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

Scagliotti, Giorgio Vittorio; Kang, Jin Hyoung; Smith, David C.; Rosenberg, Richard K.; Park, Keunchil; Kim, Sang We; Su, Wu Chou; Boyd, Thomas E.; Richards, Donald A.; Novello, Silvia; Hynes, Scott M.; Myrand, Scott P.; Lin, Ji; Smyth, Emily Nash; Wijayawardana, Sameera R.; Lin, Aimee Bence; Pinder-Schenck, Mary

doi:10.1007/s10637-016-0368-1

Cited by 58 publications

(43 citation statements)

References 29 publications

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“…LY2603618 is a selective inhibitor of CHK1 which has been investigated in two phase 1 trials in combination with gemcitabine [145,146] and subsequently entered phase 2 trials. This phase 2 trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) [147]. Expression of p53, as measured by immunohistochemistry and genomic variant analysis, was assessed as a predictive biomarker of response.…”

Section: Atr and Chk1 Inhibitors In Clinical Trialsmentioning

confidence: 99%

Targeting the ATR-CHK1 Axis in Cancer Therapy

Rundle

Bradbury

Drew

et al. 2017

Cancers

172

151

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Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. The recent development of specific inhibitors and preclinical data using these inhibitors not only as chemosensitisers and radiosensitisers but also as single agents to exploit specific pathologies of tumour cells is described. These potent and specific inhibitors have now entered clinical trial and early results are presented.

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Section: Atr and Chk1 Inhibitors In Clinical Trialsmentioning

confidence: 99%

Targeting the ATR-CHK1 Axis in Cancer Therapy

Rundle

Bradbury

Drew

et al. 2017

Cancers

172

151

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“…As a result of these data, clinical trials with early CHK1 inhibitors focused on the chemopotentiation of cytotoxic drugs. Although phase I trials demonstrated proof of concept that CHK1 inhibitors could be safely combined with chemotherapy (17)(18)(19)(20)(21)(22)(23)(24)(25), phase II studies failed to meet their primary endpoints (26,27). Early CHK1 inhibitors were not successful for a variety of reasons, including pharmacokinetic properties, unacceptable toxicities, and business considerations.…”

Section: Strategies For Clinical Development: Past and Presentmentioning

confidence: 99%

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Lin

McNeely

Beckmann

2017

Clinical Cancer Research

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All cancers are characterized by defects in the systems that ensure strict control of the cell cycle in normal tissues. The consequent excess tissue growth can be countered by drugs that halt cell division, and, indeed, the majority of chemotherapeutics developed during the last century work by disrupting processes essential for the cell cycle, particularly DNA synthesis, DNA replication, and chromatid segregation. In certain contexts, the efficacy of these classes of drugs can be impressive, but because they indiscriminately block the cell cycle of all actively dividing cells, their side effects severely constrain the dose and duration with which they can be administered, allowing both normal and malignant cells to escape complete growth arrest. Recent progress in understanding how cancers lose control of the cell cycle, coupled with comprehensive genomic profiling of human tumor biopsies, has shown that many cancers have mutations affecting various regulators and checkpoints that impinge on the core cell-cycle machinery. These defects introduce unique vulnerabilities that can be exploited by a next generation of drugs that promise improved therapeutic windows in patients whose tumors bear particular genomic aberrations, permitting increased dose intensity and efficacy. These developments, coupled with the success of new drugs targeting cell-cycle regulators, have led to a resurgence of interest in cellcycle inhibitors. This review in particular focuses on the newer strategies that may facilitate better therapeutic targeting of drugs that inhibit the various components that safeguard the fidelity of the fundamental processes of DNA replication and repair. Clin Cancer Res; 23(13); 3232-40. Ó2017 AACR.

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“…In addition, CHK1 can stabilize replication forks and promote DNA repair, control initiation of DNA replication, and coordinate mitosis . Inhibitors of CHK1 have been developed as combination therapy to augment the efficacy of DNA‐damaging chemotherapeutics . Given the central role that CHK1 has in DNA replication and regulation of the cell cycle, inhibitors of CHK1 are also being developed as single‐agent therapies.…”

Section: Introductionmentioning

confidence: 99%

Dose‐finding study of the checkpoint kinase 1 inhibitor, prexasertib, in Japanese patients with advanced solid tumors

et al. 2018

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Prexasertib is a novel inhibitor of checkpoint kinase 1. The primary objective of this study was to evaluate prexasertib tolerability in Japanese patients with advanced solid tumors. This nonrandomized single‐arm open‐label phase 1 study of prexasertib consisted of 2 dose levels, 80 mg/m2 and the global‐recommended dose based on a US study of 105 mg/m2, administered intravenously once every 14 days (n = 6 for each dose). Transition to the higher dose proceeded if the frequency of dose‐limiting toxicity observed in cycle 1 was <33% at the lower dose. Safety measures, pharmacokinetics and antitumor activity were assessed. A total of 12 patients were treated. Two patients, one in each dose group, experienced dose‐limiting toxicities of febrile neutropenia, one grade 4 and the other grade 3; both patients recovered and continued the study treatment. The grade 4 treatment‐emergent adverse events related to study treatment were neutropenia (6 patients [50.0%]), leukopenia (4 patients [33.3%]), and 1 instance each (8.3%) of anemia, febrile neutropenia and thrombocytopenia. Neutropenia was generally transient and reversible; 11 patients (91.7%) required granulocyte colony‐stimulating factor treatment during the study. There were no discontinuations due to adverse events or deaths. The prexasertib pharmacokinetics displayed dose‐independent and time‐independent behavior across both dose levels, similar to the profile observed in the US‐based phase 1 study. Eight patients had a best overall response of stable disease. These data are consistent with the known safety profile for prexasertib and confirm its tolerability in Japanese patients with advanced solid tumors.

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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

Cited by 58 publications

References 29 publications

Targeting the ATR-CHK1 Axis in Cancer Therapy

Targeting the ATR-CHK1 Axis in Cancer Therapy

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Dose‐finding study of the checkpoint kinase 1 inhibitor, prexasertib, in Japanese patients with advanced solid tumors

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