Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

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Skin and Connective Tissue Diseases

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Musculoskeletal Diseases

Rare Diseases

Carcinoma, Non-Small-Cell Lung

Breast Neoplasms

Carcinoma

Lung Neoplasms

Nasopharyngeal Carcinoma

Nose Neoplasms

Breast Diseases

Skin Diseases

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Docetaxel

Albumin-Bound Paclitaxel

patients receive fixed dose of PTX or DOC based on body surface area every cycle, PTX 175mg/m2, DOC 75mg/m2. Patients should finish up to 6 cycles chemotherapy

PTX 175mg/m2, DOC 75mg/m2 at first cycle. the dose of PTX or DOC will adjust based on the pharmacokinetic results of previous cycle. A optimal target of PTX(TC\>0.05) and DOC(AUC) have been set from published PK model with an established limited sampling strategy

the dose of PTX or DOC will adjust based on the plasma drug concentration of previous cycle

PK guided arm

patients receive PTX or DOC dose based on body surface area every cycle, PTX 175mg/m2, DOC 75mg/m2

PTX 175mg/m2, DOC 75mg/m2

YuXiang Ma

Li Zhang

Shu Sen Wang

As cytotoxic agents, DTX and PTX have a narrow therapeutic window. BSA dosing leads to great inter-individual PK variability, which is a major contributor for severe toxicity, especially in East-Asian populations. DTX exposures measured by area under plasma concentration-time curve (AUC), PTX exposures measured by the time above a plasma concentration of 0.05 µmol/L (TC\>0.05), are the most biologic effects associated PK parameters for DTX and PTX, respectively, which could positively predict related toxicities such as neutropenia, peripheral neuropathy, etc. So, we conducted a randomized clinical trial to compare the effect on related toxicities and efficacy of PK-guided dosing strategy and BSA dosing strategy.

3 populations were included: advanced NSCLC patients receive a single-agent docetaxel regimen palliative chemotherapy without restriction of lines; NPC patients receive paclitaxel and carboplatin doublet regimen whether as induction chemotherapy for local advanced patients or palliative chemotherapy for metastatic patients; BRC patients receive a single-agent docetaxel regimen after 4 cycles of adriamycin and cyclophosphamide for adjuvant chemotherapy. Patients are randomly assigned into the BSA-based dosing group and pharmacokinetically-guided dosing group. In the BSA-based dosing group, NPC patients receive paclitaxel (175mg/m2) and carboplatin (AUC=5) treatment, NSCLC and BRC patients receive docetaxel (75mg/m2) treatment, 3-weekly and for up to 6 cycles. BSA group and PK-guided group are with a same starting dose. DTX exposure (AUC) and PTX exposure (TC\>0.05) are calculated from a published PK model with an established limited sampling strategy. Dose of subsequent cycles of PK-guided group patients is calculated base on the previous cycle PK results, according to optimal target algorithm. The optimal target for DTX exposure is 2.5 - 3.7 µg•h/mL. Dose reductions were permitted in both arms according to instructions. The study had a power of 80% to detect a 23% reduction of grade \>3 neutropenia with PK-guided arm for DTX sub-study in NSCLC. A sample size of 100 NSCLC patients was estimated by using Fisher's exact test to provide a 5% two-sided alpha significance level to observe a decrease in the hematological toxicity with a power of 0.8. This is based on the reported toxicity rates of 85% with dose of 75mg/m2 and 63% with 60mg/m2. Objective response rate is evaluated by imaging examination (CT or MR scan) every 2 cycles. Toxicities are evaluated by patients' diary for toxicity reports and physician's evaluation at day 10 and day 21 at every cycle. Blood samples are collected every cycle. And survival information is collected by clinic and telephone follow-up. Research Hypothesis: 1. The concentrations variability dosed by BSA, and the limitation of BSA- and MTD-based dosing. 2. Verify that paclitaxel TC\>0.05 and docetaxel AUC are the most relevant predictor of related toxicities and clinical outcomes. 3. Verify the feasibility of dosing algorithm based on paclitaxel TC\>0.05 and docetaxel AUC, quantify its effect on both reducing toxicity and improving Effectiveness. 4. The effect of using dose modification and administration of G-CSF based on toxicity determined by paclitaxel TC\>0.05 and docetaxel AUC measurement. 5. Prove the ability of PK-guided dosing strategy in reducing DTX and PTX related hematologic and non-hematologic toxicities, and the effect on treatment efficacy.

Explore the Individual Treatment of Docetaxel and Paclitaxel in NSCLC, NPC and BRC by PK-guided Dosing Strategy

An Open-label Randomized Clinical Trial to Compare the Toxicities and Efficacy of Pharmacokinetically-guided and BSA Fixed Dosing Strategy of Docetaxel and Paclitaxel in Chinese Non-small Cell Lung Cancer, Nasopharyngeal Carcinoma, and Breast Cancer Patients.

assess the toxicities rate and severity according to CTCAE v4.03, record the toxicities incident and grades from the first cycle to last cycle until the toxicities relieve or stabilize.

assess the ORR according to RECIST v1.1, An imaging examination should be performed in 4weeks before treatment initiation, and patients are going to receive (CT or MR scan) every 2 cycles during the treatment, the methods should be identical with baseline.

after treatment discontinuation, PFS is recorded by imaging examination every 2 cycles (8 weeks) until tumor progression, other anti-cancer treatment start, trial ends or death. OS is recorded by clinic follow-up or telephone follow-up until death.

Sun Yat-sen University

Profressor

Digestive System Diseases

Gastrointestinal Stromal Tumors

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

xinhua zhang, MD

yanzhe xia, MD

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

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.

The Correlation Between Ripretinib Exposure and the Efficacy and Safety in Patients With Advanced GISTs

The Correlation Between Ripretinib Exposure and the Efficacy and Safety in Patients With Advanced Gastrointestinal Stromal Tumors: an Observational Study

The concentration of ripretinib in the plasma was measured.

The concentration of DP-5439 in the plasma was measured.

To evaluate objective response rate (ORR,CR+PR) determined by radiology assessment per mRECIST(Response Evaluation Criteriain Solid Tumours), version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with lymph nodes measuring \< 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.

To evaluate disease control rate (CBR,CR+PR+\>16 weeks continuation SD) determined by radiology assessment per mRECIST, version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with lymph nodes measuring \< 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.Stable disease lies between partial response and progressive disease.

Progression-free survival (PFS) is defined as the interval between the date of drug administration and the earliest date of disease progression or death due to any cause.

Overall survival is defined as the time from drug administration until death.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Explore the Individual Treatment of Docetaxel and Paclitaxel in NSCLC, NPC and BRC by PK-guided Dosing Strategy	NCT01891123	Non-small Cell ... Breast Cancer Nasal Cancer	PK guided arm PTX 175mg/m2, D...	18 Years - 75 Years	Sun Yat-sen University
The Correlation Between Ripretinib Exposure and the Efficacy and Safety in Patients With Advanced GISTs	NCT06431451	Gastrointestina...		18 Years -	First Affiliated Hospital, Sun Yat-Sen University

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