A 70-year-old female patient, from a rural area presented to local paramedics with generalised weakness and a blackish painful umbilical nodule. Her blood pressure was 130/80 mmHg and random blood sugar was 12.5 mmol/l. US of abdomen revealed “anterior abdominal wall sinus/abscess”. So dressing and antibiotics were advised. After 4 months, she visited our hospital, where an inflamed umbilical nodule, 2x3 cm with no ulcer was found (Figure 1).
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.
Vimala Yendluri合作论文数1Mheta Koy合作论文数1
Mabula Daud Mchembe合作论文数1Fabian Massaga合作论文数1Michelle T. Ashworth合作论文数1Sabine Loechner合作论文数1Frances Shanahan合作论文数1Tomoko Freshwater合作论文数1Randi Isaacs合作论文数1Jacques P. Fontaine合作论文数1David Mendelson合作论文数1
Tanvetyanon Tawee合作论文数H. Lee Moffitt Cancer Center & Research Institute1
Eric Toloza合作论文数1Hodul Pamela J合作论文数1
Adil Daud合作论文数Department of Medicine, University of California San Francisco;School of Medicine, University of California San Francisco;Helen Diller Family Comprehensive Cancer Center, University of California San Francisco1Shumway Stuart D合作论文数1
Jonathan Goldman合作论文数Department of Medicine, University of California Los Angeles;Santa Monica Cancer Care, University of California Los Angeles1
Lary Robinson合作论文数 Moffitt Cancer Center1Prabhu Raghunath合作论文数1
H. Nicole Tran合作论文数1Shenoy Rajgopal合作论文数Kasturba Medical College, Manipal University1Grabowsky Jennifer A合作论文数Adil I. Daud, University of California, San Francisco;Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles;Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute;Pinnacle Oncology Hematology, David Mendelson;and;University of California, Los Angeles, University of California, San Francisco1Sorge Christopher合作论文数1David Parry合作论文数1Jonathan R. Strosberg合作论文数1Soonmo Peter Kang合作论文数1
Alan P. Venook合作论文数Department of Medicine, School of Medicine, University of California San Francisco;Helen Diller Family Comprehensive Cancer Center, University of California San Francisco1Lee S. Rosen合作论文数1Phillipo L Chalya合作论文数Department of Surgery, Weill- Bugando University College of Health Sciences1
Natalia Udaltsova合作论文数1
Pamela N. Munster合作论文数University of California San Francisco Health1
