CGT9486 + Sunitinib for GIST

Not currently recruiting at 149 trial locations

Overseen By Cogent Biosciences

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Cogent Biosciences, Inc.

Must be taking: Tyrosine kinase inhibitors

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: Cardiac disease, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination for treating gastrointestinal stromal tumors (GIST), a type of cancer in the digestive tract. Researchers aim to determine if adding CGT9486 (also known as Bezuclastinib or PLX9486) to sunitinib, a current treatment, is more effective than sunitinib alone. The study will also examine how these drugs interact. The trial seeks participants with GIST who have not responded well to imatinib, a common cancer drug, or who cannot tolerate it. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot have taken sunitinib within 3 weeks before starting the study. Also, you should not be on strong CYP3A4 inhibitors or inducers.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that taking CGT9486 with sunitinib is generally safe for patients. Earlier studies found this combination safer than taking sunitinib alone, meaning patients using both drugs did not experience more severe side effects than those using just sunitinib.

In another study, patients who took CGT9486 with sunitinib mostly experienced mild to moderate side effects. Common side effects included tiredness, nausea, and diarrhea, which are typical with cancer treatments. Importantly, these studies reported no unexpected or life-threatening side effects.

Overall, evidence suggests that the combination of CGT9486 and sunitinib is safe for patients, with manageable side effects similar to those of other cancer treatments. This should reassure anyone considering joining a trial for this treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CGT9486 combined with sunitinib for treating gastrointestinal stromal tumors (GIST) because of its potential to enhance effectiveness compared to current therapies. Unlike traditional treatments like imatinib and regorafenib, which mainly target certain proteins to stop tumor growth, CGT9486 works by inhibiting a specific enzyme, KIT D816V, that plays a key role in tumor resistance. This unique mechanism could overcome resistance issues seen with standard treatments, offering hope for improved outcomes in patients with challenging cases of GIST.

What evidence suggests that this trial's treatments could be effective for GIST?

Research has shown that using CGT9486 with sunitinib may treat gastrointestinal stromal tumors (GIST) more effectively than sunitinib alone. In this trial, some participants will receive the combination of CGT9486 and sunitinib, while others will receive only sunitinib. Previous studies demonstrated that patients who received this combination treatment achieved better results compared to past data of those who only took sunitinib. This suggests that adding CGT9486 might enhance the effectiveness of sunitinib. Additionally, the combination is considered safe, making it a promising option for people with GIST. ^{3 6 7 8 9}

Who Is on the Research Team?

Jessica Sachs, MD

Principal Investigator

Cogent Biosciences

Are You a Good Fit for This Trial?

This trial is for patients with advanced, metastatic, or unresectable Gastrointestinal Stromal Tumors (GIST) who have been previously treated. Part 1 requires treatment with at least one prior therapy; Part 2 requires previous imatinib treatment only. Participants must have measurable lesions and be in stable health as indicated by ECOG scores of 0 to 2.

Inclusion Criteria

I have been treated with 2 or more TKIs for my GIST.

I have been treated with 2 or more TKIs for my GIST.

I have only been treated with imatinib before.

Exclusion Criteria

My cancer has a PDGFR mutation or lacks succinate dehydrogenase.

I have not had major surgery in the last 4 weeks.

I have taken strong medications that affect liver enzymes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part 1 - Dose Confirmation and DDI Evaluation

Confirming the dose of CGT9486 and evaluating drug-drug interactions with sunitinib in patients with prior GIST therapy

16 days

Multiple visits for pharmacokinetic assessments

Part 2 - Randomized Treatment

Randomized treatment comparing CGT9486 plus sunitinib to sunitinib alone in patients intolerant to or who failed prior imatinib treatment

Approximately 48 months

Regular visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 48 months

What Are the Treatments Tested in This Trial?

Interventions

• CGT9486
• Sunitinib

Trial Overview The study tests CGT9486 combined with sunitinib versus sunitinib alone in a Phase 3 trial involving around 426 patients. It includes initial evaluations of dosage and drug interactions followed by efficacy comparison between the two treatments for those intolerant or unresponsive to imatinib.

How Is the Trial Designed?

Group I: Part 2 - Experimental Group Experimental Treatment 1 Intervention

CGT9486 plus sunitinib 37.5 mg QD

Group II: Part 1b - DDI Cohort 2 Experimental Treatment 1 Intervention

sunitinib 37.5 mg QD plus CGT9486

Group III: Part 1b - DDI Cohort 1 Experimental Treatment 1 Intervention

CGT9486 plus sunitinib 37.5 mg QD

Group IV: Part 1a Experimental Treatment 1 Intervention

CGT9486 plus sunitinib 37.5 mg QD

Group V: DDI Substudy (Midazolam) Experimental Treatment 2 Interventions

Midazolam, CGT9486, sunitinib

Group VI: Part 2 - Control Group Active Control 1 Intervention

sunitinib 37.5 mg QD

Who Is Running the Clinical Trial?

Cogent Biosciences, Inc.

Lead Sponsor

Trials

11

Recruited

1,100+

Published Research Related to This Trial

A 62-year-old female patient with unresectable gastrointestinal stromal tumors (GIST) developed a vesicocutaneous fistula after starting treatment with the multi-kinase inhibitor sunitinib, suggesting a potential complication associated with this medication.

This case highlights the need for clinicians to be aware of the risk of vesicocutaneous fistula formation in patients receiving sunitinib, especially those with advanced GIST involving the urinary bladder and peritoneal cavity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vesicocutaneous fistula formation during treatment with sunitinib malate: Case report. Watanabe, K., Otsu, S., Morinaga, R., et al.[2021]

Sunitinib is an effective treatment for patients with gastrointestinal stromal tumors (GIST) who are resistant to imatinib, showing a response rate of 27.1% and a disease control rate of 70.8% over a median follow-up of 89 weeks.

Patients with exon 9 mutations had a significantly better overall survival compared to those with exon 11 mutations, and the 37.5 mg continuous daily dose of sunitinib was associated with fewer adverse effects compared to the 50 mg/d (4/2) regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of sunitinib on patients with imatinib-resistant gastrointestinal stromal tumor]. Liu, X., Jiang, WZ., Guan, GX., et al.[2022]

In a study of 41 patients with imatinib-resistant gastrointestinal stromal tumors (GISTs), a reduced dosage of sunitinib (37.5 mg/day) was associated with lower rates of severe adverse events compared to the standard dosage (50 mg/day), with 75% versus 90% experiencing grade 3 or higher side effects.

Despite the lower dosage, clinical efficacy was similar between the two groups, with median overall survival of 13.4 months for the reduced dosage group and 13.7 months for the standard dosage group, suggesting that the reduced dosage can be a safer alternative without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib therapy for imatinib-resistant and/or intolerant gastrointestinal stromal tumors: comparison of safety and efficacy between standard and reduced dosage regimens. Sasaki, K., Kanda, T., Matsumoto, Y., et al.[2023]

In a phase I/II trial involving 6 pediatric patients aged 6 to <18 years with advanced GIST, sunitinib was found to be tolerable at a dose of at least 20 mg/m2, with no serious adverse events reported.

While no tumor responses were observed, 50% of patients experienced disease stabilization, with a median progression-free survival of 5.8 months, indicating potential efficacy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial. Verschuur, AC., Bajčiová, V., Mascarenhas, L., et al.[2020]

Sunitinib malate significantly improves time to progression and progression-free survival in adult patients with gastrointestinal stromal tumors (GIST) who are resistant or intolerant to imatinib, with a hazard ratio for overall survival of 0.49, indicating a substantial benefit over placebo.

While sunitinib malate is effective, it is associated with a higher incidence of hematologic adverse effects such as leucopenia and neutropenia, as well as other side effects like fatigue and hand-foot syndrome, suggesting that while it is a recommended second-line therapy, monitoring for these adverse effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate-resistant patients: recommendations and evidence. Younus, J., Verma, S., Franek, J., et al.[2021]

Sunitinib is effective for patients with advanced gastrointestinal stromal tumors (GIST) who are resistant or intolerant to imatinib, particularly in those with the KIT(AY502-3ins) exon 9 mutation, but resistance can develop over time.

Research showed that sunitinib resistance often involves secondary mutations in the KIT activation loop, and in vitro studies indicated that resistant cells were sensitive to other tyrosine kinase inhibitors like dasatinib and nilotinib, suggesting potential alternative treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. Guo, T., Hajdu, M., Agaram, NP., et al.[2022]

Sunitinib malate is an effective treatment for gastrointestinal stromal tumors (GIST) after failure of Imatinib, showing significant clinical benefits such as progression-free survival (PFS), response rate (RR), and overall survival (OS) in trials conducted in the USA and Japan.

New multitargeted receptor tyrosine kinase inhibitors like Sorafenib and Nilotinib have shown promise in treating Sunitinib-resistant GIST, offering longer PFS and targeting different mutations, indicating ongoing advancements in treatment options for resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Strategy for patients with GIST after failure of imatinib]. Abe, S., Kubota, T.[2015]

In a study of 55 Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors (GISTs), sunitinib demonstrated effectiveness with a median overall survival of 86 weeks and a median progression-free survival of 35 weeks for those on a continuous daily dose of 37.5 mg.

Patients with KIT exon 9 mutations experienced significantly longer progression-free survival compared to those with KIT exon 11 mutations or wild-type GISTs, indicating that genetic factors can influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. Li, J., Gao, J., Hong, J., et al.[2022]

PLX9486, a tyrosine kinase inhibitor, effectively inhibits the growth of gastrointestinal stromal tumors (GISTs) with specific KIT mutations, demonstrating strong in vitro potency against resistant mutations that are not effectively targeted by existing treatments like imatinib and sunitinib.

In vivo studies using patient-derived xenograft models showed that PLX9486 significantly reduced tumor proliferation and MAPK activation, indicating its potential as a promising treatment for imatinib-resistant GISTs, warranting further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PLX9486 shows anti-tumor efficacy in patient-derived, tyrosine kinase inhibitor-resistant KIT-mutant xenograft models of gastrointestinal stromal tumors. Gebreyohannes, YK., Burton, EA., Wozniak, A., et al.[2020]

Imatinib and sunitinib, both targeted therapies for unresectable gastrointestinal stromal tumors (GIST), are generally well tolerated, with manageable adverse event (AE) profiles based on clinical trial data.

As new and unexpected AEs are emerging with increased use of these drugs, clinicians must be aware of their toxicity profiles and individual patient risk factors to optimize treatment benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapies in the treatment of GIST: Adverse events and maximising the benefits of sunitinib through proactive therapy management. Wolter, P., Schöffski, P.[2018]

Sunitinib has been shown to be an effective treatment for patients with advanced gastrointestinal stromal tumors (GIST) who are resistant or intolerant to imatinib, with a median overall survival of 16.6 months based on a study of 1124 patients.

The study also highlighted that modifying the initial dosing schedule of sunitinib can lead to significantly longer survival (23.5 months) compared to adhering strictly to the original dosing plan, while the treatment was generally well-tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib. Reichardt, P., Kang, YK., Rutkowski, P., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.826

Peak part 1 summary: A phase 3, randomized, open-label ... A global randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in GIST pts with imatinib ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05208047

(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib ... 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 ...

3. onclive.com onclive.com/view/bezuclastinib-plus-sunitinib-elicits-preliminary-activity-is-safe-in-pretreated-gist

Bezuclastinib Plus Sunitinib Elicits Preliminary Activity, Is ... The combination of bezuclastinib and sunitinib generated favorable efficacy outcomes vs historical data in patients with previously treated GIST.

4. targetedonc.com targetedonc.com/view/bezuclastinib-with-sunitinib-improves-safety-efficacy-in-patients-with-gist

Bezuclastinib With Sunitinib Improves Safety, Efficacy in ... Bezuclastinib plus sunitinib showed favorable safety and efficacy in GIST, outperforming sunitinib alone in phase 3 Peak study results.

5. cogentbio.com cogentbio.com/wp-content/uploads/ASCO-2024-Peak-Part-1.pdf

Peak Part 1 Summary: A Phase 3, ... ... Bezuclastinib (CGT9486) and Sunitinib. Combination Versus Sunitinib in Patients with Gastrointestinal Stromal Tumors (GIST). 1Andrew J. Wagner ...

6. cogentbio.com cogentbio.com/wp-content/uploads/2023/06/CogentBio_ASCO-2023-Peak.pdf

Safety, Pharmacokinetics (PK), and Clinical Activity of ... Most common mesenchymal tumor of the gastrointestinal tract, with about 4,000-6,000 new cases/year in the United States.1. • Activating mutations in KIT are ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.11533

Peak part 1 summary: A phase 3, randomized, open-label ... A global randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in GIST pts with imatinib ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34236401/

A Phase 1b/2a Nonrandomized Clinical Trial - PubMed - NIH Conclusions and relevance: In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT05208047

(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib ... 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 ...