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

Cogent Biosciences

Status and phase: Active, not recruiting; Phase 3

Conditions: Metastatic Cancer; Advanced Gastrointestinal Stromal Tumors

Treatments: Drug: CGT9486; Drug: Sunitinib; Drug: Midazolam; Drug: CGT9486 plus sunitinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT05208047

CGT9486-21-301

Details and patient eligibility

About

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).

Enrollment: 482 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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482 participants in 7 patient groups

Part 1a

Experimental group

Description:

CGT9486 plus sunitinib 37.5 mg QD

Treatment:

Drug: CGT9486 plus sunitinib

Drug: CGT9486 plus sunitinib

Drug: CGT9486 plus sunitinib

Part 2 - Experimental Group

Experimental group

Description:

CGT9486 plus sunitinib 37.5 mg QD

Treatment:

Drug: CGT9486 plus sunitinib

Drug: CGT9486 plus sunitinib

Drug: CGT9486 plus sunitinib

Part 2 - Control Group

Active Comparator group

Description:

sunitinib 37.5 mg QD

Treatment:

Drug: Sunitinib

Drug: Sunitinib

Part 1b - DDI Cohort 1

Experimental group

Description:

CGT9486 plus sunitinib 37.5 mg QD

Treatment:

Drug: CGT9486

Part 1b - DDI Cohort 2

Experimental group

Description:

sunitinib 37.5 mg QD plus CGT9486

Treatment:

Drug: Sunitinib

Drug: Sunitinib

DDI Substudy (Midazolam)

Experimental group

Description:

Midazolam, CGT9486, sunitinib

Treatment:

Drug: CGT9486 plus sunitinib

Drug: Midazolam

Drug: CGT9486 plus sunitinib

Drug: CGT9486 plus sunitinib

GIST 1L Substudy

Experimental group

Description:

CGT9486, sunitinib

Treatment:

Drug: CGT9486 plus sunitinib

Drug: CGT9486 plus sunitinib

Drug: CGT9486 plus sunitinib