This study (NCT04537715) investigated itraconazole (strong cytochrome P450 [CYP] 3A inhibitor) and rifampin (strong CYP3A inducer) on tazemetostat pharmacokinetics. In Part 1, patients received tazemetostat 400 mg orally on Days 1, 15, and 36, and 400 mg twice daily on Days 3‐14 and Days 21‐35. Itraconazole 200 mg orally once daily was administered on Days 18‐38. In Part 2, patients received tazemetostat 800 mg orally once daily on Days 1, 15, and 24, and 800 mg twice daily on Days 3‐14 and Days 17‐23. Rifampin 600 mg orally once daily was administered on Days 17‐25. Twenty‐one patients in each part completed had plasma concentrations quantified for pharmacokinetic assessments. Itraconazole coadministration resulted in higher tazemetostat exposures after single doses (Day 21/Day 1) and steady state (Day 36/Day 15). Compared with tazemetostat alone, itraconazole increased mean maximum plasma concentration (C max ) and area under the concentration‐time curve from time 0 to 12 hours (AUC 0‐12h ) by 2.00‐ and 3.12‐fold, respectively, after single doses. Following twice‐daily dosing, itraconazole increased mean steady‐state C max and AUC 0‐12h by 1.86‐ and 2.47‐fold, respectively. Rifampin coadministration decreased tazemetostat steady‐state (C max ) and AUC 0‐12h by approximately 84% (Day 24/Day 15). Itraconazole increased tazemetostat exposure by 2‐3‐fold, and rifampin decreased tazemetostat exposure by 84%, indicating that coadministration of tazemetostat with strong CYP3A inhibitors or inducers should be avoided.

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies, or patients with R/R FL who have no satisfactory alternative treatment options. We previously reported the efficacy and safety of TAZ in combination with lenalidomide and rituximab (R 2) in patients with R/R FL from the SYMPHONY-1 study (EZH-302; NCT04224493) after complete enrollment and following the phase 1b safety run-in period. Here, we report the updated efficacy and safety results after a median follow-up of 22.5 months. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R 2. After the initial 12 months of combination therapy, tazemetostat 800 mg BID was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoints of the phase 1b portion were safety and determination of the recommended phase 3 dose (RP3D). Secondary endpoints included pharmacokinetic (PK) parameters. Efficacy analysis was performed on the intent-to-treat (ITT) population, including best overall response, progression-free survival (PFS), and duration of response (DOR) per investigator assessment, according to Lugano 2014 response criteria. Results: As of July 10, 2023, 44 patients were enrolled and receiving TAZ + R 2 (400 [n=6], 600 [n=19], or 800 mg [n=19]). Median age was 67 years, 31.8% of patients had received >1 prior therapy, and patients had a median of 1 prior line of therapy (range, 1-4). Overall, 81.8% (n=36) of patients had wild-type (WT) EZH2 FL, 34.1% (n=15) of patients had rituximab-refractory disease, and 27.3% (n=12) of patients had POD24. Median durations of treatment exposure for TAZ, lenalidomide, and rituximab were 13.3, 10.8, and 4.6 months, respectively. In the 800-mg cohort, the median relative dose intensity was 94.1%, 92.9%, and 100% for TAZ, lenalidomide, and rituximab, respectively. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the data cutoff. The RP3D of TAZ was determined to be 800 mg BID in combination with R 2. The most common grade 3-4 TEAE was neutropenia (40.9%; n=18). The most frequent type of dose modification due to TEAEs for any study treatment was drug interruption (70.5%), followed by dose reduction (38.6%) and treatment discontinuation (20.5%); protocol-mandated dose modifications included simultaneous dose interruption and/or reduction of TAZ and lenalidomide for neutropenia and thrombocytopenia. Of the 44 patients, 42 patients were evaluable for tumor assessment and 2 patients had no postdose tumor assessments. Of 42 patients evaluable for tumor assessment, 23 (54.8%) had a complete response, 17 (40.5%) had a partial response, and 2 (4.8%) had stable disease. The ORR in the ITT population was 90.9% (n=40/44). The ORRs in patients with WT EZH2 and MT EZH2 were 88.9% (n=32/36) and 100% (n=7/7), respectively. The ORR in patients with rituximab-refractory disease was 93.3% (n=14/15) and in patients with POD24 was 91.7% (n=11/12). With a median follow-up of 22.5 months, median PFS and median DOR were not reached. In the ITT population, 18-month PFS and DOR estimates were 79.5% and 81.0%, respectively; in the 800-mg cohort (n=19), 18-month PFS and DOR estimates were 94.4% and 100%, respectively. PFS appeared to be dose dependent, with durable response in the 800-mg cohort. Conclusions: The safety profile of TAZ + R 2 combination therapy was consistent with previous reports, with no new safety signals identified in the phase 1b data of this study. The 12 months of initial combination therapy resulted in long-lasting remission. Dose-dependent response was seen with durable response in patients receiving TAZ 800 mg, regardless of their mutation status. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ 800 mg + R 2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved in the US for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or who have no satisfactory alternative treatment options. EZH2 modulates the B-cell tumor microenvironment, supporting combination approaches to treatment. SYMPHONY-1 (EZH-302; NCT04224493) is a Phase 1b/3 study designed to determine the phase 3 dose (RP3D), pharmacokinetics, efficacy, and safety of TAZ + lenalidomide and rituximab (R 2) in patients with R/R FL after ≥1 prior therapy. We report here the pharmacokinetics; drug interaction, and exposure-safety analysis of TAZ in combination with R 2, which are used to support the dose selection for RP3D. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg, bid) in 28-day cycles with standard-dose R 2. Primary endpoints of the Phase 1b portion were safety and determination of the recommended phase 3 dose (RP3D). PK of Taz and drug-drug interaction (DDI) with R 2 were also evaluated. The AEs Grade 3 or greater of treatment emergent AE (TEAE3), gastro-intestinal AE (GIAE3), neutropenia (NEU3), hepatotoxic event (HEP3), anemia (ANEM3) and thrombosis (THRM3) were assessed, and their relationships with Taz exposure when combined with R 2 were explored. Results: The PK results are based on thirty-nine (39) patients with no major protocol deviations. TAZ PK are characterized by rapid absorption with a Tmax 1.00 hours; and a short half-life which ranged from 3.2 to 3.8 hours across all dose levels. Both Cmax and AUC increased with increasing Taz doses over the dose range. Exposures of 800 mg TAZ at steady state are similar to those found in TAZVERIK Prescribing Information. These results suggest that the PK of TAZ doses 400 mg to 800 mg BID are not altered by concomitant administration of a daily oral dose of 20 mg lenalidomide. Lenalidomide PK (Cmax and AUC) are similar to those found in Revlimid FDA's Biopharm Review (fda.gov). Taken together these data suggest there is no DDI when TAZ is given in combination with R 2. The Taz exposure at 800 mg bid in the presence of R 2 is over the target engagement of > 80%. No clear increasing AE trend with increasing exposure (AUC) was observed with TEAE3. More importantly, there is no increasing trend of other AEs of gastro-intestinal AE (GIAE3), neutropenia (NEU3), hepatotoxic event (HEP3), and thrombosis (THRM3) with increasing exposure (AUC) or dose was observed. However, there is no ANEM3 observed with the available database. Conclusions: TAZ + R 2 combination demonstrates consistent and unaltered PK for TAZ and lenalidomide, and delivered an optimal target engagement, and favorable safety profile. There is no DDI when TAZ is given in combination with R 2. The exposure safety analysis demonstrated that there were no obvious trends in increasing Grade ≥3 AEs with increasing exposure when combined with R 2. Based on the totality of the PK, target engagement and exposure-safety analysis, the RP3D of TAZ was determined to be 800 mg BID in combination with R 2. The 2-arm randomized phase 3 portion is currently ongoing to further explore the efficacy and safety of TAZ 800 mg + R 2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

Background: The preferred second-line treatment for patients with relapsed/refractory (R/R) follicular lymphoma (FL) is either lenalidomide in combination with rituximab (R2) or an anti-CD20 antibody in combination with chemotherapy/immunotherapy. Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with R/R FL whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or who have no satisfactory alternative treatment options. EZH2 modulates the B-cell tumor microenvironment, supporting combination approaches to treatment. SYMPHONY-1 (EZH-302; NCT04224493) is a phase 1b/3 study designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + lenalidomide and rituximab (R2) in patients with R/R FL after ≥1 prior therapy. We report the results after complete enrollment of the phase 1b safety run-in to assess safety and clinical activity of TAZ when administered with R2, including data for subsets of patients by mutation status, rituximab-refractory disease, and progression of disease in 24 months (POD24). Methods: Patients aged ≥18 years with histologically confirmed FL grade 1-3A who were previously treated with ≥1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy were enrolled. The phase 1b portion enrolled patients regardless of EZH2 mutation status. Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R2. Protocol-mandated dose modifications included simultaneous dose interruption and/or reduction of TAZ and lenalidomide for grade 3 neutropenia and thrombocytopenia. Primary endpoints of the phase 1b portion were safety and determination of the RP3D. Secondary endpoints included pharmacokinetic (PK) parameters. Preliminary efficacy analysis was performed on the response-evaluable population, including best overall response, progression-free survival (PFS), and duration of response (DOR) per investigator assessment, according to Lugano 2014 response criteria. Results: As of June 14, 2022, 44 patients were enrolled and receiving TAZ + R2 (400 [n=6], 600 [n=19], and 800 mg [n=19]). Median age was 67 years, and 31.8% of patients had received >1 prior therapy. Overall, 35/42 patients (83.3%) had wild-type (WT) EZH2 FL. Patients with high-risk disease include 15 patients (34.1%) with rituximab-refractory disease and 12 patients (27.3%) with POD24 disease. Median duration of treatment exposure of tazemetostat was 9.1 months. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the data cutoff. The PK of TAZ at all dose levels was not altered by concomitant administration of daily oral lenalidomide 20 mg, and the PK of lenalidomide was not altered by concomitant administration of any of the TAZ doses. The RP3D of TAZ was determined to be 800 mg BID in combination with R2. The most common grade 3-4 TEAE was neutropenia (n=15; 34.1%). The most frequent type of dose modification due to TEAEs for any study treatment was drug interruption (n=30; 68.2%). In the 800-mg cohort, the median dose intensity was 98%, 93%, and 100% for tazemetostat, lenalidomide, and rituximab, respectively. Of 41 patients evaluable for tumor assessment, 21 (51.2%) had a complete response, 19 (46.3%) had a partial response, and 1 (2.4%) had stable disease. The overall response rate (ORR) in the response-evaluable population was 97.6% (n=40). The ORRs in patients with WT EZH2 and MT EZH2 were 97% (n=32) and 100% (n=7), respectively. ORRs in patients with rituximab-refractory disease was 100% (n=14) and in patients with POD24 disease was 100% (n=11). With a median follow-up of 11.2 months, median PFS and median DOR were not reached and appeared to be similar, regardless of rituximab-refractory, POD24, or EZH2 mutation status. Conclusions: TAZ + R2 combination therapy demonstrates a consistent and manageable safety profile, with no new safety signals. The combination therapy maintained its efficacy, regardless of mutation status. Durable responses were seen in patients with high-risk disease, including those with rituximab-refractory and POD24 disease. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ RP3D 800 mg + R2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

Background: Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator, suppresses key cellular checkpoints and differentiation pathways to maintain the oncogenic characteristics of germinal center B cells. In addition to activity in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), EZH2 inhibitors induced cell cycle arrest and apoptosis in preclinical studies of multiple myeloma (MM). Tazemetostat (TAZ), an oral selective EZH2 inhibitor, is approved for treatment of relapsed or refractory (R/R) follicular lymphoma. Preclinical studies demonstrated antiproliferative and synergistic effects of TAZ + lenalidomide (LEN), a Bruton tyrosine kinase inhibitor (BTKi), and daratumumab, pomalidomide, and dexamethasone (mAbPD) in DBLCL, MCL, and MM cell lines, respectively. LEN is effective for DLBCL and is approved in combination with tafasitamab-cxix, a CD19-directed cytolytic antibody (CD19 antibody [Ab]), for R/R DLBCL. Acalabrutinib, a BTKi, is approved in MCL, and mAbPD showed clinical activity in R/R MM. Aims: The aim of this study is to examine the efficacy and safety of TAZ + CD19 Ab, LEN, BTKi, or mAbPD in patients (pts) with R/R hematologic malignancies. Methods: This trial is a 2-part, multicenter, open-label, safety, efficacy, signal-finding, multi-arm phase 1b/2 study of TAZ plus various treatment regimens for hematologic malignancies (NCT05205252). Phase 1b is a dose escalation safety run-in; phase 2 is a dose expansion study. Currently, there are 4 treatment arms (Table). Written informed consent will be obtained upon enrollment. Eligible pts are adults (aged ≥18 y) with an ECOG performance status 0–1 (phase 1b) or 0–2 (phase 2) and measurable disease by Lugano classification for arms 1–3 or IMWG 2016 criteria for arm 4. Pts with severe concurrent disease are excluded from this study. During the phase 1b safety run-in portion of the study, pts will be enrolled in 3 dose escalation cohorts of TAZ 400 mg, 600 mg, and 800 mg. Pts in all novel treatment combinations (arms 1, 3, 4) will start at the lowest TAZ dose of 400 mg, and treatment combinations previously studied (arm 2) will start at TAZ 800 mg. All pts will receive TAZ orally twice daily in continuous cycles. All combination partners will be administered per their respective package insert or investigator brochure. The phase 1b portion endpoint summarizes treatment-emergent dose-limiting toxicities and adverse events to inform the recommended phase 2 dose for each arm. The primary endpoint for all arms in phase 2 is objective response rate; key secondary endpoints include progression-free survival, duration of response, overall survival, and safety. Results: As of February 9, 2022, no pts are enrolled at 1 active site; additional sites are in startup. Image:Summary/Conclusion: This phase 1b/2 study will provide insights into the efficacy and safety of TAZ + CD19 Ab, LEN, BTKi, or mAbPD in pts with R/R hematologic malignancies.

Background Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma. Methods We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (C-max), time to C-max (T-max), area under the concentration-time curve (AUC) to day 15 (AUC(0-t)), area under the curve from time 0 extrapolated to infinity (AUC0-& INFIN;), and the half-life (t(1/2)) of tazemetostat, assessed in all patients enrolled in part 1. The primary endpoint of part 2 was the disease control rate (the proportion of patients with a complete response, partial response, or stable disease) at week 12 in patients with malignant pleural mesothelioma per protocol with BAP1 inactivation determined by immunohistochemistry. The safety population included all the patients who had at least one post-dose safety assessment. This trial is now complete and is registered with ClinicalTrials.gov, NCT02860286. Findings Between July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean C-max was 829 ng/mL (coefficient of variation 56.3%), median T-max was 2 h (range 1-4), mean AUC(0-t) was 3310 h.ng/mL (coefficient of variation 50.4%), mean AUC(0-t) was 3180 h.ng/mL (46.6%), and the geometric mean t(1/2) was 3.1 h (13.9%). After a median follow-up of 35.9 weeks (IQR 20.6-85.9), the disease control rate in part 2 in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% CI 42-67; 33 of 61 patients) at week 12. No patients had a confirmed complete response. Two patients had a confirmed partial response: one had an ongoing partial response with a duration of 18 weeks and the other had a duration of 42 weeks. The most common grade 3-4 treatment-emergent adverse events were hyperglycaemia (five [7%] patients), hyponatraemia (five [7%]), and anaemia (four [5%]); serious adverse events were reported in 25 (34%) of 74 patients. Five (7%) of 74 patients died while on study; no treatment-related deaths occurred. Interpretation Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy. Copyright Crown Copyright (C) 2022. Published by Elsevier Ltd. All rights reserved.

1Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 2Late Stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 3Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 4Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA; 5Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Boston, MA, USA

7572 Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, showed antitumor activity as monotherapy in patients with relapsed or refractory (R/R) follicular lymphoma (FL) who received ≥2 prior lines of therapy. In clinical studies in patients with R/R FL, lenalidomide and rituximab (R2) demonstrated an objective response rate (ORR) of 73%–78% and median progression-free survival (PFS) of 36–39 months. This global, multicenter phase 1b/3 study is designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + R2 in patients with R/R FL after ≥1 prior therapy. We report an updated interim analysis of the phase 1b safety run-in where we assess the clinical activity and pharmacokinetics (PK) of TAZ when administered with R2 in patients with R/R FL. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily) in 28-day cycles with standard-dose R2 (NCT04224493). In addition to PK and safety, preliminary efficacy analysis was performed on the response-evaluable population, including best overall response, PFS, and duration of response (DOR) per investigator assessment according to Lugano 2014 response criteria. Results: As of January 22, 2022, 43 patients were enrolled and receiving TAZ + R2 (400 [n = 4], 600 [n = 18], and 800 mg [n = 21]). These patients had a median age of 67 years (range, 39–83) and received a median of 1 prior therapy (range, 1–4). Overall, 15/43 (34.9%) patients were refractory to rituximab, 10/39 (25.6%) had POD24, and 6/41 (14.6%) had mutant-type EZH2. Median duration of treatment exposure was 32.0 weeks (range, 4.1–68.1). Mean Cmax and AUC0–t of TAZ 800 mg + R2 at steady state were similar to those found for TAZ as monotherapy. PK of TAZ was not altered by concomitant administration of daily oral lenalidomide 20 mg, and PK of lenalidomide was not altered by concomitant administration of TAZ. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the January 2022 data cutoff. Serious treatment-emergent adverse events (TEAEs) were observed in 14 (32.6%) patients. Grade 3–4 TEAEs were observed in 24 (55.8%) patients; the most common grade 3–4 TEAE was neutrophil count decrease (n = 13; 30.2%). Of 38 patients evaluable for tumor assessment, 19 (50.0%) had a complete response, 17 (44.7%) had a partial response, and 2 (5.3%) had stable disease. ORR was 94.7% (n = 36). With a median follow-up of 5.8 months, median PFS and DOR were not reached and appeared to be similar, regardless of mutation status. Conclusions: TAZ + R2 combination demonstrates consistent and unaltered PK for TAZ and lenalidomide as well as a favorable safety profile and efficacy trend. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ RP3D 800 mg + R2 in ≈500 patients with R/R FL. Clinical trial information: NCT04224493.

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast-changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology-related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China-specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology-related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data.

WHAT IS KNOWN AND OBJECTIVE:Esomeprazole, the S-isomer of omeprazole, is a proton pump inhibitor which has been approved by over 125 countries, also known as NEXIUM® . Esomeprazole was developed to provide further improvement on efficacy for acid-related diseases with higher systemic bioavailability due to the less first-pass metabolism and lower plasma clearance. Esomeprazole is primarily metabolized by CYP2C19. Approximately <1% of Caucasians and 5%-10% of Asians have absent CYP2C19 enzyme activity. Although the influence of various CYP2C19 phenotypes on esomeprazole pharmacokinetics has been studied, this is the first report in the Japanese population where 27 low CYP2C19 metabolizers were included.METHODS:In this study, a population PK model describing the PK of esomeprazole was developed to understand the difference of CYP2C19 phenotypes on clearance in the Japanese population. The model quantitatively assessed the influence of CYP2C19 phenotype on esomeprazole PK in healthy Japanese male subjects after receiving repeated oral dosing. The inhibition mechanism of esomeprazole on CYP2C19 activity was also included in the model.RESULTS AND DISCUSSION:CYP2C19 phenotype and dose were found as statistically significant covariates on esomeprazole clearance. The apparent clearance at 10-mg dose was 17.32, 9.77 and 7.37 (L/h) for homozygous extensive metabolizer, heterozygous extensive metabolizer and poor metabolizer subjects, respectively. And the apparent clearance decreased as dose increased.WHAT IS NEW AND CONCLUSION:The established population PK model well described the esomeprazole PK and model-predicted esomeprazole PK was in good agreement with external clinical data, suggesting the robustness and applicability of the current model for predicting esomeprazole PK.

Abstract Background: DNA-dependent protein kinase (DNA-PK) is a critical sensor of DNA double-strand breaks (DSBs) and orchestrates their repair through non-homologous end joining (NHEJ). AZD7648 is a novel, potent and highly selective inhibitor of DNA-PK being evaluated as monotherapy or in combination with doxorubicin or olaparib in a Phase I/II first-in-human study. The objectives of this trial are to assess safety and tolerability, establish a Recommended Phase 2 Dose (RP2D) and evaluate early clinical activity. Pre-clinically, AZD7648 monotherapy leads to tumour growth inhibition in ATM deficient models in vivo, demonstrating potential to enhance the effects of endogenous tumour damage clinically. AZD7648 is also an efficient sensitizer of doxorubicin-induced DNA damage and demonstrates enhanced efficacy in combination with olaparib. Both combinations induce sustained regressions in vivo across a range of tumour xenografts with differing genetic alterations, accompanied by robust pharmacodynamic biomarker modulation. These data provide the rationale to explore AZD7648 as monotherapy and in combination with either doxorubicin or olaparib. Methods: This is a Phase I/IIa study comprising 3 modules: Core Module (AZD7648 monotherapy - dose escalation), combination module 1 (AZD7648 + pegylated liposomal doxorubicin [PLD]), and combination module 2 (AZD7648 + olaparib). Each combination evaluates AZD7648 in a Phase I escalation (Part A) and a Phase IIa expansion (Part B). Patients are assigned to a single study Part, but intra-patient dose escalation is permitted in Part A. The study incorporates a Bayesian adaptive dose escalation trial design which combines prior expectations about the dose toxicity relationship and applies the data at the end of each cohort to recommend a dose for the next cohort. The study will investigate pharmacodynamic (PD) and exploratory biomarker (DNA, RNA, proteins or metabolites) profiles in exclusive cohorts, and study their relationship to drug effect. Eligible patients are aged ≥18 years with advanced solid tumours, who have failed standard therapies. In Part A, patients are assessed for dose-limiting toxicities during the evaluable period. Blood samples are collected for pharmacokinetic (PK) analysis following a single dose of AZD7648 and at steady state. Single patient cohorts may occur for the first four cohorts (or until drug-related ≥ Grade 2 toxicity). From cohort 5 onwards, a minimum of 3 patients will be enrolled into each dose cohort until the Maximum Tolerated Dose, Maximum Feasible Dose or RP2D is identified. Enrolment into the study commenced in Oct 2019 and is currently enrolling cohort 3 in the monotherapy dose escalation. To date, no DLTs have been reported in prior cohorts. [clinicaltrials.gov identifier: NCT03907969] Citation Format: Timothy A. Yap, Yingxue Chen, Lisa H. Butler, Si-houy Lao-Sirieix, Elaine Cadogan, Lenka Oplustil O'Connor, Karthick Vishwanathan, Younghwa Kim, Dónal Landers, Emma Dean. AZD7648: A Phase I/IIa first-in-human trial of a novel, potent and selective DNA-PK inhibitor in patients with advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT248.

Various approaches to first‐in‐human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry‐wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100‐fold higher than the MABEL‐based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven‐based, and risk‐based approach for selecting FIH starting doses.

Inhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma. This phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 μg twice daily for 2–3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 μg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control. Fifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 μg, 34 received AZD7594 250 μg, and 34 received AZD7594 800 μg. AZD7594 800 μg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035–0.261, p = 0.011), with a dose-dependent response seen in the 250 μg (0.076 L -0·036–0·188, p = 0.183) and 58 μg (0·027 L -0·086–0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 μg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated. Two-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594. ClinicalTrials.gov number NCT02479412 .

1Clinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 2Early Product Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 3Early Phase Clinical Unit, PAREXEL, Glendale, CA, USA; 4Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 5Clinical Sample and Bioanalytical Science, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 6Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA; 7Clinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Boston, MA, USA Introduction: AZD7594 is a non-steroidal, selective, glucocorticoid receptor modulator

Objectives: PI3Kγ inhibition re-polarizes macrophages to an immuno-stimulatory phenotype, thereby activating a T-cell mediated tumor immune response. AZD3458 is a highly selective PI3Kγ inhibitor. Administration of AZD3458 in combination with checkpoint inhibitors such as α-PD-(L)1 antibodies had greater anti-tumor effects (TGI 26-86%) than checkpoint inhibitor alone in 4T1, LLC, CT-26 and MC-38 syngeneic mouse models. In these, AZD3458 remodeled the tumor microenvironment (TME), reducing immunosuppressive markers (e.g in 4T1 model there was a 20% decrease in total macrophages and 50% decrease in markers of immune suppression like CD206 by flow cytometry) and promoting cytotoxic T-cell activation (e.g. in CT-26 model there was a 2-fold increase in gzmB mRNA). We developed a predictive quantitative systems pharmacology (QSP) model, to quantitatively simulate TME effects and delineate mechanistic principles underlying AZD3458 and α-PD-(L)1 synergistic effects.Methods: The QSP model captures mechanistic, molecular and cellular interactions between PI3Kγ inhibition and checkpoint inhibitors, together with the pharmacokinetics acting on the respective targets. Features such as PI3Kγ inhibition-dependent tumor-associated macrophages, protein expression of immunosuppressive markers, reduction of MDSC activation and promotion of cytotoxic T-cell activation were included in the model. These immuno-changes were then linked to tumor cell death, resulting in macroscopic dynamic effects on tumor size. Some model parameters were taken from the literature and internal studies; some were estimated using NLME modeling of tumor size data.Results: The model adequately described individual and population tumor size patterns. Inter-animal variability was described using a random effect on a parameter related to the ability of T cells to infiltrate the tumor in response to systemic antigen. Additionally, the model incorporated in one quantitative framework data from 4 syngeneic tumors capturing respective changes in TME conditions. Simulations for the various treatments supported the mechanistic interpretation of the observed AZD3458 and α-PD-(L)1 synergistic effects. The model was further used to simulate treatment scenarios, to infer optimal dosing and scheduling for the combination and given underlying TME conditions.Conclusions: This study provides quantitative mechanistic insights into the links between PI3Kγ inhibition and anti-tumor immune responses, supporting our understanding of how AZD3458 may alleviate brakes in a myeloid immuno-suppressive TME and revert resistance to immunotherapy. This mechanistic understanding is critical when proceeding with dose escalation in an early clinical trial setting, as it allows to contextualize any potential compound-induced immuno-modulation in patients, for given doses and schedules.Citation Format: Pablo Morentin Gutierrez, Yuri Kosinsky, Kirill Peskov, Ivan Azarov, Lulu Chu, Veronika Voronova, Martin Johnson, Yingxue Chen, Larissa Carnevalli, Danielle Carroll, Michele Moschetta, Teresa Klinowska, Gabriel Helmlinger. Mechanistic insights and dose optimization for AZD3458, a novel selective PI3Kg immuno-modulator, using a quantitative systems approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 104.

INTRODUCTION:AZD7594 is a non-steroidal, selective, glucocorticoid receptor modulator (SGRM), currently in development for the treatment of asthma and chronic obstructive pulmonary disease. This paper reports a randomized placebo-controlled dose escalation study in healthy Japanese male subjects. METHODS:Inhaled AZD7594 was administered as one single dose at day 1 (day 1-4), with subsequent multiple daily doses (day 5-16) via a multiple-dose dry powder inhaler for 12 days of once-daily treatment. At each dose level, subjects were randomized to AZD7594 (n=7) or placebo (n=2). The safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD7594 were evaluated. RESULTS:Inhaled AZD7594 was safe and well tolerated up to and including the highest dose 1600 µg tested. Plasma exposure suggested dose-proportional PK. The urinary excretion of AZD7594 was negligible (<0.02%). Dose-related effects were observed for 24 hrs plasma cortisol; however, significant cortisol suppression (25%) was only seen at the highest dose level following multiple doses. There were no or only marginal effects on other biomarkers tested (dehydroepiandrosterone sulfate [DHEA-S] and osteocalcin). CONCLUSION:In conclusion, the early clinical evaluation of inhaled AZD7594 suggests that this novel SGRM is well tolerated in the dose range investigated and also in a Japanese population. It shows dose-proportional plasma exposure, moderate accumulation and has limited impact on systemic markers of glucocorticoid activity.

Abstract Background: AZD0156 is a highly selective first oral ATM inhibitor in the clinic. Coordinating DNA single and double strand break repair, AZD0156 enhances the preclinical activity of olaparib, leading to its development as an antitumor agent in combination. We report here results from an ongoing phase 1 adaptive dose escalation study of AZD0156 in combination with olaparib. Methods: This phase I study is to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of escalating doses of AZD0156 in combination with olaparib in patients with advanced malignancies. AZD0156 is mainly metabolized by CYP3A and FMO, which undergo genetic polymorphism. The flexible language incorporated in the protocol also allow rapid dose escalation beyond subtherapeutic doses. Results: PK data from the first 2 dose cohorts were lower than predicted and the AZD0156 dose was increased 4 X and dosing changed from QD (daily) to BD (twice daily). The mean terminal half-life of AZD0156 was 9-12 hours and PK was dose proportional. No significant drug-drug interactions (DDI) were observed with olaparib. Minor toxicities included nausea, vomiting and anemia in about 40% of patients in all cohorts. Grade 3 and 4 hematologic toxicities were observed in AZD0156 120mg BD with olaparib 200mg BD, and this dose level was considered intolerable. At doses of AZD0156 of 30 and 60mg BD, active target engagement was demonstrated. PK profile was similar across FMO genotype. Conclusion: Hematologic toxicities, consistent with the mode of action, emerged as dose-limiting toxicities of AZD0156 in combination with olaparib. Pharmacologically active doses of AZD0156 with olaparib were achieved more quickly in patients by using real-time PK, real-time genotyping, safety, DDI assessment, and PK/PD modelling. Citation Format: Yingxue Chen, Martin Pass, Nuria Bui Bruna, Christine Stephens, Andrew Pierce, Wouter Hanekom, Hani Gabra, Helen Tomkinson, Nidal Al-Huniti. Adaptive oncology phase 1 study of first-in-class inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib [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 4909.

ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5-c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.

Abstract Background: ATM (ataxia telangiectasia mutated protein) is a serine-threonine kinase that is a key mediator of the DNA damage response elicited by double strand breaks. AZD0156 is a potent, selective inhibitor of ATM. Preclinical data suggest a synergistic effect of AZD0156 when combined with DNA damage targeting agents, including olaparib. Materials and Methods: This is an international, modular phase I study to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of escalating doses of AZD0156 in combination with either cytotoxic chemotherapy or novel anticancer agents in patients with advanced malignancies. Here we report the results of Module 1, an evaluation of AZD0156 with olaparib. Patients with solid tumors and PS 0 or 1 were recruited in cohorts of 3 to 6 evaluable patients. Module 2 will be a combination with irinotecan. Results: 46 patients have been recruited in 8 cohorts combining AZD0156 with olaparib (Table 1). The terminal half-life of AZD0156 was approximately 9-12 hours and dose/exposure proportionality was observed. No significant PK interactions were observed with olaparib. Minor toxicities included nausea, vomiting, and anemia in about 40% of patients in all cohorts. Grade 3 and 4 hematologic toxicities were observed in cohort 7 (AZD0156 120mg po bd with olaparib 200mg po bd), and this dose level was considered intolerable. At doses of AZD0156 of 60mg bd, plasma concentrations of AZD0156 were consistent with efficacy in gastric cancer cell cultures. Further dosing schedules are being explored. There have been two confirmed partial responses (RECIST): one in a patient whose tumor harboured germline BRCA2 mutations (Cohort 2), and one in a patient whose tumor had unknown tumor genetics but no significant family history (Cohort 4a). One patient with somatic BRCA2 deletion has had stable disease for 18 months (Cohort 1). Conclusions: Hematologic toxicity, consistent with the mode of action, appears to be the treatment-limiting toxicity for AZD0156 in combination with olaparib. AZD0156 can be given at doses and schedules that achieve exposures consistent with in vitro efficacy. Continued exploration of AZD0156 in combination with olaparib and other agents in solid malignancies is a promising area for further research. Cohort / Evaluable patientsDose/Schedule AZD0156Dose/Schedule olaparibComment1 / 62mg od for 3 days out of 7100mg bd continuouslyWell tolerated2 / 58mg od for 3 days out of 7100mg bd continuouslyWell tolerated3 / 630mg od for 3 days out of 7100mg bd continuouslyWell tolerated4a / 630mg bd for 3 days out of 7100mg bd continuouslyWell tolerated4b / 615mg bd for 3 days out of 7200mg bd continuouslyWell tolerated5 / 430mg bd for 3 days out of 7200mg bd continuouslyWell tolerated6a / 460mg bd for 3 days out of 7200mg bd continuouslyWell tolerated. PK indicated AZD0156 exposures are proportional to doses and reach IC90 defined in gastric ca cell line6b / 430mg bd for 3 days out of 7300mg bd continuously1 patient experienced Grade 2 neutropenia & thrombocytopenia7 / 4120mg bd for 3 days out of 7200mg bd continuously1 patient: Grade 2 neutropenia & thrombocytopenia; 1 patient: Grade 3 anaemia, Grade 2 thrombocytopenia and Grade 4 neutropeniaAE’s occurred during Cycle 1 or 2; were not Dose Limiting Toxicities as defined in the protocol, but considered to be non-tolerated by the Safety Review Committee8 / 260mg bd for 3 days out of 7300mg bd continuouslyPotential candidate for efficacy evaluation Citation Format: Wassim Abida, Yung J. Bang, Louise Carter, Analía Azaro, Matthew Krebs, Seock-Ah Im, Yingxue Chen, Núria Buil-Bruna, Yan Li, David Eaton, Christine Stephens, Graham Ross, Martin Pass, Jordi Rodon, Emma Dean. Phase I modular study of AZD0156, a first-in-class oral selective inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib (AToM Study, Module 1) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A094.