Adil I Daud1, Michelle T Ashworth2, Jonathan Strosberg2, Jonathan W Goldman2, David Mendelson2, Gregory Springett2, Alan P Venook2, Sabine Loechner2, Lee S Rosen2, Frances Shanahan2, David Parry2, Stuart Shumway2, Jennifer A Grabowsky2, Tomoko Freshwater2, Christopher Sorge2, Soonmo Peter Kang2, Randi Isaacs2, Pamela N Munster2. 1. Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ. adaud@medicine.ucsf.edu. 2. Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
Abstract
PURPOSE: We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies. PATIENTS AND METHODS: Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine. RESULTS: As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease. CONCLUSION: MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.
PURPOSE: We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies. PATIENTS AND METHODS: Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine. RESULTS: As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease. CONCLUSION:MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.
Authors: Zhaojun Qiu; Pengyan Fa; Tao Liu; Chandra B Prasad; Shanhuai Ma; Zhipeng Hong; Ernest R Chan; Hongbing Wang; Zaibo Li; Kai He; Qi-En Wang; Terence M Williams; Chunhong Yan; Steven T Sizemore; Goutham Narla; Junran Zhang Journal: Cancer Res Date: 2020-06-10 Impact factor: 12.701
Authors: Siang-Boon Koh; Yann Wallez; Charles R Dunlop; Sandra Bernaldo de Quirós Fernández; Tashinga E Bapiro; Frances M Richards; Duncan I Jodrell Journal: Cancer Res Date: 2018-05-07 Impact factor: 12.701
Authors: Leslie A Parsels; Joshua D Parsels; Daria M Tanska; Jonathan Maybaum; Theodore S Lawrence; Meredith A Morgan Journal: Cell Cycle Date: 2018-07-18 Impact factor: 4.534