TY - JOUR
T1 - Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors
AU - Daud, Adil I.
AU - Ashworth, Michelle T.
AU - Strosberg, Jonathan
AU - Goldman, Jonathan W.
AU - Mendelson, David
AU - Springett, Gregory
AU - Venook, Alan P.
AU - Loechner, Sabine
AU - Rosen, Lee S.
AU - Shanahan, Frances
AU - Parry, David
AU - Shumway, Stuart
AU - Grabowsky, Jennifer A.
AU - Freshwater, Tomoko
AU - Sorge, Christopher
AU - Kang, Soonmo Peter
AU - Isaacs, Randi
AU - Munster, Pamela N.
N1 - Publisher Copyright:
© 2015 by American Society of Clinical Oncology.
PY - 2015/3/20
Y1 - 2015/3/20
N2 - 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 from10 to 150 mg/m2 as monotherapy and then in combination with gemcitabine 800 mg/m2 (part A, n = 26)or gemcitabine 1,000 mg/m2 (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/m2 on days 1 and 8 of a 21-day cycle.
AB - 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 from10 to 150 mg/m2 as monotherapy and then in combination with gemcitabine 800 mg/m2 (part A, n = 26)or gemcitabine 1,000 mg/m2 (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/m2 on days 1 and 8 of a 21-day cycle.
UR - http://www.scopus.com/inward/record.url?scp=84927531186&partnerID=8YFLogxK
U2 - 10.1200/JCO.2014.57.5027
DO - 10.1200/JCO.2014.57.5027
M3 - Article
C2 - 25605849
AN - SCOPUS:84927531186
SN - 0732-183X
VL - 33
SP - 1060
EP - 1066
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 9
ER -