==== Front Thorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 10.1111/1759-7714.12784TCA12784Original ArticleOriginal ArticlesPhase I safety and pharmacokinetic study of cipatinib, an original dual tyrosine kinase inhibitor Phase I clinical trial of cipatinibJ. Wang et al.Wang Jiayu 1 † Han Yiqun 1 † Shi Xiuqing 1 Li Qing 1 Zhang Pin 1 Yuan Peng 1 Ma Fei 1 Luo Yang 1 Cai Ruigang 1 Fan Ying 1 Chen Shanshan 1 Li Qiao 1 Xu Binghe http://orcid.org/0000-0002-0234-2747xubinghebm@163.com 1 1 Department of Medical Oncology National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China * Correspondence Binghe Xu, Department of Medical Oncology, National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China. Tel: +86 10 8778 8120 Fax: +86 10 8771 5701 Email: xubinghebm@163.com † These authors contributed equally to this research. 12 6 2018 8 2018 9 8 10.1111/tca.2018.9.issue-81041 1047 13 4 2018 14 5 2018 15 5 2018 © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background Cipatinib is a novel tyrosine kinase inhibitor against both EGFR and HER2/neu. This phase I trial was conducted to assess the safety, dose‐limiting toxicities (DLTs), and maximum‐tolerated dose of cipatinib in HER2‐positive patients with advanced breast cancer. Methods Eligible adults with advanced breast cancer were administered cipatinib 200 mg/day (n = 3) as an initial dose, with escalating dosages of 400 mg (n = 4), 800 mg (n = 2), 1200 mg (n = 3), 1400 mg (n = 3), 1600 mg (n = 3), and 1800 mg (n = 2) in 21 day cycles. DLTs were monitored until the end of cycle 2. Physical examinations, vital signs, blood sampling for hematology, clinical chemistry, and pharmacokinetics were performed throughout the trial. Results Of the 26 subjects enrolled, 23 completed the trial. A total of 143 adverse events (AEs) were reported, of which 87 were associated with cipatinib treatment and comprised: neutropenia (38%), hypertriglyceridemia (15%), fatigue (15%), nausea (12%), fever (19%), and myocardial ischemia (19%). Six AEs were graded 3–4 (neutropenia, increases in aspartate aminotransferase, and total bilirubin, fatigue, dizziness and nodal tachycardia), but none of the AEs observed were considered to be DLTs. Conclusion This tolerability study revealed that despite a mild toxicity profile, cipatinib was well tolerated up to the anticipated maximum dosage of 1800 mg/m2. Further clinical trials are warranted. Advanced breast cancercipatinibHER2phase I trialRTKs source-schema-version-number2.0component-idtca12784cover-dateAugust 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:01.08.2018 ==== Body Introduction EGFR/ErbB1 and HER2/ErbB2 are receptor tyrosine kinases (RTKs) and their ligand binding leads to homo‐heterodimerization, autophosphorylation of their cytosolic tyrosine residues, and activation of their intrinsic kinase function, in which cellular proteins are phosphorylated. The signaling pathway is involved in cell growth, proliferation, differentiation, and migration.1 Tyrosine kinase inhibitors (TKIs) compete with the ATP binding site of the catalytic domain of tyrosine kinases, with single or multiple target specificities.2 Lapatinib, a reversible dual TKI of HER2 and EGFR has shown efficacy in the treatment of patients with ErbB1‐expressing and/or ErbB2‐overexpressing metastatic cancers.3 Although HER2 targeting monoclonal antibodies have taken the leading role in targeted therapy,4 lapatinib has its own unique advantages: it can be orally administered, crosses the blood‐brain barrier, and has lower cardiac toxicity compared to trastuzumab.5 Cipatinib is a dual TKI, which binds to the intracellular domain of both EGFR and HER2 (Ki 3 nM and 13 nM, respectively) and like lapatinib, is a quinazoline. In preclinical experiments, cipatinib has been effective against human cancer cells, such as SK‐OV‐3, Calu‐3, and BT‐474, with an obvious concentration‐related effect in a human tumor nude mice transplantation model that examined both EGFR and HER2 overexpression (half maximal inhibitory concentrations [IC50] were 4.1 nM and 0.5 nM, respectively), and thus shows promise as a TKI. As the preclinical data strongly suggested that cipatinib should be tested in a human clinical trial, we launched this phase I trial from January to December 2012 to further clarify its clinical safety and to determine a specific safe dose. Methods Eligibility criteria The China Food and Drug Administration (Approval No.: 2010L04211 and 2010L04213) and the ethical committee of the Chinese Academy of Medical Sciences Tumor Hospital approved the trial. Written informed consent was obtained from all participants. Patients enrolled in the trial met the following criteria: (i) women aged 18–65; (ii) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1; (iii) a life expectancy of at least 12 weeks; (iv) histological or cytological confirmation of advanced solid breast tumor, with demonstrated expression of HER2 (reported grade 3+ staining intensity [on a scale of 0–3] by means of immunohistochemical analysis or grade 2+ staining intensity using immunohistochemical analysis with gene amplification on fluorescence in situ hybridization);6 (v) standard therapies were either not administered or had been unsuccessful; (vi) adequate bone marrow (a hemoglobin concentration ≥ 9 g/dL, an absolute granulocyte count ≥ 1.5 × 109/L, and a platelet count ≥ 100 × 109/L); (vii) hepatic function (total bilirubin ≤ 1.5 × upper limit of normal [ULN], aspartate transaminase [AST] or alanine transaminase [ALT] ≤ 1.5 × ULN, and blood albumin ≥ 0.5 g/dL); (viii) renal function (creatinine ≤ ULN and Cr ≥ 50 mL/min as determined by the Cockcroft‐Gault formula; (ix) blood lipids (cholesterol ≤ 7.75 mmol/L, trilaurin ≤ 2.5 × ULN); (x) cardiac function (a left ventricular ejection fraction ≥ 50%, normal electrocardiography [ECG], QT adjusted by Fridericia's formula [QTcF] < 470 ms for women/450 ms for men); (xi) any previous symptoms resulting from treatments had been cured, and the patient had received radiotherapy, chemotherapy, hormonal surgery, or molecule targeted therapy within the previous four weeks or treatment with nitrosourea or mitomycin within the previous six weeks; and (xii) a normal swallow function without absorption failure in the stomach and intestine. Safety assessments All subjects underwent a series of safety assessments: 12‐lead ECG, vital signs, and physical examinations were performed at least once a week during the medication period and one, two, and three days before the medication was administered. Blood, urine, and stool examinations were repeated after 7, 21, and 42 days of successive drug treatment. ECOG PS, hepatic and renal function, blood lipids, blood electrolytes, coagulation function, and tetraiodothyronine were examined on days 21 and 42 after the initiation of treatment. Holter monitoring, ultrasonic echocardiography, myocardial protein, and enzyme spectrums (creatinine kinase‐muscle brain [CK‐MB], lactate dehydrogenase [LDH]), as well as human chorionic gonadotropin [HCG] tests of urine and serum levels for childbearing women were performed on day 42. Tumor biopsies were performed on day 20. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3 (NCI‐CTCAE v3). Study treatments This was a dose‐climbing study in patients with advanced solid tumors. In this trial, the initial dose of cipatinib was 200 mg/day with escalation to 400, 800, 1200, 1400, 1600, and 1800 mg in seven groups of patients, following previous studies with lapatinib.3, 6 Each group consisted of at least three patients (Fig 1). Figure 1 Scheme of therapy and outcome measurements. AUC, area under the curve; CLs, clearances; Cmax, peak serum concentration; CR, complete response; Css, steady‐state concentration; DLT, dose limiting toxicity; MRT, mean residence time; PD, progressive disease; PR, partial response; SD, stable disease; Vc, volume of distribution. If there was a case of dose limiting toxicity () within the adaption time (1–5 days), three more subjects were added to the group; otherwise they were transferred into the next experimental dose group. If two cases of DLTs were recorded in the former three or six subjects, dose escalation was ceased. Cipatinib was orally administered once daily. Single dosage began on day 1, while successive dosage started at day 5 after observation of the previous four days. After completing the initial 21 days of the study, patients resumed once‐daily cipatinib until disease progression, treatment‐emergent toxicities, withdrawal of consent, or two cycles were completed. Pharmacokinetic assessments Preliminary experiments of single doses and multi‐successive doses were performed at 200 mg/day to determine the half‐life (t1/2) of cipatinib. Formal pharmacokinetic tests were performed using > 200 mg/day single doses or multi‐successive doses after the preliminary tests were completed. The blood collection point was designed based on the results from preliminary tests of cipatinib in the high, moderate, and low dose groups. At 1, 4, 5, 6, 7, and 21 days, blood was analyzed 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, and 96 hours after cipatinib uptake for single and multiple dose pharmacokinetic studies. At each time point, 3–4 mL of venous blood was collected and centrifuged at 3500 rpm for 10 minutes until the serum was separated. Samples were then stored at −80°C for subsequent analysis. Pharmacokinetic analyses were performed using WinNonlin software (Pharsight, Mountain View, CA, USA). Non‐compartmental standard methods were used to calculate the area under the serum concentration versus time curve within the dosing interval (AUCτ), peak serum concentration (Cmax), the time of Cmax and the trough concentration at steady‐state (Cmin). The drug concentration time curve (AUC), Tmax; minimum, maximum, and average steady‐state clearances (Css_min, Css_max, Css_av); and the mean residence time (MRT) in addition to apparent volume of distribution (V c) were calculated for each time point. Evaluation of clinical activity Response Evaluation Criteria in Solid Tumors (RECIST) was used to assess disease status before treatment and after two cycles (each comprising three weeks cipatinib application until withdrawal from the study) in time intervals of four weeks.7 Results Patient characteristics The study population consisted of women with HER2‐positive advanced breast cancer. Twenty‐six patients enrolled in the trial were administered cipatinib between January 2011 and September 2012; 23 (88.5%) completed the dosage course. Patients were randomly assigned to one of seven daily dose cohorts (200 mg [n = 3], 400 mg [n = 7], 800 mg [n = 3], 1200 mg [n = 3], 1400 mg [n = 4], 1600 mg [n = 3], and 1800 mg [n = 3]). Patient characteristics are presented in Table 1. The dosage of cipatinib was ultimately calculated according to body surface area. Table 1 Patient characteristics after different cipatinib dosages Characteristics Cipatinib dose (mg/day) cohorts 200 mg 400 mg 800 mg 1200 mg 1400 mg 1600 mg 1800 mg No. of patients 3 7 3 3 4 3 3 Age, years (median) Median 50 44 47 57 46 52 48.5 Range 37–52 27–56 44–52 48–64 42–54 38–59 27–64 Body surface area (median, range) 1.58 (1.54–1.70) 1.69 (1.51–1.91) 1.78 (1.77–1.79) 1.75 (1.64–1.79) 1.61 (1.60–1.72) 1.60 (1.52–1.78) 1.70 (1.61–1.91) Prior treatment Chemotherapy 10 24 20 10 19 8 14 Hormonal therapy 2 1 2 2 2 3 4 Targeted therapy 0 5 0 0 2 1 1 Radiotherapy 3 6 3 1 1 1 3 Median administration period (months) 1.5 1.4 5 2.3 4.3 1.3 1 HER2‐overexpression, n (%) 100% 100% 100% 100% 100% 100% 100% Of the 26 patients included in the trial, 23 finally received one response evaluation. Three patients (11.5%) discontinued the study: transaminase elevation did not meet the requirements of the experimental protocol; grade 3 arrhythmia associated with fever; and disease progression. One subject (3.8%) exhibited a partial response (PR) but none achieved a complete response (CR), leading to an overall response rate (ORR) of 3.8%. Four subjects (15.4%) had stable disease (SD) and 18 (69.2%) developed progressive disease (PD) (Table 2). Table 2 The baseline anti‐tumor outcomes of advanced breast cancer patients after different dosages of cipatinib Dose level (mg/day) No. of patients Median treatment duration (weeks), range Response by RECIST, n (%) CR PR SD PD Not evaluated 200 3 4 3 (11.5) 400 7 4 1 (3.8) 4 (15.4) 2 (7.7) 800 3 8 1 (3.8) 2 (7.7) 1200 3 8 2 (7.7) 1 (2.8) 1400 4 12 3 (11.5) 1 (3.8) 1600 3 4 1 (3.8) 2 (7.7) 1800 3 4 3 (11.5) Total 26 0 (%) 1 (3.8) 4 (15.4) 18 (69.2) 3 (11.5) CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. Safety and tolerability Twenty‐six subjects (100%) experienced AEs, 11 of which suffered grade 3 or 4 AEs (Fig 2). The total number of AEs was 143; 87 were associated with cipatinib. Drug‐related AEs occurred in 20 patients (200 mg [n = 3], 400 mg [n = 4], 800 mg [n = 2], 1200 mg [n = 3], 1400 mg [n = 3], 1600 mg [n = 3], and 1800 mg [n = 2]). The most frequently reported drug‐related AE was neutropenia (38%), followed by hypertriglyceridemia (15%) and fatigue (15%). Other treatment‐related AEs included nausea (12%), fever (19%), myocardial ischemia (19%), coughing (12%), dizziness (27%), skeletal muscle pain (42%), upper respiratory tract infection (35%), urine occult blood (12%), urinary tract infection (15%), peripheral nerve toxicity (12%), pruritus (12%), leukopenia (38%), and decreased hemoglobin (12%). Eleven AEs graded 3 or 4 included neutropenia (3.9%), increases in AST (3.9%) and total bilirubin (TBIL; 3.9%), fatigue (3.9%), dizziness (3.9%), and nodal tachycardia (3.9%). Two serious AEs (SAEs), right arm cellulitis without neutropenia and increases in grade 4 TBIL occurred in two patients in the 200 mg/day and 1200 mg/day groups, respectively, but improved after interrupting cipatinib and administering appropriate symptomatic treatment (Table 3). Figure 2 Distribution of adverse events (AEs) within the treatment groups. Grade 1 AE, Grade 2 AE, Grade 3 AE, Grade 4 AE. Table 3 Adverse events in the different dose level groups Adverse event Dose level (mg/day) Total Incidence 200 400 800 1200 1400 1600 1800 Number of patients 3 7 3 3 4 3 3 26 Nausea 1 (1/3) 1 (1/7) 0 1 (1/3) 0 0 0 3 12% (3/26) Coughing 1 (1/3) 1 (1/7) 0 0 0 0 1 (1/3) 3 12% (3/26) Myocardial ischemia 1 (1/3) 2 (2/7) 0 1 (1/3) 0 1 (1/3) 0 5 19% (5/26) Dizziness 1 (1/3) 3 (3/7) 0 0 2 (2/4) 1 (1/3) 0 7 27% (7/26) Fatigue 1 (1/3) 1 (1/7) 0 0 1 (1/4) 0 1 (1/3) 4 15% (4/26) Skeletal muscle pain 2 (2/3) 2 (2/7) 2 (2/3) 1 (1/3) 0 2 (2/3) 2 (2/3) 11 42% (11/26) Upper respiratory tract infection 1 (1/3) 0 2 (2/3) 2 (2/3) 3 (3/4) 1 (1/3) 0 9 35% (9/26) Urine occult blood 1 (1/3) 2 (2/7) 0 0 0 0 0 3 12% (3/26) Urinary tract infection 2 (2/3) 1 (1/7) 0 0 0 1 (1/3) 0 4 15% (4/26) Fever 1 (1/3) 1 (1/7) 1 (1/3) 1 (1/3) 0 1 (1/3) 0 5 19% (5/26) Peripheral nerve toxicity 0 1 (1/7) 0 2 (2/3) 0 0 0 3 12% (3/26) Pruritus 0 0 0 1 (1/3) 1 (1/4) 0 1 (1/3) 3 12% (3/26) Leukopenia 2 (2/3) 1 (1/7) 0 3 (3/3) 2 (2/4) 1 (1/3) 1 (1/3) 10 38% (10/26) Neutropenia 2 (2/3) 0 0 3 (3/3) 2 (2/4) 2 (2/3) 1 (1/3) 10 38% (10/26) Decreased hemoglobin 0 1 (1/7) 0 1 (1/3) 0 1 (1/3) 0 3 12% (3/26) Hypertriglyceridemia 1 (1/3) 0 0 0 0 2 (2/3) 1 (1/3) 4 15% (4/26) AEs related to drug 17 17 5 16 11 13 8 87 60.8% (87/143) AEs not related to drug 7 17 5 9 7 5 6 56 39.2% (56/143) Total 24 34 10 25 18 18 14 143 AE, adverse event. Otherwise, vital signs and physical examinations were normal and no meaningful changes during the treatments were observed in chest X‐rays and ultrasound images or adverse impacts on stool, blood coagulation function, serum urea nitrogen, serum creatinine, or blood electrolytes. Changes of tmax and t1/2 of cipatinib plasma concentrations in the different dosage treatment cohorts After the administration of single doses, successive administration of cipatinib commenced for 21 days as a first cycle. The concentration of cipatinib reached a peak (tmax) at 1.67–9.33 hours after single oral doses of 200, 400, 800, 1200, 1400, 1600, and 1800 mg at day 1, and then declined in a monophasic manner as a result of elimination. The average tmax values after 200 mg (2.33 hours), 400 mg (2.57 hours), 800 mg (3.00 hours), 1200 mg (1.67 hours), and 1400 mg (5.00 hours) were similar, while the average tmax after 1600 mg and 1800 mg was 9.33 hours, clearly longer than the other doses, which was likely caused by the tmax values of subject No. 22 in the 1600 mg cohort and subject No. 26 in the 1800 mg cohort of 24 hours (Table 4). The tmax values after successive administrations had almost the same profile as a single oral dose of cipatinib (Table 5). Table 4 Pharmacokinetics of single dose cipatinib on study day 1 Dose level (mg/day) t1/2 (h) tmax (h) Cmax (ng/mL) AUC0‐t (h*ng/mL) AUC0‐inf (h*ng/mL) AUC0–24 (h*ng/mL) AUC0–48 (h*ng/mL) AUC%extrap (%) Vc/F (L) CL/F (L/h) MRT (h) 200 12.0 2.3 23.4 239 244 199 230 2.0 14 900 954 12.2 400 11.2 2.6 79.5 539 548 437 513 3.3 26 800 1730 11.5 800 12.8 3.0 85.9 548 556 488 538 1.7 31 100 1770 10.5 1200 10.9 1.7 276.0 1590 1600 1310 1530 1.3 16 900 1140 11.1 1400 22.6 5.0 68.1 537 570 390 500 7.0 90 000 2990 20.0 1600 33.1 9.3 33.5 639 752 276 508 18.1 228 000 3800 23.6 1800 13.9 9.3 136.0 2180 2270 1090 2010 2.7 68 100 3830 15.9 AUC, area under the curve; CL/F, apparent oral clearance; Cmax, peak serum concentration; MRT, mean residence time; Vc/F, apparent volume of distribution. Table 5 Pharmacokinetics of successive cipatinib doses evaluated on study day 21 Dose level (mg/day) t1/2 (h) tmax (h) Css‐max (ng/mL) Css‐min (ng/mL) Css‐av (ng/mL) AUCss (h*ng/mL) AUC0‐t (h*ng/mL) AUC0‐inf (h*ng/mL) AUC%extrap (%) DF (%) CLSS (L/h) 200 21.5 4.7 58.3 7.8 18.9 453 609 639 10.0 293 730 400 12.9 2.2 151.0 15.3 44.6 1070 1330 1350 1.3 377 760 800 16.2 1.5 363.0 28.3 92.6 2220 2720 2800 2.9 343 393 1200 16.3 2.7 361.0 58.5 126.0 3020 4120 4280 3.7 236 430 1400 14.7 3.3 358.0 30.0 141.0 3400 4310 4410 3.0 202 656 1600 29.8 3.7 530.0 56.4 208.0 4980 6700 7560 9.2 233 344 1800 25.1 2.0 306.0 52.8 106.0 2550 3670 4190 12.5 169 949 AUC, area under the curve; CLss, steady‐state clearance; Css, steady‐state concentration; DF, coefficient of fluctuation; MRT, mean residence time. For a single dose, the average t1/2 values of 200, 400, 800, 1200, and 1800 mg were 12.0, 11.2, 12.8, 10.9, and 13.9 hours, but the average t1/2 times of 1400 mg and 1600 mg were 22.6 and 33.1 hours, likely caused by poor absorption in two patients (No. 17 and No. 20) in the 1400 mg cohort, and three patients in the 1600 mg cohort, which suggested that these patients probably exhibited enterohepatic circulation and indicated that cipatinib concentrations can be easily accumulated in the body (Table 4). After successive cipatinib applications, t1/2 values also varied between 12.9 and 29.8 hours, but were slightly higher than in the initial single cipatinib application period at day 1 (Table 5). Pharmacokinetics of different dosages of cipatinib treatments For the single dose‐levels of cipatinib at day 1 with 200, 400, 800, 1200, 1400, 1600, and 1800 mg, Cmax was 23.4, 79.5, 85.9, 276, 68.1, 33.5, and 136 ng/mL, respectively. Apparent oral clearance (CL/F) was 954, 1730, 1770, 1140, 2990, 3800, and 3830 L/h respectively, and the apparent volume of distribution (Vc/F) was 14 900, 26 800, 31 100, 16 900, 90 000, 228 000, and 68 100 L. MRT was 12.2, 11.5, 10.5, 11.1, 20.0, 23.6, and 15.9 hours. The CL/F and Vz/F values suggested that cipatinib has a low degree of biological availability (< 10%), as well as an in vivo distribution < 24.8 L/kg (Table 4). After successive daily oral dosages of cipatinib at 200, 400, 800, 1200, 1400, 1600, and 1800 mg, the steady‐state AUC of cipatinib was greater than after a single administration of AUC0‐24 (day 1) after 21 days, a result which indicated that it took time to reach a steady‐state serum concentration and suggested that drug accumulation occurred in the body (Tables 4, 5). Discussion In the present trial, the dose levels were chosen with reference to previous studies of lapatinib.3, 6 The clinical dose with effective anti‐tumor activity was 650 mg/day and the therapeutic dose in combination with capecitabine was 1250 mg/day. The loading (200 mg/day) and peak doses (1800 mg/day) of cipatinib were set up according to preclinical experimental and safety data. In all patients (n = 26) 143 cases of AEs were detected, of which 87 were drug‐related (60.8%). AEs were mostly grade 1 or 2, but two SAEs were recorded at the 400 mg and 1200 mg doses, which were cellulitis without neutrophils and grade 4 elevated TBIL, respectively, but were improved by symptomatic treatment. No DLTs were observed at doses ranging from 200 mg to 1800 mg daily in patients with ErbB2‐overexpressing advanced breast cancer. In phase I studies of lapatinib (EGFl0004),3 67 patients with EGFR or HER2 overexpression were offered this drug at doses ranging from 500 mg to 1600 mg over 20 days. The most frequently reported AEs in 44 patients were diarrhea (42%), rash (31%), nausea (13%), and fatigue (10%). In the present trial, the most frequently observed AEs were neutropenia (38%), fever (19%), myocardial ischemia (19%), hypertriglyceridemia (15%), fatigue (15%), and nausea (12%). Apparently, there is a small distinction between the side effects of lapatinib and cipatinib. The rate of dermal toxicity was higher with lapatinib, whereas hematotoxicity was milder (31% vs. 8%). Additionally, digestive tract reactions were obviously more intense after lapatinib treatment (55% vs. 7.7%). It should be noted that a potential effect on lipid metabolism and the cardiovascular system is predicted to occur during long‐term treatment. However, all toxicities could be ameliorated by symptomatic treatment and did not constitute DLTs. No anaphylaxis was observed during the trial. Detrimental effects were not detected at the injection site or in liver and renal function tests. Although a high concentration was administered to the large dose group of patients, the subjects exhibited good tolerance to the drug and roughly identical incidences of AEs. Briefly, consecutive administrations of cipatinib are a safe and feasible treatment regimen in patients with advanced breast cancer. Phase II studies are being planned to assess the anti‐tumor efficacy of this regimen, and additional preclinical studies are ongoing to develop even more effective approaches to enhance chemo‐delivery into tumor tissues. The clinical effectiveness of anti‐tumor activity will be further investigated in the near future. Disclosure No authors report any conflict of interest. Acknowledgments The patients who participated in this study and their families are gratefully acknowledged. We thank the staff at the study centers, in particular Xu B, Wang J, and Shi X for their diligence in identifying and caring for the patients who participated in the study. ==== Refs References 1 Baselga J , Arteaga CL . Critical update and emerging trends in epidermal growth factor receptor targeting in cancer . (Published erratum appears in J Clin Oncol 2005; 23:6281.) J Clin Oncol 2005 ; 23 :2445 –59 .15753456 2 Levitzki A , Mishani E . Tyrphostins and other tyrosine kinase inhibitors . Annu Rev Biochem 2006 ; 75 : 93 –109 .16756486 3 Burris HA III , Hurwitz HI , Dees EC et al Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas . J Clin Oncol 2005 ; 23 : 5305 –13 .15955900 4 von Minckwitz G , Procter M , de Azambuja E et al. Adjuvant pertuzumab and trastuzumab in early HER2‐positive breast cancer . (Published erratum appears in N Engl J Med 2017; 377:702.) N Engl J Med 2017 ; 377 :122 –31 .28581356 5 Seidman A , Hudis C , Pierri MK et al Cardiac dysfunction in the trastuzumab clinical trials experience . J Clin Oncol 2002 ; 20 : 1215 –21 .11870163 6 Chu QS , Schwartz G , de Bono J et al Phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies . J Clin Oncol 2007 ; 25 : 3753 –8 .17704424 7 Therasse P , Arbuck SG , Eisenhauer EA et al New guidelines to evaluate the response to treatment in solid tumors . J Natl Cancer Inst 2000 ; 92 : 205 –16 .10655437