Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST (REGISTRI)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02638766|
Recruitment Status : Recruiting
First Posted : December 23, 2015
Last Update Posted : December 19, 2019
|Condition or disease||Intervention/treatment||Phase|
|Gastrointestinal Stromal Tumors||Drug: regorafenib||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||39 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Study Start Date :||November 2015|
|Estimated Primary Completion Date :||December 2023|
|Estimated Study Completion Date :||December 2024|
Regorafenib 160mg once a day, frequency: 3 weeks on/1 week off in cycles of 28 days
Treatment with regorafenib 160mg once a day, 3 weeks on / 1 week off in cycles of 28 days
Other Name: Stivarga
- Disease Control Rate [ Time Frame: every 8 weeks during 36 months ]the sum of complete responses (CR) + partial responses (PR) + stable disease (SD).
- Progression free survival [ Time Frame: every 8 weeks during 36 months ]Number of months without progression
- Overall survival [ Time Frame: Every 8 weeks during 36 months ]Number of months alive
- Responses determined by CHOI [ Time Frame: every 8 weeks during 36 months ]Measure tumor size
- Correlation with translational research [ Time Frame: After 36 months of recruitment ]Relation between the clinical data obtained and the data obtained from translational research
- Safety (adverse events following CTCAE v4.03) [ Time Frame: Every 28 days until 30 days after last dose ]Evaluation of adverse events following CTCAE v4.03
- Early metabolic response by PET scan [ Time Frame: After 1 month of starting treatment ]Evaluation of metabolic response to treatment
- Quality of life by EORCT QLQ C30 questionnaire [ Time Frame: Day 1 of each cycle. Pre-treatment administration ]EORCT QLQ C30 questionnaires
- Quality of life by EQ-ED-5L questionnaire [ Time Frame: Day 1 of each cycle. Pre-treatment administration ]EQ-ED-5L questionnaires
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02638766
|Contact: Mamen De Juan, RGNemail@example.com|
|Contact: Melissa Fernandez-Pinto, MScfirstname.lastname@example.org|
|Study Chair:||Javier Martín-Broto, MD||GEIS (GRUPO ESPAÑOL DE INVESTIGACION EN SARCOMAS|
|Study Director:||Virginia Martínez-Marín, MD||GEIS (GRUPO ESPAÑOL DE INVESTIGACION EN SARCOMAS|