PK Results Research Articles

A preoperative window-of-opportunity study of oral SERD, imlunestrant, in newly diagnosed ER-positive, HER2-negative early breast cancer: Results from EMBER-2 Study.

Imlunestrant is an oral SERD with favorable safety and preliminary efficacy in patients with ABC. PD biomarker data can optimize drug dosing; herein is the PD data from the EMBER-2 study. Postmenopausal women with untreated, operable ER-positive, HER2-negative EBC were randomized to 400mg vs 800mg of imlunestrant daily for ~2 weeks before surgery. A single arm testing 200mg daily was later accrued. PD biomarker changes (ER, PR, Ki-67 by IHC, and mRNA expression of ER-related genes) were evaluated in paired tumor samples (pre-/ post-treatment). Safety and PK were also assessed. Among evaluable paired samples (n=75), PD profiles demonstrated consistent ER targeting between 400 and 800mg doses with less toxicity at the 400mg dose. Although inducing the lowest rate of CCCA, PD and PK results were similar for the 200mg dose. EMBER-2 combined with existing phase 1 data has identified 400mg as the optimal imlunestrant dose.

Abstract 7161: Preclinical pharmacology modeling (pharmacokinetics/efficacy) of narazaciclib (HX301 or ON123300) to predict its clinical effective dose

Abstract Background: Acute myeloid leukemia (AML) is an aggressive leukemia of myeloid lineage. CSF1R (colony-stimulating factor 1 receptor) regulates the proliferation, differentiation and polarization of cells of myeloid lineages, e.g. monocytes/macrophages. CSF1R expression is aberrantly upregulated in many AML, leading to a hypothesis that CSF1R is a putative leukemogenic driver in a subset of AML and thus could be a potential target for treating AML. Previous studies demonstrated that Narazaciclib (HX301 or ON123300), an investigational kinase inhibitor (TKi), exhibited high potency activity against CSF1R (IC50 0.285 nM) and inhibition of macrophage proliferation and AML tumor growth both in vitro/in vivo, implicating its potential use as an AML therapeutic1 (An et al., 2023 AACR Annual Meeting). In addition, narazaciclib has recently completed the dose escalation phase 1 study in advanced solid tumors. However, the therapeutic window of narazaciclib as a CSF1Ri for treating AML remains to be determined. The present study attempted to utilize both preclinical PK and in vivo efficacy models to predict the effective clinical dose of narazaciclib for guiding the future AML clinical trials. Methods: A single dose of narazaciclib at various of dose levels was orally administrated in NOD/Scid mice, and plasma samples were collected at designated timepoints. The concentrations of narazaciclib in plasma were analyzed by LC-MS. In a Ba/F3-ETV6-CSF1R in vivo xenograft tumor model in Nod/Scid mice, narazaciclib at various dose levels was orally administrated daily. Tumor volumes were measured twice weekly. Results: The mouse PK study showed that narazaciclib displayed overall similar absorption pattern as seen in unpublished human clinical data. Narazaciclib was absorbed rapidly after oral dosing with a mean Tmax ranging from 1 to 2 hours in mouse. However, narazaciclib was cleared faster in mouse, with a mean T1/2 ranging from 1.9 to 2.8 hours, than in human. In addition, the exposures of narazaciclib, as measured by Cmax and AUC in plasma, increased in a relatively dose-proportional manner, as seen in human patients. In the Ba/F3-ETV6-CSF1R xenograft model where the tumor cell growth is solely dependent on the CSF1R kinase activity, narazaciclib at 10 mg/kg did not induce any anti-tumor effects with a TGI of -14.61%. In contrast, narazaciclib at 50 mg/kg and 100 mg/kg exerted significant anti-tumor effects with a TGI of 85.49% and 94.55%, respectively. Based on the mouse PK results, narazaciclib at 50 mg/kg in mouse is estimated to have an AUC of approximate 2000 h*ng/mL, which is equivalent to the dose of 160 - 200 mg/d in human patients. Therefore, 160 mg dose level is predicted to be an effective dose for narazaciclib in AML patients. Conclusions: Narazaciclib at 160 mg/d is predicted to be an effective dose in AML patients. Citation Format: Tao Yang, Hang Ke, Jinping Liu, Kefeng Gong, Henry Qixiang Li. Preclinical pharmacology modeling (pharmacokinetics/efficacy) of narazaciclib (HX301 or ON123300) to predict its clinical effective dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7161.

Clinical trials of R-(-)-gossypol (AT-101) in newly diagnosed and recurrent glioblastoma: NABTT 0602 and NABTT 0702.

AT-101 is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of the parent compound, racemic gossypol, demonstrated objective and durable responses in patients with malignant glioma. AT-101 has demonstrated synergy with radiation in animal models. The objectives of trial NABTT 0602 were to determine the MTD of AT-101 concurrent with temozolomide (TMZ) and radiation therapy (RT) (Arm I) and to determine the MTD of AT-101 when given with adjuvant TMZ after completion of standard chemoradiation (Arm 2). Separately in trial NABTT 0702, the survival and response rates of single agent AT-101 were evaluated in patients with recurrent glioblastoma. In NABTT 0602 Phase I, a 3+3 design was used to define MTDs after maximal safe resection, patients with newly diagnosed glioblastoma received standard concurrent RT (60 Gy) and TMZ 75 mg/m2/day followed by adjuvant TMZ 150-200 mg/m2 days 1-5 in 28-day cycles (Stupp regimen). In Arm I, AT-101 was administered M-F during the six weeks of RT beginning 20 mg qd. In Arm 2, concurrent with each adjuvant cycle of TMZ, AT-101 was administered at a starting dose of 20 mg, days 1-21 followed by 7-day break for a maximum of 6 cycles. The PK blood samples were collected in the first three patients in each cohort of arm 1. In NABTT 0702 patients with recurrent glioblastoma received 20 mg p.o. per day for 21 of 28 days in repeated cycles to assess overall survival (OS). A total of sixteen patients were enrolled on the two study arms of NABTT 0602. In Arm 1 AT-101 was escalated from 20 to 30 mg where one of six patients experienced DLT (grade 3 GI ulcer). On Arm 2 one patient treated at 20 mg experienced DLT (grade 3 ileus, nausea and diarrhea). The cohort was expanded to include seven patients without observation of DLT. PK results were consistent with drug levels from non-CNS studies. At study closure six patients are still alive. The median survival times for Arm I and Arm II are 15.2 months and 18.2 months, respectively. In NABTT 0702 fifty-six patients were enrolled and forty-three were eligible for imaging response. Sixteen patients (29%) had stable disease as best response and one partial response was observed. The median OS with single agent AT-101 was 5.7 months (95%CI: 3.8-7.6 months) for patients with rGBM. AT-101 can be safely administered with radiation therapy and TMZ in patients with newly diagnosed glioblastoma without toxicity unique to patients with CNS tumors. Because of toxicity observed in non-CNS AT-101 clinical trials, further dose-escalation was not attempted. The recommended dose for future studies that utilize continual AT-101 exposure is 20 mg days M-F concurrent with RT/TMZ and 20 mg days 1-21 for each 28-day cycle of TMZ. AT-101 has limited activity as a single agent in unselected patients with recurrent glioblastoma. Future trials should attempt to better understand resistance mechanisms and consider combination therapy.

Pharmacokinetics, Drug Interaction, and Exposure-Safety Analyses of Tazemetostat When Co-Administered with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Phase 1b Results of Symphony-1

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.

383. Pharmacokinetics and Safety in Healthy Adults of RSM01, a Novel RSV Monoclonal Antibody, and Population PK Modeling to Support Pediatric Development

Abstract Background RSV is a common cause of infant respiratory infection and hospitalization. RSM01 is a novel anti-RSV mAb targeting the F glycoprotein essential for viral entry with a YTE mutation for half-life extension. Phase 1a PK and safety results are presented, along with an adult population PK model used to predict pediatric exposures via simulation. Methods In this double-blind Phase 1a study, healthy males and non-childbearing females aged 18-49 yrs were randomized 6:1 within dose cohorts to receive a single dose of RSM01 or placebo (PBO) in the following RSM01 dose sequence: 300mg IV, 300mg IM or 1000mg IV, 3000mg IV and cohort at 600mg IM. Serial serum samples were taken to measure RSM01 PK using a validated immunoassay method. A noncompartmental analysis (NCA) was conducted, and a population PK model was developed to characterize adult PK and predict pediatric PK using allometric scaling. Pediatric RSM01 PK was predicted for African infants at different IM doses. Results Overall, 56 participants received RSM01 (n=48) or PBO (n=8): median age 30 yrs (range 19-48), 52% male (n = 29), 66% White (n=37), median BMI 24.6 kg/m2 (range 18.1-29.4). 12/48 (25%) RSM01 recipients and 2/8 (25%) PBO recipients reported an AE, with no hypersensitivity reactions, serious AEs, or deaths reported. The median Tmax was ∼6–7 days after IM injection. Cmax and AUClast increased dose proportionally following IV administration. RSM01 adult PK was characterized using a two-compartment model with first-order elimination. IM absorption was described using a zero-order rate constant. Inter-individual variability was included for clearance (CL), central and peripheral volumes (V2 and V3). The RSM01 model estimated that distribution and a terminal half-life were 1.3 and 79.1 days, respectively, and IM bioavailability was ∼82%. The model predicted that following a 50 mg IM dose, median serum RSM01 concentration on day 150 in African infants 0-12 months old to be ∼ 28 mcg/mL, higher than the target exposure based on preclinical models (6.8 mcg/mL). Serum RSM01 NCA PK summary Note: AUClast and Cmax values are presented as geometric mean (CV). Tmax and Tlast are presented as median (min-max). Arithmetic Mean (±SD) Serum RSM01 Concentration-Time Curve by Treatment Note: Horizontal blue dashed line represents the target exposure based on preclinical models (6.8 mcg/mL). Conclusion RSM01 was shown to be well tolerated in healthy adults. Its long half-life and the predicted infant PK profiles support further pediatric development and indicate the potential for dosing once every RSV season. Disclosures Micha Levi, PhD, Bill & Melinda Gates Medical Research Institute: Salary as a full-time employee Shayne Watson, MSc, Bill & Melinda Gates Medical Research Institute: Salary as a full-time employee Dale Taylor, MD, Sanara Medtech Inc: Stocks/Bonds Luisa M. Stamm, MD, PhD, Bill & Melinda Gates Medical Research Institute: Salary as a full-time employee Michael W. Dunne, MD, Bill & Melinda Gates Medical Research Institute: Salary as a full-time employee

Abuse liability of two electronic nicotine delivery systems compared with combustible cigarettes and nicotine gum from an open-label randomized crossover study

An assessment of the likelihood of use and abuse potential for new tobacco products is an important part of tobacco product regulation in the United States and abroad. This paper reports the results of a randomized, open-label, crossover clinical study that assessed factors related to product adoption and abuse liability (AL), comparing two closed electronic nicotine delivery system (ENDS) products to combustible cigarettes and nicotine gum, high- and low-AL comparator products, respectively. During an 11-day confinement period that included multiple product familiarization sessions, healthy adult smokers participated in AL test sessions to evaluate the abuse liability of each product. During these test sessions, changes in subjective measures; speed and amount of nicotine uptake; and maximum changes in physiological effects before, during, and after use of each assigned product were assessed over 4 h. Positive subjective effects measures scores such as product-liking and overall intent to use again were highest for cigarettes, followed by the Vuse ENDS, with nicotine gum consistently having the lowest scores. The PK results (Cmax and Tmax) of the Vuse ENDS products are between UB cigarettes and nicotine gum, which correlates with the subjective effects. All nicotine uptake measures for the Vuse ENDS products were lower than that of usual brand (UB) cigarettes, including peak nicotine uptake and overall nicotine uptake, and were either similar to or lower than nicotine gum. The time course of nicotine uptake after use of the ENDS was more similar to that of combustible cigarettes than nicotine gum. The results indicate that the AL of each ENDS product is lower than that of UB cigarettes and similar to that of nicotine gum.

WS05.06 Phase 1/2a randomized, double-blind, placebo-controlled study: safety, Pk, and Efficacy outcome measures of inhaled Gallium Citrate (AR-501) in P Aeruginosa infected Cystic Fibrosis patients

Background: AR-501, an inhaled novel iron analog disrupts microbial iron-dependent metabolic pathways, resulting in antimicrobial activity against bacteria, NTM, and fungi. This Ph1/2a study will have data readout by mid-2023 (www.clinicaltrials.gov NCT03669614). Inhaled AR-501 in HV’s was generally well tolerated once weekly for 5 weeks. Here we report the preliminary safety, PK, and exploratory efficacy results of once-weekly inhaled AR-501 for 3 doses over four weeks.

Abstract CT031: A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors

Abstract Background: BGB-3245 is a RAF dimer inhibitor with preclinical activity in MAPK-altered tumor models harboring BRAF V600 mutations, atypical BRAF mutations/fusions, and RAS mutations. This study is investigating the safety, pharmacokinetics, and preliminary antitumor activity of BGB-3245 in patients (pts) with advanced or refractory MAPK-altered solid tumors. Methods: Eligible pts were ≥18 yrs old with ECOG 0-1 and had solid tumors harboring MAPK pathway alterations. Dose-escalation and cohort-size decisions were made using the Modified Toxicity Probability Interval Design. The starting dose was 5 mg QD. Treatment emergent adverse events (TEAEs) were graded per NCI CTCAE v5.0. Tumor responses were assessed by investigators using RECIST v1.1. Results: As of 1 Sep 2022, 42 pts were treated across 6 cohorts (5-60 mg QD). The median age was 60 yrs; pts had received a median of 3 prior lines of treatment. All pts had TEAEs; 79% had treatment-related (TR) AEs. The most common TRAEs (≥ 10%) were rash acneiform (33%), rash maculopapular (24%), fever (17%), ALT elevations and nausea (both 12%). Gr ≥3 TRAEs were reported in 29% of pts, events in ≥ 2 pts included decreased platelet count and rash maculopapular (3 each), ALT and AST elevations, and fever (2 each). Dose reductions occurred in 5 pts: rhabdomyolysis (1), LVEF decreased (1), hand-foot syndrome (1), rash maculopapular (1), and liver function abnormalities (1). Dose interruptions due to AEs occurred in 60% of pts. Dose discontinuations occurred in 79% of pts, 57% due to disease progression or death, 21% due to AE. Dose limiting toxicities were observed at 10 mg, 40 mg, and 60 mg. 40 mg QD was determined as the MTD. PK results showed generally dose-proportional increases in exposure. Tmax was at ~2 h; BGB-3245 had a long terminal half-life and 7.4-fold average accumulation in exposure at steady-state. 79% of pts were efficacy evaluable. The disease control rate was 48% with 1 CR, 5 cPR, 2 uPR and 8 SD≥24 wks. Objective responders included BRAF V600E melanoma pts post-BRAF/MEK and checkpoint inhibitors (2; 1 CR, 1 cPR), 1 NRAS G12S melanoma and 1 NRAS Q61K melanoma (post checkpoint inhibitors), 1 BRAF V600E LGSOC (progressed on BRAF inhibitor), 1 BRAF V600E cholangiocarcinoma (progressed on BRAF/MEK inhibitors), 1 BRAF K601E/PIK3CA endometrial cancer, and 1 KRAS G12D appendiceal cancer. Preliminary analysis of circulating tumor DNA showed correspondence to clinical response. Conclusions: BGB-3245 has a manageable safety profile and a generally dose-proportional PK. Antitumor activity was observed in pts with no approved targeted therapy options. The safety and early efficacy profile of BGB-3245 supports further investigation in selected MAPK-altered tumors. Citation Format: Alison M. Schram, Vivek Subbiah, Ryan Sullivan, Rasha Cosman, Jia Liu, Eric I. Sbar, Thuy Hoang, Jiarong Chen, Mark Johnson, Vincent Amoruccio, Todd Shearer, Adeela Kamal, Jocelyn Lewis, Wenlin Shao, Badreddin Edris, Lusong Luo, Jayesh Desai. A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT031.

Optimization of Therapy and the Risk of Probiotic Use during Antibiotherapy in Septic Critically Ill Patients: A Narrative Review.

Optimizing the entire therapeutic regimen in septic critically ill patients should be based not only on improving antibiotic use but also on optimizing the entire therapeutic regimen by considering possible drug-drug or drug-nutrient interactions. The aim of this narrative review is to provide a comprehensive overview on recent advances to optimize the therapeutic regimen in septic critically ill patients based on a pharmacokinetics and pharmacodynamic approach. Studies on recent advances on TDM-guided drug therapy optimization based on PK and/or PD results were included. Studies on patients <18 years old or with classical TDM-guided therapy were excluded. New approaches in TDM-guided therapy in septic critically ill patients based on PK and/or PD parameters are presented for cefiderocol, carbapenems, combinations beta-lactams/beta-lactamase inhibitors (piperacillin/tazobactam, ceftolozane/tazobactam, ceftazidime/avibactam), plazomicin, oxazolidinones and polymyxins. Increased midazolam toxicity in combination with fluconazole, nephrotoxic synergism between furosemide and aminoglycosides, life-threatening hypoglycemia after fluoroquinolone and insulin, prolonged muscle weakness and/or paralysis after neuromuscular blocking agents and high-dose corticosteroids combinations are of interest in critically ill patients. In the real-world practice, the use of probiotics with antibiotics is common; even data about the risk and benefits of probiotics are currently spares and inconclusive. According to current legislation, probiotic use does not require safety monitoring, but there are reports of endocarditis, meningitis, peritonitis, or pneumonia associated with probiotics in critically ill patients. In addition, probiotics are associated with risk of the spread of antimicrobial resistance. The TDM-guided method ensures a true optimization of antibiotic therapy, and particular efforts should be applied globally. In addition, multidrug and drug-nutrient interactions in critically ill patients may increase the likelihood of adverse events and risk of death; therefore, the PK and PD particularities of the critically ill patient require a multidisciplinary approach in which knowledge of clinical pharmacology is essential.

Updated Results from the Momentum Phase 3 Study of Momelotinib (MMB) Versus Danazol (DAN) in Symptomatic and Anemic Myelofibrosis (MF) Patients Previously Treated with a JAK Inhibitor

Updated Results from the Momentum Phase 3 Study of Momelotinib (MMB) Versus Danazol (DAN) in Symptomatic and Anemic Myelofibrosis (MF) Patients Previously Treated with a JAK Inhibitor

994P Efficacy and safety of capmatinib plus spartalizumab in treatment-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation

Capmatinib (cap) is a selective MET inhibitor approved for patients (pts) with advanced NSCLC (aNSCLC) harboring MET exon 14 skipping mutation (METex14) showing ORR [95% CI] of 66.7% [53.3, 78.3] in treatment (tx)-naïve pts. Spartalizumab (sparta) is a monoclonal antibody targeting programmed death protein-1 (PD-1). Cap enhances T cell mediated antitumor response in mice treated with PD-1 inhibitors. Combining cap with sparta may be beneficial in aNSCLC pts with METex14. This phase II study consisted of 2 parts: open-label, single-arm run-in part, where pts received cap 400 mg orally BID + sparta 400 mg i.v Q4W followed by randomized, double-blind, placebo-controlled part to evaluate the efficacy and safety of cap+sparta vs cap+placebo. Tx-naïve aNSCLC pts with METex14 and without ALK or EGFR alterations were included. The primary endpoint was investigator-assessed ORR as per RECIST v1.1. Herein, we report data from the run-in part. At data cut-off (DCO) of Feb 01, 2022, 31 pts were included in the run-in part; median age: 73 (range: 52-89) years; females (51.6%) and ECOG PS of 0/1 in 38.7%/61.3% of pts. The ORR [95% CI] was 38.7% [21.8, 57.8] and DCR [95% CI] was 77.4% [58.9, 90.4]. Median DOR has not been reached. Median PFS [95% CI] is 13.3 months [9.3, NA] but data remains to mature further. The preliminary PK results of both drugs showed consistency with prior monotherapy studies. Most common Tx-related AEs (any grades [GR], ≥30%) were peripheral edema (71%), elevated serum creatinine (45.2%), elevated ALT and AST (35.5% each). No Tx-related GR 3/4 pneumonitis and no fatal toxicity has been reported. Higher rates of tx-related AEs leading to dose reduction/interruption (80.6%) and/or discontinuation (35.5%) were seen with cap+sparta regimen vs other cap monotherapy studies, suggesting poor tolerability to the combination. Thus, study enrollment was halted, and all ongoing pts were discontinued from sparta. At DCO, 15 pts remain on cap monotherapy. The addition of sparta to cap treatment was not well tolerated and resulted in modest antitumor activity when compared with data from other cap monotherapy studies in tx-naïve aNSCLC pts with METex14.

CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study

CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study

SO-12 Updated safety, efficacy, and PK results from an open-label, multicenter, phase I/II study of avapritinib in Chinese patients with unresectable or metastatic gastrointestinal stromal tumors

More than 85% of gastrointestinal stromal tumors (GIST) patients (pts) have tumors associated with KIT/PDGFRA mutations. Avapritinib is a potent, selective, small-molecule, KIT/PDGFRA inhibitor and has been approved in the US for pts with GIST harboring PDGFRA exon 18 mutation. However, these pts have no standard of care in China. This abstract reports safety, efficacy, and PK results of avapritinib in Chinese pts.

Quantification and Pharmacokinetics Study of Pedunculoside in Rats by Using UPLC-MS/MS

Background: Pedunculoside (PE) is a triterpene saponin from the barks of Ilex rotunda, a Traditional Chinese Medicine called Jiubiying, which is used for the treatment of cold and fever, tonsillitis, sore throat, acute and chronic hepatitis, etc. Previous studies have confirmed that crude extract orally has a significant therapeutic effect on myocardial infarction. Methods: A simple, sensitive, and specific method by using UPLC-MS/MS to study the pharmacokinetics of PE in rats was developed and validated, with ilexsaponin A as an internal standard. Methanol was used as a protein precipitation reagent for blood sample extraction. A Waters Acquity C18 column (2.1 mm × 50 mm, 1.7 μm) was used for chromatographic separation with a gradient elution of CH3CN: 0.1% formic acid (0.3 mL·min-1). Negative ion electrospray ionization was used for detection in multiple reaction monitoring mode. Results: PE was linear within the concentration range of 0.14-1118.00 ng/mL. The LLOQ was 0.14 ng/mL for the plasma samples. The intra-day and inter-day precision were ranged from 1.18% to 10.48%, while the accuracy ranged from -1.32% to 1.68%, indicating satisfactory precision and accuracy of the assay. The extraction recoveries for PE and IS were ranged from 81.40% to 86.65%, with no significant variation among the three concentrations, respectively. PE remained stable at room temperature (25°C) for 3 h, in auto-sampler (4°C) for 24 h, after three freeze-thaw cycles, and in long-term storage at ‒20°C for 30 days. The PK results of PE indicated its poor oral bioavailability (3.37%). Conclusion: Non-compartmental pharmacokinetics parameters indicated that PE was rapidly distributed to the tissues and metabolized. The pharmacokinetic data of this paper highlighted the first-time report of PE oral bioavailability with two different administration manners, which will help to better understand how PE metabolized in rats and exert its pharmacological effect in vivo.

Pharmacodynamic, safety, and efficacy results of a phase I/II trial of intratumoral INT230-6 alone (IT-01) or in combination with pembrolizumab (PEM) (Keynote A10) in patients with advanced solid tumors.

3016 Background: INT230-6 is comprised of cisplatin (CIS), vinblastine (VIN) and an amphiphilic penetration enhancer which facilitates dispersion throughout tumors and diffusion into cancer cells when given IT. Preclinical experiments show strong synergy with a PD1 antibody. Methods: Solid tumors pts that progressed on standard treatment were enrolled. INT230-6 dose was set by tumor volume, injected Q2weeks x 5. Escalation occurred by increasing number of tumors injected, loading per tumor, and total dose. In another arm, PEM (200mg IV Q3weeks) was combined with INT230-6. Patients were monitored for safety weekly while on INT230-6. Blood and tumors were assessed for PK and PD. Results: 46 pts (17 unique cancer types) were enrolled in the monotherapy arm and 4 pts in the PEM combo arm with a median of 3 prior treatments. Doses from 0.3 ml up to-160 ml of INT230-6 (80 mg CIS and 16mg of VIN) were injected. PK results indicate 95% of the drugs are retained in the tumor when compared to historical IV dosing. No dose limiting toxicity was reported. Two pts experienced drug-related SAE’s of tumor pain. The most frequent treatment-related AEs were: pain at injected site (48%), fatigue (40%) and nausea (33%). Most AE’s were grade 1 and 2, 17% were grade 3, and none ≥ grade 4. Several injected and non-injected tumors had &gt; 30% decreases in diameter. Assessments revealed substantial reductions in tumor volume ( &gt; 50%). Stable pts had a median increase of 50% in circulating CD4 and CD8 T-cells, while PD subjects showed decreases in circulating T-cells (p &lt; 0.05). Dose-response suggests that monotherapy subjects receiving &gt; 50% of tumors injected at dose/tumor volume ratio of &gt; 1:4 (target dosing), predicts for prolonged SD with 88%(7/8) having SD ≥ 4mo, correlating with reduced tumor viability on IHC, and increase in tumor-infiltrating lymphocytes (TIL’s). Conclusions: Proof of concept was demonstrated that INT230-6 delivers high drug doses into the tumor without systemic exposure and typical cytotoxic AEs. Systemic and local immune activation was observed. INT230-6 was safe and well tolerated in &gt; 175 deep tumor injections with tumor burden reduction in injected and non-injected tumors (an abscopal effect). Patients who received target dosing often had prolonged disease control post treatment. Updated safety, response and biomarker data from the monotherapy and PEM combo arm will be presented. Clinical trial information: 03058289 .

Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM).

100 Background: Teclistamab (JNJ-64007957) is a bispecific BCMA x CD3 antibody that induces T cell-mediated cytotoxicity against BCMA-expressing myeloma cells. Initial results from an ongoing study of teclistamab in RRMM (NCT03145181) are presented. Methods: Pts have MM and are RR to standard therapies. Primary objective for part 1 is to identify a recommended phase 2 dose(s). Multiple intravenous (iv) doses ± priming doses were explored. Adverse events (AEs) were graded per CTCAE v4.03 and cytokine release syndrome (CRS) per Lee et al 2014. Response was investigator-assessed using IMWG criteria; minimal residual disease (MRD) in bone marrow was assessed by next generation sequencing. Results: As of 31 Jan 2020, 66 pts had received iv teclistamab (0.3–270 µg/kg). Median age was 64 y (24–82), median prior therapies was 6 (2–14), 97% triple-class exposed, 83% triple-class refractory, and 38% penta-drug refractory. Most common treatment-related AEs (all grade) were CRS (56%), neutropenia (26%), and anemia (23%). CRS events were all grade 1–2 and generally confined to initial doses. 8% of pts had treatment-related neurotoxicity (3% grade ≥3), and 9% had infusion related reaction. Infection-related AEs were reported in 61% of pts (21% grade ≥3). 2 dose-limiting toxicities were reported: grade 4 delirium (resolved after 16 days) and grade 4 thrombocytopenia (resolved after 1 day). 36% of pts had treatment-related grade ≥3 AEs; neutropenia (20%) and anemia (14%) were most frequent. Only 1 grade 5 AE was reported (respiratory failure in the setting of pneumonia deemed unrelated by the investigator). PK results indicate that the half-life of teclistamab supports weekly dosing. On-target pharmacodynamic activity (T cell redistribution and activation along with transient release of cytokines) was observed at doses ≥9.6 µg/kg. Cytokine production was modulated with step-up dosing while T cell activation was maintained. 65 pts were evaluable for response. Activity was observed starting at treatment doses ≥38.4 µg/kg, with 20/52 (38%) pts achieving a response. At the highest dose, 7/9 (78%) pts responded (1 response pending confirmation). Of MRD-evaluable pts who had complete response, 2/2 were MRD negative at 10−6 with treatment ongoing &gt; 12 mo. Conclusions: Teclistamab has manageable safety across all doses explored. A 78% overall response rate was observed at the highest weekly treatment dose in pts with advanced RRMM, supporting further evaluation of teclistamab in expansion cohorts. Clinical trial information: NCT03145181.

458P - Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours

458P - Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours

87P - Preclinical pharmacokinetic/pharmacodynamic (PK/PD) relationship of ABN401, a highly selective met inhibitor, in gastric and non-small cell lung cancer models

BackgroundABN401 is a highly selective best-in-class Met inhibitor that is targeting MET-driven cancers. Met which is also known as a hepatocyte growth factor (HGF) receptor is encoded by the MET gene. MET alterations, including amplification and mutation, and Met overexpression are well known for tumorigenic transformation, tumor growth, angiogenesis, invasion, and metastasis in several cancer types, including gastric and non-small-cell lung cancer (NSCLC). ABN401 shows significant MET signaling inhibition in in vitro and in vivo preclinical studies, especially for cell lines, xenograft, and PDx models which have high MET amplification and/or MET exon 14 deletion. MethodsIn this study, to confirm the pharmacokinetic and pharmocodynamic correlation of ABN401, gastric cancer and NSCLC xenograft models were used. SNU-5, a gastric cancer cell line and EBC-1, a NSCLC cell line both of which has high MET amplification, were used for the xenograft model and dosed at 10mg/kg and 30mg/kg of ABN401 by oral administration. Pharmacokinetic parameters were analyzed in both plasma and tumor tissue samples. Pharmacodynamic biomarkers including Met and phospho-Met (T1234/1235) and downstream signaling were analyzed by immunoblotting. In addition, an expression of Met and phospho-Met were analyzed by immunohistochemistry. ResultsThe PK results demonstrated that in both gastric and NSCLC xenograft models ABN401 drug was readily distributed to tumor tissues. According to both PD studies, ABN401 showed inhibitory effects of Met and downstream signaling in a time dependent manner for both cancer types. There was also correlated between the PK parameters in plasma and tumor samples and pharmacodynamics studies. ConclusionsThis preclinical PK/PD correlation study of ABN401 provides evidence for human dose predictions and dosing strategy for clinical studies. Legal entity responsible for the studyThe authors. FundingAbion Inc. DisclosureAll authors have declared no conflicts of interest.

RAT AND DOG PHARMACOKINETIC STUDIES OF GB-5001, A ONCE MONTHLY DONEPEZIL INJECTABLE FOR ALZHEIMER’S DISEASE

Donepezil is an acetylcholinesterase inhibitor and is the most commonly prescribed medication for treating Alzheimer's disease. However, the currently marketed donepezil products are once daily oral formulations with side effects such as nausea, vomiting and weight loss, etc. and the patient's compliance is also very low. Recently, once or twice weekly donepezil patch formulations have been developed but these formulations still have disadvantages such as skin irritation, effect of sweating, shower, etc. on in vivo donepezil release rate. One month release injectable of donepezil using biodegradable polymers can be a good alternative to increase patient compliance and reduce these side effects or disadvantages. In this study, GB-5001, once monthly donepezil depot injectable was prepared using InnoLAMP technology, which enables easy mass production of uniform biodegradable microspheres. Pharmacokinetic studies were performed after a single intramuscular injection of GB-5001 in male SD rats and Beagle dogs. Dose dependency and PK parameters were evaluated by analyzing plasma donepezil concentration by LC/MS/MS after administering three different doses of GB-5001 in each species. GB-5001, one-month release donepezil microspheres with uniform size, was successfully prepared by InnoLAMP technology. In rat PK study of GB-5001 after a single intramuscular injection, plasma donepezil concentration was kept within the therapeutic range for more than one month. Three different doses of GB-5001 showed Tmax of 14 days and dose dependent Cmax values. Moreover, the area under the curve of GB-5001 was also observed to be increased with accordance with the dose. Dog PK study after a single intramuscular injection of GB-5001 at three different doses also showed similar in vivo donepezil release profiles and dose dependent Cmax and AUC values as in rat experiments. Using proprietary InnoLAMP platform technology, we successfully produced uniform sustained release donepezil microspheres for Alzheimer's disease. Dose dependent and longer than one month releasing PK Results in rats and dogs of this formulation, GB-5001, indicate that GB-5001 could be used as an excellent alternative delivery Methods of donepezil for Alzheimer's disease treatment. Currently, scale-up and GMP manufacturing processes are under development to initiate human clinical trial of GB-5001.

Phase II pharmacokinetics of oral SM-88 in heavily pretreated advanced pancreatic ductal adenocarcinoma (PC).

277 Background: SM88 is an oral tyrosine isomer ( TI) and repurposed drugs (CYP3a4 inducer, mTOR inhibitor, oxidative stress catalyst). This regimen has reported no drug related grade 3, 4 or 5 adverse events (JCO 2013 31: e22095) and potential clinical activity in PC (JCO 2018 36: TPS 4156). PC patients have risk factors for malabsorption and a cachexia syndrome rendering some oral therapies potential unreliable. We present PK data from the completely enrolled first stage of an ongoing dose finding phase II in PC. Methods: Open label randomized TI (control – 230 mg bid vs. experimental - 430 mg bid) along with the lowest approved doses of the other agents. Samples were drawn from four patients at pre-dose and up to six h post dosing on cycle day one for two cycles after a single dose of all four components. Results: Mean age: 71.3 (59 – 80), BMI = 25.3 (21.9 – 28.8) and median three prior chemo lines, two post-pancreas surgery and one s/p RT. There was no evidence that the combination altered the expected PKs at C2. There were no serious drug related adverse events. Favorable RECIST, PERCIST or biomarker activity was documented at both TI dose levels. The PK results of the repurposed drugs were consistent with the published data for these agents, despite the combination use and lower than typical label doses; data will be provided. These results were consistent with previous animal and healthier patient PK of SM88. Conclusions: Single dose C1 and C2 TI PKs are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (supp_6): 1605P) and those previously reported in a healthier population of cancer patients (JCO 2018 36: TPS 4156). Based on these results and PK ones from the repurposed drugs, additional data is being collected in order to define the ongoing phase II expansion cohort dose. SM-88 appears to have predictable PK even in heavily pretreated PC patient with prior radiotherapy and surgery. Clinical trial information: NCT03512756. [Table: see text]