New trial scheduled to launch, LY2606368.........
clinicaltrials.gov
Results of phase I, a second Lilly inhibitor.......
Anticancer Drugs. 2015 Aug 18. [Epub ahead of print]
Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors.
Doi T1, Yoshino T, Shitara K, Matsubara N, Fuse N, Naito Y, Uenaka K, Nakamura T, Hynes SM, Lin AB.
Author information
1aDepartment of Gastrointestinal Oncology bDepartment of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan cEli Lilly Japan K.K., Kobe, Japan dEli Lilly and Company, Indianapolis, Indiana, USA.
Abstract
This phase I trial evaluated LY2603618, a selective inhibitor of the DNA damage checkpoint kinase 1, in combination with gemcitabine. Japanese patients with advanced solid tumors were enrolled. All patients received gemcitabine (1000?mg/m on days 1, 8, and 15 every 28 days) and either 170?mg (cohort 1) or 230?mg (cohort 2) of LY2603618. The primary objective was assessment of safety/tolerability. Pharmacokinetic/pharmacodynamic marker profiles were secondary objectives. Of the 17 patients enrolled, dose-limiting toxicities were observed in one patient in cohort 1 (n=7) and in two patients in cohort 2 (n=10). The most common grade 3 or more drug-related treatment-emergent adverse events were hematological. Three patients discontinued because of adverse events. Dose-dependent decreases in LY2603618 exposure were observed, but the LY2603618 pharmacokinetics at each dose were consistent within and between cycles and did not influence gemcitabine pharmacokinetics. Circulating plasma DNA decreased from baseline in all four patients who achieved a partial response. Administration of 170 or 230?mg of LY2603618 following a standard dose of gemcitabine showed acceptable safety and tolerability in Japanese patients with solid tumors.
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A list of all LY2606368 trials listed at ct.gov.........
clinicaltrials.gov
And there is also this recent publication from Lilly.......
Mol Cancer Ther. 2015 Jul 3. pii: molcanther.1037.2014. [Epub ahead of print]
LY2606368 causes replication catastrophe and anti-tumor effects through CHK1-dependent mechanisms.
King C1, Diaz HB1, McNeely S1, Barnard D2, Dempsey J1, Blosser W1, Beckmann R1, Barda D3, Marshall MS4.
Author information
1Oncology Discovery Research, Lilly Research Laboratories.2Oncology Discovery Research, Eli Lilly and Company.3Chemistry Discovery Research, Lilly Research Laboratories.4Oncology Discovery Research, Lilly Research Laboratories mmarshall@lilly.com.
Abstract
CHK1 is a multi-functional 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 supports 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. |
