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

Trial Summary

What is the purpose of this trial?

The purpose of this research is to test if mutations (changes in DNA) in exons (segment of DNA or RNA containing information that has the instructions for making proteins) in the KIT gene can be used to predict the body's response to standard of care treatment.

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.

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

Research shows that regorafenib is effective for patients with advanced GIST who have not responded to other treatments like imatinib and sunitinib. In clinical trials, regorafenib significantly improved the time patients lived without their disease getting worse, compared to those who did not receive the drug. ^{1 2 3 4 5}

Is the combination of Sunitinib and Regorafenib safe for humans?

Regorafenib, used after other treatments like Sunitinib, is generally well tolerated in patients with advanced gastrointestinal stromal tumors (GIST), with common side effects including hand-foot skin reaction, high blood pressure, diarrhea, and fatigue. Most side effects can be managed by adjusting the dose or providing supportive care. ^{1 3 6 7 8}

How is the drug combination of Sunitinib and Regorafenib unique for treating GIST?

The combination of Sunitinib and Regorafenib is unique for treating gastrointestinal stromal tumors (GIST) because Regorafenib is used as a third-line treatment after the failure of standard therapies like Imatinib and Sunitinib. Regorafenib is an oral drug that targets multiple kinases involved in tumor growth and blood vessel formation, offering a new option for patients whose tumors have become resistant to other treatments. ^{1 2 3 9 10}

Research Team

Jonathan Trent, Dr.

Principal Investigator

University of Miami

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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 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, 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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

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

2. New Zealand pubmed.ncbi.nlm.nih.gov

Targeting gastrointestinal stromal tumors: the role of regorafenib. [2020]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review of Its Use in Patients with Advanced Gastrointestinal Stromal Tumours. [2018]

4. United States 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. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Toxicity management of regorafenib in patients with gastro-intestinal stromal tumour (GIST) in a tertiary cancer centre. [2022]

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

Regorafenib in gastrointestinal stromal tumors. [2014]

7. England 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Regorafenib-induced hyperammonemic encephalopathy. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Regorafenib. [2018]

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

Regorafenib for treatment of advanced gastrointestinal stromal tumors. [2022]