Bezuclastinib + Sunitinib for GIST

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

40 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Bezuclastinib + Sunitinib for GIST?

Research shows that Sunitinib, one of the drugs in the treatment, is effective for patients with gastrointestinal stromal tumors (GIST) who no longer respond to another drug called imatinib. It has been shown to help manage the disease and is considered a key part of therapy for advanced GIST. ^{1 2 3 4 5}

Is the combination of Bezuclastinib and Sunitinib safe for humans?

Sunitinib, used for treating gastrointestinal stromal tumors (GIST), can cause severe side effects that sometimes lead to stopping the treatment. It's important to monitor for these side effects to ensure patients can safely continue the therapy. ^{1 4 5 6 7}

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

The combination of Bezuclastinib and Sunitinib for treating gastrointestinal stromal tumors (GIST) is unique because Sunitinib is a multitargeted tyrosine kinase inhibitor that is effective for GIST after failure of Imatinib, and Bezuclastinib may offer additional benefits by targeting different pathways or mutations that cause resistance to Sunitinib. ^{6 8 9 10 11}

What is the purpose of this trial?

This is an open label, single arm, phase 2 trial investigating bezuclastinib plus sunitinib in patients with GIST who have previously progressed on sunitinib.

Research Team

Andrew Wagner, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Candace Haddox, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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 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 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 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 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 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 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]

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 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]

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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

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

3. United States pubmed.ncbi.nlm.nih.gov

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

4. 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]

5. China pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

Tyrosine kinase inhibition in renal cell carcinoma and gastrointestinal stromal tumours: case reports. [2020]

7. 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]

8. Japan pubmed.ncbi.nlm.nih.gov

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

9. United States pubmed.ncbi.nlm.nih.gov

Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. [2022]

10. England pubmed.ncbi.nlm.nih.gov

The potential of sunitinib as a therapy in ovarian cancer. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Molecular basis for sunitinib efficacy and future clinical development. [2022]