In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT154-CT154
Kurzfassung:
Background: ErbB receptor tyrosine kinases: EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4) are part of a complex network activating signaling pathways involved in cell growth and survival. Mutations causing errant ErbB activation is an oncodriver in many cancers. Inhibitors targeting ErbB mutations have transformed patient outcomes; however, treatment resistance develops rapidly and crosstalk between ErbB family members is associated with acquired resistance. The development of next-generation agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor with superior CNS penetration targeting ErbB1, ErbB2 and ErbB4. Preclinical data suggests a favorable pharmacokinetic and toxicity profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Methods: This study examines the safety and tolerability of EO1001 to define a recommended dose for advanced human clinical trials and to assess efficacy. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS disease involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (%gt=G2) is observed in the first dosing cycle, after which the dose escalation scheme will revert to a 3+3 design in a modified-Fibonacci dose-escalation scheme to determine the maximum tolerated dose (MTD). Dose Escalation: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2-6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD Expansion: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). Toxicity will be assessed based on NCI CCTCAEv5 and tumor response will be assessed by RECIST 1.1 or RANO for CNS disease. CNS exposure will be evaluated in patients via CSF collection with confirmed CNS disease involvement. Citation Format: Jeffrey A. Bacha, Dennis Brown, Sarath Kanekal, Ian Nisbet, Neil Sankar, Wang Shen, Helen Wheeler, Kathy Skoff, Zhen Zhong Wang. An ascending single and multiple dose study of the safety, tolerability, pharmacokinetics and antitumor activity of once-daily oral treatment with EO1001, a novel irreversible pan-ErbB inhibitor with promising brain penetration, in patients with advanced cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT154.
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-CT154
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2020
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
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