CGT9486 + Sunitinib for GIST
Recruiting in Palo Alto (17 mi)
+130 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
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
Pivotal Trial (Near Approval)
Prior Safety Data
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.
12345What 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.
35678How 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.
3491011Eligibility 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.
+8 more
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.
+6 more
Trial 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
Participant Groups
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.
6Treatment groups
Experimental Treatment
Active Control
Group I: Part 2 - Experimental GroupExperimental Treatment1 Intervention
CGT9486 plus sunitinib 37.5 mg QD
Group II: Part 1b - DDI Cohort 2Experimental Treatment1 Intervention
sunitinib 37.5 mg QD plus CGT9486
Group III: Part 1b - DDI Cohort 1Experimental Treatment1 Intervention
CGT9486 plus sunitinib 37.5 mg QD
Group IV: Part 1aExperimental Treatment1 Intervention
CGT9486 plus sunitinib 37.5 mg QD
Group V: DDI Substudy (Midazolam)Experimental Treatment2 Interventions
Midazolam, CGT9486, sunitinib
Group VI: Part 2 - Control GroupActive Control1 Intervention
sunitinib 37.5 mg QD
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Cleveland Clinic FoundationCleveland, OH
Oregon Health and Science UniversityPortland, OR
Mayo ClinicRochester, MN
Washington UniversitySt. Louis, MO
More Trial Locations
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Who Is Running the Clinical Trial?
Cogent Biosciences, Inc.Lead Sponsor
References
Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate-resistant patients: recommendations and evidence. [2021]Is sunitinib malate-marketed as Sutent (Pfizer Canada, Kirkland, QC)-superior to placebo or other interventions for primary outcomes of interest in adult patients with gastrointestinal stromal tumour (GIST) who have developed resistance or who exhibit intolerance to imatinib mesylate (IM)?
Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial. [2020]Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance.
Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors. [2022]To assess the efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors (GISTs), and evaluate the impact of genotype on sunitinib efficacy.
[Strategy for patients with GIST after failure of imatinib]. [2015]Sunitinib malate(SU11248)is an oral multitargeted receptor tyrosine kinase inhibitor(MTI)that has antitumor activities for patients with gastrointestinal stromal tumor; GIST after failure of Imatinib. Sunitinib has demonstrated significant clinical benefits, including PFS, RR and OS in the USA and Japan. However, cis-mutations in the activation loop of the KIT gene tend to develop Sunitinib-resistant GIST. Two clinical trials revealed that new multitargeted receptor tyrosine kinase inhibitors, Sorafenib and Nilotinib, had antitumor activities for Sunitinib-resistant GIST with longer PFS and a different spectrum. Now, clinical trials of several new MTIs are ongoing in Western countries. Inhibition of the KIT gene cis-mutations and antiangiogenesis activities may be essential for the strategy for Imatinib/Sunitinibresistant GIST.
Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib. [2022]The objectives of this study were to provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain it and to collect broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure. (ClinicalTrials.gov identifier NCT00094029).
Sunitinib therapy for imatinib-resistant and/or intolerant gastrointestinal stromal tumors: comparison of safety and efficacy between standard and reduced dosage regimens. [2023]Sunitinib therapy for patients with imatinib-resistant and/or intolerant gastrointestinal stromal tumors (GISTs) often causes severe adverse events (AEs) that lead to treatment discontinuation.
Targeted therapies in the treatment of GIST: Adverse events and maximising the benefits of sunitinib through proactive therapy management. [2018]The introduction of targeted therapies has led to improved clinical outcomes in patients with unresectable gastrointestinal stromal tumours (GIST). The receptor tyrosine kinase (RTK) inhibitor imatinib mesylate has been approved as the first-line choice of therapy for this group of patients, while the RTK inhibitor, sunitinib malate, has been approved for the treatment of GIST after disease progression or intolerance to imatinib. Here we discuss and compare the tolerability profiles of imatinib and sunitinib based on published clinical trial data. We also review available data on the potential mechanisms by which these agents may cause adverse events (AEs) and we propose some general strategies to help clinicians to optimise treatment benefit with these agents.
[Efficacy and safety of sunitinib on patients with imatinib-resistant gastrointestinal stromal tumor]. [2022]To investigate the efficacy and safety of sunitinib on the management of gastrointestinal stromal tumors (GIST) patients with imatinib resistance.
Vesicocutaneous fistula formation during treatment with sunitinib malate: Case report. [2021]The oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described.
Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. [2022]Although tyrosine kinase inhibitors have improved survival in advanced gastrointestinal stromal tumor (GIST), complete response is rare and most patients eventually fail the first-line treatment with imatinib. Sunitinib malate is the only approved second-line therapy for patients with imatinib-resistant or imatinib-intolerant GIST. The clinical benefit of sunitinib is genotype-dependent in regards to both primary and secondary mutations, with GIST patients harboring the KIT(AY502-3ins) exon 9 mutation being the most sensitive.
PLX9486 shows anti-tumor efficacy in patient-derived, tyrosine kinase inhibitor-resistant KIT-mutant xenograft models of gastrointestinal stromal tumors. [2020]The purpose of the present study was to investigate the in vitro and in vivo activity of PLX9486, a tyrosine kinase inhibitor (TKI) targeting both primary KIT exon 9 and 11 and secondary exon 17 and 18 mutations in gastrointestinal stromal tumors (GISTs). Imatinib, a potent inhibitor of mutated KIT, has revolutionized the clinical management of advanced, metastatic GIST. However, secondary resistance develops mainly through acquired mutations in KIT exons 13/14 or exons 17/18. Second-line sunitinib potently inhibits KIT exon 13/14 mutants but is ineffective against exon 17 mutations. In our study, PLX9486 demonstrated in vitro nanomolar potency in inhibiting the growth and KIT phosphorylation of engineered BaF3 cells transformed with KIT exon 17 mutations (p.D816V) and with the double KIT exon 11/17 mutations (p.V560G/D816V). The in vivo efficacy of PLX9486 was evaluated using two imatinib-resistant GIST patient-derived xenograft (PDX) models. In UZLX-GIST9 (KIT: p.P577del;W557LfsX5;D820G), PLX9486 100 mg/kg/day resulted in significant inhibition of proliferation. Pharmacodynamic analysis showed a pronounced reduction in mitogen-activated protein kinase (MAPK) activation and other downstream effects of the KIT signaling pathway but no significant effect on KIT Y703 and Y719 phosphorylation. Similarly, in MRL-GIST1 (KIT: p.W557_K558del;Y823D) PLX9486 treatment led to significant tumor regression and strong inhibition of MAPK activation. Interestingly, the inhibitory effect on MAPK activation was evident even after a single dose of PLX9486. In conclusion, PLX9486 showed anti-tumor efficacy in patient-derived imatinib-resistant GIST xenograft models, mainly through inhibition of KIT signaling. These preclinical efficacy data encourage further testing of PLX9486 in the clinical setting.