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

Chien-Chang Kao; Ching-Liang Ho; Ming-Hsin Yang; Yi-Ta Tsai; Shu-Yu Liu; Ping-Ying Chang; Yi-Ying Wu; Jia-Hong Chen; Tzu-Chuan Huang; Ren-Hua Yehn; Ming-Shen Dai; Yeu-Chin Chen; Guang-Huan Sun; Tai-Lung Cha

doi:10.3390/jcm11082183

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

J Clin Med. 2022 Apr 14;11(8):2183. doi: 10.3390/jcm11082183.

Authors

Chien-Chang Kao^{1

2}, Ching-Liang Ho³, Ming-Hsin Yang^{1

2}, Yi-Ta Tsai², Shu-Yu Liu², Ping-Ying Chang³, Yi-Ying Wu³, Jia-Hong Chen³, Tzu-Chuan Huang³, Ren-Hua Yehn³, Ming-Shen Dai³, Yeu-Chin Chen³, Guang-Huan Sun¹, Tai-Lung Cha^{1

2}

Affiliations

¹ Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
² Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
³ Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.

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.

Keywords: DAPK; GW5074; advanced tumor; sorafenib.

Grants and funding

MOST 108-2314-B-016-012, MOST 107-2314-B-016-039-MY3, MOST 110-2314-B-016-020-MY3, MOST 110-2314-B-016-019-MY2,MOST 109-2314-B-016-032/Ministry of Science and Technology