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Background: For non-small-cell lung cancer (NSCLC) patients who progressed after first-line chemotherapy, immunotherapy targeting programmed cell death (ligand) 1 has shown promising activity. However, the activity is relatively limited in patients harboring epidermal growth factor receptor (EGFR) mutations. Objectives: This study aimed to evaluate the efficacy and safety of camrelizumab plus famitinib in previously treated patients with locally advanced and metastatic NSCLC. Design: A single-center, single-arm, phase II study. Methods: Previously treated patients with locally advanced and metastatic NSCLC were enrolled to receive camrelizumab (200 mg, administered intravenously every 3 weeks) and famitinib (20 mg, administered orally once daily). Patients harboring EGFR mutation genes had received at least one EGFR tyrosine kinase inhibitor and no more than two lines of chemotherapy regimen before the enrollment. The other patients had progressed on first-line chemotherapy with or without immunotherapy before the enrollment. The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by the investigator. Results: Our study encompassed 23 NSCLC patients between October 2019 and October 2022. For all patients, the confirmed ORR was 30.4%, and the disease control rate was 95.7%. The median progression-free survival (PFS) was 6.9 months (95% CI: 4.9 months–not reached). The median overall survival (OS) was not reached. 1- and 2-year OS rates were 85.6% (95% CI: 71.8%–100.0%) and 56.8% (95% CI: 37.7%–85.7%). Especially, for the 6 patients with EGFR genetic aberrations, the confirmed ORR was 33.3%, the median PFS was 10.3 months (95% CI: 1.8–18.8 months), and the median OS was 20.3 months (95% CI: 0.8–39.8 months). The most common grade 3 and above treatment-related adverse events were platelet count decreased, white blood cell count decreased, and hypertension. No unexpected adverse events were reported. Conclusion: Camrelizumab plus famitinib demonstrated encouraging clinical activity with a manageable safety profile in previously treated patients with locally advanced and metastatic NSCLC. The results warranted further validation. Trial registration: Chinese Clinical Trial Registry identifier: ChiCTR1900026641. [ABSTRACT FROM AUTHOR]

Background: The combination of immune checkpoint inhibitors and antiangiogenic agents has been effective in treating multiple cancers. This was further explored in an open-label, multicenter phase 2 basket study (NCT04346381), which evaluated the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients with advanced solid tumors. We herein report the findings from the cohort of advanced NSCLC patients who progressed after treatment with platinum-doublet chemotherapy and immunotherapy. Methods: Eligible patients were enrolled and treated with camrelizumab (200 mg once every 3 weeks via intravenous infusion) and oral famitinib (20 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: Forty patients were enrolled in this cohort, with a median follow-up duration of 11.5 months. Three patients (7.5%) achieved a partial response, and 29 patients (72.5%) achieved stable disease. The ORR and DCR with this combination regimen were 7.5% (95% CI, 1.6–20.4) and 80.0% (95% CI, 64.4–90.9), respectively. The median DoR was 12.1 months (95% CI, 10.3-not reached). The median PFS was 5.4 months (95% CI, 4.1–7.5), and the median OS was 12.1 months (95% CI, 9.1–16.7). The estimated 12-month OS rate was 51.5% (95% CI, 34.9–65.9). The most frequent grade 3 or higher treatment-related adverse events occurring in more than 5% of patients included hypertension (27.5%), palmar-plantar erythrodysesthesia syndrome (10%), decreased neutrophil count (10%), and proteinuria (7.5%). Conclusion: Camrelizumab plus famitinib demonstrated favorable benefits in PFS and OS, along with manageable safety profiles, in patients with advanced NSCLC who progressed after platinum-doublet chemotherapy and immunotherapy. This finding warrants further exploration. [ABSTRACT FROM AUTHOR]

ABSTRACTBiliary tract cancer (BTC) is an aggressive malignancy with few options for advanced-stage treatment. The combination of PD-1/PD-L1 inhibitors with famitinib, a receptor tyrosine kinase (RTK) inhibitor, has demonstrated improved clinical outcomes in several clinical trials. We herein reported a case of a gallbladder cancer (GBC) patient with liver metastases, previously resistant to traditional chemotherapy. Remarkably, the patient achieved a complete response (CR) with a long-lasting survival benefit exceeding 3 years. This was achieved using a novel regimen combining SHR-1701, an anti-PD-L1/TGF-βR fusion protein, and famitinib, even though the patient had proficient mismatch repair (pMMR) and tested negative for PD-L1. Adverse events were limited and manageable. This is the first report of such a treatment regimen being applied in a clinical setting, suggesting that the SHR-1701 and famitinib combination may be a promising immunotherapeutic approach for patients with refractory advanced GBC.

Famitinib is a tyrosine kinase inhibitor under clinical investigation for the treatment of solid tumors. Here, a 3‐period crossover trial investigated the effect of high‐fat or low‐fat food intake on the single‐dose pharmacokinetic properties of oral famitinib. Twenty‐four healthy Chinese participants were enrolled and received a single 25‐mg dose of famitinib malate capsule following a high‐fat or low‐fat breakfast before dosing. Blood samples were collected before dosing (0 hour) to 192 hours after dosing, and famitinib concentrations in plasma were determined with validated liquid chromatography–tandem mass spectrometry. Compared with the fasting condition, the geometric mean ratios for low‐fat/fasting were 98.6%, 107.7%, and 107.5% for maximum plasma concentration, area under the plasma concentration–time curve (AUC) over the dosing interval, and AUC from time 0 to infinity, respectively. Those for high‐fat/fasting were 84.4%, 105.0%, and 105.1% for maximum plasma concentration, AUC over the dosing interval, and AUC from time 0 to infinity, respectively. There was no significant difference in adverse events between fasting and fed conditions, and no serious adverse events occurred during the trial. In conclusion, oral famitinib bioavailability is not affected by food intake, implying that patients with cancer do not need to consider dietary status when using famitinib. This is considered important for convenience and treatment compliance. [ABSTRACT FROM AUTHOR]

Summary: Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6–55.4) and the DCR was 77.8% (90% CI, 56.1–92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0–not reach), and the median PFS was 7.2 months (90% CI, 4.4–13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3–4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.

Summary: To evaluate the potential gastric pH-dependent drug-drug interaction (DDI), safety and tolerability of famitinib co-administered with omeprazole in healthy subjects. Twenty healthy subjects were enrolled in a single-center, single-arm, open-label, fixed-sequence study. Famitinib was administered as a single oral 25 mg under a fasting condition on day 1, omeprazole (40 mg once daily) was given on days 10–14, concomitantly with famitinib on day 15, and for the follow-up 7 additional days (days 16–22). Blood samples were collected for the pharmacokinetic analysis of famitinib and its metabolite SHR116637 following each famitinib dose. Safety and tolerability were assessed during the whole progress via clinical laboratory tests. The least-squares geometric mean ratios (GMRs) (90% CI) of Cmax, AUC0-t and AUC0-∞ for famitinib combined with omeprazole to famitinib alone were 0.989 (0.953, 1.027), 0.956 (0.907, 1.007) and 0.953(0.905, 1.005) respectively. For the metabolite SHR116637, their GMRs (90% CI) of the above parameters were 0.851 (0.786, 0.920), 0.890 (0.838, 0.946)and 0.887 (0.835, 0.943), indicating the absence of significant differences in the parameters. During the treatment period, 9(45%) subjects reported 16 treatment emergent adverse events (TEAE), among which 6 subjects (30%) reported 9 TEAEs and 1 subject (5%) reported 1 TEAE during famitinib or omeprazole administered alone respectively, 5 subjects (25.0%) reported 6 TEAEs during in the combined administration phase. Omeprazole did not have a significant influence on the pharmacokinetics (PK) of famitinib and SHR116637, and the safety profile was good upon co-administration. ClinicalTrials.gov identifier NCT 05,041,920. [ABSTRACT FROM AUTHOR]

Abstract Background Anaplastic thyroid cancer (ATC) is considered the most lethal thyroid cancer, with an overall 5‐year survival rate below 10%. The FDA approved a BRAF/MEK inhibitor combination for the treatment of patients with BRAF‐mutated ATC. However, effective therapeutic options for patients with wild‐type BRAF are lacking. Case In our phase II study, patients having advanced/metastatic solid ATCs were treated with famitinib and camrelizumab, a combination therapy involving a multi‐targeted kinase inhibitor and an anti‐PD‐1 antibody. We report a case of a patient with locally advanced unresectable ATC who underwent this combination therapy, allowing us to perform complete surgical resection followed by post‐operative radiation therapy. Conclusion To the best of our knowledge, this is the first report describing the use of famitinib and camrelizumab as a neoadjuvant treatment for ATC with wild‐type BRAF. Clinical trial for a novel neoadjuvant approach for ATC are currently open for enrollment.

Background: Famitinib is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor under clinical investigation for the treatment of solid tumors. As famitinib is metabolized mainly by cytochrome P450 3A4 (CYP3A4), the study was conducted to investigate the effect of potent CYP3A4 inducer rifampin on the pharmacokinetics of famitinb.Methods: This single-center, single-arm and fixed-sequence drug-drug interaction study enrolled 21healthy Chinese male subjects. Subjects received a single oral dose of famitinib 25 mg on days 1 and 16 and repeated administration of oral rifampin 600 mg once daily on days 10-23. Blood samples were collected and plasma concentrations of famitinib were measured by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated using noncompartmental analysis and safety was assessed.Results: In the presence of rifampin, the famitinib geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) decreased by 48% and 69%, respectively, and the mean elimination half-life was shortened from 33.9 to 18.2 h. The geometric mean ratio (GMR) of famitinib Cmax and AUC0-∞ and their 90% CI were 0.52 (0.50, 0.54) and 0.31 (0.29, 0.33). Single dose of famitinib 25 mg was well tolerated and eight subjects (38.1%) reported treatment emergent adverse events, which were all grade 1-2 in severity.Conclusion: Co-administration of rifampin considerably reduces plasma concentration of famitinb due to CYP3A4 induction. Concomitant administration of famitinib and strong CYP3A4 inducers should be avoided, whereas when simultaneous use with inducers of CYP3A4, dose adjustment of famitinb is recommended.Clinical Trial Registration Number: NCT04494659 (July 31, 2020). [ABSTRACT FROM AUTHOR]

Abstract Background As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy. Methods The combined antitumor effects of HS‐10296, a third‐generation EGFR inhibitor targeting EGFR T790M mutation, with the multitargeted tyrosine kinase inhibitor (TKI) famitinib in non‐small cell lung cancer (NSCLC) were evaluated by in vitro methods such as cell proliferation, apoptosis, angiogenesis assays, and in vivo animal efficacy studies. Results Famitinib strengthened the effects of HS‐10296 on inhibiting proliferation and inducing apoptosis of NSCLC cells, possibly by synergistic inhibition of AKT and ERK phosphorylation. Meanwhile, HS‐10296 significantly potentiated the effects of famitinib on inhibiting the proliferation and migration of HUVEC, which may be through synergistic inhibition of ERK phosphorylation in HUVEC, suggesting that HS‐10296 may improve the inhibition of angiogenesis by famitinib. Moreover, combination of HS‐10296 and famitinib exerted synergistic antitumor activity in NCI‐H1975 and PC‐9 xenograft models, and this effect may be accomplished by synergistic inhibition of phosphorylation of AKT and ERK and tumor angiogenesis in tumor tissues. Conclusions Collectively, our results indicate that HS‐10296 and famitinib exhibit significant synergistic antitumor activity, suggesting that the third‐generation EGFR inhibitor combined with VEGFR inhibitor provides a promising strategy in the treatment of EGFR‐mutant NSCLC.

Background: As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy. Methods: The combined antitumor effects of HS‐10296, a third‐generation EGFR inhibitor targeting EGFR T790M mutation, with the multitargeted tyrosine kinase inhibitor (TKI) famitinib in non‐small cell lung cancer (NSCLC) were evaluated by in vitro methods such as cell proliferation, apoptosis, angiogenesis assays, and in vivo animal efficacy studies. Results: Famitinib strengthened the effects of HS‐10296 on inhibiting proliferation and inducing apoptosis of NSCLC cells, possibly by synergistic inhibition of AKT and ERK phosphorylation. Meanwhile, HS‐10296 significantly potentiated the effects of famitinib on inhibiting the proliferation and migration of HUVEC, which may be through synergistic inhibition of ERK phosphorylation in HUVEC, suggesting that HS‐10296 may improve the inhibition of angiogenesis by famitinib. Moreover, combination of HS‐10296 and famitinib exerted synergistic antitumor activity in NCI‐H1975 and PC‐9 xenograft models, and this effect may be accomplished by synergistic inhibition of phosphorylation of AKT and ERK and tumor angiogenesis in tumor tissues. Conclusions: Collectively, our results indicate that HS‐10296 and famitinib exhibit significant synergistic antitumor activity, suggesting that the third‐generation EGFR inhibitor combined with VEGFR inhibitor provides a promising strategy in the treatment of EGFR‐mutant NSCLC. [ABSTRACT FROM AUTHOR]

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

Abstract Background Metastatic colorectal cancer (mCRC) patients with progressive disease after all available standard therapies need new medication for further treatment. Famitinib is a small-molecule multikinase inhibitor, with promising anticancer activities. This multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial was designed to evaluate the safety and efficacy of famitinib in mCRC. Methods Famitinib or placebo was administered orally once daily. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality-of-life (QoL), and safety. Results Between July 18, 2012 and Jan 22, 2014, a total of 167 patients were screened, and 154 patients were randomized in a 2:1 ratio to receive either famitinib (n = 99) or placebo (n = 55). The median PFS was 2.8 and 1.5 months in the famitinib and placebo groups (hazard ratio = 0.60, 95% confidence interval = 0.41–0.86, P = 0.004). The DCR was 59.8% and 31.4% (P = 0.002) and the ORR was 2.2% and 0.0% (P = 0.540) in the famitinib and placebo groups, respectively. The most frequent grade 3–4 adverse events were hypertension (11.1%), hand-foot syndrome (10.1%), thrombocytopenia (10.1%), and neutropenia (9.1%). Serious adverse events occurred in 11 (11.1%) patients in the famitinib group and 5 (9.1%) in the placebo group (P = 0.788). The median OS of the famitinib and placebo groups was 7.4 and 7.2 months (P = 0.657). Conclusion Famitinib prolonged PFS in refractory mCRC patients with acceptable tolerability. Trial registration This study was registered on ClinicalTrials.gov (NCT01762293) and was orally presented in the 2015 ASCO-Gastrointestinal Symposium

Background: Famitinib, the novel oral multitargeting tyrosine kinase inhibitor, was developed for treatment of patients with advanced solid cancer. This investigation assessed the pharmacokinetic (PK) effects of itraconazole, an officially recommended CYP3A4 strong inhibitor, on famitinib and its metabolite (SHR116637)., Methods: A single-center, single-arm, open-label, and fixed sequence study was conducted in 22 healthy subjects. Famitinib was administered as a single oral 15 mg on Day1. Itraconazole 200 mg once daily was given from Day12 to Day24, concomitantly with famitinib on Day15 and for follow-up during Day30 to Day32. Blood sampling followed each famitinib dosage for PK analysis of famitinib and SHR116637. Safety and tolerability were also assessed throughout the treatment., Results: C max , AUC 0-t and AUC 0-∞ were raised by 40.6%, 77.7% and 81.6%, respectively, and t 1/2 was prolonged from 36.08 hours to 48.24 hours for famitinib. In contrast, C max , AUC 0-t and AUC 0-∞ were reduced by 63.5%, 42.6%, and 39.0%, respectively, for SHR116637. Eight (36.4%) subjects reported seventeen treatments that emerged adverse events (all grade 1-2 in severity) all recovered at follow-up period., Conclusions: Single oral dose of 15 mg famitinib and co-therapy with 200 mg intraconazole were safe and well tolerated in healthy subjects. Famitinib should be avoided in conjunction with strong CYP3A inhibitors if possible., Trial Registration: This trial was registered at http://www.chinadrugtrials.org.cn/index.html. (Registration number: CTR20201824.).

Famitinib (SHR1020), a novel multi-targeted tyrosine kinase inhibitor, has antitumor activity against several solid tumors via targeting vascular endothelial growth factor receptor 2, c-Kit and platelet-derived growth factor receptor β. The present study investigated famitinib's activity against human gastric cancer cells in vitro and in vivo. Cell viability and apoptosis were measured, and cell cycle analysis was performed following famitinib treatment using 3-(4,5-dimethylthiazol -2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling assay and western blotting. Subsequently, cluster of differentiation 34 staining was used to evaluate microvessel density. BGC-823-derived xenografts in nude mice were established to assess drug efficacy in vivo. Famitinib inhibited cell proliferation by inducing cell cycle arrest at the G2/M phase and caused cell apoptosis in a dose-dependent manner in gastric cancer cell lines. In BGC-823 xenograft models, famitinib significantly slowed tumor growth in vivo via inhibition of angiogenesis. Compared with other chemotherapeutics such as 5-fluorouracil, cisplatin or paclitaxel alone, famitinib exhibited the greatest tumor suppression effect (>85% inhibition). The present study demonstrated for the first time that famitinib has efficacy against human gastric cancer in vitro and in vivo, which may lay the foundations for future clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Famitinib is a novel tyrosine kinase inhibitor. We investigated the effects of famitinib on the radiosensitivity of human nasopharyngeal carcinoma (NPC) cell radiosensitivity in vitro and in vivo, and explored its possible mechanisms. Materials and methods: Human nasopharyngeal carcinoma cell line (CNE-2) were treated with famitinib and radiation, and analyzed by3-(4,5-dimethylthaizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic survival assay, and Western blot. A xenograft model using CNE-2 cells was established to analyze the effects of famitinib and radiation on tumor volume and microvessel density (MVD). Results: Famitinib dose-dependently inhibited CNE-2 cells growth and significantly reduced clonogenic survival (p< 0.05), with a sensitivity enhancement ratio (SER) of 1.45. The tumor inhibition rate of the combined treatment group was 91%, which was significantly higher than the radiation group (35%,p< 0.05) and famitinib group (46%,p< 0.05). Famitinib attenuated radiation-induced phosphorylation of the platelet-derived growth factor receptor (PDGFR) and stem cell factor (c-kit) at 0, 30, 60 min after radiation treatment. Furthermore, radiation combined with famitinib decreased tumor MVD (p< 0.05). Conclusions: Famitinib significantly increased CNE-2 cell radiosensitivity in vitro and in vivo by attenuating radiation-induced PDGFR and c-kit phosphorylation and by inhibiting microvessel formation. [ABSTRACT FROM PUBLISHER]

Purpose: Hypothyroidism is a common adverse event in patients treated with anti-VEGFR-2 targeting agents and may be a valuable predictive factor of efficacy. Famitinib is an inhibitor of multiple tyrosine kinases mainly targeting VEGFR-2. The objectives of this study were to assess the efficacy and safety of famitinib in patients with pretreated HER2-negative metastatic breast cancer (MBC) and to explore potential of famitinib-induced hypothyroidism and serum vascular endothelial growth factor (VEGF) level for efficacy prediction. Materials and methods: The primary end point was objective response rate (ORR). Famitinib was administered 25 mg/d. Thyroid function assessments were done at baseline and then every 4 weeks. Plasma levels of VEGF were determined at baseline and 2 cycles after treatment. Results: A total of 28 patients were enrolled. ORR was 14.3 %. The most common grade 3/4 AEs were hand-foot syndrome (25.0 %), proteinuria (21.4 %) and hypertension (17.9 %). 64.0 % patients were observed with elevated thyroid-stimulating hormone (TSH) (>4.94 mIU/L) at any time during the entire treatment period. Sixteen patients with an elevated TSH had a significantly longer PFS than nine patients with no TSH elevation (107 vs. 53 days, respectively, P = 0.002). TSH elevation was also an independent predictor of PFS in a Cox regression model. Plasma VEGF levels did not correlate significantly with clinical outcomes. Conclusions: Famitinib did show substantial anti-tumor activities with a good safety profile in heavily pretreated patients with HER2-negative MBC. Famitinib-related TSH increase may be an early indicator of its efficacy. Serial monitoring of serum TSH may help define VEGFR-2-dependent or VEGFR-2-independent drug resistance. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety, tolerability, pharmacokinetics and antitumor activities of famitinib (famitinib l-malate), a novel oral multitargeting tyrosine kinase inhibitor that acts against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor, stem cell factor receptor (c-kit), FMS-like tyrosine kinase-3 receptor and protooncogene tyrosine kinase receptor in patients with advanced solid cancer. Methods: Patients received once daily oral famitinib. Doses were increased from 4 to 8, 13, 20, 27, 24, 25 and eventually 30 mg. Each cycle was defined as 28 days. The pharmacokinetic profile and various biomarkers were evaluated during the first cycle. Antitumor efficacy was evaluated every 8 weeks. Results: Fifty-four patients were evaluable for safety and efficacy. Dose-limiting toxicities were observed in 2 of 3 patients at 30 mg. The dose-limiting toxicities observed in the first cycle of famitinib treatment included hypertension, hand-foot skin reaction and diarrhea. Grade 3 hypertriglyceridemia/hypercholesterolemia and proteinuria were notable side effects in the subsequent treatment cycles. Other common side effects included bone marrow suppression, oral mucositis, fatigue, pain, elevated transaminase or bilirubin, peripheral sensory disturbance and hypothyroidism, most of which were mild to moderate in severity. Pharmacokinetic studies revealed no significant accumulation of famitinib or its major metabolite, M3. The half-lives of famitinib and M3 were approximately 28.7-33.8 and 41.3-47.7 h, respectively. Food demonstrated a minimal effect on the pharmacokinetics of famitinib. Eight partial responses were determined, including 6 cases of renal cell carcinoma, 1 case of gastrointestinal stromal tumor (GIST) and 1 case of alveolar soft part sarcoma. Fourteen patients demonstrated stable disease with various degrees of tumor shrinkage. Conclusions: Famitinib is generally well tolerated. Famitinib demonstrates a wide spectrum of antitumor activities, which warrants further study in renal cell carcinoma, GIST, hepatocellular carcinoma and soft tissue sarcoma. The recommended dose for future phase II clinical trials is 25 mg. [ABSTRACT FROM AUTHOR]

Background and Purpose Famitinib is a novel multi-targeted receptor tyrosine kinase inhibitor under development for cancer treatment. This study aims to characterize the metabolic and bioactivation pathways of famitinib. Experimental Approach The metabolites in human plasma, urine and feces were identified via ultra-high performance liquid chromatography-quadrupole-time of flight-mass spectrometry and confirmed using synthetic standards. Biotransformation and bioactivation mechanisms were investigated using microsomes, recombinant metabolic enzymes and hepatocytes. Key Results Famitinib was extensively metabolized after repeated oral administrations. Unchanged famitinib was the major circulating material, followed by N-desethylfaminitib ( M3), whose steady-state exposure represented 7.2 to 7.5% that of the parent drug. Metabolites in the excreta were mainly from oxidative deamination ( M1), N-desethylation ( M3), oxidative defluorination ( M7), indolylidene hydroxylation ( M9-1 and M9-5) and secondary phase- II conjugations. CYP3A4/5 was the major contributor to M3 formation, CYP3A4/5 and aldehyde dehydrogenase to M1 formation and CYP1A1/2 to M7, M9-1 and M9-5 formations. Minor cysteine conjugates were observed in the plasma, urine and feces, implying the formation of reactive intermediate(s). In vitro microsomal studies proved that famitinib was bioactivated through epoxidation at indolylidene by CYP1A1/2 and spontaneously defluorinated rearrangement to afford a quinone-imine species. A correlation between famitinib hepatotoxicity and its bioactivation was observed in the primary human hepatocytes. Conclusion and Implications Famitinib is well absorbed and extensively metabolized in cancer patients. Multiple enzymes, mainly CYP3A4/5 and CYP1A1/2, are involved in famitinib metabolic clearance. The quinone-imine intermediate formed through bioactivation may be associated with famitinib hepatotoxicity. Co-administered CYP1A1/2 inducers or inhibitors may potentiate or suppress its hepatotoxicity. [ABSTRACT FROM AUTHOR]

Aim: To establish and validate an ultra-high-performance liquid chromatography-tandem mass spectrometry method for the rapid and simultaneous determination of famitinib and its metabolites in human plasma., Results: All analytes demonstrated good correlation coefficients (R 2  > 0.99), and the LLOQ was 0.05 ng/ml. The inter- and intraday accuracy and precision, as well as the stability of the samples, met the requirements of the US FDA. The extraction recovery and the matrix effect ranged from 87.58 to 116.06% and from 84.57 to 120.53%, respectively., Conclusion: The assay was successfully validated and applied to gastroenteropancreatic neuroendocrine tumor patients, and the assay may be used as a valuable tool in the clinic to determine the drug concentration of famitinib in the plasma of solid tumor patients.