IL-5, a key mediator of type 2 inflammation, underlies various diseases, including severe asthma, CRSwNP, EGPA, and HES. Reduction in blood eosinophil count (BEC), a biomarker of IL-5 activity, is commonly used to evaluate the efficacy of anti-IL-5 biologic therapies. Model-informed drug development (MIDD) and quantitative decision making (QDM) were used to shorten the clinical development of depemokimab (an ultra-long-acting anti-IL-5 biologic). A Bayesian nonlinear mixed effects dose-time response model predicted the depemokimab dose in severe asthma achieving comparable BEC reductions to those observed in mepolizumab (an approved anti-IL-5 biologic) Phase III MUSCA and MENSA trials. Prespecified QDM go/no-go criteria were applied to assess success probability. Phase IIb efficacy-based trial simulations were conducted using negative binomial distribution to simulate individual annualized exacerbation rate. A depemokimab PK/PD (BEC) model predicted Phase III trial doses in CRSwNP/EGPA/HES. Single depemokimab doses were well-described by the Bayesian model; a single depemokimab dose ≥ 60 mg had probability ≥ 80% of exceeding Minimum (78%; MUSCA) and ≥ 10% probability of exceeding Target (84%; MENSA) values for trough BEC reduction from baseline vs. placebo. Clinical trial simulations demonstrated < 3% probability of more precise estimation of the Phase III dosing regimen with a conventional efficacy-based dose-ranging study. Depemokimab 100 mg for severe asthma/CRSwNP and 200 mg for EGPA/HES, administered subcutaneously every 26 weeks, were selected for Phase III trials. MIDD and QDM shortened the depemokimab development program by 2-3 years, emphasizing the potential of this approach for progressing new therapies from Phase I directly to Phase III.

Model-based meta-analysis allows integration of aggregated-level data (AD) from different clinical trials in one model to assess population efficacy/safety. However, AD is limited in individual-level information, while individual-patient-level data (IPD) are hard to obtain. Combined modeling may take advantage of both sources. Chronic obstructive pulmonary disease (COPD) is a leading cause of poor health and death. This study established a combined ADIPD model of COPD clinical trials with forced expiratory volume in 1 s (FEV1) as an endpoint and explored methods for estimating interstudy variability (ISV), interindividual variability (IIV), and aggregation bias. Stochastic simulation and estimations (SSE) showed the best method in NONMEM to estimate ISV/IIV: using $LEVEL with equal weight of studies; for the AD part, ISVs from the AD model were fixed, estimating IIV with separate ETAs for each arm; the IPD part shared the fixed ISV and estimated IIV. An approximated normal distribution was derived for lognormal IIV to avoid aggregation bias. Covariate correlations were different at aggregated and individual levels, but did not introduce aggregation bias according to SSE. A separate AD model (published) and IPD model were built, then combined to form the ADIPD model. The ADIPD model included FEV1 baseline, disease progression, placebo effect, and Emax/constant dose-responses for 23 compounds. Identified covariate relationships: higher age, female, higher disease severity, non-current smoker related to lower baseline; higher baseline related to faster disease progression and higher drug effects. Covariate coefficients were estimated more precisely in the ADIPD model than the AD model. ADIPD modeling allows more informed clinical trial simulations for study design. Trial Registration: ClinicalTrials.gov identifier: NCT01053988 and NCT01054885.

Therapeutic neutralization of Oncostatin M (OSM) causes mechanism-driven anemia and thrombocytopenia, which narrows the therapeutic window complicating the selection of doses (and dosing intervals) that optimize efficacy and safety. We utilized clinical data from studies of an anti-OSM monoclonal antibody (GSK2330811) in healthy volunteers (n = 49) and systemic sclerosis patients (n = 35), to quantitatively determine the link between OSM and alterations in red blood cell (RBC) and platelet production. Longitudinal changes in hematopoietic variables (including RBCs, reticulocytes, platelets, erythropoietin, and thrombopoietin) were linked in a physiology-based model, to capture the long-term effects and variability of therapeutic OSM neutralization on human hematopoiesis. Free serum OSM stimulated precursor cell production through sigmoidal relations, with higher maximum suppression (Imax) and OSM concentration for 50% suppression (IC50) for platelets (89.1% [95% confidence interval: 83.4-93.0], 6.03 pg/mL [4.41-8.26]) than RBCs (57.0% [49.7-64.0], 2.93 pg/mL [2.55-3.36]). Reduction in hemoglobin and platelets increased erythro- and thrombopoietin, respectively, prompting reticulocytosis and (partially) alleviating OSM-restricted hematopoiesis. The physiology-based model was substantiated by preclinical data and utilized in exploration of once-weekly or every other week dosing regimens. Predictions revealed an (for the indication) unacceptable occurrence of grade 2 (67% [58-76], 29% [20-38]) and grade 3 (17% [10-25], 3% [0-7]) anemias, with limited thrombocytopenia. Individual extent of RBC precursor modulation was moderately correlated to skin mRNA gene expression changes. The physiological basis and consideration of interplay among hematopoietic variables makes the model generalizable to other drug and nondrug scenarios, with adaptations for patient populations, diseases, and therapeutics that modulate hematopoiesis or exhibit risk of anemia and/or thrombocytopenia.

Supplementary Figure 1. Single dose ceralasertib PK. PK from patients in cohorts 1 to 4 was in line with the PK model predictions (shadowed area) built with data from other studies. Supplementary Figure 2. ATM protein expression by IHC in patients with melanoma. Supplementary Figure 3. ctDNA clearance of mutant alleles from a responder to ceralasertib+paclitaxel; example 1. ctDNA was sequenced at baseline, day 61 and day 403. Re-staging scans were performed at day 63, day 117, intermediate days at approximate 8 week intervals (not shown) and day 426 (at the time of PD). The stream plot shows rapid clearance of the mutant alleles in line with RECIST v1.1 response. Supplementary Figure 4. CtDNA clearance of mutant alleles from a responder to ceralasertib+paclitaxel; example 2. ctDNA was sequenced at baseline, day 24, day 52 and day 241. Re-staging scans were performed at day 46, day 98, intermediate days at approximate 8 week intervals (not shown) and day 235. The stream plot shows rapid clearance of the mutant alleles prior to the day of the first re-staging scan which showed a RECIST v1.1 response.

Supplementary Table 1. Treatment Outcomes for individual trial participants and dose cohort (N=57)

Aims Concentration-QT modelling (C-QTc) of first-in-human data has been rapidly adopted as the primary evaluation of QTc interval prolongation risk. Here, we evaluate the performance of C-QTc in early oncology settings (i.e., patients, no placebo or supratherapeutic dose, 3 + 3 designs). Methods C-QTc performance was evaluated across three oncology scenarios using a simulation-estimation approach: (scen1) typical dose-escalation testing six dose levels (n = 21); (scen2) small dose-escalation testing two dose levels (n = 9); (scen3) expansion cohorts at one dose level (n = 6-140). True Delta Delta QTc effects ranged from 3 ms ("no effect") to 20 ms ("large effect"). Performance was assessed based on the upper limit of the Delta QTc two-sided 90% CI against a threshold of 10 or 20 ms. Results The performance against the 10 ms threshold was limited based on C-QTc data from typical dose escalation (scen1) and acceptable performance was observed only for relatively large expansions (n >= 45; scen3). Performance against the 20 ms threshold was acceptable based on C-QTc data from a typical dose escalation (scen1) or dose expansion cohort n > 10 (scen3). In general, pooling C-QTc data from dose escalation and expansion cohorts substantially improved the performance and reduced the Delta QTc 90% CI width. Conclusion C-QTc performance appeared limited using a 10 ms threshold, but acceptable against a 20 ms threshold. Selection of threshold may be informed by the benefit-risk balance in a specific disease area. Acceptable precision (i.e., confidence intervals) of the estimated Delta QTc, regardless of its magnitude, can be facilitated by pooling data from dose escalation and expansion cohorts.

The International Conference on Harmonisation (ICH) E14 guidance provides recommendations to assess the potential of a drug to delay cardiac repolarization (QT prolongation), including general guidelines for cases in which a conventional thorough QT study (TQT) might not be feasible. These guidelines have been updated through the ICH question-and-answer process, with the last revision in 2015. We conducted a comprehensive analysis of QT prolongation evaluation of small-molecule new drug applications (NDAs) approved in oncology between 2011 and 2019 to extract learning experience. The following information was analysed: (1) methods to assess QT prolongation, (2) electrocardiogram data collection, (3) QT-related label language, and (4) postmarketing requirements. Overall, every NDA included a QT assessment. The concentration-QTc modeling approach (studies in which QT was not the primary objective) was the most common approach (59%), followed by the TQT and the dedicated QT studies (20% and 21%, respectively). The quality and quantity of the QT assessments were different across NDAs, which suggested relatively large flexibility in the designs and approaches to characterizing QT liability. The QT-related label language reflected the QT results, but also the safety events and the study design limitations because of the oncology settings. There was no delay in approval because of less robust QTc studies as long as the benefit-to-risk ratio of the drug was acceptable, and the implications were reflected in the label. This work offers a structured understanding of the QT evaluation criteria by the Food and Drug Administration and can assist in planning QT prolongation assessments in oncology settings.

AbstractPurpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein. Patients and Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. Results: The RP2D was established as ceralasertib 240 mg BD days 1–14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5–35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0–51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0–5.8), the median duration of response was 9.9 months (95% CI, 3.7–23.2), and the mOS was 7.4 months (95% CI, 5.7–11.9). Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment. See related commentary by Ashworth, p. 4667

Purpose: This study reports the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity of ceralasertib combined with carboplatin in patients with advanced solid tumors. It also examined exploratory predictive and pharmacodynamic biomarkers. Patients and Methods: Eligible patients (n = 36) received a fixed dose of carboplatin (AUC5) with escalating doses of ceralasertib (20 mg twice daily to 60 mg once daily) in 21-day cycles. Sequential and concurrent combination dosing schedules were assessed. Results: Two ceralasertib MTD dose schedules, 20 mg twice daily on days 4–13 and 40 mg once daily on days 1–2, were tolerated with carboplatin AUC5; the latter was declared the RP2D. The most common treatment-emergent adverse events (Common Terminology Criteria for Adverse Events grade ≥3) were anemia (39%), thrombocytopenia (36%), and neutropenia (25%). Dose-limiting toxicities of grade 4 thrombocytopenia (n = 2; including one grade 4 platelet count decreased) and a combination of grade 4 thrombocytopenia and grade 3 neutropenia occurred in 3 patients. Ceralasertib was quickly absorbed (tmax ∼1 hour), with a terminal plasma half-life of 8–11 hours. Upregulation of pRAD50, indicative of ataxia telangiectasia mutated (ATM) activation, was observed in tumor biopsies during ceralasertib treatment. Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed RECIST v1.1 partial responses. Eighteen of 34 (53%) response-evaluable patients had RECIST v1.1 stable disease. Conclusions: The RP2D for ceralasertib plus carboplatin was established as ceralasertib 40 mg once daily on days 1–2 administered with carboplatin AUC5 every 3 weeks, with pharmacokinetic and pharmacodynamic studies confirming pharmacodynamic modulation and preliminary evidence of antitumor activity observed.

Developing a new drug is a long, costly and highly uncertain journey. Commonly, more than 10 years and investments of more than 2 billion US dollars are needed to develop a medicine with over 90% of the clinical-stage compounds failing. Inadequate dose selection accounted for one-fourth of recently failed new drug application in the United States, and led to dose change in about one-fifth of the approved drugs. This highlights that improved knowledge about how drugs interact with disease processes could increase efficiency of clinical trials, and greater quality of development decisions could bring great value. This article introduces and describes the impact of the use of clinical pharmacology modeling and simulation (pharmacometrics) in clinical drug development to inform key decision-making and to increase the rate of success of new drugs. The phases of clinical drug development are briefly described and general principles for quantitative clinical pharmacology are introduced. Typical modeling tools are described, and real-world examples are then given to illustrate the concrete impact of quantitative clinical pharmacology in drug project decision making, regulatory approval and clinical practice. Finally, we give a brief future lookout.

Two-pore physiologically-based pharmacokinetic (PBPK) models can be expected to describe the tissue distribution and elimination kinetics of soluble proteins, endogenous or dosed, as function of their size. In this work, we amalgamated our previous two-pore PBPK model for an inert domain antibody (dAb) in mice with the cross-species platform PBPK model for monoclonal antibodies described in literature into a unified two-pore platform that describes protein modalities of different sizes and includes neonatal Fc receptor (FcRn) mediated recycling. This unified PBPK model was parametrized for organ-specific lymph flow rates and the endosomal recycling rate constant using an extended tissue distribution time-course dataset that included an inert dAb, albumin and IgG in rats and mice. The model was evaluated by comparing the ab initio predictions for the tissue distribution and elimination properties of albumin-binding dAbs (AlbudAbsTM) in mice and rats with the experimental observations. Due to the large number of molecular species and reactions involved in large-scale PBPK models, we have also developed and deployed a MatlabTM script for automating the assembly of SimBiologyTM-based two-pore biologics PBPK models which drastically cuts the time and effort required for model building.

The aim of this work was to allow combination of information from recent and historical trials in Parkinson’s Disease (PD) by developing bridging methodology between two versions of the clinical endpoint. A previously developed Item Response Model (IRM), that described longitudinal changes in Movement Disorder Society (MDS) sponsored revision of Unified Parkinson’s Disease Rating Scale (UPDRS) [MDS–UPDRS] data from the De Novo PD cohort in Parkinson’s Progression Markers Initiative, was first adapted to describe baseline UPDRS data from two clinical trials, one in subjects with early PD and another in subjects with advanced PD. Assuming similar IRM structure, items of the UPDRS version were mapped to those in the MDS-UPDRS version. Subsequently, the longitudinal changes in the placebo arm of the advanced PD study were characterized. The parameters reflecting differences in the shared items between endpoints were successfully estimated, and the model diagnostics indicated that mapping was better for early PD subjects (closer to De Novo cohort) than for advanced PD subjects. Disease progression for placebo in advanced PD patients was relatively shallow. An IRM able to handle two variants of clinical PD endpoints was developed; it can improve the utilization of data from diverse sources and diverse disease populations.

Olaparib is a poly ADP‐ribose polymerase inhibitor that induces synthetic lethality in tumors with deficient homologous recombination repair. Population exposure‐response analyses were performed to evaluate the efficacy and safety of olaparib exposure in patients with cancer. Data from multiple phase I/II/III clinical studies from both capsule and tablet formulations were combined for efficacy (N = 410) and safety (N = 757) analyses. Exposure‐progression‐free survival (Cox proportional hazards model indicated that a 300 mg b.i.d. tablet was statistically superior to the 200 mg b.i.d. tablet dose (hazard ratio of 0.96), although the difference was small. Exposure‐safety logistic regression models and hemoglobin models predicted similar probability of safety events or hemoglobin decrease with largely overlapping 95% confidence intervals at 300 mg b.i.d. tablet, 200 mg b.i.d. tablet, and 400 mg b.i.d. capsule. The analyses provided key assessments to support the approval of olaparib 300 mg tablet therapeutic dose in patients with ovarian and breast cancer, regardless of their breast cancer (BRCA) mutation status.

Introduction: AZD6738 is a potent inhibitor of the ATR protein kinase that is being tested in patients with solid malignancies. In Phase I dose escalation studies, AZD6738 was dosed as monotherapy (continuous schedule from 40 - 480 mg per day), or in combination (intermittent schedule from 80 - 320 mg per day) with olaparib, durvalumab, carboplatin, or radiation. In those studies, thrombocytopenia was the main dose limiting toxicity and changes in peripheral monocytes and proliferating T-cells were seen with AZD6738, with up to 80% decrease on-drug and return to baseline upon cessation of dosing. This effect on monocytes and proliferating T cells was not observed with either single agent olaparib or durvalumab. Based on these observations, we developed two PKPD models linking AZD6738 dose, AZD6738 plasma exposure, and differential blood cell counts to support dose and schedule selection. Methods and Results: The first model characterized the quantitative relationship between the plasma exposure of AZD6738 monotherapy, and the difference between monocyte decrease (on-target activity) and platelet decrease (on-target toxicity). This model was a sigmoid function and predicted biological activity starting at exposures of 2.5 ug/mL (aligned with the in vitro IC90 in LoVo cells, and obtained in ≥ 50% of patients with 80 mg per day) increasing in a concentration dependent manner to 10 ug/mL (obtained in almost all patients dosed at 480 mg per day), after which negligible monocyte response over platelet decrease was observed. Those data were consistent with the preclinical observations which showed tumour regression after at least 3-day concomitant treatment of olaparib and AZD6738 at exposure maintaining IC90[1]. The second model was a PK-safety model describing the temporal relationship between circulating platelets and exposure of AZD6738 administered in combination with olaparib dosed at 300 mg twice daily continuously. This model allowed generation of various platelet/ time profiles in the most sensitive patient group (10% of the patients) for different AZD6738 doses and schedules. The simulations indicated that, for doses considered biologically relevant by the first model, a period of 21-days free of AZD6738 is needed to give full recovery of potential thrombocytopenia in a 28-day cycle. Conclusion: Using monocyte and proliferative T-cell decreases as biological activity indicators and platelet decrease as a safety indicator, we quantified the exposure/activity/safety relationship for AZD6738. The recommended Phase II dose of AZD6738 (in combination with olaparib) was then driven by maintaining maximally active exposure consistent with manageable safety. Reference: [1]. 2017 AACR Abstract 2494. Acknowledgements: T.A. Yap (The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK) and J.C. Soria (Institut Gustave Roussy, Paris, France) Citation Format: Alienor Berges, S. Y. Amy Cheung, Andrew J. Pierce, Emma Dean, Brunella Felicetti, Nathan Standifer, Simon Smith, James Yates, Alan Lau, Christine Stephens, Matthew Krebs, Kevin Harrington, Simon J. Hollingsworth. PK-Biomarker-Safety modelling aids choice of recommended Phase II dose and schedule for AZD6738 (ATR inhibitor) [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 CT118.

Background: AZD6738 is a potent selective oral ATR inhibitor. Therapeutic combinations aim to inhibit ATR-dependent cycle arrest and repair induced by the PARP inhibitor Olaparib (Ola), and to exploit DNA damage-induced immune responses with the anti-PD-L1 antibody Durvalumab (Durva). Here we present the results of the ongoing Phase I study D5330C00004 (NCT02264678) dose escalation combinations of AZD6738 with Ola or Durva. Methods: A trial assessing AZD6738 in combination with continuous Ola tablets or Durva IV infusion per 28-day cycle. Pharmacokinetic (PK) and pharmacodynamic evaluations were conducted. Results: 70 pts with advanced cancer were treated with +Ola (45 pts) or +Durva (25 pts). Tumor types included breast, ovary, prostate, pancreas, lung, HNSCC and gastric cancers. +Ola: AZD6738 was assessed in 10 cohorts from 60 mg od to 240 mg bd for 5-14 days (D), co-dosing with Ola 100-300 mg bd continuously. All causality toxicity occurring in ≥20% subjects (pts with ≥G3 events) included: thrombocytopenia (5 pts), anemia (7 pts), neutropenia (6 pts), fatigue (1 pt), decreased appetite (1 pt), nausea, vomiting, constipation, diarrhea and cough. Thrombocytopenia and neutropenia were dose- and schedule limiting toxicities (DLTs). The Recommended Phase 2 Dose is AZD6738 160 mg od D1-7 + Ola 300 mg bd D1-28. Of 39 evaluable pts, 1 RECIST complete response (CR), 5 partial responses (PR) and 1 unconfirmed (uPR) were observed in pts with advanced breast (3 pts), ovarian, prostate, pancreatic and ampullary cancer and BRCA1/2 mutations independent of ATM status. Dose expansions are ongoing in pts with advanced gastric and breast cancer. +Durva: AZD6738 was evaluated in 5 cohorts with 1-2 weeks monotherapy run-in, followed by Durva 1500 mg on D1 + AZD6738 80-240 mg od or bd for 1 (D22-28) or 2 (D15-28) weeks. Toxicity occurring in ≥20% subjects included: anemia (≥G3 in 1 pt), fatigue, nausea, decreased appetite, cough, vomiting, dizziness, pruritus, constipation, diarrhea, musculoskeletal chest pain and dyspnea. One DLT of thrombocytopenia was observed. Of 21 pts, 1 RECIST CR, 2 PRs and 1 uPR were observed in pts with advanced NSCLC (3 pts) and HNSCC (1 pt), independent of tumor PD-L1 expression. Peripheral monocytes and proliferating T-cells were suppressed; both rebounding to levels ≥ baseline during the off-drug interval. GM-CSF increased reciprocally to on-target decreases in monocytes. Preliminary PK data showed rapid absorption of AZD6738 with peak plasma concentration ≈1.5h post dose, a biphasic decline with an elimination half-life of 11h. Despite ≈45% variability in clearance, there was dose proportionality and no evidence of drug-drug interaction with Ola or Durva. Conclusions: The combinations of AZD6738 with Ola or Durva were tolerated in dose escalation with preliminary signals of antitumor activity in pts with advanced solid tumors. Citation Format: Matthew G. Krebs, Juanita Lopez, Anthony El-Khoueiry, Yung-Jue Bang, Sophie Postel-Vinay, Wassim Abida, Louise Carter, Wen Xu, Seock-Ah Im, Andrew Pierce, Paul Frewer, Alienor Berges, S.Y. Amy Cheung, Christine Stephens, Brunella Felicetti, Emma Dean, Simon J. Hollingsworth. Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers [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 CT026.

Olaparib is a first-in-class potent oral poly(ADP-ribose) polymerase inhibitor.

Abstract Background: The annual incidence of head and neck cancers is >550,000 cases worldwide and approximately 90% are HNSCC. Treatment for locoregionally advanced (stage III/IV) HNSCC involves primary surgery, radiation and/or chemotherapy. Cancer cells with DDR defects can activate the immune system and immunotherapy (IO) has shown therapeutic benefit in pts with advanced recurrent HNSCC. This study assesses the immunological effects of DDR agents in both tumor tissue and peripheral blood samples to inform optimal combinations with IO therapies. The overall hypothesis is that DDR agents will convert an “immunologically cold” tumor into an “immunologically hot” tumor that is both responsive to IO and improved prognosis. Objectives: The primary objective is to assess immune activation due to DDR inhibition by monitoring the induction of genes interacting with the immune system and potentially linked to prognosis. The secondary objective is to assess increasing prevalence of tumor infiltrating CD8+ and CD3+ T-cells also linked to prognosis. Exploratory measurements of tumour proliferative and DDR-relevant markers, peripheral T/B/NK and regulatory T cells, key immuno-regulatory cytokines, TCR repertoire, levels of circulating tumour cells and relevant genomic changes in both tumour and circulating tumour DNA will be conducted. Safety and tolerability of the investigational agents is also monitored. Methods: This ongoing, randomised multi-centre, window of opportunity biomarker study is enrolling patients with newly diagnosed, treatment naïve, HNSCC suitable for surgical resection followed by radiotherapy and/or chemotherapy (NCT03022409). Two oral DDR agents are currently under evaluation as monotherapy: AZD6738 is a potent selective inhibitor of the serine/threonine-specific protein kinase, ataxia telangiectasia and Rad3-related protein (ATR), and olaparib is a poly-ADP ribose polymerase (PARP) inhibitor. Eligible pts are randomised to receive a DDR agent for between 10 to 21 days (D), followed by surgery. After surgery, pts do not receive further investigational treatment and attend a follow-up visit at D31. Tumor tissue is collected pre- (archival diagnostic biopsy) and post-treatment (surgical specimen), and evaluated for changes in key biomarkers related to immune response and DNA damage inhibition. If surgery is scheduled between D11-21 (+3D) following three successive days of DDR agent, an on-treatment biopsy is also required between D10-12. Pts undergo a weekly assessment for adverse events, hematology, biochemistry, and electrocardiogram. Plasma samples are also included to characterise the pharmacokinetics of each agent, relative to any biomarker changes observed. Enrolment commenced in December 2017 and the study is designed to permit the addition of treatment arms, including different combinations, sequences and doses. Citation Format: Umamaheswar Duvvuri, Emma Dean, Paul Frewer, Alienor Berges, S. Y. Cheung, Christine Stephens, Musaddiq Khan, Simon J. Hollingsworth, Andrew J. Pierce. A pre-surgical window of opportunity study to investigate the biomarker effects of DNA damage response (DDR) agents in patients (pts) with head and neck squamous cell carcinoma (HNSCC) [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 CT135.

Background: AZD6738 is a potent oral selective inhibitor of ATR (ataxia telangiectasia Rad3-related). The ongoing dose escalation Phase I study D5330C00004 (NCT02264678) combines AZD6738 with Durvalumab (Durva) to exploit ATR-dependent cycle arrest and DNA damage-induced immune responses. Methods: Five cohorts with 1-2 weeks monotherapy run-in, followed by Durva 1500 mg on D1 + AZD6738 80-240 mg od or bd for 1 (D22-28) or 2 (D15-28) weeks have completed (cohort 6 is ongoing), with concurrent translational blood borne and biomarker assessment. Results: Twenty-five pts have been treated to date with either NSCLC, or HNSCC cancer. Toxicities that occurred in ≥ 20% subjects included: anemia (≥G3 in 1 pt), fatigue, nausea, decreased appetite, cough, vomiting, dizziness, pruritus, constipation, diarrhea, musculoskeletal chest pain and dyspnea. One DLT of thrombocytopenia was observed, an on-target AZD6738 effect. Of 21 pts, 1 RECIST CR, 2 PRs and 1 uPR were observed in advanced NSCLC (3 pts) and HNSCC (1 pt) with no clear correlation with tumor PD-L1 or ATM expression. Expansion of the final cohort 6 is ongoing with one reported DLT in the initial 3 of the planned 6 pts. Preliminary PK data showed rapid absorption of AZD6738 with peak plasma concentration ≈1.5h post dose, a biphasic decline with an elimination half-life of 11h. Despite ≈45% variability in clearance, there was dose proportionality and no evidence of drug-drug interaction with Durva. Peripheral monocytes and proliferating T-cells were suppressed during the AZD6738 dosing interval; both rebounding to levels ≥ baseline during the off-drug interval; the immunostimulatory cytokine IL-12 behaved similarly. These cyclical changes were observed across multiple treatment cycles. GM-CSF increased reciprocally to on-target decreases in monocytes. Durvalumab was dosed to saturation and therefore these changes are attributable to AZD6738. AZD6738 consistently increased pRAD50 in post treatment tumour biopsies. Conclusions: The combination of AZD6738 with Durva was tolerated in dose escalation with signals of antitumor activity and pharmacodynamic evidence of AZD6738 target engagement. Clinical trial identification: NCT02264678. Legal entity responsible for the study: AstraZeneca plc. Funding: AstraZeneca plc. Disclosure: Y-J. Bang: Consultancy work: AstraZeneca plc; Research funding to institution: AstraZeneca. W. Abidah: Consulting: Clovis Pharmaceuticals. L.T. Khoja, G.N. Jones, P. Marco-Casanova: Full time employee: AstraZeneca plc. N. Standifer: Full time employee: Medimmune/AstraZeneca plc. P. Frewer, A. Berges, A. Cheung, C. Stephens, B. Felicetti, E. Dean, A. Pierce, S. Hollingsworth: Full time employee and shareholder: AstraZeneca plc. All other authors have declared no conflicts of interest.