Dataset Information

Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors.

ABSTRACT:

Background

Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers.

Methods

Twelve patients were enrolled. Eligible subjects received different dosages of GW5074 in one of the three dose cohorts (Cohort 1: 750 mg daily, Cohort 2: 1500 mg daily, Cohort 3: 750 mg twice daily) plus 200 mg of sorafenib daily to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) at phase 1. Furthermore, the expression level of phosphorylated DAPK^S308 in primary tumor, metastatic tumor, and circulating tumor cells (CTC) were evaluated to investigate the relationship between biomarker and the efficacy profile.

Results

Among the 12 enrolled patients in this phase 1 trial, most adverse effects (AE) were grade 1, with two being grade 3. The most frequent AE of all grades were weight loss and hypertension, occurring in 16.7% of participants. Eight patients (66.7%) had the disease controlled by receiving co-administration therapy of GW5074 and sorafenib. GW5074 was found to have poor absorption, as increasing the dosage did not result in a significant increase in the bioavailability of GW5074 in subjects. Furthermore, the expression level of phosphorylated DAPK^S308 in tumor and CTCs were correlated with the disease control rate (DCR) and duration of response (DOR).

Conclusions

Co-administration therapy of GW5074 and sorafenib demonstrated a favorable safety profile and showed anti-tumor activity in a variety of tumor types. However, the solubility of GW5074 is not satisfactory. A future phase 2a trial will be carried out using the new salted form that has been proven to be more effective.

SUBMITTER: Kao CC

PROVIDER: S-EPMC9031611 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors.

Kao Chien-Chang CC Ho Ching-Liang CL Yang Ming-Hsin MH Tsai Yi-Ta YT Liu Shu-Yu SY Chang Ping-Ying PY Wu Yi-Ying YY Chen Jia-Hong JH Huang Tzu-Chuan TC Yehn Ren-Hua RH Dai Ming-Shen MS Chen Yeu-Chin YC Sun Guang-Huan GH Cha Tai-Lung TL

Journal of clinical medicine 20220414 8

<h4>Background</h4>Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers.<h4>Methods</h4>Twelve patients wer ...[more]

PMID: 35456276

Similar Datasets

Project description:Lessons learnedMET overexpression is uncommon, and positive MET immunohistochemistry (1+/2+) was an independent positive prognostic factor for response rate and progression-free survival. Whether MET overexpression can be considered a potential predictive biomarker and be used as an inclusion criterion is worth investigating in a future study.BackgroundMetatinib tromethamine tablet (metatinib) is a small molecule receptor kinase inhibitor targeting both c-MET and vascular endothelial growth factor receptor 2. This phase I trial aimed to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), pharmacokinetics, safety, and efficacy of metatinib in patients with advanced solid tumors.MethodsEligible patients received a single dose of metatinib in a 3 + 3 dose-escalation design with dose levels of 25-800 mg/day, after a single dose on day 1, then 2 days off, and then a multidose schedule of once-daily doses for 25 consecutive days (days 4-28). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), efficacy, and biomarkers.ResultsEighteen patients (including nine patients with hepatocellular carcinoma [HCC]) received at least one dose of study drug (one patient quit the study without continuous multiple-dose administration after receiving a single dose of metatinib). Hand-foot skin reaction, diarrhea, and liver dysfunction were the DLTs, and 200 mg/day was the MTD. The most common treatment-related adverse events (TRAEs) were skin toxicity (50%), diarrhea (33.3%), and liver dysfunction (27.8%). Three patients (only one of six in the 200 mg/day cohort; the other two in the 300 mg/day cohort) experienced severe TRAEs: one patient with severe liver dysfunction and two patients with severe liver dysfunction and skin toxicity, respectively. Pharmacokinetics assessment indicated that metatinib was rapidly absorbed and metabolized to the formation of reactive metabolite, SCR-1510, after single-dose administration. The mean time taken to achieve maximum concentration and terminal elimination half-life of SCR-1510 was approximately 2.0-3.0 hours and ranged from 8 to 14 hours. Two patients had partial responses. The objective response rate and disease control rate (DCR) were 11.1% and 61.1%, respectively. The median progression-free survival (PFS) was 2.75 months.ConclusionMetatinib administration of 200 mg/day was well tolerated, safe, and effective. The MTD was 200 mg/day, which should be recommended in further investigations.

Dataset Information

Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors.

Background

Methods

Results

Conclusions

Publications

Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets