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27.06.2016 | PHASE II STUDIES | Ausgabe 5/2016

Investigational New Drugs 5/2016

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer

Zeitschrift:
Investigational New Drugs > Ausgabe 5/2016
Autoren:
Giorgio Scagliotti, Jin Hyoung Kang, David Smith, Richard Rosenberg, Keunchil Park, Sang-We Kim, Wu-Chou Su, Thomas E. Boyd, Donald A. Richards, Silvia Novello, Scott M. Hynes, Scott P. Myrand, Ji Lin, Emily Nash Smyth, Sameera Wijayawardana, Aimee Bence Lin, Mary Pinder-Schenck
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10637-016-0368-1) contains supplementary material, which is available to authorized users.
Key Message
This open-label, single-arm, phase II trial assessed the overall response rate, safety, and pharmacokinetics of CHK1 inhibitor LY2603618 and pemetrexed in patients with advanced or metastatic non-small cell lung cancer. No significant clinical activity of LY2603618 and pemetrexed combination therapy was observed, with results being comparable with historical pemetrexed single-agent data.

Summary

Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m2, day 1) and LY2603618 (150 mg/m2, day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7–18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0–27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

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10637_2016_368_MOESM1_ESM.docx
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