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Background: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC). Patients and Methods: This was a parallel-cohort phase II study of 105 mg/m2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m2 days 1-3, 14-day cycle). Results: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ?3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified. Conclusion: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC. © 2021 The Authors Boehringer Ingelheim; Amgen; Bristol-Myers Squibb; Eli Lilly and Company; Pfizer; Astellas Pharma US; AstraZeneca; Merck; Novartis; Roche; AbbVie; University of Michigan; Takeda Pharmaceuticals U.S.A.; Merck Sharp and Dohme; PTC Therapeutics; TG Therapeutics; NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research; Bayer Fund; National Institute for Health Research; European Commission; Daiichi-Sankyo; Oryzon Genomics; Otsuka Pharmaceutical; UCLH Biomedical Research Centre We thank the patients who participated in this trial and the study coordinators, nurses, nurse practitioners, clinical research assistants, and doctors who assisted with the research. The authors also thank Erin Wagner from BioStat Solutions, Inc., for statistical support and Lisa Golden, Rod Decker, and Elizabeth Spoljoric for their input and contributions to the study. MDF is supported by the University College London/University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility supported by the University College London Experimental Cancer Medicine Centre. Eli Lilly and Company contracted with Syneos Health for writing support provided by Andrea D. Humphries, PhD, and editing support provided by Noelle Gasco. L.A. Byers reports receiving research funding and fees as an advisor or consultant from AstraZeneca, GenMab, and Sierra Oncology; research funding from Tolero Pharmaceuticals; and fees as an advisor or consultant from Bristol Myers Squibb, Althia, Merck, Pfizer, PharmaMar, AbbVie, Jazz Pharmaceuticals, Genentech, and Debiopharm Group. A. Navarro reports receiving fees as an advisor or consultant from Pfizer and Boehringer Ingelheim; fees from Roche and AstraZeneca speakers’ bureaus; fees for expert testimony from Oryzon Genomics and MedSIR; and fees or reimbursement for travel, accommodations, or other expenses from Roche, Pfizer, and Boehringer Ingelheim. M. Johnson reports grant funding to her institution from Eli Lilly and Company, Abbvie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Onclogy, Novartis, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Regeneron Pharmaceuticals, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, TMUNITY Therapeutics, University of Michigan, and WindMIL; receiving fees for consulting services from Eli Lilly and Company, Abbvie, Amgen, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Daiichi Sankyo, EMD Serono, Genentech/Roche, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, WindMIL, Achilles Therapeutics, Bristol Myers Squibb, Eisai, G1 Therapeutics, and Association of Community Cancer Centers; and receiving fees for consulting services performed by her spouse from Astellas and Otsuka Pharmaceuticals. K.H. Dragnev reports funding to the institution for the conduct of the trial from Eli Lilly and Company and support to the institution for conduct of company-sponsored trials from Merck, Roche/Genentech, G1 Therapeutics, Io Therapeutics, and Novartis. S. McNeely reports receiving personal fees and non-financial support from Eli Lilly and Company. A.B. Lin and spouse are both employees and shareholders of Eli Lilly and Company. M. Forster reports receiving educational grants from Merck Sharp & Dohme for the EACH study and the POPPY study, from Boehringer Ingelheim for the DARWIN1 study, and from AstraZeneca for the ORCA2 study, as well as fees for advisory and consultancy work from Achilles, AstraZeneca, Bristol Myers Squibb, Merck, Nanobiotix, Novartis, Pfizer, Pharmamar, Roche, Takeda, Bayer, and Guardant Advisory. The remaining authors have stated that they have no conflicts of interest.

The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [14C]prexasertib (50 µCi) to 6 patients with adv...

Purpose The primary objective was to determine the recommended Phase 2 dose (RP2D) of checkpoint kinase 1 inhibitor, prexasertib, in combination with the p38 mitogen-activated protein kinase inhibitor, ralimetinib, which may be safely administered to patients with advanced cancer. Methods This Phase 1, nonrandomized, open-label, dose-escalation study of prexasertib+ralimetinib included patients with advanced and/or metastatic cancer, followed by a planned cohort expansion in patients with colorectal or non-small-cell lung cancer with KRAS and/or BRAF mutations. Intravenous prexasertib was administered at 60 mg/m2 (days 1 and 15 of a 28-day cycle), together with oral ralimetinib every 12 h (days 1 to 14 at 100 mg [Cohort 1, n = 3] or 200 mg [Cohort 2, n = 6]). Dose escalations for each agent were planned using a model-based 3 + 3 escalation paradigm. Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0X. Tumor response was determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results Nine patients were treated; 3 experienced dose-limiting toxicities, all in Cohort 2, prohibiting further dose escalation. The most common ≥Grade 3 adverse event was neutrophil count decreased; other reported ≥Grade 3 hematological toxicities included febrile neutropenia and anemia. The pharmacokinetics of prexasertib+ralimetinib was comparable to the monotherapy population profile for each agent. One patient achieved a best overall response of stable disease (for 2 cycles); there were no complete/partial responses. Conclusions This study did not achieve its primary objective of establishing an RP2D of combination prexasertib + ralimetinib that could be safely administered to patients with advanced cancer.

The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer. Patients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model. Dose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1. Although this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy.

This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY+Pem+Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized (2:1) to LY+Pem+Cis or pemetrexed and cisplatin (Pem+Cis). Induction therapy comprised four 21-day cycles of 500 mg/m2 pemetrexed and 75mg/m2 cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m2 pemetrexed on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm) until disease progression. The primary endpoint was progression-free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY+Pem+Cis arm. Sixty-two patients were enrolled (LY+Pem+Cis, n=39; Pem+Cis, n=23). Bayesian and frequentist analysis demonstrated superior PFS in the LY+Pem+Cis arm vs the Pem+Cis arm (median [90% confidence interval]: LY+Pem+Cis, 4.7 months [4.-7.1]; Pem+Cis, 1.5 months [1.3-2.9]; P=0.022). Seven patients in the LY+Pem+Cis arm (vs 0 in the Pem+Cis arm) experienced serious thromboembolic events: pulmonary embolism (n=5), ischemic stroke (n=1), and cerebrovascular accident (n=1). Although the primary endpoint was met, the combination of LY2603618+Pem+Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials.gov Identifier: NCT01139775.

The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [

Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m2 (schedule 1) and 105 mg/m2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.

Purpose The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer. Methods Patients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model. Results Dose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1. Conclusions Although this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy. Electronic supplementary material The online version of this article (10.1007/s00280-018-3623-7) contains supplementary material, which is available to authorized users.

LY2603618 is a selective inhibitor of deoxyribonucleic acid damage checkpoint kinase 1 (CHK1) and has been in development for the enhancement of chemotherapeutic agents. The study described was to assess the potential interaction between LY2603618 and cytochrome P450 isoform 2D6 (CYP2D6) substrate desipramine in patients with cancer. Before clinical investigation, in silico simulations (using Simcyp®) were conducted. An open-label, two-period, fixed-sequence study was planned in 30 patients with advanced or metastatic cancers, in which a 50 mg oral dose of desipramine was administered alone and in combination with 275 mg of LY2603618 (i.v. infusion). An interim analysis was planned after 15 patients completed both periods. Ratios of geometric least squares means (LSMs) of primary pharmacokinetic (PK) parameters and 90% repeated confidence intervals (RCIs) between desipramine plus LY2603618 and desipramine alone were calculated. Lack of an interaction was declared if the 90% RCI fell between 0.8 and 1.25. The LSM ratios (90% RCI) for areas under the plasma concentration–time curve from time zero to tlast (AUC[0-tlast]) and to infinity (AUC[0-∞]) and maximum plasma concentration (Cmax) were 1.14 (1.04, 1.25), 1.09 (0.99, 1.21) and 1.16 (1.05, 1.29). In silico simulations were predictive of clinical results. Single doses of 275 mg LY2603618 administered with 50 mg desipramine were generally well tolerated. In conclusion, no clinically significant interaction was observed between LY2603618 and desipramine in patients with cancer. In silico predictions of clinical results demonstrated that mechanistic and physiologically based PK approaches may inform clinical study design in cancer patients. Copyright © 2014 John Wiley & Sons, Ltd.

3091 Background: Prexasertib inhibits CHK1, a kinase involved in DNA repair and replication. LY3023414 inhibits PI3K/mTOR signaling, implicated in the development of malignant disease. Prexasertib + LY3023414 has resulted in enhanced antitumor activity in triple negative breast cancer (TNBC) in vitro models. Methods: This Phase 1b study in patients (pts) with solid tumors assessed escalating doses of prexasertib (60-105 mg/m2 IV every 14 days [q14d]) and LY3023414 (100-200 mg orally twice daily [BID]). Dose escalation ceased once the maximum tolerated dose of each monotherapy was reached. An initial expansion cohort (Arm E) explored prexasertib 105 mg/m2 q14d + LY3023414 200 mg BID. Subsequent expansion cohorts evaluated prexasertib 105 mg/m2 q14d + LY3023414 150 mg BID in pts with solid tumors with PIK3CA mutations (Arm E2) or TNBC (Arm E3). Results: Fifty pts were enrolled (escalation: n = 13; Arm E: n = 9; Arm E2: n = 15; Arm E3: n = 13). No dose-limiting toxicities (DLTs) were observed during escalation however DLT-equivalent toxicities were observed in 2 pts in Arm E (anemia, neutropenia, thrombocytopenia, oral mucositis, abdominal pain, fatigue). Due to toxicity, a reduced dose of LY3023414 (150 mg BID) was assessed in Arm E2/E3. In the 28 patients treated in Arms E2/E3, common treatment-related adverse events (any grade; grade ≥3) were: leukopenia/neutropenia (82%; 79%), thrombocytopenia (46%; 36%), nausea (46%; 0%), stomatitis (39%, 4%), vomiting (36%; 0%), and anemia (29%; 18%). Febrile neutropenia was reported in 25% of pts. Dose reductions in Arm E2/E3 were common. In escalation, 2 pts achieved a partial response (PR) and 3 pts achieved stable disease (SD). In Arm E, 78% of pts achieved SD. Of the pts evaluable at the time of data transfer, PRs were achieved in 1 pt with an unknown primary (Arm E2) and 2 pts with TNBC (Arm E3). Each agent’s pharmacokinetic profile was consistent with prior monotherapy data. Conclusions: Prexasertib + LY3023414 showed preliminary efficacy in heavily pretreated pts with solid tumors but was associated with toxicity, suggesting supportive care may be required. Clinical trial information: NCT02124148.

The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer. Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m2 gemcitabine combined or 1000 mg/m2 gemcitabine alone. OS was assessed using both a Bayesian augment control model and traditional frequentist analysis for inference. Progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics (PK), and safety (Common Terminology Criteria for Adverse Events [AEs] v 3.0) were also evaluated. Ninety-nine patients (n = 65, LY2603618/gemcitabine; n = 34, gemcitabine) were randomized (intent-to-treat population). The median OS (months) was 7.8 (range, 0.3–18.9) with LY2603618/gemcitabine and 8.3 (range, 0.8-19.1+) with gemcitabine. Similarly, in a Bayesian analysis, the study was not positive since the posterior probability that LY2603618/gemcitabine was superior to gemcitabine in improving OS was 0.3, which did not exceed the prespecified threshold of 0.8. No significant improvements in PFS, ORR, or duration of response were observed. Drug-related treatment-emergent AEs in both arms included nausea, thrombocytopenia, fatigue, and neutropenia. The severity of AEs with LY2603618/gemcitabine was comparable to gemcitabine. The LY2603618 exposure targets (AUC(0-∞) ≥21,000 ng∙hr/mL and Cmax ≥2000 ng/mL) predicted for maximum pharmacodynamic response were achieved after 230 mg of LY2603618. LY2603618/gemcitabine was not superior to gemcitabine for the treatment of patients with pancreatic cancer. NCT00839332 . Clinicaltrials.gov. Date of registration: 6 February 2009

This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/m2/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/m2/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle.

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.

Purpose This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. Experimental design This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40–195 mg/m2) were combined with 500 mg/m2 of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. Results A total of 31 patients were enrolled into six cohorts (three at 40 mg/m2 over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m2, 70 mg/m2, and 195 mg/m2; 13 at 105 mg/m2; six at 150 mg/m2). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m2); reversible infusion-related reaction (150 mg/m2); thrombocytopenia (195 mg/m2); and fatigue (195 mg/m2). The maximum tolerated dose was defined as 150 mg/m2. The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m2. Conclusion LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

2579Background: CHK1 is a key kinase for DNA replication and repair. Prexasertib, a CHK1 inhibitor, enhanced the nonclinical activity of cisplatin and is predicted to potentiate the clinical activi...

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.

The disposition and metabolism of a Chk-1 inhibitor (LY2603618) was characterized following a 1-h intravenous administration of a single 250-mg dose of [14C]LY2603618 (50 µCi) to patients with advanced or metastatic solid tumors. LY2603618 was well tolerated with no clinically significant adverse events. Study was limited to three patients due to challenges of conducting ADME studies in patients with advanced cancer. Plasma, urine and feces were analyzed for radioactivity, LY2603618 and metabolites. LY2603618 had a half-life of 10.5 h and was the most abundant entity in plasma, accounting for approximately 69% of total plasma radioactivity. The second most abundant metabolites, H2 and H5, accounted for10% of total circulating radioactivity. The major route of clearance was via CYP450 metabolism. The mean total recovery of radioactivity was 83%, with approximately 72% of the radioactivity recovered in the feces and approximately 11% in the urine. LY2603618 represented approximately 6% and 3% of the administered dose in feces and urine, respectively. A total of 12 metabolites were identified. In vitro phenotyping indicated that CYP3A4 was predominantly responsible for the metabolic clearance of LY2603618. Additionally, aldehyde oxidase was involved in the formation of a unique human and non-human primate metabolite, H5.

LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) and escalating doses of LY2603618: 130-275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses ≥240 mg. The pharmacokinetics of LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.

LY2603618 is a selective inhibitor of deoxyribonucleic acid damage checkpoint kinase 1 (CHK1) and has been in development for the enhancement of chemotherapeutic agents. The study described was to assess the potential interaction between LY2603618 and cytochrome P450 isoform 2D6 (CYP2D6) substrate desipramine in patients with cancer. Before clinical investigation, in silico simulations (using Simcyp®) were conducted. An open-label, two-period, fixed-sequence study was planned in 30 patients with advanced or metastatic cancers, in which a 50 mg oral dose of desipramine was administered alone and in combination with 275 mg of LY2603618 (i.v. infusion). An interim analysis was planned after 15 patients completed both periods. Ratios of geometric least squares means (LSMs) of primary pharmacokinetic (PK) parameters and 90% repeated confidence intervals (RCIs) between desipramine plus LY2603618 and desipramine alone were calculated. Lack of an interaction was declared if the 90% RCI fell between 0.8 and 1.25. The LSM ratios (90% RCI) for areas under the plasma concentration-time curve from time zero to tlast (AUC[0-tlast]) and to infinity (AUC[0-∞]) and maximum plasma concentration (Cmax) were 1.14 (1.04, 1.25), 1.09 (0.99, 1.21) and 1.16 (1.05, 1.29). In silico simulations were predictive of clinical results. Single doses of 275 mg LY2603618 administered with 50 mg desipramine were generally well tolerated. In conclusion, no clinically significant interaction was observed between LY2603618 and desipramine in patients with cancer. In silico predictions of clinical results demonstrated that mechanistic and physiologically based PK approaches may inform clinical study design in cancer patients.

To develop a population pharmacokinetic model to quantitate the distribution kinetics of glycylsarcosine (GlySar), a substrate of peptide transporter 2 (PEPT2), in blood, CSF and kidney in wild-type and PEPT2 knockout mice.A stepwise compartment modeling approach was performed to describe the concentration profiles of GlySar in blood, CSF, and kidney simultaneously using nonlinear mixed effects modeling (NONMEM). The final model was selected based on the likelihood ratio test and graphical goodness-of-fit.The profiles of GlySar in blood, CSF, and kidney were best described by a four-compartment model. The estimated systemic elimination clearance, volume of distribution in the central and peripheral compartments were 0.236 vs 0.449 ml/min, 3.79 vs 4.75 ml, and 5.75 vs 9.18 ml for wild-type versus knockout mice. Total CSF efflux clearance was 4.3 fold higher for wild-type compared to knockout mice. NONMEM parameter estimates indicated that 77% of CSF efflux clearance was mediated by PEPT2 and the remaining 23% was mediated by the diffusional and bulk clearances.Due to the availability of PEPT2 knockout mice, we were able to quantitatively determine the significance of PEPT2 in the efflux kinetics of GlySar at the blood-cerebrospinal fluid barrier.

Background: LY2606368 mesylate hydrate (LY2606368) is a Chk1/2 inhibitor. In addition to its role in DNA damage response, Chk1 also phosphorylates multiple downstream targets that regulate DNA replication, chromosome alignment, spindle checkpoints, and exit from cytokinesis. Since potent inhibition of Chk1 is predicted to generate DNA damage and mitotic catastrophe, this study evaluated LY2606368 as a single agent. Methods: Two schedules of LY2606368 were assessed in this dose escalation study: dosing on days 1-3 every 14 days (Schedule [Sch] 1) and dosing on day 1 every 14 days (Sch 2). Patients were assessed for safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD), and dose-limiting toxicities (DLT). Results: A total of 45 patients were enrolled, 27 of which were treated on Sch 1 at doses of 10-50 mg/m2 while 18 patients were treated on Sch 2 at doses of 40-130 mg/m2. The most frequently reported AE, regardless of schedule, was a transient (typically < 5 days) decrease in neutrophil count, which occurred in 93% of patients (Grade 4 in 73% of patients). A total of 3 patients (6.7%) experienced febrile neutropenia. Other common toxicities, regardless of causality, included white blood cell decrease (84%), anemia (73%), fatigue (56%), platelet count decreased (53%), nausea (36%), constipation (29%), anorexia (27%), vomiting (27%), dyspnea (20%), and fever (20%). The majority of the non-hematologic toxicities were CTCAE Grade 1/2 in severity. Hematologic toxicity was the dose limiting toxicity on both schedules. The MTD for Sch 1 was 40 mg/m2 and for Sch 2 was 105 mg/m2. The systemic exposure of LY2606368 increased in a dose-dependent manner across the dose range of 10-130 mg/m2 for both schedules. The LY2606368 half-life is suitable for achieving acceptable exposure while minimizing intra- and intercycle accumulation for either schedule. The exposure at MTD for both schedules is in the range that correlates to the minimal tumor response in nonclinical xenograft models. The nonclinical PK/PD model predicts an average pChk1% inhibition of ∼50% and ∼70% for 72 hours is required for minimum and maximum tumor responses, respectively. Simulations of human PK/PD profiles predict that the exposure and average pChk1% inhibition at the MTD of each schedule achieve the requirements for the minimum tumor response. One patient with SCC of the anus achieved a PR (60% reduction). Ten of the 45 patients (22%) achieved SD including 4/7 (57%) HNSCC patients (range on treatment: 3-7.5mo) that had received multiple prior therapies. Conclusions: Based on the nonclinical PK/PD model, clinical human PK, human PD simulations, the similar safety profile, and the increased patient convenience, a dose of 105 mg/m2 of LY2606368, administered once every 14 days was selected as the schedule to further evaluate in Part B of the study, a dose expansion component which will focus on patients with squamous histology tumors. Citation Format: Johanna C. Bendell, Filip Janku, Jeffrey Infante, Suzanne Jones, Howard Burris, Lisa Golden, Scott M. Hynes, Ji Lin, Aimee K. Bence, Susan Tse, Razelle Kurzrock, David Hong. Dose and schedule determination of the Chk1/2 inhibitor LY2606368 in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-200. doi:10.1158/1538-7445.AM2013-LB-200

Background: LY2603618 is a selective inhibitor of Chk1, a protein kinase that plays a key role in the DNA damage checkpoint. Inhibition of Chk1 is predicted to enhance the effects of antimetabolites, such as gemcitabine. Methods: This study is a Phase 1–2 study in patients with solid tumors (Phase 1) and advanced pancreatic adenocarcinoma (Phase 2). In Phase 1, gemcitabine (1000 mg/m2) was administered on Days 1, 8, and 15 of a 28-day cycle. LY2603618 was administered on Days 2, 9, and 16. Patients were assessed for safety, tolerability, and dose-limiting toxicity (DLT). A recommended Phase 2 dose (RP2D) was determined based on safety, dose intensity, and pharmacokinetics (PK). Results: A total of 50 patients were enrolled. Patients were treated at 70 (n =3), 105 (n=3), 150 (n=7), 200 (n=11), 250 (n=6) mg/m2and at 2 additional flat-fixed dose cohorts of 200 (n=10) and 230 (n=10) mg. The most frequent AEs reported included fatigue, thrombocytopenia, anemia, nausea, neutropenia, and constipation, which are consistent with those reported with gemcitabine monotherapy. During escalation, DLTs included neutropenia, infusion-related reaction and thrombocytopenia, with thrombocytopenia being dose limiting. The maximum tolerated dose (MTD) was determined to be 200 mg/m2. The systemic exposure of LY2603618 increased in a dose-dependent manner and the LY2603618 systemic clearance was dose-independent across all doses on average. The mean LY2603618 half-life varied across doses but was consistent with a half-life (i.e., >10 hr and 21,000 ng hr/mL and Cmax > 2000 ng/mL) were achieved by all but one patient. Based on safety/tolerability, the ability to maintain dose intensity, and PK, a RP2D of 230 mg was selected. A total of 17 of 30 patients received more than 2 cycles of therapy. Conclusions: LY2603618 administered in combination with gemcitabine demonstrated an acceptable safety profile; the MTD for this regimen was defined at 200 mg/m2 in the originally designed study. However at a fixed dose of 230 mg, LY2603618 in combination with gemcitabine had an acceptable safety profile and the observed exposures exceed those required for biological effect in nonclinical models. This dose is being evaluated in the Phase 2 component of the study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A94.

Background: LY2523355 is a potent allosteric inhibitor of the motor protein Eg5 which selectively inhibits bipolar mitotic spindle formation. The objective of this Phase 1 study was to determine a Phase 2 dose and schedule of LY2523355 that may be safely administered to patients with advanced malignancy. Methods: Study I1Y-MC-JFBA is an open-label, multicenter, dose-escalation study in patients with advanced malignancy. A modified 3+3 dose-escalation scheme was used, followed by a dose confirmation phase with pre- and post-treatment tumor biopsies. Patients received LY2523355 as a 1hr infusion on days 1, 2 and 3 of a 21-day cycle with determination of the MTD with and without pegfilgrastim administration on day 4. Patients were assessed every other cycle by RECIST. Treatment related PD changes in phosphohistone H3 (pHH3) and Eg5 expression were assessed in skin and tumor biopsies by immunohistochemistry. Results: 46 patients were enrolled in the study as of October 2010. The most frequent related AEs reported (>10%) include leukopenia, neutropenia, fatigue, nausea, stomatitis, vomiting, alopecia, anemia, diarrhea, lymphopenia, pruritis/itching and rash. Dose-limiting toxicities include increased INR, leukopenia, diarrhea, rash (palmar plantar erythrodysesthesia), febrile neutropenia, and mucositis. The single and multiple dose pharmacokinetics of LY2523355 and metabolite were characterized. Dose dependent increase in LY2523355 plasma exposure and a minor degree of intra- and inter-cycle accumulation were observed. An exposure-dependent increase in pHH3 and Eg5 expression and increase in apoptotic cells in tumor and skin biopsies has been demonstrated. One patient with ovarian cancer had a confirmed partial response. Nine other patients had stable disease for at least 2 cycles. Conclusions: The MTD of LY2523355 for this schedule has been established with and without pegfilgrastim at 6mg/m2/d and 4 mg/m2/d, respectively. These doses have shown a quantifiable PD response in skin and tumor biopsies confirming the importance of maximizing exposure intensity for maximum PD response. Dose confirmation is on-going. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A86.

2600 Background: LY2523355 is an allosteric inhibitor of Eg5 which selectively inhibits bipolar mitotic spindle formation. The objective of this Phase 1 study is to determine the Phase 2 dose and s...