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Supplementary Table S1. JTJA Study Dose Expansion Cohorts; Supplementary Table S2. Baseline Disease Classifications of SCCHN Patients Supplementary Table S3. Treatment-Emergent Adverse Events Related to Study Treatment in >10% of Patients with Any Tumor Type; Supplementary Table S4. Genetic Alterations in Tumors Corresponding to SCC of the Anus (n=14) and SCCHN (n=34); Supplementary Figure S1. Progression-free Survival by HPV Status in Patients with SCCHN.

Purpose: Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC.Patients and Methods: Patients were given prexasertib 105 mg/m2 as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.Results: Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non–small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9–4.2] for SCC of the anus, 1.6 months (90% CI, 1.4–2.8) for SCCHN, and 3.0 months (90% CI, 1.4–3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.Conclusions: Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m2 was confirmed as the recommended phase II dose. Clin Cancer Res; 24(14); 3263–72. ©2018 AACR.

Purpose: Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC.Patients and Methods: Patients were given prexasertib 105 mg/m2 as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.Results: Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non–small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9–4.2] for SCC of the anus, 1.6 months (90% CI, 1.4–2.8) for SCCHN, and 3.0 months (90% CI, 1.4–3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.Conclusions: Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m2 was confirmed as the recommended phase II dose. Clin Cancer Res; 24(14); 3263–72. ©2018 AACR.

Objective This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer. Methods Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1–10 (q21d) in combination with G (1000 mg/m2, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1–14, q28d. Results 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm. Conclusions Addition of ralimetinib to GC resulted in a modest improvement in PFS.

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.

5537 Background: p38 mitogen-activated protein kinase (MAPK) regulates cytokine production in the tumor microenvironment and enables therapeutic resistance of cancer cells. Ralimetinib (R) is a selective small-molecule inhibitor of p38α and p38β MAPKs. Methods: Main inclusion criteria: ≥18 y; recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal, cancer after first-line treatment. Phase (Ph)1b was to determine the recommended Ph2 dose (RP2D) of R administered 12-hourly (Q12H) on Days 1-10 (21-day cycle [Q21D]) in combination with gemcitabine (G: 1000 mg/m2 on Days 3 and 10) and carboplatin (C: AUC 4 on Day 3) for 6 cycles. In Ph2, patients (pts) were randomized double-blind, 1:1 to RP2D R+GC or placebo (P)+GC, for 6 cycles, followed by R 300 mg Q12H or P on Days 1-14, Q28D until disease progression. The stratified log-rank test compared progression-free survival (PFS; primary endpoint) between treatment groups in Ph2, at a 1-sided α level of 0.2. ClinicalTrials.gov, NCT01663857. Results: 118 pts received ≥1 dose of R or P (safety population); 8 in Ph1b and 110 in Ph2 (R+GC N = 58; P+GC N = 52). The RP2D for R in combination with GC was 200 mg Q12H. The study met its primary objective (median PFS: R+GC 10.3 mo vs P+GC 7.9 mo; HR = 0.773, 2-sided p = 0.246). The secondary objectives of median overall survival (R+GC 29.2 mo vs P+GC 25.1 mo; HR = 0.827, p = 0.469) or overall response rate (R+GC 46.6% vs P+GC 46.2%; p = 0.967) were not statistically significant, and 32.4% vs 25.0% of pts had normalized CA125 at the end of cycle 6. Most pts (safety population) experienced ≥1 Grade 3/4 treatment-emergent adverse event (TEAE: R+GC 63/66 [95.5%]; P+GC 48/52 [92.3%]). Decreased neutrophil count (60.6% vs 76.9%), platelet count (43.9% vs 38.5%), and white blood cell count, (30.3% vs 26.9%), anemia (22.7% vs 25.0%), and increased alanine aminotransferase (ALT) (19.7% vs 3.8%) were the Grade 3/4 TEAEs in ≥10% of pts in the R+GC and P+GC arms, respectively. Conclusions: Addition of ralimetinib to GC resulted in modest improvements in PFS. Grade 3/4 elevated ALT was more common in the ralimetinib arm. Clinical trial information: NCT01663857.

Background: 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, LY2606368 was evaluated as a single agent in expansion cohorts of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods: This was a phase I, multicenter, nonrandomized, open-label study in patients with advanced cancer (NCT01115790). Based on results from the dose-escalation phase, dose-expansion cohorts were comprised of patients with SCC given LY2606368 at the maximum tolerated dose (MTD) of 105 mg/m2 on day 1 of a 14-day schedule. Cohorts were defined by tumor location and by line of treatment. Patients were assessed for safety, tolerability, and preliminary efficacy. Pretreatment biopsies were obtained for pharmacogenomic analysis, including human papillomavirus (HPV) status. Aggregate results from patients with recurrent/metastatic SCCHN are presented. Results: Fifty-seven patients with recurrent/metastatic SCCHN were enrolled in the dose-expansion phase. Over 50% of patients had received ≥2 prior lines of treatment (median of 3 cycles; range: 1 to 5) in the recurrent/metastatic setting. The most frequently reported adverse event (AE) was a transient (typically 10% of patients included thrombocytopenia (44%), anemia (25%), fatigue (23%), and headache (14%). The majority of non-hematologic AEs were grade 1 or 2 (per Common Terminology Criteria) in severity. Three patients (5%) had a partial response and 25 patients (44%) had stable disease for at least 3 cycles. The duration of response ranged from 4.8-7.8+ months, and the median progression-free survival (PFS) was 1.6 months (90% confidence interval: 1.4, 2.8). Biopsy samples were evaluable from 34 patients. The median PFS by HPV status was 4.5 months in 15 patients who were HPV positive, and 1.4 months in 19 patients who were HPV negative (log-rank test, p = .0012). Conclusions: LY2606368 has an acceptable safety profile and demonstrates modest preliminary activity in a subset of patients with recurrent/metastatic SCCHN. The MTD of 105 mg/m2 is confirmed as the recommended dose for phase II testing. Citation Format: Johanna Bendell, Stefan Grant, Filip Janku, Jeffrey Infante, William N. William, Todd M. Bauer, Sarina Piha-Paul, Ricardo Martinez, Sameera Wijayawardana, Ji Lin, Lisa Golden, Aimee Bence Lin, David Hong. Checkpoint kinase (CHK) 1/2 inhibitor LY2606368 in a phase I dose-expansion study in patients with squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT240. doi:10.1158/1538-7445.AM2015-CT240

Methods: A nurse delivered pre-procedure phone call for all scheduled procedures was instituted in October 2013 at a single tertiary care endoscopy center. In addition to standardized bowel prep instructions received in the mail, the nurse would call 2-7 days prior to the procedure to discuss the prep instructions in a scripted manner. The standard preparation used was bisacodyl 15mg and Miralax-Gatorade (238g of PEG-3350 in 64oz of Gatorade) in a non-split dose regimen. We performed a retrospective cohort study using the EndoWorks® database (Olympus America) and EPIC medical record (Epic Systems Corp., Verona, WI). All colonoscopy records from October 2012 to February 2013 (control, n = 1928) and October 2013 to February 2014 (intervention, n = 2088) were queried. Colonoscopy and pathology records were reviewed for patient demographics, indication, reported prep quality on the Aronchick scale, adenoma and sessile adenoma detection, size and location of polyps and incomplete procedures. In-patient (n = 115, 106) and diagnostic/therapeutic procedures (n = 702, 769) were excluded from the final analysis. Results: Patient demographics and procedure indication were similar amongst the control (n =1221) and intervention (n = 1309) groups on the basis of age (59.5 + 10.1 v. 59.8 + 9.8, p = .56), male gender (45.2% v. 48.7%, p = .08) and indication: screening (42.1% v. 41.1%, p = .55) and surveillance (21.5% v. 22%, p = .73). Of the colonoscopies performed for a screening indication, there was no difference among the control (n = 808) and intervention group (n = 854) in the rate of adequate preparation (78% v. 74.4%, p = .08), ADR (30.3% v. 28.9%, p = .53) including detection of right sided adenomas less than 5mm (7.1% v 7.6%, p = .66), sessile serrated adenoma detection rate (3.3% v. 4.5%, p = .24) or incomplete examination (6.2% v. 4.7%, p = .18). If colonoscopy performed for adenoma surveillance is added, there was no difference among the control (n = 1221) and intervention group (n = 1309) in adenoma detection rate (35.3% v. 35.4%, p = .997). Conclusion: A nurse delivered pre-procedure phone call to discuss bowel preparation prior to colonoscopy has no effect on adequacy of bowel preparation, adenoma detection or incomplete examinations.

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