Proportional Increase In Exposure Research Articles

Safety and preliminary efficacy of ivaltinostat, an HDAC inhibitor, plus capecitabine in patients with pretreated metastatic pancreatic adenocarcinoma (mPDAC): Results of a phase Ib study.

742 Background: Front-line chemotherapy for patients (pts) with mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses cell proliferation, and promotes apoptosis. Preclinical data demonstrated synergy with 5-FU/capecitabine (cape) in mouse models. We report here results of the Phase Ib portion of a Ib/2 trial evaluating the safety and recommended phase 2 dose (RP2D) of this combination to use in a randomized study of ival + cape vs cape as maintenance therapy. Methods: Key eligibility criteria for phase 1b included unresectable or metastatic PDAC; ≥18 years old; ≥1 prior therapy; ECOG PS 0-1; and no known germline BRCA1/2 mutation. Three cohorts were enrolled, receiving ivaltinostat at 60, 125, or 250mg/m 2 iv (weekly on days 1 and 8) in combination with cape (1000mg/m 2 po BID on days 1-14) of a 21-day cycle. 1o objectives: safety, tolerability and RP2D; 2o objectives: pharmacokinetics (PK) of ival + cape. Results: A total of 28 patients were enrolled at the 60 (n=6), 125 (n=10) and 250 (n=12) mg/m 2 ival dose levels. Median prior lines of therapy: 2 (range 1-7). Median age: 67 years (range 50-83). Only one DLT (G4 thrombocytopenia) was observed at 250mg/m 2 dose level. Treatment-emergent AE profile was similar across dose levels, with common TEAEs including fatigue (n=15, 53.6%), nausea (n=14, 50.0%), palmar-plantar erythrodysesthesia syndrome (n=12, 42.9%), diarrhea (n=10, 35.7%), and constipation (n=9, 32.1%). G3 AEs included neutropenia (n=6, 21.4%), anemia (n=4, 14.3%), abdominal pain (n=3, 10.7%) and diarrhea (n=3, 10.7%). G4 AEs included 1 (3.6%) event of neutropenia and 1 (3.6%) of thrombocytopenia. No SAEs related to study drugs occurred in any of the 3 dose cohorts. PK analyses indicated dose proportional increases in exposure with increasing doses of ival. Histone H3K27 acetylation for ival showed the similar trend in optical density evaluation. Across all dose levels and prior treatments, median OS and PFS were 9.6 and 3.3 months, respectively. Conclusions: The combination of ival and cape was generally well tolerated in this heavily pretreated patient population. Ival 250 mg/m 2 is the dose selected for the ongoing randomized study of ival + cape vs cape in the maintenance setting for mPDAC pts post-FOLFIRINOX, which is expected to finish accrual in 2025. Clinical trial information: NCT05249101 .

Preclinical evaluation and phase 1 study of the PI3Kα/δ inhibitor TQ-B3525 in Chinese patients with advanced cancers.

Phosphatidylinositol 3-kinase (PI3K) inhibitors transformed management of various malignancies. This study preclinically characterized TQ-B3525 (dual PI3Kα/δ inhibitor) and assessed the recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics in relapsed or refractory (R/R) lymphoma or advanced solid tumors (STs). Oral TQ-B3525 was given at eight dose levels on a 28-day cycle. Primary end points were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and safety. TQ-B3525 showed high selectivity and suppressed tumor growth. Between June 12, 2018, and November 18, 2020, 80 patients were enrolled (63 in dose-escalation cohort; 17 in dose-expansion cohort). Two DLTs occurred in two (two of 63, 3.2%) DLT-evaluable patients; MTD was not identified. TQ-B3525 at 20 mg once daily was selected as RP2D. Grade 3 or worse treatment-related adverse events mainly included hyperglycemia (16.3%), neutrophil count decreased (15.0%), and diarrhea (10.0%). Two (2.5%) treatment-related deaths were reported. Sixty patients with R/R lymphoma and 11 advanced STs demonstrated objective response rates of 68.3% and 9.1%, disease control rates of 91.7% and 54.6%, median progression-free survivals of 12.1 and 1.1 months; median overall survivals were not reached. TQ-B3525 exhibited rapid absorption and a nearly proportional increase in exposure. Acceptable safety and promising efficacy support further investigation of TQ-B3525 (20 mg once daily) for R/R lymphoma.

Preclinical Systemic Pharmacokinetics, Dose Proportionality, and Central Nervous System Distribution of the ATM Inhibitor WSD0628, a Novel Radiosensitizer for the Treatment of Brain Tumors.

Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier. The objective of this study was to evaluate the systemic pharmacokinetics and mechanisms that influence the central nervous system (CNS) distribution of WSD0628, a novel and potent ATM inhibitor, in the mouse. Further, we have used these observations to form the basis of predicting effective exposures for clinical application. We observed a greater than dose proportional increase in exposure, likely due to saturation of clearance processes. Our results show that WSD0628 is orally bioavailable and CNS penetrant, with unbound partitioning in CNS (i.e., unbound tissue partition coefficient) between 0.15 and 0.3. CNS distribution is not limited by the efflux transporters P-glycoprotein and breast cancer resistant protein. WSD0628 is distributed uniformly among different brain regions. Thus, WSD0628 has favorable pharmacokinetic properties and potential for further exploration to determine the pharmacodynamics-pharmacokinetics efficacy relationship in CNS tumors. This approach will provide critical insights for the clinical translation of WSD0628 for the treatment of primary and secondary brain tumors. SIGNIFICANCE STATEMENT: This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM inhibitor for the treatment of brain tumors. Results indicate that WSD0628 is orally bioavailable and CNS penetrant without efflux transporter liability. We also observed a greater than dose proportional increase in exposure in both the plasma and brain. These favorable pharmacokinetic properties indicate WSD0628 has potential for further exploration for use as a radiosensitizer in the treatment of brain tumors.

ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics

PurposeAlzeCure Pharma AB is developing novel positive allosteric modulators of Trk-receptors for treatment of Alzheimer’s disease, depression, other psychiatric conditions and other disorders where cognition is impaired. The preceding candidate drug ACD855 was shown to have a too long half-life in humans to allow further development. To de-risk the development of the follow-up compound ACD856, the oral single ascending dose study of ACD856 in humans was preceded by an intravenous microdose study, assessing the elimination half-life in plasma.MethodsA phase 0 study with a microdose of ACD856 (0.100 mg), was conducted in six healthy male subjects all receiving ACD856. Sequentially, a randomized, placebo-controlled, double-blind Phase I single ascending oral dose study (1 – 150 mg) was conducted, including 56 healthy subjects. Both studies assessed the safety and tolerability, as well as the PK properties of ACD856 after single dose intravenous and oral administration.ResultsACD856 was well tolerated with no treatment emergent, or dose related adverse events or other safety assessments. In the microdose study, ACD856 exhibited a bi-exponential plasma decline, low distribution volume, low plasma clearance with a half-life of approximately 20 hours. Orally, ACD856 exhibited rapid absorption, an almost complete bioavailability and a dose proportional increase in exposure. While the Cmax was lowered and delayed by food intake, the effect on plasma half-life and the overall bioavailability was low. No renal elimination of ACD856 was detected. ConclusionThe prediction proved accurate demonstrating the value of conducting a microdose study prior to ascending dose studies.Trial registrationNCT05783830 March 24, 2023 (microdose study, retrospectively registered) and NCT05077631 October 14, 2021 (single ascending dose study).

P633 First-in-Human Pharmacokinetic and Safety Study of an Anti-TL1A Antibody, TEV-48574, in Healthy Volunteers and Asthma Patients

Abstract Background TEV-48574 is a human antibody that targets tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15). TEV-48574 is in clinical development as a potential treatment for ulcerative colitis (UC) and Crohn’s disease (CD); and has been shown to reduce fibrosis, inflammation, and mortality in animal models of IBD and asthma.1 The main objectives of this phase 1 study were to characterize the pharmacokinetics (PK) and safety of TEV-48574 in healthy subjects and mild asthmatic patients. Methods In the single ascending dose part of the study (SAD), healthy subjects were randomized 6:2 to active and placebo treatment; specifically participants were either administered TEV-48574 single dose (1, 4, 12, 36, 90, 200, 400, or 1000 mg) or placebo by subcutaneous route (SC). In the multiple ascending dose part of the study (MAD) patients with asthma were randomized 9:3 to active and placebo treatment in three cohorts. Cohort 1 received TEV-48574 200 mg Q2W or placebo (days 1, 15, and 29). Cohort 2 received a loading TEV-48574 dose of 800 mg on day 1 followed by 2 maintenance doses of 600 mg on days 15 and 29 (800/600 mg Q2W) or placebo. Cohort 3 received a loading TEV-48574 dose of 2300 mg on day 1 followed by 2 maintenance doses of 1600 mg on days 15 and 29 or placebo. Safety, tolerability, PK, and anti-drug antibody (ADA) levels were assessed at predetermined times. Measurement of total and free TL1A using ligand binding assays will be reported elsewhere. Results TEV-48574 was absorbed slowly with peak concentrations appearing at 72- 96 hours following SAD and MAD administration. It was eliminated gradually in a monophasic manner and the rate of elimination appeared similar across dose levels (Figure 1). Exposures as defined by maximum concentration (Cmax) and area under the curve (AUC) of TEV-48574 increased in a dose-proportional manner with no accumulation. Mean t½ estimates ranged from 6.5 to 9.6 days (Table 1). Administration of TEV-48574 was generally well tolerated at doses up to 2300 mg. ADA-positive responses were observed at doses of 200 mg or lower in 23 of 48 TEV-48574-treated subjects in the SAD portion of the study and in 3 of 27 TEV-48574-treated patients in the MAD portion of the study and were not associated with safety signals. Conclusion TEV-48574 was well tolerated at all tested doses in healthy subjects and participants with asthma, with dose proportional increases in exposure and minimal accumulation after multiple dosing every two weeks. The data support further development of TEV-48574 in patients with IBD. 1. Clarke A. et al. mAbs.2018;10:664-677.

Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging

Basmisanil, is a lipophilic drug substance, exhibiting poor solubility and good permeability (BCS class 2). A validated physiologically based biopharmaceutics model (PBBM) has been previously described for tablets dosed in the fed state. The PBBM captured the less than proportional increases in exposure at higher doses well and indicated that absorption was dissolution rate-limited below 200 mg while solubility was limiting for higher doses. In this study, a model for dosing in the fasted state is described and is verified for simulation of the food effect where exposures were ~1.5 fold higher when a 660 mg tablet was given with food. The model is then applied to simulate the food effect for a granules formulation given at a lower dose (120 mg). The food effect at the lower dose was reasonably simulated with a ratio of simulated/observed food effect of 1.35 for Cmax and 0.83 for AUC. Sensitivity analysis was carried out for uncertain model parameters to confirm that the model could predict the magnitude of the positive food effect with moderate to high confidence. This study suggests that a verified PBBM can provide a useful alternative to a repeat food effect study when formulation changes are minor. However, there is need for further evaluation of the approach and a definition of what formulation changes are minor in this context. In addition, this work highlights some uncertainties in the handling of solubility in PBBM, in particular around temperature dependency of solubility and the parameterization of bile salt solubilization using measurements in biorelevant media.

Dose-Exposure-Response Relationships of Biomarkers and Efficacy Measures with Iptacopan, a Complement Factor B Inhibitor, in Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) with or without Concomitant Anti-C5 Therapy

Background: Standard of care treatment for pts with PNH targets C5 in the complement pathway; however, residual intravascular hemolysis (IVH) and emerging C3-mediated extravascular hemolysis (EVH) can still occur. In two Phase II trials (X2201 [NCT03439839] and X2204 [NCT03896152]), the oral, selective, reversible complement factor B inhibitor iptacopan provided hematologic benefit in pts with PNH who had active hemolysis, both as add-on therapy in anti-C5-treated pts and monotherapy in anti-C5-naïve pts (Risitano et al. Lancet Haematol 2021; Jang et al. Blood Adv 2022). Using data from these two studies, this integrated analysis aimed to evaluate dose-exposure-response relationships of biomarkers and efficacy measures to support dose selection for iptacopan. Methods: X2201 and X2204 were open-label studies that enrolled pts with PNH who had active hemolysis, despite treatment with anti-C5 therapy, or in the absence of prior anti-C5 therapy, respectively. In X2201, pts with lactate dehydrogenase (LDH) ≥1.5 x upper limit of normal (ULN) received iptacopan 200 mg twice daily (bid; Cohort 1) and pts with LDH ≥1.25 x ULN and hemoglobin (Hb) <10.5 g/dL received iptacopan 50 mg bid (Cohort 2). Pts in Cohort 2 could have their dose increased to 200 mg bid if hemolysis persisted. Both cohorts received iptacopan as add-on therapy to eculizumab; eculizumab treatment could be adjusted or withdrawn after 26 weeks (wks) at the investigator's discretion. In X2204, pts with LDH ≥1.5 x ULN and Hb <10.5 g/dL who were naïve to anti-C5 treatment were randomized to receive iptacopan 25 mg bid for 4 wks followed by iptacopan 100 mg bid for 8 wks (Cohort 1), or iptacopan 50 mg bid for 4 wks followed by iptacopan 200 mg bid for 8 wks (Cohort 2). To quantify the exposure-response relationship, trough concentrations of iptacopan (Ctrough) were correlated with LDH, Hb, factor Bb fragments, Wieslab® alternative complement pathway activity assay data, C3 fragment deposition on red blood cells (RBCs) and PNH RBC clone size using sigmoid maximum effect (Emax) models. Analyses were performed after pts had received iptacopan at the same dose for 4 wks. Results: A total of 29 pts with PNH were enrolled (X2201, N=16; X2204, N=13). The pharmacokinetic parameters of iptacopan were in line with previous reports in these two studies (Risitano et al. Lancet Haematol 2021; Jang et al.Blood Adv 2022) and were similar between the two study populations. In the dose range 25-200 mg bid, increases in dose resulted in a less than proportional increase in exposure, probably because of on-target binding to the highly abundant plasma factor B. Age and sex did not significantly impact exposure; the impact of ethnicity was not assessed because it was confounded by the study populations (15/16 pts in X2201 were Caucasian; all pts in X2204 were Asian). When assessing LDH, Hb, factor Bb fragments and Wieslab® assay data, 95% of the maximum response was reached with Ctrough >700 ng/mL, >650 ng/mL, >500 ng/mL and >750 ng/mL (EC95), respectively. C3 deposition was only informative in X2201; in X2204, C3 deposition was negligible at baseline and throughout the study because the pts were anti-C5-naïve. Complete abrogation of C3 deposition was reached at all dose levels in X2201 (Ctrough >600 ng/mL). PNH RBC cell clone size increased in both studies, but no clear dose-dependent relationship was observed. Accounting for interpatient variability in exposure, iptacopan 200 mg bid was identified as the optimum regimen to achieve Ctrough >750 ng/mL in most pts. Conclusions: Results from this pooled dose-exposure-response analysis of the X2201 and X2204 studies indicate that iptacopan 200 mg bid is the optimum dose to achieve Ctrough >750 ng/mL and consequently to provide maximal disease control via alternative complement pathway inhibition. The dose-exposure-response relationship was similar between pts regardless of whether they had a partial response to C5 inhibition (X2201) or were anti-C5-naïve (X2204), supporting the use of iptacopan 200 mg bid in both populations. Based on clinical efficacy and safety data from these two studies (Risitano et al. Lancet Haematol 2021; Jang et al. Blood Adv 2022) and supported by data from this integrated dose-exposure-response analysis, two ongoing Phase III trials are investigating iptacopan monotherapy at a dose of 200 mg bid in anti-C5 treated (APPLY-PNH; NCT04558918) and anti-C5-naïve (APPOINT-PNH; NCT04820530) pts with PNH.

Dose-dependent bioavailability and tissue distribution of the ATR inhibitor AZD6738 (ceralasertib) in mice.

Ataxia telangiectasia and Rad3-related (ATR) initiates and regulates cellular responses to DNA damage, such as those caused by cancer treatments. Several ATR inhibitors (ATRi) are in clinical development including AZD6738. Therapeutic indices among ATRi may differ as a result of varying potencies and concentrations at both tumor and off-target sites. Additionally, AZD6738 contributes to anti-tumor immune responses necessitating evaluation of exposure at immunological sites. Using mouse models and a highly sensitive LC-MS/MS assay, the pharmacokinetics of AZD6738 were studied, including dose linearity, bioavailability, metabolism, and tissue distribution in tumor-bearing mice. Initial studies identified dose-dependent bioavailability, with greater than proportional increases in exposure as dose increased resulting in a ~ twofold increase in bioavailability between the lowest and highest investigated doses. These behaviors were successfully captured with a compartmental PK model. Analysis of metabolite PK revealed decreasing metabolic ratios with increasing dose, indicative of saturable first-pass metabolism. Further analysis revealed that intestinal and gut metabolism contribute to metabolism and these saturable mechanisms. Studies of tumor and tissue distribution found rapid and extensive drug distribution to most tissues except brain and spinal cord. The complex non-linear behavior of AZD6738 PK in mice was due to pre-systemic saturation and which appears to be recapitulated clinically at low doses. PK reported here will allow future correlation of tissue related toxicities with drug exposure as well as exposure with immunological responses. These results can also be compared with those from similar studies of other ATRi to contrast drug exposure with responses.

Phase 1 Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-946 in Healthy Volunteers

Background: Glycolysis is the primary source of ATP in red blood cells (RBCs), which is critical for maintaining RBC health. Pyruvate kinase red cell isoform (PKR) catalyzes the final step of glycolysis to generate ATP. Enhancing ATP production via PKR activation is under investigation as a potential therapeutic approach in hemolytic anemias. Increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG) in sickle cell disease (SCD) decreases hemoglobin oxygen affinity and results in increased RBC sickling. PKR activation has been shown to reduce 2,3-DPG. In previous clinical studies in pyruvate kinase deficiency, thalassemia and SCD, treatment with mitapivat, a PKR activator, led to improvements in hemoglobin and markers of hemolysis.AG-946 is an investigational, next-generation, oral small molecule activator of wild-type and mutant PKR isoforms, with high potency. Modelling from preclinical studies suggest that AG-946 is likely to have a pharmacokinetic (PK) profile that allows for once daily (QD) dosing and long duration of pharmacodynamic (PD) effects in humans. Here we report preliminary blinded results from an ongoing study assessing the safety, tolerability, PK and PD of AG-946 in healthy volunteers (NCT04536792).Methods: In this phase 1, randomized, double-blind, placebo (P)-controlled study, single ascending oral doses (SAD) or multiple ascending oral doses (MAD) of AG-946 were administered under fasting conditions to healthy men and women (18-55 years of age) in sequential cohorts. In SAD (4 cohorts of 8 subjects each) and in MAD (2 cohorts of 8 subjects each) subjects were planned to be randomized to receive either AG-946 (n=6) or P (n=2). The dose levels studied so far are 1, 3, 10, and 30 mg in SAD and 1 mg QD and 2 mg QD for 14 days in MAD. Safety assessments included vital signs, physical exams, electrocardiograms, clinical laboratory parameters and adverse events (AEs). Serial blood samples were drawn for PK and PD (2,3-DPG; ATP) assessments at regular intervals throughout the study period.Results: As of June 02, 2021, 39 (median age 33 years; n = 33 male) subjects in SAD and 17 (median age 36 years; all male) subjects in MAD received AG-946 or P. There were 6 (SAD, n = 5; MAD, n = 1) early discontinuations; all were unrelated to study treatment. In SAD, 4/39 (10.3%) subjects experienced ≥ 1 treatment-emergent AE (TEAE); all TEAEs were assessed as mild (Grade [Gr] 1). In MAD 4/17 (23.5%) subjects experienced ≥ 1 TEAE; the majority of the TEAEs were mild (Gr 1), with 1 subject experiencing a serious AE (Gr 2) of exercise-induced rhabdomyolysis 14 days after last dose, considered unrelated to study treatment. All other AEs in SAD and MAD were also considered unrelated to study treatment.In both SAD and MAD, AG-946 exhibited rapid absorption with median T max (time to maximum concentration) ranging from 0.5 to 1 hour. Following SAD, dose-normalized AG-946 exposures (AUC and C max [area under the curve and maximum concentration observed]) increased with increasing AG-946 doses, suggesting a greater than dose proportional increase in exposure over the tested dose range. Following MAD, AG-946 exposures were higher on Day 14 compared with Day 1, with mean accumulation ratios based on AUC of 3.6 at 1 mg QD and 3.3 at 2 mg QD, and mean accumulation ratios based on C max of 1.95 at 1 mg QD and 1.6 at 2 mg QD.In both SAD and MAD, an increase in AG-946 dose was associated with a decrease in 2,3-DPG concentrations (Figure 1), and an increase in ATP concentrations (Figure 2). The PD changes were sustained up to 168 hours after a single dose and > 7 days after the last day of multiple QD dosing, consistent with the slow off-rate from PKR.As expected, no clinically significant changes in Hb have been observed in the SAD or MAD cohorts, to date.Conclusions: AG-946, a highly potent PKR activator, was well tolerated in healthy volunteers following single dose administrations up to 30 mg and multiple 14-day dosing with 1 mg QD and 2 mg QD. The PK profile of AG-946 supports QD dosing, and is accompanied by sustained dose-dependent increases in ATP and decreases in 2,3-DPG, consistent with activation of the glycolytic pathway. Enrollment into additional SAD and MAD cohorts is ongoing and will be followed by an open-label phase in subjects with SCD. [Display omitted] DisclosuresIyer: Novartis: Current equity holder in publicly-traded company; Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Ronseaux: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Gamache: Agios Pharmaceuticals: Current Employment. Callaghan: Agios Pharmaceuticals: Current Employment.

The Dolaflexin-based Antibody-Drug Conjugate XMT-1536 Targets the Solid Tumor Lineage Antigen SLC34A2/NaPi2b.

Target selection for antibody-drug conjugates (ADC) frequently focuses on identifying antigens with differential expression in tumor and normal tissue, to mitigate the risk of on-target toxicity. However, this strategy restricts the possible target space. SLC34A2/NaPi2b is a sodium phosphate transporter expressed in a variety of human tumors including lung and ovarian carcinoma, as well as the normal tissues from which these tumors arise. Previous clinical trials with a NaPi2b targeting MMAE-ADCs have shown objective durable responses. However, the protein-based biomarker assay developed for use in that study was unable to discern a statistically significant relationship between NaPi2b protein expression and the probability of response. XMT-1536 is a NaPi2b targeting ADC comprised of a unique humanized antibody conjugated with 10-15 auristatin F- hydroxypropylamide (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is a cell-permeable, antimitotic compound that is slowly metabolized intratumorally to an active, very low-permeable metabolite, auristatin F (AF), resulting in controlled bystander killing. We describe the preclinical in vitro and in vivo antitumor effects of XMT-1536 in models of ovarian and lung adenocarcinoma. Pharmacokinetic analysis showed approximately proportional increases in exposure in rat and monkey. Systemic free AF-HPA and AF concentrations were observed to be low in all animal species. Finally, we describe a unique IHC reagent, generated from a chimeric construct of the therapeutic antibody, that was used to derive a target expression and efficacy relationship in a series of ovarian primary xenograft cancer models.

Abstract PS11-26: A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer

Abstract Background: Targeting the estrogen receptor (ER) has proven to be one of the most successful strategies in treating HR+ (ER+ and PR+) and HER2- breast cancer. Selective estrogen receptor degraders (SERD) can be used as single agents or in combination with CDK4/6 inhibitors such as palbociclib. Fulvestrant is currently the only approved agent in its class and is limited by poor oral bioavailability necessitating monthly intramuscular injections. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft models and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development. Methods: A first-in-human phase 1 study was conducted to evaluate D-0502 in women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objectives are to evaluate the PK properties and the preliminary anti-tumor activities. Patients received D-0502 orally once daily in 28-day cycles. The study has completed dose escalation (phase 1a), and dose expansion and combination studies (phase 1b) are ongoing. In phase Ia, patients were enrolled and evaluated using conventional 3+3 dose-escalation to identify the MTD of D-0502 as a single agent. The phase 1b was divided into 2 stages. In Stage 1, D-0502 was evaluated with palbociclib at a dose below the MTD first before escalating to the MTD. Stage 1 also included patients in China treated at a dose below and at the MTD as single agent as well as in combination with palbociclib. Stage 2 will further evaluate the MTD for both single agent and combination of D-0502 with palbociclib. Results: At the time of this abstract submission, phase 1a dose escalation is completed, R2PD has been identified, and no DLTs were observed. PK analysis of D-0502 indicates a dose proportional increase in exposure as the dose increases, and the exposure has exceeded the potential therapeutic exposure level based on preclinical studies. The Phase Ib Stage 1 portion has also completed enrollment and the study is currently enrolling patients into phase Ib Stage 2. D-0502 as a single agent or in combination has been well tolerated with radiological tumor response and clinical benefit response (CBR) observed. Safety, PK and preliminary efficacy data will be reported at the meeting presentation. Conclusion: A first-in-human phase 1 study of D-0502 has been initiated in women with advanced or metastatic HR-positive and HER2-negative breast cancer. D-0502 has been well tolerated and achieved significant exposure and preliminary clinical activity in patients. Further results will be presented at the meeting. Citation Format: Cynthia Osborne, Donald A Richards, Sharon T Wilks, Sami Diab, Dejan Juric, Kate Lathrop, Andrea Silber, William Edenfield, Amardeep Aulakh, Ben Cho, Binghe Xu, Tao Sun, Quchang Ouyang, Yanxia Shi, Kathryn Stazzone, Zhe Shi, Ling Zhang, Yaolin Wang, Erika P Hamilton. A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-26.

First-in-man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M1 -receptor partial agonist for the treatment of dementias.

AimsHTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses.MethodsThis randomized, double‐blind, placebo‐controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1–35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross‐over design in 14 healthy subjects.ResultsPharmacokinetics of HTL0018318 were well‐characterized showing dose proportional increases in exposure from 1–35 mg. Single doses of HTL0018318 were associated with mild dose‐related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2–16.3], 35‐mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9–18.9], 15‐mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance.ConclusionHTL0018318 showed well‐characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias.

1283. New Generation Antiviral Conjugate (AVC): Stable, Safe, and Single

BackgroundCD377 is a novel antiviral Fc-conjugate (AVC) development candidate for influenza prevention and treatment, comprising multiple copies of a novel potent small-molecule antiviral and the Fc domain of human IgG1. CD377 was designed as a stable, long-acting molecule for treatment and prevention of influenza A and B. Studies were conducted to characterize CD377 stability/pharmacokinetics (PK), single-dose efficacy in influenza models, and safety/toxicology.MethodsPK in the mouse (1-100 mg/kg), rat (5-50 mg/kg), ferret (3 mg/kg), and monkey (5-20 mg/kg) were studied by sampling plasma over a 1-2 week interval. Plasma levels of intact molecule and total Fc were measured by neuraminidase (NA)-capture and Fc-capture with Fc-detection ELISA, respectively. Two-week safety/toxicology (bodyweight, coagulation, clinical signs, chemistries, hematology, cytokines, urinalsis, histopathology) was evaluated in monkeys (5-20 mg/kg on days 1 and 8). Prophylaxis efficacy was studied in a lethal influenza mouse model using a single dose of CD377 (0.3–3 mg/kg) 28 days prior to intranasal (IN) challenge with 3x the LD95 of A/California/07/2009 (H1N1)pdm, A/Hong Kong/1/68 (H3N2), or B/Malaysia (Victoria lineage). Treatment efficacy was studied in a similar mouse model using a single dose of CD377 (0.3–3 mg/kg) administered 2 hours after IN challenge with A/CA/12/2012 (H1N1)pdm.ResultsPlasma concentrations measured by Fc-capture/Fc-detection and NA-capture/Fc-detection were comparable, indicating that CD377 remained intact in vivo. In species tested, CD377 t1/2 was 3–10 days. Dose proportional increases in exposure were observed, notably from 1–100 mg/kg in mouse. High bioavailability (77%) was observed after subcutaneous (SC) or intramuscular (IM) administration. A single SC dose of 1 mg/kg administered 28 days prior to infection provided 100% protection against H1N1, B, and H3N2 subtypes in mouse (Fig. 1). Treatment efficacy was observed with a single 0.3 mg/kg IM dose. The 2-week monkey toxicology study showed no adverse effects.Figure 1. Efficacy (Survival and Body Weight) of CD377 in a 28-Day Prevention Model Against Influenza H1N1, H3N2, and B Subtypes in Mouse (IN infection challenge on Day t=0 and CD377 dosed t–28 days). ConclusionThe stability and safety of CD377, together with its long half-life and efficacy with a single dose, support the potential of CD377 as a long-acting, novel AVC for the prevention and treatment of influenza.DisclosuresVoon Ong, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) James Levin, PhD, Cidara Therapeutics (Shareholder) Allen Borchardt, PhD, Cidara Therapeutics (Employee) Thomas P. Brady, PhD Chemistry, Cidara Therapeutics (Employee) Thanh Lam, PhD, Cidara Therapeutics (Shareholder) Alain Noncovich, PhD, Cidara Therapeutics (Shareholder) Joanne Fortier, BSc, Cidara Therapeutics (Employee, Shareholder) Karin Amundson, B.S., Cidara Therapeutics (Shareholder) Jeffrey B. Locke, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Amanda Almaguer, Bachelors, Cidara Therapeutics, Inc. (Employee, Shareholder) Nicholas Dedeic, n/a, Cidara Therapeutics (Employee) Grayson Hough, MS - Chemistry, Cidara Therapeutics (Employee) Jason Cole, PhD, Cidara Therapeutics (Shareholder) Simon Döhrmann, PhD, Cidara Therapeutics (Shareholder) Rajvir Grewal, n/a, Cidara Therapeutics, Inc. (Employee, Shareholder) Elizabeth Abelovski, B.S., Cidara Therapeutics (Shareholder) James M. Balkovec, PhD, Cidara Therapeutics (Consultant, Shareholder) Ken Bartizal, PhD, Cidara Therapeutics, Inc. (Consultant, Shareholder) Les Tari, PhD, Cidara Therapeutics (Shareholder)

Abstract 3019: Non-linear absorption pharmacokinetics (PK) of the ATR inhibitor AZD6738 in mice

Abstract Introduction: AZD6738 is an inhibitor of the apical kinase Ataxia telangiectasia and Rad-3 related (ATR) and can block induction of DNA damage response signaling cascades that are initiated by ATR following chemotherapy or radiation cancer treatment. AZD6738 is in clinical development and also being used preclinically to mechanistically probe ATR signaling. Currently, little is known about AZD6738 PK, including bioavailability, and tissue distribution, and this information is valuable in both clinical and preclinical settings. Here we describe the intravenous (IV) and oral (PO) PK of AZD6738 in mice. Methods: Single doses of AZD6738 (IV 10 mg/kg, PO 2.0, 7.5, 20, or 75 mg/kg) were administered to female Balb/c mice. Mice were euthanized from 5 min to 24 h after dosing and plasma and tissues were collected and analyzed by an LC-MS/MS assay modified to include a sulfoxide and sulfone metabolite semiquantitatively. PK parameters and PO bioavailability were determined non-compartmentally (NCA) and compartmentally (CA). Dose linearity was assessed using naively pooled data and statistical comparison of dose normalized Cmax and AUC. ADAPT5 software was used to develop a CA model. Extraction ratio (EH) was calculated from IV administered mice to discern the contribution of hepatic first-pass metabolism to observed bioavailability. Results: IV data was best described by a two-compartment linear model. Negligible differences were observed between PO half-life at any dose (95.3 to 116 min) compared to the IV half-life (104 min). Increases in PO dose resulted in greater than proportional increases in exposure with statistical differences observed for dose-normalized Cmax and AUC. Concordantly, the bioavailability increased as dose increased, ranging from an F of 31.3% at 2.0 mg/kg to 81.3% at 75 mg/kg. A decrease in Tmax was also observed as dose increased, with a Tmax of 60 min at 2.0 mg/kg and 15 min at all other PO doses. As PO dose increased, decreases in sulfoxide dose-normalized AUC metabolic ratios were observed. A two-compartment model with an absorption compartment containing a saturable component capturing both efflux and first-pass metabolism was developed that adequately described the data with non-linear bioavailability. An empirical Emax fit to bioavailability as a function of dose determined the maximum bioavailability (Emax) to be 87.6% (95%CI 66.7-114%) and Km to be 3.99 (95% CI 1.06-11.3). Comparison of the EH of IV administered mice to the observed 2 mg/kg bioavailability determined ~50% passes the gut wall. Conclusion:AZD6738 was observed to display saturable intestinal efflux/first-pass metabolism resulting in dose-dependent bioavailability. Increased PO doses yield greater than proportional increases in exposure in mice. Presence of non-linear absorption PK in humans is conjecture. Funding: TL1TR001858, R50CA211241, P30CA047904 and American Foundation for Pharmaceutical Education, PA DoH Tobacco grant. Citation Format: Brian F. Kiesel, Jianxia Guo, Christopher J. Bakkenist, Jan H. Beumer. Non-linear absorption pharmacokinetics (PK) of the ATR inhibitor AZD6738 in mice [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 3019.

Safety, Pharmacokinetics, and Pharmacodynamics of the TLR4 Agonist GSK1795091 in Healthy Individuals: Results from a Randomized, Double-blind, Placebo-controlled, Ascending Dose Study

PurposeInterest in Toll-like receptor (TLR) agonists for cancer treatment has been renewed after promising preliminary clinical data in combination with checkpoint inhibitors. This first-in-human study assessed the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of intravenous GSK1795091, a synthetic TLR4 agonist, in healthy volunteers as a precursor to evaluation in patients with cancer. MethodsHealthy participants were randomized (1:3; double-blinded manner) to receive placebo or a single intravenous injection of GSK1795091 at doses of 7–100 ng. The primary objective was to evaluate the safety and tolerability of GSK1795091; secondary and exploratory objectives were to characterize GSK1795091 PK and PD properties. FindingsForty participants received study treatment (10 received placebo and 30 received GSK1795091). Overall, 3 of the 10 participants (30%) who received placebo and 16 of the 30 (53%) who received GSK1795091 experienced ≥1 adverse event (AE). The most common AEs were influenza-like illness, headache, back pain, and increased body temperature. One participant experienced late-occurring AEs (alanine aminotransferase and aspartate aminotransferase increases), considered possibly related to GSK1795091. No serious AEs were reported. GSK1795091 PK properties were characterized by dose proportional increase in exposure. Transient and dose-dependent changes in induced cytokine and chemokine concentrations and immune cell counts were observed 1–4 h after GSK1795091 administration and returned to baseline within 24 h. ImplicationsIntravenously administered GSK1795091 was acceptably tolerated in healthy volunteers, had favorable PK properties, and stimulated immune cell changes in a dose-dependent manner, providing evidence of target engagement and downstream pharmacology. These results supported the design and initiation of a repeat-dose study of intravenous GSK1795091 in combination with other immunotherapies in patients with advanced cancer.ClinicalTrials.gov identifier: NCT02798978.

Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition.

To evaluate the pharmacokinetics (PK) of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in mice after IV and oral administration and to develop mechanistic PK models to assess the potential enterohepatic circulation (EHC) and target-mediated drugdisposition (TMDD) of AZD3965. Female BALB/c mice were administered AZD3965 by IV injection (10, 50 and 100mg/kg) or oral gavage (100mg/kg). Plasma samples were analyzed using LC/MS/MS, and PK parameters determined by compartmental and non-compartmental analyses. AZD3965 exhibited a large volume of distribution and rapid oral absorption, with a high oral bioavailability. Prominent reentry peaks were observed after both oral and IV administration, suggesting potential EHC of AZD3965 or of a potential glucuronide conjugate. The dose-dependent studies indicated greater than proportional increases in exposure, an increase in the terminal half-life, and decrease in clearance and volume of distribution with increasing IV doses, indicating nonlinear pharmacokinetics and potential TMDD of AZD3965. Mechanistic compartmental models were developed to characterize the complex pharmacokinetics of AZD3965. The current study represents the first comprehensive report of the pharmacokinetics of AZD3965 in mice, indicating the potential contribution of EHC and TMDD in the disposition of AZD3965.

Abstract A086: Phase Ib study of a novel MDM2 inhibitor APG-115, in combination with pembrolizumab in patients with metastatic solid tumors in U.S.

Abstract Keywords: MDM2; Immuno-oncology; PD-1 Background APG-115 is an orally active small-molecule MDM2 inhibitor that potently binds MDM2 protein, restores TP53 function, and activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. Preclinical studies demonstrated that APG-115 promoted the production of proinflammatory cytokines in T cells, enhanced CD4+ T cell activation, and increased PD-L1 expression on tumor cells. Enhanced antitumor activity was demonstrated in syngeneic tumor models after APG-115 combined with PD-1 blockade. Retrospective clinical analyses suggested that MDM2 amplification is associated with hyper-progression in the patients treated with check point inhibitors. Keywords: MDM2; Immuno-oncology; PD-1 In general, by targeting MDM2-p53 pathway, APG-115 in combination with PD-1/PD-L1 blockade may provide a novel strategy to reverse immunosuppression and/or enhance antitumor immunity in the cancer patients who were either failed to standard therapies or resistant to IO therapies. Methods This dose escalation study (NCT03611868) combines APG-115 with pembrolizumab for the treatment of patients with metastatic solid tumors. Four dose levels of APG-115 have been tested: 50, 100, 150, and 200mg. APG-115 is administrated orally every other day (QOD) for consecutive 2 weeks of a 21-day-cycle with pembrolizumab at 200mg IV on day1 of a 21-day-cycle. Results Through June 15, 2019, a total of 14 patients have been treated in 4 cohorts of APG-115 in combination with pembrolizumab IV q3weeks. No cycle 1 DLTs have been observed up to and including 200 mg APG-115 at total doses of APG115 that are equivalent to the single agent MTD of APG-115 alone. Eleven patients experienced at least 1 TEAE. The most common TRAEs (≥10%) were nausea (42.9%), neutrophil count decreased (21.4%), vomiting (14.3%), decreased appetite (14.3%), diarrhea (14.3%), platelet count decreased (14.3%), white blood cell count decreased (14.3%), and fatigue (14.3%). Four patients experienced at least 1 grade 3 or higher TRAE beyond course 1 including neutrophil count decreased (21.4%). Five SAEs occurred in 3 patients, but only one grade 3 febrile neutropenia was treatment related. One patient with advanced ovarian cancer with a germline ATM mutation, refractory to 6 prior lines of therapy, has a sustained “confirmed CR” that continues beyond 12 cycles at the 100mg cohort. A patient with advanced NSCLC in 100mg cohort has received “confirmed PR” (still ongoing) after failed prior 5 lines of therapies including 3 months’ nivolumab treatment; 5 patients had SD after two cycle treatments, 2 of them ongoing. PK analyses indicates an approximately dose proportional increase in exposure across dose levels from 50 to 100 mg with plasma concentrations that exceed those that portend MDM2 inhibition. Preliminary pharmacodynamic (PD) results showed that the serum macrophage inhibitory cytokine-1 (MIC-1) levels are elevated in the APG-115 treated patients, suggesting a potential p53 activation in patients. Conclusion APG-115 in combination with pembrolizumab is well tolerated. The MTD has not been exceeded at full doses of APG-115. Promising anti-tumor effects have been seen in several tumor types when in combination with pembrolizumab. Expansion cohorts in molecularly selected patients is planned. Citation Format: Anthony W Tolcher, Raghad Karim, Yuefen Tang, Jiao Ji, Hengbang Wang, Lichuang Meng, Angela Kaiser, Jennifer Coe, Eric Liang, Christina Rosas, Dajun Yang, Yifan Zhai. Phase Ib study of a novel MDM2 inhibitor APG-115, in combination with pembrolizumab in patients with metastatic solid tumors in U.S. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A086. doi:10.1158/1535-7163.TARG-19-A086

An Updated Safety and Efficacy Results of Phase 1 Study of HQP1351, a Novel 3rd Generation of BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI Resistant Chronic Myeloid Leukemia

Background: HQP1351, a novel, orally active potent 3rd generation TKI, was designed for treatment of patients with chronic myeloid leukemia (CML) resistant to current TKI-therapies including those with T315I mutation. This is an updated report of the safety and efficacy of HQP1351. Methods: It is an open-label, dose escalation and expansion phase 1 trial of HQP1351 which was designed to determine maximum tolerated dose (MTD) and to identify dose-limiting toxicities (DLTs) in patients with CML in the chronic phase (CP) or accelerated phase (AP) resistant or intolerant to ≥ 2 prior TKIs or those with T315I mutation after ≥1 prior TKI. HQP1351 was orally administered once every other day (QOD) in 28-day cycles at 11 dose cohorts ranging from 1mg to 60 mg. The eligible patients received continuous treatments until disease progression to AP or BP, developing intolerant toxicity, consent withdrawal, or death. Blood samples were collected at certain time points on Day 1-2 and Day 27-28 during cycle 1 for PK analyses. Results: From 26 October, 2016 to 27 May, 2019, 101 patients including 87 CP patients and 14 AP patient were enrolled in this study. Seventy-one (70.3%) patients were male. Median duration of follow-up was 12.8 (range, 1.2-31.5) months. Median age was 40 (range, 20-64) years. Median interval from CML diagnosis to starting HQP1351 treatment was 5.8 (range, 0.3-15.2) years. Eighty-three (83.8%) patients received ≥2 prior lines of TKI-therapy. Sixty-two (61.4%) patients harbored T315I mutation. Seventeen patients who initially assigned to the dose escalation cohorts ranging from 1mg to 20 mg moved to 30 mg or higher dose cohorts via intra-patient dose escalation. Fifty-six patients enrolled in the dose expansion part of the trial, including 30mg,40mg and 50mg dose cohorts. Two out of 3 patients at 60mg dose cohort experienced DLT and 50mg QOD was considered as the MTD. During the follow-up period, HQP1351 was well-tolerated in each dose cohort with an exception of 60 mg cohort. All patients experienced ≥1 treatment related adverse events (TRAEs), most of the non-hematologic TRAEs were reported as grade 1 or grade 2. The most common hematologic TRAE of grade 3/4 was thrombocytopenia (49.5%). The incidences of TRAEs tended to be dose-dependent. No death and grade 5 AEs occurred. The incidence of common TRAEs (≥ 10% any grade) are summarized in Table1. HQP1351 showed potent anti-leukemic activities in CML patients. In the 68 evaluable patients with non-CHR at baseline, 63 (92.6%) achieved CHR including 52 out of 55 (94.5%) CP patients and 11 out of 13 (84.6%) AP patients, respectively. In the 95 evaluable patients with non-CCyR at baseline, 56 out of 81 (69.1%) CP patients achieved MCyR including 49 (60.5%) CCyR; and 6 out of 14 (42.9%) AP patients, achieved MCyR including 5 (35.7%) CCyR, respectively. In the 100 evaluable patients, 32 out of 86 (37.2%) CP patients and 5 out of 14 (35.7%) AP patients achieved MMR, respectively. HQP1351 showed highly efficacious in the patients with T315I mutation (Figure A, B). The probability and the depth of response increased with prolonged treatment period (Figure C). As the cut-off date of May 27 2019, 9 patients (5 CP and 4 AP) withdrawn from the study, including progression to AP or BP (n=5), intolerant AEs (n=2), consent withdrawal (n=1), and newly diagnosis of breast cancer (n=1). The progression free survival (PFS) rate at 18-month was 94% in the CP patients and 61% in the AP patients (Figure D). PK analyses indicated an approximately dose proportional increase in exposure (AUC and Cmax) following oral administration of HQP1351 at doses from 1mg to 60 mg. The peak concentration of HQP1351 was reached at 4-8h. The elimination appeared to be linear with a mean terminal T1/2 of 17.5 to 42.5 h. Slight to moderate accumulation was observed on Day 27 following multiple dosing. Reduction of CRkL phosphorylation in PBMCs, a biomarker of BCR-ABL inhibition, has shown to be dose and time dependent in 53 evaluable patients treated with HQP1351. Conclusions: HQP1351 was well tolerated and exhibited significant and durable antitumor activity in the patients with TKI-resistant CML, including those with T315I mutation. Two pivotal studies of HQP1351 in CML-CP and CML-AP patients with T315I mutation are ongoing in China. Disclosures Chen: HealthQuest Pharma Inc.: Employment. Niu:HealthQuest Pharma Inc.: Employment. Men:HealthQuest Pharma Inc.: Employment. Wang:HealthQuest Pharma Inc.: Employment. JI:HealthQuest Pharma Inc.: Employment. Huang:HealthQuest Pharma Inc.: Employment. Yang:Ascentage Pharma Group: Employment. Zhai:Ascentage Pharma Group Inc.: Employment; HealthQuest Pharma Inc.: Employment.

1393P - Safety and tolerability of surufatinib in western patients with solid tumours

1393P - Safety and tolerability of surufatinib in western patients with solid tumours

Abstract CT011: First-in-human Phase I study of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase-1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid malignancies

Abstract BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) and the related enzyme tryptophan 2,3-dioxygenase 2 (TDO2) are enzymes that mediate the rate limiting step in the metabolism of tryptophan (Trp) into the immunosuppressive metabolite kynurenine (Kyn). The accumulation of Kyn suppresses effector T and activates suppressor T regs generating an immune suppressive environment and escape mechanism for anti-PD-L1/anti-PD-1 agents. While both enzymes are upregulated in various tumors, the expression of IDO1 and TDO2 in human cancers is distinct and not overlapping, suggesting that the use of dual inhibitor should provide an enhanced anti-tumor effect. This is a first in human Phase I study investigating the safety, PK, pharmacodynamic effect and preliminary clinical activity of M4112, a highly selective dual IDO1/TDO2 inhibitor. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with M4112 (100, 200, 400, 600, or 800mg twice daily [BID] oral). The dose-escalation evaluated patients in 28-day cycles. Treatment was continued until disease progression, or unacceptable toxicity. RESULTS: 15 patients were enrolled. One dose-limiting toxicity (DLT) occurred at 800 mg BID (grade 3, rash, with fever and hypotension). The adverse events regardless of causality in &amp;gt;20% of patients were fatigue, nausea, rash, cough, CK increase, vomiting, diarrhea and decreased appetite. Exposure for 100mg and 200mg doses were proportional, with greater than proportional increase in exposure observed at 400mg and 600mg but less than proportional increase at 800mg. The observed Cmin (C1D15) at doses ≥ 400mg BID was above the IC50 based on animal studies. M4112 treatment resulted in dose-dependent IDO1 inhibition in ex vivo stimulated blood with approximately &amp;gt;90% IDO1 activity inhibited throughout the dosing period at 800mg BID. In contrast, M4112 did not show sustained reduction of plasma Kyn levels up to 800mg BID: 12-35% decrease in plasma Kyn levels were observed on C1D1 up to 6h post dosing, that returned to or exceeded baseline values on C1D15. Consistent with preclinical findings, the plasma Trp increased during C1D1 at dose levels ≥200mg, suggesting liver TDO2 inhibition responsible for this increase. There were no objective responses, however in 7 of 15 cancer patients time until documented progressive disease was ≥16 weeks. These are preliminary data. CONCLUSIONS: M4112 was generally well tolerated, with stable disease as best response. M4112 achieved &amp;gt;90% IDO1 inhibition in ex vivo stimulated blood assay. Unlike IDO1 specific inhibitors, ex vivo IDO1 inhibition did not translate into plasma Kyn reduction following M4112 treatment. This is the first report of a dual inhibition of IDO1 and TDO2 showing acceptable safety profile and prolonged time to progression in cancer patients. Further investigation is warranted. Citation Format: Kyriakos Papadopoulos, Paul Eder, Sarina A. Piha-Paul, Claude Gimmi, Elizabeth Hussey, Sen Zhang, Lu Li, Christina Habermehl, Aung Naing. First-in-human Phase I study of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase-1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid malignancies [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 CT011.