Bezuclastinib + Sunitinib for GIST

Not currently recruiting at 3 trial locations

Overseen By SARC Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sarcoma Alliance for Research through Collaboration

Must be taking: Sunitinib

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: HIV, Cardiac disease, others

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

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two oral drugs, bezuclastinib and sunitinib, to determine if they work better together for treating Gastrointestinal Stromal Tumors (GIST) that have not responded to sunitinib alone. The focus is on patients whose GIST has specific genetic mutations (exon 11 or 9 in the KIT gene) and who have experienced disease progression despite previous treatments. This trial may suit those whose GIST has progressed after taking sunitinib and who have a mutation in the KIT gene. Participants must be able to swallow pills and have a specific genetic profile of their tumor. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong CYP3A4 inhibitors or inducers at least 14 days before starting the study drug. If you are on any anticancer drugs, you must stop them at least 5 half-lives or 14 days before the trial, whichever is shorter. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

Is there any evidence suggesting that bezuclastinib plus sunitinib is likely to be safe for humans?

Research has shown that the combination of bezuclastinib and sunitinib is generally safe. Studies have found that patients with gastrointestinal stromal tumors (GIST) who have undergone previous treatments tolerate this combination well. One study showed that this drug combo had better safety results compared to sunitinib alone.

Some patients experienced side effects, which is common with most medications, but these were usually manageable. The combination treatment aims to improve both safety and effectiveness for those with GIST. So far, the data appears promising for individuals considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about the combination of bezuclastinib and sunitinib for treating gastrointestinal stromal tumors (GIST) because it introduces a novel approach to tackling this condition. While standard treatments like imatinib and sunitinib target specific pathways in cancer cells, bezuclastinib is a newer agent that inhibits KIT, a protein that plays a key role in cell growth, in a way that could overcome resistance seen with existing therapies. This dual approach aims to enhance the effectiveness of sunitinib and potentially provide better outcomes for patients who have limited options when resistance develops.

What evidence suggests that bezuclastinib plus sunitinib might be an effective treatment for GIST?

Research has shown that combining bezuclastinib with sunitinib may treat gastrointestinal stromal tumors (GIST) more effectively than sunitinib alone. This trial will evaluate the combination, which studies have found to benefit patients who have already received treatment. It targets various changes in the KIT gene, often associated with GIST. Specifically, patients who took both drugs experienced better safety and effectiveness. These results suggest that adding bezuclastinib could enhance treatment for those who have already tried sunitinib. ^{1 3 4 5 6}

Who Is on the Research Team?

Andrew Wagner, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Candace Haddox, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for patients with Gastrointestinal Stromal Tumors (GIST) who have already tried sunitinib but their disease has progressed. Specific eligibility details are not provided, so interested individuals should inquire further to determine if they meet the inclusion and exclusion criteria.

Inclusion Criteria

Life expectancy of > 12 weeks

I had hepatitis C but have been treated and cured.

My scans show at least one area of cancer that can be measured.

Exclusion Criteria

I haven't had major surgery in the last 4 weeks or I've fully recovered from recent surgery.

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen may be included after discussion with the Principal Investigator

I have previously been treated with bezuclastinib.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Washout

Patients undergo a washout period before starting treatment

2 weeks

Treatment

Participants receive bezuclastinib and add sunitinib 2 weeks later, continuing until progression, unacceptable toxicity, or withdrawal of consent

Up to 2 years

Imaging response assessments every 8 weeks until 15 months, then every 3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bezuclastinib
• Sunitinib

Trial Overview The study is testing a combination of two drugs: Bezuclastinib and Sunitinib, in people with GIST. It's an open-label, single-arm phase II trial, meaning all participants will receive the same treatment without a comparison group or placebo.

How Is the Trial Designed?

Group I: bezuclastinib in combination with sunitinib Experimental Treatment 1 Intervention

Bezuclastinib 600 mg (tablet) administered orally daily Sunitinib 37.5 mg administered orally daily Patients will begin bezuclastinib and add sunitinib 2 weeks later. Each cycle is 28 days.

Sunitinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Sutent for:

• Renal Cell Carcinoma
• Gastrointestinal Stromal Tumor

Approved in European Union as Sutent for:

• Renal Cell Carcinoma
• Gastrointestinal Stromal Tumor
• Pancreatic Neuroendocrine Tumors

Approved in Canada as Sutent for:

• Renal Cell Carcinoma
• Gastrointestinal Stromal Tumor

Approved in Japan as Sutent for:

• Renal Cell Carcinoma
• Gastrointestinal Stromal Tumor

Who Is Running the Clinical Trial?

Sarcoma Alliance for Research through Collaboration

Lead Sponsor

Trials

26

Recruited

2,000+

Cogent Biosciences, Inc.

Industry Sponsor

Trials

11

Recruited

1,100+

The Life Raft Group

Collaborator

Trials

1

Recruited

40+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Published Research Related to This Trial

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]

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]

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 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 malate (Sutent) was approved by the FDA for treating gastrointestinal stromal tumors (GIST) after patients showed disease progression or intolerance to imatinib, demonstrating a median time-to-tumor progression of 27.3 weeks compared to 6.4 weeks for placebo.

In advanced renal cell carcinoma, sunitinib showed partial response rates of 25.5% and 36.5% in two studies, with median response durations of 27.1 and 54 weeks, although it was associated with common side effects like diarrhea and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Goodman, VL., Rock, EP., Dagher, R., et al.[2022]

Sunitinib malate is an effective multitargeted tyrosine kinase inhibitor that has shown strong anti-angiogenic and antitumor effects, particularly in advanced renal cell carcinoma and gastrointestinal stromal tumors that do not respond to imatinib.

The article highlights the importance of understanding response markers and resistance development in cancer treatment, which are crucial for optimizing the use of sunitinib and similar multikinase inhibitors in future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular basis for sunitinib efficacy and future clinical development. Faivre, S., Demetri, G., Sargent, W., et al.[2022]

Sunitinib is an effective tyrosine kinase inhibitor used for treating advanced gastrointestinal stromal tumors (GIST) in patients who have not responded to imatinib, showcasing its role as a second-line therapy.

The review highlights the unique side effect profile of sunitinib, emphasizing the importance of understanding both its therapeutic benefits and potential adverse effects in the management of GIST.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib, a multitargeted tyrosine kinase inhibitor, in the management of gastrointestinal stromal tumor. George, S.[2019]

Sunitinib malate has shown long-term efficacy and safety in treating metastatic renal cell carcinoma (mRCC) and advanced imatinib-refractory gastrointestinal stromal tumors (GIST), as demonstrated in four patient cases.

Effective management of adverse events (AEs) allowed patients to continue long-term therapy with sunitinib, leading to sustained clinical benefits and prolonged responses in both mRCC and GIST cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tyrosine kinase inhibition in renal cell carcinoma and gastrointestinal stromal tumours: case reports. Schöffski, P., Bukowski, R., Flodgren, P., 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 a multi-kinase inhibitor approved for treating advanced renal cell carcinoma and other specific tumors, showing modest antitumor activity in ovarian cancer based on Phase I and II trials.

The drug has an acceptable safety profile, but further research is needed to better understand its toxicity and to explore combination therapies for enhanced efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potential of sunitinib as a therapy in ovarian cancer. Leone Roberti Maggiore, U., Valenzano Menada, M., Venturini, PL., et al.[2018]

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]

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 ... (Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors. ClinicalTrials.gov ID NCT05208047.

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

Peak Part 1 Summary: A Phase 3, ... The selectivity profile of bezuclastinib allows for combination with sunitinib, resulting in broad activity against a spectrum of KIT mutations, ...

5. 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.

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

Safety, Pharmacokinetics (PK), and Clinical Activity of ... ... Bezuclastinib + Sunitinib in Previously-Treated Gastrointestinal Stromal. Tumor (GIST): Results from Part 1 of the Phase 3 Peak Study. 1William D. Tap, MD ...