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Phase I study of QLNC120, a novel EGFR and HER2 kinase inhibitor, in pre-treated patients with HER2-overexpressing advanced breast cancer.

ABSTRACT: This study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and preliminary antitumor activity of QLNC120, an inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), in HER2 overexpressing advanced breast cancer patients. In addition, the prognostic biomarkers of QLNC120 were investigated. QLNC120 was administered as a single dose, followed by 7 days observation, and then once daily consecutively. Scheduled dose escalation was 450mg, 750mg, 1000mg and 1250mg. For pharmacokinetic analysis, blood samples were collected after the single dose and after the first 7 days of continuous administration. Tissue samples were collected for biomarker analysis. Twenty-four heavily treated HER2 overexpressing advanced breast cancer patients were enrolled. No DLT was observed. MTD was not found. QLNC120 and its active metabolite-lapatinib exposure did not increase in a dose-dependent manner ranging from 450 to 1250mg QLNC120. From 450 to 1250mg QLNC120, the exposure of combination of QLNC120 and its active metabolite-lapatinib was equal to or greater than the exposure of 1250mg lapatinib. Common QLNC120-related toxicities included rash, diarrhea, oral mucositis, hematuria and white blood cell decrease. Seven of twenty-two evaluable patients achieved partial response (PR) or stable disease (SD)?24 weeks. In biomarker analysis, nine of fifteen patients (60%) had a mutation in HRAS exon 1. Patients with HRAS mutation achieved longer progression free survival(PFS) (24.9 vs 12.9 weeks, p=0.023, HR=0.291). QLNC120 is well-tolerated and safe with encouraging antitumor activity in HER2 overexpressing advanced breast cancer. HRAS mutation was associated with the anti-tumor activity of QLNC120. (Trial registration: NCT01931943, http://ClinicalTrials.gov/show/NCT01931943).

SUBMITTER: Zhang T

PROVIDER: S-EPMC5482694 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Phase I study of QLNC120, a novel EGFR and HER2 kinase inhibitor, in pre-treated patients with HER2-overexpressing advanced breast cancer.

Zhang Tongtong T Li Qing Q Chen Shanshan S Luo Yang Y Fan Ying Y Xu Binghe B

Oncotarget 20170501 22

This study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and preliminary antitumor activity of QLNC120, an inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), in HER2 overexpressing advanced breast cancer patients. In addition, the prognostic biomarkers of QLNC120 were investigated. QLNC120 was administered as a single dose, followed by 7 days observation, and then once daily consecutivel ...[more]

PMID: 27902470

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Project description:BackgroundAST1306 is an orally active irreversible small molecule inhibitor of EGFR (erbB1), HER2 (erbB2) and HER4 (erbB4) signaling. This is a phase I, open-label, dose-escalation study to evaluate the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor effects of oral AST1306. In addition the effects of food on PK was tested.MethodsA modified Fibonacci 3 plus 3 dose-escalation design was employed to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) in patients with advanced solid tumors. The following dose levels were investigated: once daily (QD) at two dose levels (400-and 800 mg), twice daily (BID) in five dose levels (600-, 800-, 1000-, 1200- and 1500 mg), and three times daily (TID) in three dose levels (800-, 1000- and 1200 mg). In the PK and extension study, at least eight patients per dose cohort in three dose levels (maximum tolerated dose [MTD], one or two doses level lower than the MTD) were enrolled to evaluate the PK profiles.ResultsSeventy-one patients were enrolled, with breast (n?=?22) and lung cancers (n?=?14) being the most common primary cancers. The most frequent drug-related adverse events were grade 1 to 3 diarrhea and rash, grade 1 to 2 fatigue. During dose escalation, the key DLT was grade 3 diarrhea observed in 5 patients at 1000 mg BID (n?=?1), 1500 mg BID (n?=?1), 800 mg TID (n?=?1) and 1200 mg TID (n?=?2). AST1306 was rapidly absorbed and had moderate to high clearance. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Under fed conditions, the mean T(max) was prolonged, C(max) was increased, and AUC(0-?) was raised. Of the 55 evaluable patients, 7 patients experienced partial responses, including 5 with breast cancer, 1 with lung cancer, and 1 with gastric cancer. The best response with stable disease for???6 months was achieved in 7 patients.ConclusionsBased on the DLT and PK profile, the RP2D was defined as 1000 mg TID with evidence of preliminary anti-tumor activity. Further studies are recommended.

Dataset Information

Phase I study of QLNC120, a novel EGFR and HER2 kinase inhibitor, in pre-treated patients with HER2-overexpressing advanced breast cancer.

Publications

Phase I study of QLNC120, a novel EGFR and HER2 kinase inhibitor, in pre-treated patients with HER2-overexpressing advanced breast cancer.

Similar Datasets

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