Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST (REGISTRI)
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ClinicalTrials.gov Identifier: NCT02638766 |
Recruitment Status :
Completed
First Posted : December 23, 2015
Last Update Posted : March 27, 2023
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Tracking Information | |||||||
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First Submitted Date ICMJE | November 11, 2015 | ||||||
First Posted Date ICMJE | December 23, 2015 | ||||||
Last Update Posted Date | March 27, 2023 | ||||||
Study Start Date ICMJE | November 2015 | ||||||
Actual Primary Completion Date | August 31, 2021 (Final data collection date for primary outcome measure) | ||||||
Current Primary Outcome Measures ICMJE |
Disease Control Rate [ Time Frame: every 8 weeks during 36 months ] the sum of complete responses (CR) + partial responses (PR) + stable disease (SD).
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Original Primary Outcome Measures ICMJE | Same as current | ||||||
Change History | |||||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE |
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Current Other Pre-specified Outcome Measures | Not Provided | ||||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||||
Descriptive Information | |||||||
Brief Title ICMJE | Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST | ||||||
Official Title ICMJE | Phase II, Single Arm, Non-randomized and Multicenter Clinical Trial of Regorafenib as a Single Agent in the First-line Setting for Patients With Metastatic and/or Unresectable KIT/PDGFR Wild Type GIST | ||||||
Brief Summary | Evaluate the treatment with regorafenib in patients with metastatic and/or unresectable KIT/PDGFR wild type GIST in the first line setting. | ||||||
Detailed Description | The SDH complex is involved in mitochondrial Krebs cycle and defects in the succinate dehydrogenase (SDH) complex have identified, as previously mentioned, in KIT/PDGFR WT. This complex, SDH, has 4 subunits (A-D) and SDH-A or SDH-B are involved in oxidization succinate to fumarate. Therefore, loss of function owing to mutational inactivation leads to the cytoplasmic accumulation of succinate which downregulates prolyl hydroxylase. This enzyme has a negative regulator role of hypoxia-inducible factor 1α (HIF1α) since promotes its proteasomal degradation. Increased levels of HIF1α can enter the nucleus and activate the transcription of vascular endothelial growth factor (VEGFR)24. In fact, the VEGFR expression is higher in KIT/PDGFR WT than in KIT mutant GISTs25. Approximately 50% of KIT/PDGFR WT show high expression of insulin-like growth factor 1 receptor (IGFR1). This expression may correlate also with the loss of SDH due to IGF autocrine loop26. IGFR signals through both MAPK and PI3K-AKT pathways. As previously mentioned, Regorafenib is able to block MAPK signaling pathway at different levels. Interestingly, early interstitial Cajal cell (ICC) progenitors have a phenotype of KITlowCD44+CD34+IGFR+ while committed lineage of progenitors have KIThighCD44+CD34-IGFR-. Unlike mature or more committed lineage of ICCs, the KITlowCD44+CD34+IGFR+ display resistance to Imatinib in spite of kit signaling pathway activation. Thus Regorafenib could gain advantage over Imatinib for treating KIT/PDGFR WT27,28. On the other hand, other subsets within of KIT/PDGFR WT as B-RAF mutants or NF1-associated GIST could also be sensitive to Regorafenib. In this later subset, protein expression of phospho-MAPK was seen in 92% of cases in a series of 25 patients29. Theoretically Regorafenib could also act blocking STAT3, which is activated by RET proto-oncogen, through RET inhibition. STAT3 is implicated as downstream pathway signal in GIST30. Taken together, the previous data suggests Regorafenib could play a relevant role as upfront treatment of metastatic or unresectable locally advanced KIT/PDGFR WT GIST. Subjects will receive 160mg (4 tablets) of regorafenib once a day every day for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off). The study drug will be orally administered. Doses of study drug may be delayed or reduced in case of clinically significant hematologic and other toxicities. Toxicities will be graded using the CTCAE v 4.03. The modifications of regorafenib are detailed in the protocol for general event, Hand Foot Skin Reaction, Hypertension and drug-related liver function test abnormalities. |
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Study Type ICMJE | Interventional | ||||||
Study Phase ICMJE | Phase 2 | ||||||
Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment |
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Condition ICMJE | Gastrointestinal Stromal Tumors | ||||||
Intervention ICMJE | Drug: regorafenib
Treatment with regorafenib 160mg once a day, 3 weeks on / 1 week off in cycles of 28 days
Other Name: Stivarga
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Study Arms ICMJE | Unique arm
Regorafenib 160mg once a day, frequency: 3 weeks on/1 week off in cycles of 28 days
Intervention: Drug: regorafenib
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Publications * | Not Provided | ||||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||
Recruitment Status ICMJE | Completed | ||||||
Actual Enrollment ICMJE |
15 | ||||||
Original Estimated Enrollment ICMJE |
39 | ||||||
Actual Study Completion Date ICMJE | August 31, 2021 | ||||||
Actual Primary Completion Date | August 31, 2021 (Final data collection date for primary outcome measure) | ||||||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
NOTE: It is not necessary to demonstrate disease progression or imatinib intolerance to offer the study entrance. |
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||||
Accepts Healthy Volunteers ICMJE | No | ||||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||||
Listed Location Countries ICMJE | France, Italy, Spain | ||||||
Removed Location Countries | |||||||
Administrative Information | |||||||
NCT Number ICMJE | NCT02638766 | ||||||
Other Study ID Numbers ICMJE | REGISTRI (GEIS 40) | ||||||
Has Data Monitoring Committee | No | ||||||
U.S. FDA-regulated Product | Not Provided | ||||||
IPD Sharing Statement ICMJE |
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Current Responsible Party | Grupo Espanol de Investigacion en Sarcomas | ||||||
Original Responsible Party | Same as current | ||||||
Current Study Sponsor ICMJE | Grupo Espanol de Investigacion en Sarcomas | ||||||
Original Study Sponsor ICMJE | Same as current | ||||||
Collaborators ICMJE | Bayer | ||||||
Investigators ICMJE |
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PRS Account | Grupo Espanol de Investigacion en Sarcomas | ||||||
Verification Date | March 2023 | ||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |