Sunitinib + Regorafenib for GIST

Overseen By Jonathan Trent, Dr.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Miami

Must be taking: Imatinib

Must not be taking: Sunitinib, Regorafenib, CYP3A4 inhibitors

Disqualifiers: Cardiovascular disease, Brain metastases, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if changes in a specific gene can predict the response of patients with gastrointestinal stromal tumors (GIST) to treatment. The study will test two cancer drugs, Sunitinib and Regorafenib, to identify the best approach based on gene changes. Individuals with GIST that cannot be surgically removed and have not responded to other treatments may be suitable for this trial. Participants will be grouped according to specific gene mutations and will receive one of the drugs to assess which is more effective. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot take medications that strongly affect CYP3A4, an enzyme that processes drugs in the body. It's best to discuss your current medications with the trial team.

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

Research has shown that Sunitinib and Regorafenib treat gastrointestinal stromal tumors (GIST), a type of cancer in the digestive system. Both drugs have undergone safety studies.

The FDA has approved Sunitinib for GIST when other treatments, like imatinib, are ineffective. Studies indicate that the most common side effects of Sunitinib include tiredness, diarrhea, and nausea. About 25% or more of patients experience these effects, but they are common and often manageable.

Regorafenib is also FDA-approved for GIST, particularly after other treatments have failed. Common side effects include redness, swelling, or pain on the palms or soles (hand-foot skin reactions) and high blood pressure. Some patients may experience liver problems, so doctors closely monitor liver health during treatment.

Both treatments have been used for some time, and their side effects are well-known, aiding doctors in managing them effectively. Overall, while side effects exist, these treatments have been successful for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Sunitinib and Regorafenib for treating gastrointestinal stromal tumors (GIST) because these drugs target specific mutations in the KIT gene, which is a key driver of this cancer. Unlike traditional treatments that may work broadly, Sunitinib and Regorafenib are designed to home in on mutations in exon 13 and exon 17 of the KIT gene, respectively. This targeted approach can potentially improve effectiveness and reduce side effects by honing in on the cancer cells' unique characteristics. Additionally, the ability to switch treatments if the disease progresses offers a flexible strategy to manage the condition more effectively over time.

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

This trial will compare Sunitinib and Regorafenib for treating gastrointestinal stromal tumors (GIST) based on specific genetic mutations. Studies have shown that Sunitinib can extend the lives of patients with GIST, with many living more than 1.5 years after starting treatment. It is particularly effective for those who have already tried other treatments, such as Imatinib. Participants in this trial with a KIT mutation on exon 13 will receive Sunitinib.

Regorafenib is another treatment option in this trial, and it has also proven effective for people with advanced GIST. Research indicates that it can slow disease progression and significantly extend the time patients live without the disease worsening. Participants with a KIT mutation on exon 17 will receive Regorafenib. Both treatments target specific proteins that promote cancer growth, helping to control the disease. ^{6 7 8 9 10}

Who Is on the Research Team?

Jonathan Trent, Dr.

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

Adults with advanced or inoperable Gastrointestinal Stromal Tumors (GIST) who have previously been treated with imatinib but didn't respond well or couldn't tolerate it. They must be able to perform daily activities with minimal assistance (ECOG PS 0-2) and have specific mutations in the KIT gene, which will be checked through a blood test or biopsy.

Inclusion Criteria

I am able to care for myself and up to being unable to work but can still move around.

My GIST cannot be removed by surgery as confirmed by a surgeon.

I've had imatinib or other treatments for my cancer but they didn't work or caused side effects.

Exclusion Criteria

I have a wound, ulcer, or bone fracture that is not healing.

Patients who have poor organ function as defined by one or more of the following laboratory parameters: Persistent proteinuria of NCI-CTCAE version 4.03 Grade 3 or higher, Alanine aminotransferase and aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) if no hepatic metastases are present; > 5 × ULN if hepatic metastases are present, Total bilirubin >1.5 × ULN; and in presence of Gilbert's syndrome, total bilirubin > 3 × ULN or direct bilirubin > 1.5 × ULN, Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min, Platelet count < 90 × 10^9/L and absolute neutrophil count (ANC) < 1.0 × 10^9/L, Hemoglobin < 9 g/dL. Transfusion and erythropoietin may be used to reach at least 9 g/dL, but must have been administered at least 2 weeks before screening, Patients who have received neutrophil growth factor support within 14 days of screening, Patients who require therapy with a concomitant medication that is a strong inhibitor or strong inducer of CYP3A4, Patients who have had a major surgical procedure (minor surgical procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures) within 14 days of screening. Patient has significant traumatic injury within 28 days before screening, Patients who have a history of another primary malignancy that has been diagnosed or required therapy within 2 years before screening. (The following are exempt from the 2-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site), Patients who have a history of a seizure disorder requiring anti-seizure medication, Patients who have metastases to the brain, Patients who are unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions, Patients who have a QT interval corrected using Fridericia's formula (QTcF) of > 450 msec, Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of randomization and for at least 30 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of randomization and for at least 90 days after the last dose of study drug. Refer to Appendix G for acceptable methods of contraception, Women who are pregnant, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days before the treatment assignment. Females with β-hCG values that are within the range for pregnancy but are not pregnant (false positives) may be enrolled with written consent of the investigator, after pregnancy has been ruled out. Females of non-childbearing potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral oophorectomy; hysterectomy) do not require a serum β-hCG test, Women who are breastfeeding, Patients who have prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results, Patients with impaired decision-making capacity

I do not have serious heart problems or uncontrolled high blood pressure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Sunitinib or Regorafenib based on KIT mutation for up to 12 months

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

13 months

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Regorafenib
• Sunitinib

Trial Overview The trial is testing whether changes in certain parts of the DNA of the KIT gene can predict how well patients respond to Sunitinib and Regorafenib, which are standard treatments for GIST. The study aims to guide therapy choices based on individual genetic profiles.

How Is the Trial Designed?

Group I: Group B: KIT Exon 17 receiving Regorafenib Experimental Treatment 2 Interventions

Participants with KIT mutation on exon 17 will receive Regorafenib. Participants showing disease progression after first-assigned Regorafenib therapy have the option to receive Sunitinib therapy. Total allotted time for treatment is up to 12 months.

Group II: Group A: KIT Exon 13 receiving Sunitinib Experimental Treatment 2 Interventions

Participants with KIT mutation on exon 13 will receive Sunitinib. Participants showing disease progression after first-assigned Sunitinib therapy have the option to receive Regorafenib therapy. Total allotted time for treatment is up to 12 months.

Regorafenib is already approved in United States, European Union for the following indications:

Approved in United States as Stivarga for:

• Metastatic colorectal cancer
• Gastrointestinal stromal tumors (GIST)
• Hepatocellular carcinoma (HCC)

Approved in European Union as Stivarga for:

• Metastatic colorectal cancer
• Gastrointestinal stromal tumors (GIST)
• Hepatocellular carcinoma (HCC)

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

Published Research Related to This Trial

Regorafenib is established as the only proven third-line therapy for advanced gastrointestinal stromal tumors (GISTs), showing improved progression-free survival in patients who have developed resistance to first-line (imatinib) and second-line (sunitinib) treatments.

The efficacy of regorafenib is attributed to its action against oncogenic forms of KIT and PDGFRA, although it does come with common side effects that can be managed through supportive care and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib for treatment of advanced gastrointestinal stromal tumors. Overton, LC., Heinrich, MC.[2022]

Regorafenib is an oral multi-kinase inhibitor that has shown significant survival benefits in metastatic colorectal cancer and has been FDA approved for this use since 2012.

The drug also improves progression-free survival in patients with metastatic gastrointestinal stromal tumors and advanced hepatocellular carcinoma, leading to its FDA approval for these conditions as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2018]

In a phase III trial, regorafenib significantly improved median progression-free survival in patients with advanced gastrointestinal stromal tumors (GIST), increasing it by more than five times compared to best supportive care alone.

While regorafenib is linked to some adverse events, it is generally well tolerated when proper dose modifications and precautions are implemented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: a guide to its use in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib and sunitinib. Lyseng-Williamson, KA.[2018]

In a phase 3 trial involving 199 patients with metastatic gastrointestinal stromal tumors (GIST) who had previously failed treatment with imatinib and sunitinib, regorafenib significantly improved progression-free survival (PFS) to a median of 4.8 months compared to just 0.9 months for placebo (p<0.0001).

Regorafenib was associated with a high incidence of drug-related adverse events, with 98% of patients experiencing side effects, the most common being hypertension (23%), hand-foot skin reaction (20%), and diarrhea (5%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Demetri, GD., Reichardt, P., Kang, YK., et al.[2022]

Regorafenib is an effective treatment for advanced gastrointestinal stromal tumors (GIST) in patients who have not responded to previous therapies like imatinib and sunitinib, as demonstrated in a pivotal Phase III trial.

The US FDA approved regorafenib in February 2013 based on evidence showing significant improvement in progression-free survival for patients taking the drug compared to those on a placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib in gastrointestinal stromal tumors. Sirohi, B., Philip, DS., Shrikhande, SV.[2014]

In a study of 50 patients with metastatic GIST treated with regorafenib, the median progression-free survival was 7.7 months and overall survival was 15.7 months, indicating a durable clinical benefit from the treatment.

While 46% of patients experienced grade 3-4 adverse events, the main reason for discontinuation was disease progression rather than toxicity, highlighting the importance of effective toxicity management and dose adjustments in improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity management of regorafenib in patients with gastro-intestinal stromal tumour (GIST) in a tertiary cancer centre. Chamberlain, F., Farag, S., Williams-Sharkey, C., et al.[2022]

Regorafenib has been established as the standard treatment for advanced gastrointestinal stromal tumors (GIST) that do not respond to imatinib and sunitinib, providing a crucial option for patients with refractory disease.

The development of small molecule tyrosine kinase inhibitors like imatinib has significantly improved survival rates for patients with metastatic GIST, but challenges remain for those whose disease does not respond to these initial therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting gastrointestinal stromal tumors: the role of regorafenib. Schroeder, B., Li, Z., Cranmer, LD., et al.[2020]

Regorafenib, a treatment for metastatic gastrointestinal stromal tumors (GIST), was linked to hyperammonemic encephalopathy in a 61-year-old patient, causing acute confusion that resolved upon discontinuation of the drug.

The case suggests a probable relationship between regorafenib and metabolic encephalopathy, indicating that similar adverse effects may occur with other multitargeted tyrosine kinase inhibitors, highlighting the need for careful monitoring of neurological symptoms in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib-induced hyperammonemic encephalopathy. Kuo, JC., Parakh, S., Yip, D.[2022]

In a phase II trial involving 34 patients with advanced GIST who had previously failed imatinib and sunitinib, regorafenib demonstrated a clinical benefit rate of 79%, indicating significant efficacy in managing this challenging condition.

The median progression-free survival for patients on regorafenib was 10.0 months, with common side effects including hypertension and hand-foot-skin reactions, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. George, S., Wang, Q., Heinrich, MC., et al.[2022]

Regorafenib is an effective treatment for advanced gastrointestinal stromal tumors (GISTs) after patients have not responded to imatinib and sunitinib, showing significant improvement in progression-free survival and disease control rates compared to placebo in the phase III GRID trial.

The drug has a manageable safety profile, with common side effects including hand-foot skin reactions, hypertension, diarrhea, and fatigue, which can often be addressed with dose adjustments or supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review of Its Use in Patients with Advanced Gastrointestinal Stromal Tumours. Shirley, M., Keating, GM.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4206614/

Regorafenib in gastrointestinal stromal tumors: clinical ... Regorafenib, an orally available multitargeted tyrosine kinase inhibitor with antiangiogenic activity, has also demonstrated preclinical evidence of activity.

2. stivargahcp.com stivargahcp.com/gastrointestinal-stromal-tumor/efficacy-in-grid

Efficacy Data in GRID Trial | STIVARGA® (regorafenib) Harness the proven efficacy of STIVARGA to significantly improve progression-free survival in previously treated patients with GIST.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38952554/

Large-scale, prospective observational study of ... Background: Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after ...

4. stivarga.com stivarga.com/gist/efficacy

Efficacy Data in Gastrointestinal Stromal Tumor 73% reduction in risk of disease progression or death in the GRID trial1 · PFS at 3 months: 60% with STIVARGA + BSC vs 11% with placebo + BSC · PFS at 6 months: ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06321055?term=AREA%5BConditionSearch%5D(GIST)%20AND%20AREA%5BBasicSearch%5D(dasatinib)&rank=8

An Observational Study to Learn More About Treatment ... An Observational Study to Learn More About Treatment With Regorafenib in People With Advanced Gastrointestinal Stromal Tumors in the United States.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3675695/

Efficacy and Safety of Regorafenib in Patients With ... Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is ...

7. stivarga.com stivarga.com/gist/safety

Safety Data in Gastrointestinal Stromal Tumor Monitor AEs frequently during the first 8 weeks1. STIVARGA® (regorafenib) treatment-emergent AEs most frequently occur early and do not increase over time1.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6942401/

Toxicity management of regorafenib in patients with gastro ... Regorafenib is a multi-kinase inhibitor approved as third line treatment for metastatic GIST. Dose limiting toxicities are frequently seen and many patients ...

9. stivargahcp.com stivargahcp.com/repository/downloads/pp-sti-us-1293-1_comprehensive_stivarga_gist_hcp_brochure.pdf

for your 3l gist patients Important Safety Information (cont). Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all ...

10. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2013/204369Orig1s000MedR.pdf

204369Orig1s000 - accessdata.fda.gov “Regorafenib is indicated in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) who have received at least two prior therapies ...