Clinical trial NCT06431451: The Correlation Between Ripretinib Exposure and the Efficacy and Safety in Patients with Advanced GISTs
Official title: The Correlation Between Ripretinib Exposure and the Efficacy and Safety in Patients with Advanced Gastrointestinal Stromal Tumors: an Observational Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Gastrointestinal Stromal Tumors
Keywords: Ripretinib
plasma drug concentration
Lead sponsor: First Affiliated Hospital, Sun Yat-Sen University
Sponsor class: OTHER
First posted: 2024-05-28
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Gastrointestinal stromal tumor patients who are receiving treatment with Ripretinib at the research center.

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 progression.Ripretinib 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 6.3 months in the Ripretinib group and 1.0 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 5.6, 3.3, and 4.6 months, respectively, indicating that the increase of Ripretinib's 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 mg.The 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 14.1%, 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: 7.2 vs. 6.3 months; ORR: 18.4% vs. 11.8%). 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.

Eligibility criteria: Inclusion Criteria:

* Patients who are aged ≥ 18 years.
* Gastrointestinal stromal tumors confirmed by histopathological examination, and CD117 and/or DOG-1-positive by immunohistochemistry.
* patients who are currently receiving Ripretinib treatment.
* Subjects must have at least one measurable lesion based on mRECIST v1.1 criteria, and have undergone at least one radiographic evaluation for efficacy analysis.
* Patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 4
* Patient informed consent and signed written consent form.
* The patient was compliant and voluntarily scheduled for follow-up, treatment, laboratory tests, and other study procedures.

Exclusion Criteria:

* Unable to complete at least 15 consecutive days of Ripretinib due to intolerance or disease progression.
* Individuals with other serious acute or chronic physical or mental health problems, or abnormal laboratory test results that increase the risk associated with participation in the study or use of the drug, or that could interfere with the interpretation of study results, and who, in the opinion of the investigator, are not suitable for participation in the study.

Primary outcomes:
measure: Plasma Concentration of ripretinib
timeFrame: Before Dosing and at 0.5, 1, 2, 4, 6, 8,12 and 24 Hours after Dosing
measure: Plasma Concentration of DP-5439
timeFrame: Before Dosing and at 0.5, 1, 2, 4, 6, 8,12 and 24 Hours after Dosing
measure: Objective Response Rate
timeFrame: 2 years
measure: Disease control rate
timeFrame: 2 years
Secondary outcomes:
measure: Progression-free survival
timeFrame: 2 years
measure: overall survival
timeFrame: 2 years
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The First Affiliated Hospital, Sun Yat-sen University
Study officials:
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