Ignite Creation Date:
2024-06-16 @ 11:50 AM
Last Modification Date:
2024-10-26 @ 3:30 PM
Study NCT ID:
NCT06431451
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-29
First Post:
2023-12-24
Brief Title:
The Correlation Between Ripretinib Exposure and the Efficacy and Safety in Patients With Advanced GISTs
Sponsor:
First Affiliated Hospital Sun Yat-Sen University
Organization:
First Affiliated Hospital Sun Yat-Sen University
Study Overview
Official Title:
The Correlation Between Ripretinib Exposure and the Efficacy and Safety in Patients With Advanced Gastrointestinal Stromal Tumors an Observational Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a prospective single-center observational study to explore the correlation between ripretinib exposure and the efficacy and safety in patients with advanced gastrointestinal stromal tumors
Detailed Description:
INTRODUCTION AND RATIONALE
Gastrointestinal stromal tumors GISTs are a rare mesenchymal sarcoma that most commonly occur in the stomach and small intestine but can occur in any region of the entire gastrointestinal tract For advanced GISTs that cannot be surgically removed or metastasized imatinib sunitinib and regorafenib are recommended TKIs in the current clinical guidelines for the first- second- and third-line therapy respectively Although imatinib has significant effect in the first-line treatment of GIST improving the prognosis and survival outcome GISTs often develop primary or secondary drug resistance resulting in disease progressionRipretinib is a broad-spectrum switch-control kinase inhibitor that specifically inhibits KIT and PDGFRA kinase signaling through dual mechanisms of action In clinical studies of advanced GIST patients Ripretinib has shown good safety and efficacy In the phase III clinical study INVICTUS Ripretinib 150 mg QD was used to treat patients with metastatic or unresectable GIST who failed to treatment with imatinib sunitinib and regorafenib The median progression-free survival mPFS was 63 months in the Ripretinib group and 10 month in the placebo group The phase III clinical trial INTRIGUE showed that although there was no significant advantage in progression-free survival PFS compared with sunitinib Ripretinib had better safety lower incidence of adverse events and better patient tolerability In May 2020 Ripretinib was approved by the US FDA for the treatment of adult patients with advanced GIST who have failed to three or more kinase inhibitors including imatinib It is also recommended as a preferred fourth-line drug in the 2023 version of the NCCN guidelines and the 2022 version of the CSCO guidelines for GISTs
In vitro kinase and cell studies have shown that Ripretinib is effective against wild-type KIT and PDGFRA as well as a wide range of KIT and PDGFRA mutations including major and resistant mutations in KIT exons 9 11 13 14 17 and 18 as well as the regorafenib-resistant D816V mutation It is more effective than other type I and type II TKI inhibitors However the inhibitory effect of Ripretinib varies depending on the mutation type At the same time in the phase III clinical study INVICTUS gene mutation analysis it was found that patients with primary mutations in KIT exon 11 and secondary mutations in KIT exon 17 had a relatively longer PFS
The preclinical study of Ripretinib suggests that its inhibitory effect on KIT is concentration-dependent and time-dependent With the increase of in vivo concentration the inhibitory effect of KIT phosphorylation also increases Increasing the dosage or dosing frequency can increase tumor regression and survival rates In the phase I clinical study of Ripretinib it was found that increasing the dose to 150 mg BID after oral administration of 150mg QD with disease progression PD can obtain a further benefit The median progression-free survival mPFS of second-line third-line and fourth-line patients was 56 33 and 46 months respectively indicating that the increase of Ripretinibs exposure in vivo is associated with improved efficacy
Preclinical and clinical studies have found that the main metabolic pathway of Ripretinib is N-demethylation Ripretinib and its active metabolite DP-5439 are mainly metabolized in the liver through CYP3A4 metabolic enzymes and DP-5439 has pharmacological activity similar to the parent drug Ripretinib In a phase I clinical study of pharmacokinetics there was significant inter-patient variability in PK parameters after administration of Ripretinib The variation CV of Cmax and AUC0-24h reached 35 to 60 The AUC of DP-5439 after a single dose of 150 mg was about 49 of Ripretinib and the AUC after 15 days of dosing at 150 mg QD was about 129 of Ripretinib At the same time the AUC0-24h of Ripretinib increased proportionally with dose within the range of 20-250 mg but the Cmax increased less than dose proportionally The Cmax and AUC0-24h of DP-5439 increased less than dose proportionally within the range of 50-250 mgThe above findings suggest that therapeutic drug monitoring TDM may be clinically relevant for patients receiving Ripretinib treatment and further exploration of the relationship between blood concentration or exposure level of Ripretinib and clinical efficacy is warranted
In terms of safety in the phase I dose-escalation trial of Ripretinib no maximum tolerated dose MTD was found and the dose-limiting toxicity DLT was elevation of lipase and creatine kinase which occurred in dose groups of 100 mg BID 200 mg BID and 150 mg QD The most common treatment-related adverse events included fatigue alopecia nausea muscle pain constipation loss of appetite palmoplantar erythrodysesthesia syndrome PPES diarrhea and elevation of lipase Most of these events were mild to moderate The incidence of serious adverse events was 141 including elevation of creatine kinase elevation of lipase elevation of bilirubin myocardial infarction and heart failure In the phase I dose-escalation trial it was shown that the incidence of adverse events such as muscle pain muscle spasms PPES and hypertension increased with dose escalation indicating a possible dose-related toxicity Therefore in order to reduce the occurrence of adverse reactions and improve medication safety it is of great significance to find a relatively safe dose range to guide clinical safe drug use
In addition although the results of the phase II clinical trial of Ripretinib in China suggested that the efficacy safety and PK characteristics of Ripretinib in Chinese patients were consistent with the global patient population a comparison of the results between Chinese patients and global patients in the phase I clinical trial showed that the clinical efficacy of Chinese patients receiving Ripretinib as a fourth-line treatment at a dose of 150 mg QD was slightly better than that of global patients mPFS 72 vs 63 months ORR 184 vs 118 Meanwhile the overall exposure of Ripretinib and DP-5439 was slightly higher in the Chinese population compared to global data This suggests that it is worth further exploring the relationship between the pharmacokinetics and exposure of Ripretinib in the Chinese population and its efficacy which has implications for personalized treatment in Chinese patients
This study aims to establish a method for monitoring the blood concentrations of Ripretinib and its active metabolite DP-5439 and to monitor the blood concentrations of advanced GIST patients receiving Ripretinib treatment The study will explore the relationship between the exposure of Ripretinib and its efficacy and safety in real-world advanced GIST patients determine the therapeutic window of Ripretinib and explore the effective exposure levels required for different KIT mutation types
Gastrointestinal stromal tumors GISTs are a rare mesenchymal sarcoma that most commonly occur in the stomach and small intestine but can occur in any region of the entire gastrointestinal tract For advanced GISTs that cannot be surgically removed or metastasized imatinib sunitinib and regorafenib are recommended TKIs in the current clinical guidelines for the first- second- and third-line therapy respectively Although imatinib has significant effect in the first-line treatment of GIST improving the prognosis and survival outcome GISTs often develop primary or secondary drug resistance resulting in disease progressionRipretinib is a broad-spectrum switch-control kinase inhibitor that specifically inhibits KIT and PDGFRA kinase signaling through dual mechanisms of action In clinical studies of advanced GIST patients Ripretinib has shown good safety and efficacy In the phase III clinical study INVICTUS Ripretinib 150 mg QD was used to treat patients with metastatic or unresectable GIST who failed to treatment with imatinib sunitinib and regorafenib The median progression-free survival mPFS was 63 months in the Ripretinib group and 10 month in the placebo group The phase III clinical trial INTRIGUE showed that although there was no significant advantage in progression-free survival PFS compared with sunitinib Ripretinib had better safety lower incidence of adverse events and better patient tolerability In May 2020 Ripretinib was approved by the US FDA for the treatment of adult patients with advanced GIST who have failed to three or more kinase inhibitors including imatinib It is also recommended as a preferred fourth-line drug in the 2023 version of the NCCN guidelines and the 2022 version of the CSCO guidelines for GISTs
In vitro kinase and cell studies have shown that Ripretinib is effective against wild-type KIT and PDGFRA as well as a wide range of KIT and PDGFRA mutations including major and resistant mutations in KIT exons 9 11 13 14 17 and 18 as well as the regorafenib-resistant D816V mutation It is more effective than other type I and type II TKI inhibitors However the inhibitory effect of Ripretinib varies depending on the mutation type At the same time in the phase III clinical study INVICTUS gene mutation analysis it was found that patients with primary mutations in KIT exon 11 and secondary mutations in KIT exon 17 had a relatively longer PFS
The preclinical study of Ripretinib suggests that its inhibitory effect on KIT is concentration-dependent and time-dependent With the increase of in vivo concentration the inhibitory effect of KIT phosphorylation also increases Increasing the dosage or dosing frequency can increase tumor regression and survival rates In the phase I clinical study of Ripretinib it was found that increasing the dose to 150 mg BID after oral administration of 150mg QD with disease progression PD can obtain a further benefit The median progression-free survival mPFS of second-line third-line and fourth-line patients was 56 33 and 46 months respectively indicating that the increase of Ripretinibs exposure in vivo is associated with improved efficacy
Preclinical and clinical studies have found that the main metabolic pathway of Ripretinib is N-demethylation Ripretinib and its active metabolite DP-5439 are mainly metabolized in the liver through CYP3A4 metabolic enzymes and DP-5439 has pharmacological activity similar to the parent drug Ripretinib In a phase I clinical study of pharmacokinetics there was significant inter-patient variability in PK parameters after administration of Ripretinib The variation CV of Cmax and AUC0-24h reached 35 to 60 The AUC of DP-5439 after a single dose of 150 mg was about 49 of Ripretinib and the AUC after 15 days of dosing at 150 mg QD was about 129 of Ripretinib At the same time the AUC0-24h of Ripretinib increased proportionally with dose within the range of 20-250 mg but the Cmax increased less than dose proportionally The Cmax and AUC0-24h of DP-5439 increased less than dose proportionally within the range of 50-250 mgThe above findings suggest that therapeutic drug monitoring TDM may be clinically relevant for patients receiving Ripretinib treatment and further exploration of the relationship between blood concentration or exposure level of Ripretinib and clinical efficacy is warranted
In terms of safety in the phase I dose-escalation trial of Ripretinib no maximum tolerated dose MTD was found and the dose-limiting toxicity DLT was elevation of lipase and creatine kinase which occurred in dose groups of 100 mg BID 200 mg BID and 150 mg QD The most common treatment-related adverse events included fatigue alopecia nausea muscle pain constipation loss of appetite palmoplantar erythrodysesthesia syndrome PPES diarrhea and elevation of lipase Most of these events were mild to moderate The incidence of serious adverse events was 141 including elevation of creatine kinase elevation of lipase elevation of bilirubin myocardial infarction and heart failure In the phase I dose-escalation trial it was shown that the incidence of adverse events such as muscle pain muscle spasms PPES and hypertension increased with dose escalation indicating a possible dose-related toxicity Therefore in order to reduce the occurrence of adverse reactions and improve medication safety it is of great significance to find a relatively safe dose range to guide clinical safe drug use
In addition although the results of the phase II clinical trial of Ripretinib in China suggested that the efficacy safety and PK characteristics of Ripretinib in Chinese patients were consistent with the global patient population a comparison of the results between Chinese patients and global patients in the phase I clinical trial showed that the clinical efficacy of Chinese patients receiving Ripretinib as a fourth-line treatment at a dose of 150 mg QD was slightly better than that of global patients mPFS 72 vs 63 months ORR 184 vs 118 Meanwhile the overall exposure of Ripretinib and DP-5439 was slightly higher in the Chinese population compared to global data This suggests that it is worth further exploring the relationship between the pharmacokinetics and exposure of Ripretinib in the Chinese population and its efficacy which has implications for personalized treatment in Chinese patients
This study aims to establish a method for monitoring the blood concentrations of Ripretinib and its active metabolite DP-5439 and to monitor the blood concentrations of advanced GIST patients receiving Ripretinib treatment The study will explore the relationship between the exposure of Ripretinib and its efficacy and safety in real-world advanced GIST patients determine the therapeutic window of Ripretinib and explore the effective exposure levels required for different KIT mutation types
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None