Preclinical analyses and phase I evaluation of LY2603618 administered in combination with Pemetrexed and cisplatin in patients with advanced cancer

Calvo, Emiliano; Chen, Victor; Marshall, Mark S.; Ohnmacht, U.; Hynes, Scott M.; Kumm, Elizabeth; Diaz, H. Bruce; Barnard, Darlene; Merzoug, Farhana F.; Huber, Lysiane; Kays, Lisa; Iversen, Philip W.; Calles, Antonio; Voss, Beatrice; Lin, Aimee Bence; Dickgreber, N; Wehler, Thomas; Sebastian, Martin

doi:10.1007/s10637-014-0114-5

Cited by 54 publications

(42 citation statements)

References 36 publications

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“…A growing body of literature suggests that CHK1 inhibitors in combination with chemotherapy may enhance clinical outcomes [9,15,16,17,18]. The CHK1 inhibitor MK-8776 was well tolerated in combination with gemcitabine in a phase I study in patients with advanced solid tumors, and early evidence of clinical efficacy was observed [15].…”

Section: Discussionmentioning

confidence: 99%

“…In nonclinical in vitro and in vivo studies, LY2603618 alone has little effect on tumor cells, but enhances the activity of cytotoxic chemotherapy agents, including gemcitabine [8,9,10]. Given the longstanding role of gemcitabine therapy in multiple cancers and the role of CHK1 in repair of DNA damage caused by gemcitabine, the feasibility of combining LY2603618 with gemcitabine was assessed in patients with advanced cancer.…”

Section: Introductionmentioning

confidence: 99%

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Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

et al. 2016

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Objective: LY2603618, a selective inhibitor of checkpoint kinase 1 (CHK1) and key regulator of the DNA damage checkpoint, may enhance the effects of antimetabolites. This phase I study defined the recommended phase II dose of LY2603618 combined with gemcitabine. Patients and Methods: Patients with advanced/metastatic disease were administered doses of LY2603618 (70-250 mg/m² or flat-fixed doses of 200 or 230 mg) after gemcitabine (1,000 mg/m²). Safety and pharmacokinetics (PK) were assessed. Results: Among the 50 patients enrolled, frequent adverse events possibly related to study drug treatment included fatigue (44%), decreased platelets (42%), decreased neutrophils (32%), nausea (26%), and decreased hemoglobin (20%). Systemic exposure of LY2603618 increased dose dependently, while clearance was relatively dose independent. The mean LY2603618 half-life varied; however, the durations were still suitable for maintaining human exposures while minimizing accumulation. LY2603618 PK were not altered by gemcitabine administration. Plasma exposures that correlate with the maximal pharmacodynamic effect in nonclinical models were achieved for all doses. One patient with non-small cell lung cancer carcinoma achieved a partial response; 22 patients had stable disease. Conclusions: The maximum tolerated dose of LY2603618 combined with gemcitabine was 200 mg/m², but a fixed LY2603618 dose of 230 mg combined with gemcitabine was selected as the recommended phase II dose.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

et al. 2016

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“…Lysates were analyzed by immunoblot analysis for protein phosphorylation levels. Group means, SEs and P values were calculated using Kronos (22).…”

Section: In Vivo Biochemistry and Tumor Growth Inhibitionmentioning

confidence: 99%

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

King

Diaz

McNeely

et al. 2015

Molecular Cancer Therapeutics

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CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.

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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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Preclinical analyses and phase I evaluation of LY2603618 administered in combination with Pemetrexed and cisplatin in patients with advanced cancer

Cited by 54 publications

References 36 publications

Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

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

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