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Cancer Commun (Lond). 2018 Nov 1;38(1):66. doi: 10.1186/s40880-018-0330-z.

Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study.

Chen Q1,2, Tang L1,2, Liu N1, Han F1,3, Guo L1,2, Guo S1,2, Wang J1,3, Liu H4, Ye Y5, Zhang L6, Liu L1,2, Wang P1,2, Li Y1, He Q1, Yang X1, Tang Q1,2, Li Y1,2, Liang Y1,2, Sun X1,2, Xie C1,7, Mo Y1,7, Guo Y1,8, Sun R1,2, Mo H1,2, Cao K1,2, Guo X1,2, Zeng M1, Mai H9,10, Ma J11,12.

Author information

1
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
2
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
3
Department of Ultrasound, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
4
Department of Radiation Oncology, Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, P. R. China.
5
Department of Science and Education, Sun Yat-sen Memorial Hospital, Guangzhou, 510120, P. R. China.
6
Department of Radiation Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, P. R. China.
7
Department of Imaging, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
8
Department of Clinical Trial Center, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
9
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. maihq@sysucc.org.cn.
10
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. maihq@sysucc.org.cn.
11
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. majun@sysucc.org.
12
Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. majun@sysucc.org.

Abstract

BACKGROUND:

Famitinib is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet-derived growth factor receptor, and stem cell factor receptor (c-kit). Previous studies have demonstrated anti-tumour activities of famitinib against a wide variety of advanced-stage solid cancers. We aimed to determine the safety and efficacy of famitinib with concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We also evaluated the feasibility of contrast-enhanced ultrasound (D-CEUS) as a predictor of early tumour response to famitinib and to correlate functional parameters with clinical efficacy.

METHODS:

The trial was conducted in subjects with stage III or IVa-b NPC using a 3 + 3 design of escalating famitinib doses. Briefly, subjects received 2 weeks of famitinib monotherapy followed by 7 weeks of famitinib plus CCRT. D-CEUS of the neck lymph nodes was performed at day 0, 8 and 15 after famitinib was administered before starting concurrent chemoradiotherapy. End points included safety, tolerability and anti-tumour activity.

RESULTS:

Twenty patients were enrolled (six each for 12.5, 16.5 and 20 mg and two for 25 mg). Two patients in the 25 mg cohort developed dose-limiting toxicities, including grade 4 thrombocytopenia and grade 3 hypertension. The most common grade 3/4 adverse events were leukopenia, neutropenia and radiation mucositis. D-CEUS tests showed that more than 60% of patients achieved a perfusion parameter response after 2 weeks taking famitinib alone, and the parameter response was associated with disease improvement. In the famitinib monotherapy stage, three patients (15%) showed partial responses. The complete response rate was 65% at the completion of treatment and 95% 3 months after the treatment ended. After a median follow-up of 44 months, the 3-year progression-free survival (PFS) and distant metastasis-free survival were 70% and 75%, respectively. Subjects with a decrease of perfusion parameter response, such as peak intensity decreased at least 30% after 1 week of famitinib treatment, had higher 3-year PFS (90.9% vs. 44.4%, 95% CI 73.7%-100% vs. 11.9%-76.9%, P < 0.001) than those with an increase or a reduction of less than 30%.

CONCLUSIONS:

The recommended famitinib dose for phase II trial is 20 mg with CCRT for patients with local advanced NPC. D-CEUS is a reliable and early measure of efficacy for famitinib therapies. Further investigation is required to confirm the effects of famitinib plus chemoradiotherapy.

KEYWORDS:

Concurrent chemoradiotherapy; Famitinib; Nasopharyngeal carcinoma; Phase I, dynamic contrast-enhanced ultrasound

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