudy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1a; CGT9486 plus sunitinib 37.5 mg QD	Drug: CGT9486 plus sunitinib; Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.; Drug: CGT9486 plus sunitinib; Patients will receive CGT9486 orally starting on Day 2 and sunitinib starting on Day 16 until study stopping rules are met.
Experimental: Part 2 - Experimental Group; CGT9486 plus sunitinib 37.5 mg QD	Drug: CGT9486 plus sunitinib; Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.; Drug: CGT9486 plus sunitinib; Patients will receive CGT9486 orally starting on Day 2 and sunitinib starting on Day 16 until study stopping rules are met.
Active Comparator: Part 2 - Control Group; sunitinib 37.5 mg QD	Drug: Sunitinib; Participants will receive sunitinib until steady state then both sunitinib and CGT9486 orally until study stopping rules are met.; Other Names: sunitinib - Part 1b; Drug: Sunitinib; Participants will receive sunitinib orally until study stopping rules are met.; Other Names: sunitinib - Part 2
Experimental: Part 1b - DDI Cohort 1; CGT9486 plus sunitinib 37.5 mg QD	Drug: CGT9486; Participants will receive CGT9486 until steady state then both CGT9486 and sunitinib orally until study stopping rules are met.
Experimental: Part 1b - DDI Cohort 2; sunitinib 37.5 mg QD plus CGT9486	Drug: Sunitinib; Participants will receive sunitinib until steady state then both sunitinib and CGT9486 orally until study stopping rules are met.; Other Names: sunitinib - Part 1b; Drug: Sunitinib; Participants will receive sunitinib orally until study stopping rules are met.; Other Names: sunitinib - Part 2
Experimental: DDI Substudy (Midazolam); Midazolam, CGT9486, sunitinib	Drug: CGT9486 plus sunitinib; Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.; Drug: CGT9486 plus sunitinib; Patients will receive CGT9486 orally starting on Day 2 and sunitinib starting on Day 16 until study stopping rules are met.; Drug: Midazolam; Participants will receive a single-dose of midazolam on Day 1 and Day 16
Experimental: GIST 1L Substudy; CGT9486, sunitinib	Drug: CGT9486 plus sunitinib; Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.; Drug: CGT9486 plus sunitinib; Patients will receive CGT9486 orally starting on Day 2 and sunitinib starting on Day 16 until study stopping rules are met.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1a - pharmacokinetics - Cmax	Maximum plasma concentration (Cmax)	16 days
Part 1a - pharmacokinetics - AUC	Area under the plasma concentration-time curve (AUC)	16 days
Part 1b - pharmacokinetics - Cmax	Maximum plasma concentration (Cmax)	14 days
Part 1b - pharmacokinetics - AUC	Area under the plasma concentration-time curve (AUC)	14 days
Part 1b - pharmacokinetics - Tmax	Time to maximum observed plasma concentration (Tmax)	14 days
Part 2 - Progression Free Survival (PFS)	Time from first dose to documented disease progression or death due to any cause, whichever occurs first	Approximately 48 months
DDI Substudy - pharmacokinetics - AUC	Area under the plasma concentration-time curve (AUC)	16 days
DDI Substudy - pharmacokinetics - Cmax	Maximum plasma concentration (Cmax)	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All Study Parts - observing the safety of each treatment regimen.	Incidence and severity of Adverse Events from first dose of study drug	Approximately 48 months
All Study Parts - observing the safety of each treatment regimen.	Incidence and severity of Serious Adverse Events from first dose of study drug	Approximately 48 months
All Study Parts - observing the safety of each treatment regimen.	Incidence of Adverse Events leading to dose modifications from first dose of study drug	Approximately 48 months
All Study Parts - observing the safety of each treatment regimen.	Change from baseline in laboratory results	Approximately 48 months
Part 2 Only - European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30)	Change in individual scores in patients with locally advanced, unresectable, or metastatic GIST treated with CGT9486 in combination with sunitinib compared with patients treated with sunitinib monotherapy. The scale comprises 30 questions, 24 of which are aggregated into 9 multi-item scales, to include 5 functioning scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain and nausea/vomiting) and 1 global health status scale. The remaining 6 single-item scales assess symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea and the financial impact). All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning, while higher scores on the symptom and single-item scales indicate a higher level of symptoms.	Approximately 48 months
Part 1a, Part 1b, Part 2 - Overall Survival (OS)	Time from first dose to death due to any cause	Approximately 48 months
Part 1a, Part 1b, Part 2 - Objective Response Rate (ORR)	Percentage of subjects who achieved documented complete response (CR) + confirmed partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	Approximately 48 months
Part 1a, Part 1b, Part 2 - Disease Control Rate (DCR)	Percentage of subjects who achieved CR + PR + stable disease (SD) at 16 weeks	Approximately 48 months
Part 1a, Part 1b. Part 2 - Time to response (TTR)	Time from first dose to first documented response based on modified Response Evaluation Criteria in Solid Tumors Version 1.1	Approximately 48 months
Part 1a, Part 1b, Part 2 - Duration of Response (DOR)	Time from first response (CR or PR) to the date of progression or death from any cause, whichever occurs first	Approximately 48 months

Collaborators and Investigators

• Sponsor: Cogent Biosciences, Inc.
• Investigators: Study Director: Jessica Sachs, MD, Cogent Biosciences

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2022
• Primary Completion (Actual): September 30, 2025
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: December 23, 2021
• First Submitted That Met QC Criteria: January 14, 2022
• First Posted (Actual): January 26, 2022

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Metastatic; Unresectable; Midazolam; Solid Tumors; Gastrointestinal; GIST; KIT; Sunitinib; Drug-drug interaction; Gastrointestinal Stromal Tumors; Growth Inhibitors; Kinase Inhibitors; CGT9486; Bezuclastinib; PLX9486
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Neoplastic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis; Gastrointestinal Stromal Tumors; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Azoles; Indoles; Benzazepines; Pyrroles; Benzodiazepines; Sunitinib; Midazolam
• Other Study ID Numbers: CGT9486-21-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No