Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors

Tjulandin, S.; Moiseyenko, Vladimir; Semiglazov, V.V.; Manikhas, George; Learoyd, Maria; Saunders, A.; Stuart, Melissa K.; Keilholz, Ulrich

doi:10.1007/s10637-013-9963-6

Cited by 23 publications

(10 citation statements)

References 26 publications

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“…Additionally, 3 patients in the PK extension study and 12 patients in food-effect study were treated with 1000 mg TID, and no grade ≥ 3 toxicities were found, indicating that 1000 mg TID was well tolerated. There were no unexpected toxicities observed in this study and safety profiles were similar to the agents that target erbB signaling [11-14]. Diarrhea was manageable by appropriate medications and dose interruption or reduction in this study.…”

Section: Discussionmentioning

confidence: 61%

A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors

Zhang

Cao

et al. 2014

J Hematol Oncol

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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 Tmax was prolonged, Cmax was increased, and AUC0-∞ 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.

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Section: Discussionmentioning

confidence: 61%

A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors

Zhang

Cao

et al. 2014

J Hematol Oncol

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“…Both of these AstraZeneca agents demonstrated greatly reduced V D ss and half-lives in the intended manner, and both compounds demonstrated very low in vivo clearance, necessary to ensure good exposure for compounds with shortened half-lives. In a Phase I study in cancer patients, AZD8931 was rapidly absorbed and demonstrated a half-life of approximately 11 h, validating the approach taken within medicinal chemistry to reduce this parameter relative to gefitinib [13]. In 2012, further value of the programme of work associated with the gefitinib project was realised when a team at AstraZeneca's Innovation Centre China (ICC) had the idea of generating a brain-penetrant EGFR inhibitor to treat lung cancer patients that relapse on therapy with brain or leptomeningeal metastases.…”

Section: Anilinoquinazoline Egfr Inhibitors Beyond Gefitinibmentioning

confidence: 78%

Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

Kettle

Wilson

2016

Drug Discovery Today

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“…The four DLTs observed in the escalation phase included the AEs diarrhoea and vomiting, reflecting the most commonly reported AEs across all dose levels. A dose finding study of AZD8931 in patients with advanced solid tumours by Tjulandin et al [26], gave bi-daily single-agent dosing from 40 to 300 mg. Here, diarrhoea was also the most common AE across all doses and contributed to two DLTs in the 300-mg cohort.…”

Section: Discussionmentioning

confidence: 99%

Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma

Thomas

Virdee

Eatock

et al. 2020

European Journal of Cancer

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Background: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 þ chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). M e t h o d s : AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin þ capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 þ Xelox at RP2D or Xelox only for two

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Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors

Abstract: The MTD of AZD8931 determined from the 21-day DLT period was 240 mg bid, although more long-term data are needed to confirm a dose of AZD8931 suitable for chronic treatment.

Cited by 23 publications

References 26 publications

A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors

A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors

Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma

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