CGT9486 + Sunitinib for GIST

Recruiting at 130 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

442 Participants Needed

Trial Summary

What is the purpose of this trial?

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 442 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. Additionally, 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.

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.

What data supports the effectiveness of the drug CGT9486 + Sunitinib for treating gastrointestinal stromal tumors (GIST)?

Research shows that Sunitinib is effective for patients with GIST who no longer respond to or cannot tolerate another drug called Imatinib. It has been shown to provide significant benefits in terms of progression-free survival (the time during which the disease does not get worse) and overall survival. ^{1 2 3 4 5}

What safety data exists for the treatment CGT9486 + Sunitinib for GIST?

Sunitinib, used for treating gastrointestinal stromal tumors (GIST), can cause severe side effects that sometimes lead to stopping the treatment. These side effects have been observed in patients who are resistant or intolerant to another drug called imatinib. ^{3 5 6 7 8}

How is the drug CGT9486 + Sunitinib unique for treating GIST?

The combination of CGT9486 and Sunitinib is unique for treating gastrointestinal stromal tumors (GIST) because CGT9486 targets a broader range of mutations in the KIT gene, including those resistant to other treatments, while Sunitinib is effective against certain mutations but not others. This combination aims to overcome resistance seen with existing therapies by addressing multiple mutation sites. ^{3 4 9 10 11}

Research Team

Jessica Sachs, MD

Principal Investigator

Cogent Biosciences

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

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 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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate-resistant patients: recommendations and evidence. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. [2022]

4. Japan pubmed.ncbi.nlm.nih.gov

[Strategy for patients with GIST after failure of imatinib]. [2015]

5. United States 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. [2022]

6. England 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

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

8. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of sunitinib on patients with imatinib-resistant gastrointestinal stromal tumor]. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Vesicocutaneous fistula formation during treatment with sunitinib malate: Case report. [2021]

10. United States 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. [2022]

11. Italy 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. [2020]