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Pharmacokinetic results at Day 29, by cohort (median [range])

LYC-55716 toxicology thermometer plot indicating a pharmacologically active exposure of 18.6μg·h/mL, based on the upregulation of target genes in mouse thymus

Baseline RORgt (RORC2) expression is variable from patient to patient.

Purpose:Transcription factor retinoic acid receptor–related orphan receptor γ (RORγ) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORγ agonists modulate immune cell gene expression to increase effector T-cell activity and decrease immune suppression. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/refractory metastatic cancer.Patients and Methods:Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate.Results:No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1–2 and included diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORγ pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 months (6 received >4 months of treatment).Conclusions:These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

Post-treatment changes in IL-17A and pharmacokinetic profiles for Cohort 4a (600 mg QD) and Cohort 4b (300 mg BID). D, day; PD, pharmacodynamics; PK, pharmacokinetics.

Fold induction over Day 1 pre-dose.

Purpose:Transcription factor retinoic acid receptor–related orphan receptor γ (RORγ) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORγ agonists modulate immune cell gene expression to increase effector T-cell activity and decrease immune suppression. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/refractory metastatic cancer.Patients and Methods:Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate.Results:No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1–2 and included diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORγ pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 months (6 received >4 months of treatment).Conclusions:These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

B iospecimens and data are increasingly needed to support biomedical research and clinical care. Biobanks are created to support the ready access to fit-for-purpose biospecimens and data for drug target identification, drug discovery and development, and are vital in efforts focused on precision medicine. To support the increasing need for quality biospecimens and data, the infrastructure of biobanking must be strong and sustainable. Each biobank should be supported with a business model that is deliberately and methodically planned in advance of the collection, processing, storage and usage of the biospecimens and data. The business plan should address ways to achieve sustainability in operations, social acceptance, as well as financial support over the intended duration of the repository. Financial sustainability may be achieved through various means including institutional support, shortand long-term grants, cost recovery, and sales of services. Biopreservation and Biobanking asked several biobanking professionals their views on financial sustainability and the means to achieve it as addressed in their business plan.

Background: LYC-55716, a first-in-class, oral, small-molecule agonist of the retinoic acid receptor-related orphan receptor γ (RORγ), is under development as a novel immuno-oncology agent for solid tumors. Preclinical data show that LYC-55716 modulates gene expression to reprogram immune cells for improved anti-tumor effector function as well as decreased immunosuppressive mechanisms, resulting in slower tumor growth and enhanced survival. An ongoing, open-label, Phase I/IIa trial is evaluating the safety and tolerability of the investigational agent LYC-55716 in patients with advanced solid tumors. Methods: The Phase I portion of the trial (NCT02929862) enrolled adults with locally advanced or metastatic solid tumors (no specific exclusions) who had progressed on standard therapy. Patients received 28-day treatment cycles of LYC-55716 in which dose and dosing regimen were determined according to PK profile and safety. Primary endpoints were safety (monitoring of adverse events [AEs], physical examination, lab results) and incidence of dose-limiting (Grade 3-4) toxicities during the first treatment cycle. Secondary endpoints included pharmacokinetics (PK) and response assessment. Pharmacodynamic markers of RORγ activation were also evaluated. Results: Data to date: Thirty-two patients were enrolled (23-79 y; 63% female); 27 completed ≥1 (28-day) treatment cycle. Treatment-related AEs occurring in ≥3 patients included diarrhea (n=7 [22%]); fatigue (n=5 [16%]); and anemia, poor appetite, and dry mouth (n=3 [9%] each). No dose-limiting toxicities were observed during Phase 1. The majority of treatment-related AEs were Grade 1-2; Grade 3 treatment-related AEs were reported only for anemia, elevated gamma-glutamine transferase, and hypophosphatemia; no Grade 4 treatment-related AEs occurred. None of the 5 deaths or 14 serious AEs (in 11 patients) were considered treatment-related, and no subjects withdrew due to AEs. LYC-55716 demonstrated an estimated elimination half-life of ~12 h. Twice daily dosing resulted in minimum plasma concentrations that were consistently higher than QD dosing and the highest BID dose resulted in a median minimum plasma concentration that exceeded by ~24-fold the 50% effective concentration that preclinical studies had indicated was required for target gene regulation. Pharmacodynamic data indicated target engagement, consistent with PK evidence of exposure levels in the predicted efficacious range. Updated data, including details of Phase II dose selection and response assessment, will be presented. Conclusion: Phase I data support the safety of LYC-55716 and selection of a BID dosing regimen for the ongoing Phase 2a phase of the trial in patients with non-small cell lung, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers. Citation Format: Devalingam Mahalingam, Judy S. Wang, Erika P. Hamilton, Garry Weems, Marshall Schreeder, H. Jeffrey Wilkins. Safety and dose selection for LYC-55716, a first-in-class RORγ agonist to treat solid tumors: Phase I results from an open-label, multicenter Phase I/IIa trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT132.

Reports have demonstrated the superior activity of combining both irinotecan and oxaliplatin (FOLFOXIRI) therapy. An option for gaining similar benefits with less toxicity would be the administration of irinotecan through a hepatic artery approach. The aim of this study was to assess the response and adverse event rates for irinotecan drug-eluting beads (DEBIRI) with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis.Patients with colorectal liver metastases were randomly assigned to modified FOLFOX (mFOLFOX) and bevacizumab or mFOLFOX6, bevacizumab, and DEBIRI (FOLFOX-DEBIRI). The primary endpoint was the response rate. The secondary endpoints were adverse events, the rate of conversion to resection, and progression-free survival.The intention-to-treat population comprised 70 patients: 10 patients in the pilot and then 30 patients randomly assigned to the FOLFOX-DEBIRI arm and 30 patients randomly assigned to the FOLFOX/bevacizumab arm. The 2 groups were similar with respect to the extent of liver involvement (30% vs 30%), but a greater percentage of patients in the FOLFOX-DEBIRI arm had an Eastern Cooperative Oncology Group performance status of 1 or 2 (57% vs 31%) and extrahepatic disease (56% vs 32%, P = .02). The median numbers of chemotherapy cycles were similar (10 vs 9), and there were similar rates of grade 3/4 adverse events (54% for the FOLFOX-DEBIRI group vs 46% for the FOLFOX/bevacizumab group). The overall response rate was significantly greater in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm at 2 (78% vs 54%, P = .02), 4 (95% vs 70%, P = .03), and 6 months (76% vs 60%, P = .05). There was significantly more downsizing to resection in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm (35% vs 16%, P = .05), and there was improved median progression-free survival (15.3 vs 7.6 months).The simultaneous administration of mFOLFOX6 (with or without bevacizumab) and DEBIRI through the hepatic artery (FOLFOX-DEBIRI) is safe and does not cause treatment delays or increase the systemic toxicity of chemotherapy. This strategy leads to improved overall response rates, improved hepatic progression-free survival, and more durable overall progression-free survival in patients downsized to resection.

Introduction The tyrosine kinase KIT has variable expression in small-cell lung cancer (SCLC) and may be a prognostic factor. Imatinib targets KIT expression, providing rationale for studying its role in combination with chemotherapy in SCLC in a multicenter phase II trial. Methods Patients with untreated extensive-stage SCLC received carboplatin area under the concentration-time curve of 4 on day 1; irinotecan 60 mg/m 2 on days 1, 8, and 15; and imatinib 600 mg/day. Treatment cycles were 28 days. Patients remained on imatinib until progressive disease or significant toxicity. Results Between September 2002 and May 2004, 68 patients were enrolled in this multicenter trial. Median age was 60 years (range, 37–81). The objective response rate was 66% (95% confidence interval: 54%–76%). Median progression-free survival was 5.4 months (95% CI: 4.3–6.0 months). Median overall survival was 8.4 months (95% CI: 6.3–10.5 months). Thirty-five percent of patients were alive at 1 year. Grade 3/4 hematologic toxicity included neutropenia (43%), anemia (16%), and thrombocytopenia (9%). Grade 3 nonhematologic toxicity included diarrhea (19%), fatigue (24%), and nausea (26%). Forty-eight of 56 patients (86%) with available tumor specimens had KIT expression detected. KIT expression did not appear to correlate with progression-free survival or overall survival in a retrospective analysis. Conclusions Irinotecan, carboplatin, and imatinib is a safe and generally well-tolerated regimen in patients with SCLC. However, the addition of imatinib did not improve results from those expected with chemotherapy alone.

A combination of image processing with neural network sorting was conducted to demonstrate feasibility of automated cervical smear screening. Nuclei were isolated to generate a series of data points relating to the density and size of individual nuclei. This was followed by segmentation to isolate entire cells for subsequent generation of data points to bound the size of the cytoplasm. Data points were taken on as many as ten cells per image frame and included correlation against a series of filters providing size and density readings on nuclei. Additional point data was taken on nuclei images to refine size information and on whole cells to bound the size of the cytoplasm, twenty data points per assessed cell were generated. These data point sets, designated as neural tensors, comprise the inputs for training and use of a unique neural network to sort the images and identify those indicating evidence of disease. The neural network, named the Fast Analog Associative Memory, accumulates data and establishes lookup tables for comparison against images to be assessed. Six networks were trained to differentiate normal cells from those evidencing various levels abnormality that may lead to cancer. A blind test was conducted on 77 images to evaluate system performance. The image set included 31 positives (diseased) and 46 negatives (normal). Our system correctly identified all 31 positives and 41 of the negatives with 5 false positives. We believe this technology can lead to more efficient automated screening of cervical smears.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Nineteen patients with locoregional non-small-cell lung cancer (NSCLC) were treated with two courses of cisplatin/VP-16/MGBG, followed by involved field radiotherapy and, subsequently, the same chemotherapy alternating with mitomycin-C/vinblastine. Five of 17 patients obtained a response (CR + PR) after induction chemotherapy. Following radiotherapy, an additional two patients responded. The median survival was 7.5 months, with the two longest survivors at 30 and 32 months. Hematologic toxicity was severe, with two deaths from severe neutropenia. Renal and gastrointestinal toxicities were moderate. This program of aggressive therapy did not increase the response rate or median survival compared with those of comparable patients treated in recent trials using radiotherapy alone or combined radiotherapy plus chemotherapy.