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A Phase I dose-escalation, pharmacokinetics and food-effect study of oral donafenib in patients with advanced solid tumours

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Abstract

Purpose

This Phase I study evaluated the safety, tolerability, food effects, pharmacodynamics, and pharmacokinetics of donafenib in patients with advanced solid tumours.

Methods

Eligible patients received a single dose of donafenib (50 mg, 100 mg, 200 mg, 300 mg, or 400 mg) and were then observed over a 7-day period; thereafter, each patient received the corresponding dose of donafenib twice daily for at least 4 weeks. Safety assessment and pharmacokinetic sampling were performed for all patients at the given time points; preliminary tumour response was also assessed.

Results

Twenty-five patients were enrolled in this study. Gastrointestinal reactions were the most common treatment-related adverse event, followed by skin toxicity. The maximum tolerated dose (MTD) was 300 mg bid. The dose-limiting toxicities (DLTs) were grade 3 diarrhoea and fatigue at 300 mg bid and grade 3 skin toxicity at 400 mg bid. In the dose range of 100 ~ 400 mg, T1/2 and AUC0–t after multiple doses were 26.9 ~ 30.2 h and 189 ~ 356 h*μg/mL, respectively. Food did not have a significant effect on the pharmacokinetics of donafenib. Twenty-one patients were assessed for efficacy, and two patients achieved a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST), with a disease control rate of 57.1%.

Conclusion

Oral donafenib was generally well tolerated and appeared to provide some clinical benefits; adverse events were manageable. Based on the results of this study, oral donafenib at 200 mg ~ 300 mg twice daily is recommended for further studies.

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Abbreviations

AUC:

Area under the concentration–time curve

AUC0–12 :

Area under the concentration–time curve for 0–12 h

AUC0–24 h :

Area under the plasma concentration–time cuvre from 0 to 24 h

AUC0–t :

Area under the concentration–time curve from time zero to 120 h

AUC 0–∞ :

Area under the plasma concentration–time curve from time zero to infinity

ALT:

Alanine transaminase

AST:

Aspartate transaminase

CR:

Complete response

CTCAE:

The common terminology criteria for adverse events

C max :

Peak concentration in plasma

C avg :

Average plasma drug concentration

C min :

Minimum plasma drug concentration

Cl/F:

Apparent total clearance of the drug from plasma after oral administration

CV:

Coefficient of variation

DF:

Degree of fluctuation

R :

Ratio of accumulation factor

DLT:

Dose-limited toxicity

ECOG:

Eastern Cooperative Oncology Group

FDA:

Food and Drug Administration

GCP:

Good clinical practice

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

ICH:

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

MRT0–∞ :

Mean residence time from time zero to infinity

MTD:

Maximum tolerated dose

NCI CTC:

National Cancer Institute common terminology criteria

NCA:

Non-compartment analysis

PDGFR:

Platelet-derived growth factor receptor

PR:

Partial response

PD:

Progressive disease

RE:

Relative error

RECIST:

Response Evaluation Criteria in Solid Tumors

RSD:

Relative standard deviation

SD:

Stable disease

Tmax:

Time to Cmax

t 1/2 :

Half-life

TBIL:

Total bilirubin

ULN:

Upper limit of normal

VEGFR:

Vascular endothelial growth factor receptor

Vz/F :

Apparent volume of distribution during terminal phase after non-intravenous administration

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Funding

The work was supported by Zelgen Biopharmaceuticals and grants from National Science and Technology Specific Projects of China (No. 2017ZX09304023), the Major Specific Project of Sichuan province (No. 20ZDYF3127), and the National Science and Technology Specific Projects of China (No. 2018ZX09201018-020).

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Author notes

  1. Xiaoyu Li and Meng Qiu contribute equally as first authors.

  2. Feng Bi and Li Zheng contribute equally as corresponding authors.

Authors and Affiliations

  1. Institute of Clinical Pharmacology, GCP Center, West China Hospital, Sichuan University, Guoxuexiang 37#, Chengdu, 610041, Sichuan, China

    Xiaoyu Li, ShengJun Wang & Li Zheng

  2. Department of Abdominal Oncology, West China Hospital, Sichuan University, Guoxuexiang 37#, Chengdu, 610041, Sichuan, China

    Meng Qiu, Hong Zhu & Bi Feng

Authors
  1. Xiaoyu Li
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  2. Meng Qiu
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  4. Hong Zhu
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  5. Bi Feng
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Correspondence to Bi Feng or Li Zheng.

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Li, X., Qiu, M., Wang, S. et al. A Phase I dose-escalation, pharmacokinetics and food-effect study of oral donafenib in patients with advanced solid tumours. Cancer Chemother Pharmacol 85, 593–604 (2020). https://doi.org/10.1007/s00280-020-04031-1

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  • DOI: https://doi.org/10.1007/s00280-020-04031-1

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