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Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors
Chien-Chang Kao1,2, Ching-Liang Ho3, Ming-Hsin Yang1,2
1Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
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 DAPKS308 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 DAPKS308 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.
Insights
This phase 1 trial combined GW5074 and sorafenib in advanced cancers. The combination showed anti-tumor activity and a good safety profile, warranting further investigation.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Preclinical studies showed GW5074 and sorafenib combination therapy induced cancer cell death and suppressed tumor growth in animal models.
- The combination therapy demonstrated potential for treating primary and metastatic lesions, prolonging survival in animal models.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of combined GW5074 and sorafenib in patients with advanced solid cancers.
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the combination therapy.
Main Methods:
- A phase 1 clinical trial enrolled 12 patients with refractory advanced solid cancers.
- Patients received escalating doses of GW5074 (750 mg daily, 1500 mg daily, or 750 mg twice daily) plus 200 mg of sorafenib daily.
- Evaluated safety, tolerability, pharmacokinetics, and assessed phosphorylated DAPK S308 expression in tumors and circulating tumor cells (CTCs) as a potential biomarker.
Main Results:
- The combination therapy was generally well-tolerated, with most adverse events being grade 1. Weight loss and hypertension were the most frequent adverse events.
- Eight out of 12 patients (66.7%) experienced disease control.
- GW5074 exhibited poor absorption, with increased dosage not significantly improving bioavailability. Phosphorylated DAPK S308 levels correlated with disease control rate and duration of response.
Conclusions:
- The co-administration of GW5074 and sorafenib demonstrated a favorable safety profile and anti-tumor activity across various cancer types.
- The solubility of GW5074 was identified as a limitation.
- A future phase 2a trial will utilize a more effective salted form of GW5074.
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