Sunitinib + Regorafenib for GIST
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
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
Prior Safety Data
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.
12345Is 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.
13678How 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.
123910Eligibility 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.
+3 more
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.
+7 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Group B: KIT Exon 17 receiving RegorafenibExperimental Treatment2 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 SunitinibExperimental Treatment2 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)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of MiamiMiami, FL
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Who Is Running the Clinical Trial?
University of MiamiLead Sponsor
References
Regorafenib: a guide to its use in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib and sunitinib. [2018]Regorafenib (Stivarga(®)), a new inhibitor of multiple kinases, is indicated as third-line treatment in patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib and sunitinib in the USA. In a phase III trial in patients with progressive GIST after failure of standard therapies, regorafenib plus best supportive care increased median progression-free survival by >5-fold relative to best supportive care alone. Although regorafenib is associated with several specific drug-related adverse events, it is reasonably well tolerated if recommendations for dose modifications (i.e. treatment interruption, dose reductions and/or permanent treatment discontinuation based on tolerability) and other precautions are followed.
Targeting gastrointestinal stromal tumors: the role of regorafenib. [2020]Gastrointestinal stromal tumor (GIST) is a devastating disease in the metastatic setting, but its natural history has been dramatically altered by the development of small molecule tyrosine kinase inhibitors, most notably imatinib. Although patients with advanced GIST live much longer today than they did in the past, imatinib-refractory disease remains a tremendous problem. For disease that is refractory to imatinib and sunitinib, regorafenib is an excellent option. In this review, we discuss the biology and clinical work establishing regorafenib as the standard of care for advanced GIST refractory to both imatinib and sunitinib.
Regorafenib: A Review of Its Use in Patients with Advanced Gastrointestinal Stromal Tumours. [2018]Regorafenib (Stivarga(®)) is an orally administered small molecule inhibitor of multiple protein kinases, including kinases involved in oncogenesis and tumour angiogenesis. It was initially approved for use in patients with previously treated metastatic colorectal cancer. Based on the findings of the phase III GRID clinical trial, approval for regorafenib has been expanded to include the treatment of advanced gastrointestinal stromal tumours (GISTs) following the failure of imatinib and sunitinib. In the GRID trial, regorafenib significantly improved progression-free survival and was associated with a significantly higher disease control rate than placebo. No significant between-group difference was observed in overall survival (OS) in the trial; however, the high proportion of patients who crossed over from placebo to regorafenib likely impacted the OS analysis. Regorafenib has an acceptable tolerability profile, with most adverse events being manageable with dose modification and/or supportive measures. The most commonly reported drug-related adverse events among patients receiving regorafenib in the GRID trial were hand-foot skin reaction, hypertension, diarrhoea and fatigue. In conclusion, regorafenib presents a valuable new tool in the treatment of patients with advanced GISTs following the failure of imatinib and sunitinib.
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]Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib.
Toxicity management of regorafenib in patients with gastro-intestinal stromal tumour (GIST) in a tertiary cancer centre. [2022]Regorafenib is a multi-kinase inhibitor approved as third line treatment for metastatic GIST. Dose limiting toxicities are frequently seen and many patients require dose reductions. This study aimed to evaluate regorafenib toxicities and their management in a real-world GIST population.
Regorafenib in gastrointestinal stromal tumors. [2014]Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the GI tract and constitute less than 1% of all digestive tract tumors--the stomach is the most common site. Regorafenib is a multi-tyrosine kinase inhibitor with regulatory approvals granted for colorectal cancers and GIST. The US FDA granted approval for the use of regorafenib in February 2013 in patients with advanced GIST for those who had failed on imatinib and sunitinib. This was based on a pivotal Phase III double-blind placebo controlled randomized trial that showed that there was a significant improvement in progression-free survival for patients on regorafenib.
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]Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib.
Regorafenib-induced hyperammonemic encephalopathy. [2022]Regorafenib improves progression-free survival as a late-line treatment for patients with metastatic gastrointestinal stromal tumour (GIST). As a multitargeted tyrosine kinase inhibitor (TKI), the expected adverse events of regorafenib are similar to those reported with imatinib, sunitinib or sorafenib. We report the first case of hyperammonemic encephalopathy related to regorafenib in a patient with metastatic GIST.
Regorafenib. [2018]Regorafenib (BAY 73-4506, Stivarga®) is an oral diphenylurea multi-kinase inhibitor that targets angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic receptor tyrosine kinases (KIT, RET, and RAF). Regorafenib is the first small-molecule multi-kinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. Consequently, Regorafenib was FDA approved for this indication in 2012. In addition, Regorafenib treatment resulted in a significant improvement in progression-free survival (PFS) compared to placebo in patients with metastatic gastrointestinal stromal tumors (GIST) after progression on standard treatments and is also FDA-approved in this indication since 2013. In 2017, Regorafenib has been FDA approved for the treatment of patients with advanced hepatocellular carcinoma (HCC) previously treated with Sorafenib. In this situation, Regorafenib significantly improved PFS and overall survival (OS) compared to placebo. Regorafenib has also been examined in several clinical trials (mostly phase II) in different tumor entities, including renal cell carcinoma (RCC), soft-tissue sarcoma (STS), and additional phase II trials ongoing (e.g., second- and third-line treatment for medullary thyroid cancer, NCT02657551).
Regorafenib for treatment of advanced gastrointestinal stromal tumors. [2022]Gastrointestinal stromal tumors (GISTs) are abdominal sarcomas which are extremely refractory to chemotherapy treatment. The treatment of GISTs has been revolutionized by use of KIT/platelet-derived growth factor receptor-α (PDGFRA) kinase inhibitors. Unfortunately, most tumors develop resistance to front-line (imatinib) or second-line (sunitinib) therapy. Regorafenib, a KIT/PDGFRA/vascular endothelial growth factor receptor (VEGFR) oral kinase inhibitor, has been shown to improve progression-free survival in the third- or fourth-line setting.