BID Regimen Research Articles

The Impact of a Twice-daily Versus Once-daily Proton Pump Inhibitor Dosing Regimen on Laryngopharyngeal Reflux Symptoms: A Prospective Randomized Controlled Trial.

Proton pump inhibitors (PPIs) play a crucial role in managing laryngopharyngeal reflux (LPR), but the optimal dosing regimen remains unclear. We aim to compare the effectiveness of the same total PPI dose administered twice daily versus once daily in LPR patients. We conducted a prospective randomized controlled trial at a tertiary referral hospital, enrolling a total of 132 patients aged 19 to 79 with LPR. These patients were randomly assigned to receive either a 10 mg twice daily (BID) or a 20 mg once daily (QD) dose of ilaprazole for 12 weeks. The Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) were assessed at 8 weeks and 16 weeks. The primary endpoint was the RSI response, defined as a reduction of 50% or more in the total RSI score from baseline. We also analyzed the efficacy of the dosing regimens and the impact of dosing and duration on treatment outcomes. The BID group did not display a higher response rate for RSI than the QD group. The changes in total RSI scores at the 8-week and 16- week visits showed no significant differences between the 2 groups. Total RFS alterations were also comparable between both groups. Each dosing regimen demonstrated significant decreases in RSI and RFS. Both BID and QD PPI dosing regimens improved subjective symptom scores and objective laryngoscopic findings. There was no significant difference in RSI improvement between the 2 dosing regimens, indicating that either dosing regimen could be considered a viable treatment option.

An open-label, multicenter, phase Ib/II study of the ATR inhibitor SC0245 in combination with irinotecan in patients with relapsed and refractory extensive stage small cell lung cancer (ES-SCLC).

8102 Background: Ataxia telangiectasia and Rad3 related (ATR) is activated in response to replication stress induced by topoisomerase 1 inhibitors (TOP1i) and other DNA damaging agents. SC0245 is a novel potent ATR inhibitor, showing synergistic inhibitory effects when combined with TOP1i in DMS-114 and H446 small cell lung cancer. This is the first report on an ongoing phase Ib/II study of SC0245 in combination with irinotecan (IRI) in patients (pts) with ES-SCLC (ClinicalTrials.gov: NCT05731518). Methods: Multiple escalating doses of SC0245 are being administered orally with a fixed dose of IRI. Pts are being enrolled into five escalating dose cohorts (80 mg once daily (QD), 120 mg QD, 80 mg twice daily (BID), 120 mg BID, 160 mg BID) using a BOIN design. SC0245 is administered daily for 3 days weekly x 3 (e.g, Days 1-3, 8-10 and 15-17) with IRI 80 mg/m2 on Days 1, 8 and 15. Cycles are repeated every 4 weeks. The primary endpoint is the rate of dose-limiting toxicity (DLT). Tumor assessments are being performed every 8 weeks using RECIST v1.1. Dose expansion in ES-SCLC patients will follow after definition of the recommended phase 2 dose (RP2D). Results: As of the data cut-off-date (December 21, 2023), 15 pts (median age, 65; male, 73.3%) with previously treated solid tumors have been enrolled, with 3, 4, 3 and 5 pts in 80mg QD, 120mg QD, 80mg BID and 120 mg BID dose cohorts, respectively. 12 of 15 pts were DLT evaluable, and one DLT event (Grade 3 febrile neutropenia) occurred in the 80 mg QD dose cohort. Cytopenia, diarrhea, and liver function test elevations, were the main adverse events (AEs) experienced in 73.3%, 46.7% and 40% pts, respectively. Most AEs were grade 1 or 2 in severity and manageable. The only ≥ Grade 3 TRAEs experienced by more than 2 subjects has been leukopenia (3/15, 20.0%). No drug-related deaths occurred. Among the 9 pts who were evaluable for tumor response, one confirmed partial response (PR) was reported in a pt with ES-SCLC (progressed on prior 1st line of etoposide + carboplatin + serplulimab treatment) treated in the 120mg QD dose cohort, and the response sustained for 32+ weeks; five pts (5/9, 55.6%) had stable disease (SD) as their best response. PK characteristics indicated that SC0245 was rapidly absorbed (median Tmax, 1.0 to 2.0 h), and drug exposure was proportional to dose for the QD and BID regimens. No drug-drug interactions (DDI) between SC0245 and either IRI or its active metabolite SN38 were observed. Conclusions: SC0245 exhibited favorable safety and PK characteristics when administered in combination with IRI at doses ranging from 80mg QD to 120mg BID and the regimen has demonstrated preliminary antitumor activity in ES-SCLC, supporting further evaluation of the regimen in ES-SCLC and other relevant malignancies. Clinical trial information: NCT05731518 .

Comparison of medication persistence and adherence in type 2 diabetes using a once-weekly regimen of DPP-4 inhibitor compared with once-daily and twice-daily regimens: a retrospective cohort study of Japanese health insurance claims data.

Assess medication persistence and adherence for dipeptidyl peptidase-4 inhibitors (DPP-4i) administered once weekly (QW), once daily (QD), and twice daily (BID) among patients with type 2 diabetes (T2D), and explore factors associated with discontinuation and non-adherence for DPP-4i regimens. This retrospective T2D cohort study used medical claims data for three DPP-4i regimens in patients newly prescribed DPP-4i between December 2016 and February 2019. Medication persistence rates were calculated at 3, 6, and 12months by the Kaplan-Meier method. Adherence was measured as Proportion of Days Covered (PDC). We used Cox proportional hazards models for DPP-4i discontinuation and logistic regression models for non-adherence. In the analysis population of 52,762 patients, DPP-4i prescriptions were 84.2% QD, 11.8% BID, and 4.0% QW. Medication persistence rates were similar up to 6 months for all regimens: approximately 90% at 3 and 80% at 6 months. The 12-month persistence rates for QD, BID, and QW were 74.8%, 67.5%, and 68.0%, respectively. Median PDC was 94.0% for QD, 91.8% for BID, and 93.2% for QW. Five specific factors were associated with discontinuation: BID or QW regimen, younger age, no concomitant medications, comorbid dementia, and comorbid chronic pulmonary disease. Non-adherence was associated with those factors plus male sex and treatment at clinics with 0-19 beds. The 12-month medication persistence rates were highest for QD, followed by QW and then BID. Adherence was similar for all three regimens. Medication persistence for DPP-4i may be improved by tailoring regimens to patient characteristics and needs. The online version contains supplementary material available at 10.1007/s13340-024-00714-9.

Abstract 1228: Selective FGFR4 inhibitor Irpagratinib (ABSK011) exhibits broad synergistic and combinatory anti-tumor effects with other therapeutic agents in preclinical HCC models

Abstract Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, ranking as the sixth most prevalent cancer and the third leading cause of death worldwide. Approved therapeutic drugs, including chemotherapy, anti-angiogenesis agents and immunotherapy-based combination regimen (atezolizumab plus bevacizumab), have shown suboptimal clinical benefits for patients with HCC. There are critical unmet medical needs for additional therapeutic options to address this challenge. Deregulation of FGF19-FGFR4 signaling accounts for roughly 30% of HCC and plays a pivotal role in driving HCC tumorigenesis. To date, several FGFR4 inhibitors have advanced to the clinical stage for the treatment of HCC patients. Among them, a recently discovered novel and highly selective inhibitor, Irpagratinib (ABSK011), has demonstrated the potential to become a first-in-class or best-in-class FGFR4 inhibitor. It showed promising anti-tumor activity in an ongoing phase Ib clinical study, with an ORR of 40.7% observed in FGF19 overexpressed late line HCC patients in cohorts treated with BID regimens. To further expand the therapeutic potential of irpagratinib, we carried out an array of combination treatments and revealed its broad synergistic effects with various immune and targeted agents in treating HCC. Methods: We evaluated the combination effects of Irpagratinib with a variety of therapeutic agents, covering both targeted and immune-oncology agents, in preclinical HCC in vivo models. The tested agents, including lenvatinib, atezolizumab plus bevacizumab, anti-PD-(L)1, SHP2 inhibitors and EGFR antagonists, were assessed across a range of preclinical models, such as cell-derived or patient-derived xenografts, engineered syngeneic models and humanized models. Results: Synergistic anti-tumor effects of irpagratinib were observed in combination with the indicated agents, demonstrating more profound effects than either single agent alone in the selected preclinical in vivo models. This resulted in significant effects on inducing tumor regression or inhibiting tumor progression. Conclusions: In summary, these findings collectively illustrate very broad synergistic anti-tumor effects of irpagratinib when combined with various other therapeutic agents. These results may pave the road for potential novel combinatory therapeutic strategies that could expand the utility of irpagratinib and provide innovative and more effective therapies to HCC patients. Citation Format: Nannan Zhang, Bin Shen, Zhidong He, Cheng Dai, Jie Wang, Jie Zhang, Manqi Liu, Yongxian Zhang, Zhui Chen. Selective FGFR4 inhibitor Irpagratinib (ABSK011) exhibits broad synergistic and combinatory anti-tumor effects with other therapeutic agents in preclinical HCC models [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 1228.

Pharmacokinetic and Pharmacodynamic Modeling Analysis of Delpazolid (LCB01-0371) in Adult Patients with Pulmonary Tuberculosis.

Delpazolid (LCB01-0371) is a novel oxazolidinone derivative with a good safety profile for treating gram-positive pathogenic infections such as Mycobacterium abscessus, a highly pathogenic drug-resistant Mycobacterium. In this study, we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of delpazolid after 14 days of multiple oral administration, using data from adult patients with pulmonary tuberculosis. 800 mg once a day, 400 mg twice a day, 800 mg twice a day, and 1200 mg once a day delpazolid for 14 days were tested in 63 patients with pulmonary tuberculosis. For PK blood collection, inpatient and outpatient scheduling were separately implemented. Plasma concentrations of delpazolid were measured at visits 2, 4, 6, and 8 in outpatients, and four sparse blood samples were measured in inpatients. PD models were sequentially fitted using individual PK parameter estimates obtained from PK compartmental models. For PK modeling, 180 plasma concentrations of delpazolid from 56 patients were included. A two-compartment mixed first- and zero-order absorption model best described the time course of plasma concentration. For the PD model, 448 bacterial titer data from 60 patients were used. The time course of bacterial titers (log10 CFU/mL) was described by a model that consists of the growth and killing rate of bacteria with the sigmoid Emax model. The PK-PD simulation suggested that the bacterial titers are the lowest on the 800 mg bid regimen among the four, consistent with observed data, as all regimens substantially decrease. In the dose-response relationship, the effectiveness of delpazolid was suggested.

ASC4KIDS: A Multicenter, Open-Label, Phase Ib/II Study to Determine the Dose and Safety of Asciminib in Pediatric Patients with Chronic Myeloid Leukemia in the Chronic Phase

Background Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients with chronic myeloid leukemia in the chronic phase (CML-CP). More treatment options with improved efficacy and safety profiles are needed for pediatric patients. Asciminib is a first-in-class allosteric inhibitor of ABL (non-receptor tyrosine) kinases, specifically targeting the ABL myristoyl pocket (STAMP), and does not inhibit other protein kinases. Asciminib was approved by the US Food and Drug Administration (FDA) with subsequent approvals worldwide for patients aged ≥18 years with Philadelphia chromosome-positive (Ph+) CML-CP treated with ≥2 prior TKIs in October 2021. Asciminib 40 mg twice daily (bid) has demonstrated improved major molecular response rates (25.5% vs 13.2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). This study aims to characterize the pharmacokinetics (PK), long-term safety profile, and antileukemic effects of asciminib in pediatric patients and identify a pediatric formulation dose that will lead to asciminib exposure comparable to 80 mg qd or 40 mg bid in adult patients. Methods This multicenter, open-label study (NCT04925479) includes patients aged 1 to <18 years with Ph+ CML-CP, without a BCR::ABL1 T315I mutation, treated with ≥1 prior TKI. For the pediatric formulation group, at least 15 patients will be included in each of the two age groups (1 to <12 years and 12 to <18 years), consisting of Part 1, 2 and 3. The study started with an exploratory adult formulation group of Adolescent patients (aged 14 to <18 years, body weight ≥40 kg) treated with the adult formulation dose (40 mg bid or 80 mg qd tablet) under fasting conditions. The primary endpoint includes PK parameters; secondary endpoints include: hematologic and molecular responses, safety, and acceptability/palatability of the pediatric formulations. Part 1 (dose-determining cohort): 4 to 6 patients will receive the asciminib pediatric formulation bid (a mini-tablet of 1.3 mg/kg with food) to assess safety, and to assess if the exposure in pediatric patients is comparable to exposure with the adult formulation over the first 28 days (patients either from pediatric or adult categories). After the interim analysis, if a dose adjustment is required, an additional 4 to 6 patients will be assessed at an adjusted dose. Part 2 (expansion cohort, 40 mg bid regimen): 14 to 16 patients will receive the dose determined in part 1. The second interim PK and safety analysis will be conducted after all patients from parts 1 and 2 complete 28 days of treatment. Part 3 (expansion cohort, 80 mg qd regimen): 10 patients (5 from each age group) will receive the same total daily dose of asciminib qd. The PK, safety profile, and pharmacodynamic endpoints will be assessed for the bid regimen after all patients in parts 1 and 2 complete 52 weeks of treatment. The primary analysis for the combined bid and qd regimen will be performed after all patients complete 52 weeks of treatment (total treatment period: 5 years [ Figure]). A final analysis will be performed after all patients complete treatment. Patients who discontinue treatment early will be followed up for survival until the end of the study. There are 32 study sites open out of planned 35 study sites in 14 countries worldwide. The exploratory and the pediatric formulation groups recruited 4 patients and 9 patients, respectively, as of June 07, 2023, with a total of 13 patients in the study. The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

Anticoagulant Treatment Adherence and Persistence in German Patients with Atrial Fibrillation.

Treatment adherence and persistence impact the effectiveness of edoxaban for the prevention of thromboembolism in patients with atrial fibrillation (AF). The objective of this analysis was to assess adherence and persistence of edoxaban vs. other non-vitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKAs). Utilizing a German claims database, adults with AF with the first pharmacy claim identified for edoxaban, apixaban, dabigatran, rivaroxaban, or VKAs from January 2013 to December 2017 were included in a propensity score-matched analysis. The first pharmacy claim was the index claim. Adherence (i.e., proportion of days covered [PDC]) and persistence (proportion of patients who continued therapy) were compared between edoxaban and other therapies. Patients receiving once-daily (QD) vs. twice-daily (BID) NOAC were also analyzed. Overall, 21,038 patients were included (1236 edoxaban, 6053 apixaban, 1306 dabigatran, 7013 rivaroxaban, and 5430 VKA). After matching, baseline characteristics were well balanced across cohorts. Adherence was significantly higher for edoxaban vs. apixaban, dabigatran, and VKAs (all P < 0.0001). Significantly more edoxaban patients continued therapy vs. rivaroxaban (P = 0.0153), dabigatran (P < 0.0001), and VKAs (P < 0.0001). Time to discontinuation was significantly longer for edoxaban vs. dabigatran, rivaroxaban, and VKAs (all P < 0.0001). More patients receiving NOACs QD had a PDC ≥ 0.8 compared with those receiving NOACs BID (65.3 vs. 49.6%, respectively; P < 0.05); persistence rates were comparable between QD and BID groups. Patients with AF receiving edoxaban had significantly higher adherence and persistence compared with those receiving VKAs. This trend was also seen in NOAC QD regimens vs. NOAC BID regimens for adherence. These results provide insight into how adherence and persistence may contribute to the effectiveness of edoxaban for stroke prevention in patients with AF in Germany.

Abstract CT152: A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophogeal junction adenocarcinomas or gastric cancer

Abstract Background: MET gene amplification is associated with poor prognosis in gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ). Savolitinib is a potent and highly selective oral MET tyrosine-kinase inhibitor. Here we reported the preliminary efficacy and safety from a phase 2 trial of savolitinib monotherapy in patients (pts) with MET-amplified advanced or metastatic GC/GEJ. (NCT04923932). Methods: Eligible pts had 2L+ GEJ or GC, with MET amplification and measurable lesions. Pts received savolitinib at 600 mg QD for body weight (BW) ≥50 kg, while 400 mg QD for BW &amp;lt;50 kg in 21-day cycles until disease progression or meeting other criteria for end of treatment. Savolitinib BID regimen has also been additionally explored. The primary endpoint was objective overall response rate (ORR) evaluated by Independent Review Committee (IRC). One interim analysis (IA) was pre-defined at the first 20 QD pts who had at least 2 tumor assessments. Results: As of IA, 20 pts were enrolled for QD regimen. Demographics and clinical outcomes are shown in table 1. The mean relative dose intensity of 93.07%. Median duration of exposure was 2.09 months. Confirmed ORR by IRC was 45%, and reached 50% in 16 patients with MET GCN (high) while only 1 PR was observed in 4 patients with MET GCN (low). Duration of response rate at 4-month was 85.7% with median follow up time of 5.5 months. The most common Gr≥3 TRAE (≥5%) were platelet count decreased, hypersensitivity, anemia, neutropenia and hepatic function abnormal. In all pts, only 1 patient discontinued treatment due to grade 4 liver function abnormal (TRAE) and no patient died due to TRAE. Conclusion: Savolitinib monotherapy had manageable safety and showed promising efficacy in pts with MET-amplified GEJ or GC, particularly in pts with MET high GCN. BID regimen is being investigated to further evaluate the efficacy and safety of savolitinib in pts with MET high GCN. Table 1. Pts baseline characteristics and clinical efficacy Baseline Characteristics ITT in IA (n=20) Median age (min, max), yearsSex (male/female), nECOG (0/1/2)Median BMI (min, max), (kg/m2)Primary location of tumor (GC/GEJ)Tumor stage (IV)Prior line of therapy (1/2/≥3)MET GCN (high/low) 57.00 (39.5, 76.8)17/33/15/220.8 (14.9, 25.8)16/4205/10/516/4 Clinical Efficacy By IRC By Investigator Confirmed objective response rateDisease control rate4m-DoR rate,% (95% CI) 45%65%85.7 (33.4, 97.9) 40%55%71.4 (25.8, 92.0) Citation Format: Zhi Peng, Hua Wang, Baorui Liu, Huiting Xu, Zhenyang Liu, Tianshu Liu, Jun Zhang, Yuxian Bai, Ying Yuan, Tao Wu, Feng Ye, Qinghua Pan, Jufeng Wang, Enxiao Li, Diansheng Zhong, Yueyin Pan, Yanru Qin, Yan Yang, Yusheng Wang, Aiping Zhou, Yongshun Chen, Dianbao Zhang, Hongli Liu, Xiujuan Qu, Shubin Wang, Ning Liu, Jinsheng Wu, Wei Li, Kejun Nan, Hongming Pan, Jianming Xu, Chunmei Bai, Heling Liu, Jia Wei, Runzhi Chen, Rongrong Li, Wei Li, Jinghong Zhou, Hongyan Yin, Qian Xu, Songhua Fan, Yongxin Ren, Weiguo Su, Lin Shen. A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophogeal junction adenocarcinomas or gastric cancer [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 CT152.

Abstract 6033: RA123, a new GLS1 allosteric inhibitor demonstrates in vitro and in vivo activity in multiple myeloma models

Abstract The conditional essential amino acid glutamine is utilized by tumors to sustain bioenergetic requirements in a nutrient-poor microenvironment. Based on this specific tumor need, efforts have been made to target the glutamine metabolism using glutaminase inhibitors. In this study, we present in vitro and in vivo studies demonstrating activities and target engagement of a new specific GLS1 allosteric inhibitor (RA123). In vitro, RA123 was tested in imid-resistant, CD38 low RPMI8226 multiple myeloma cell line using the ATP Cell titer Glo assay over a 72h treatment period. In vivo, RA123 was tested in mice xenografted with RPMI8226 multiple myeloma cell line. Compound was given at three different under a BID (twice a day) regimen. Tumor growth under treatment was monitored by caliper measurement for 20 days. A terminal PK/PD study on the same model was setup measuring impact of the drug on the glutamine and glutamate tumor content post 24 hours after the last administration. Over the same period, PK measurements were planned to document drug exposure in the plasma and in the tumor. Finally, in a stand-alone study, target engagement was documented using imaging modality. [18F]FSPG PET radiotracer was used to visualize and quantify impact of RA123 on tumor (RPMI8226) glutamate pool. RA123 was given at three doses under a BID regimen. Treatment was administered for 3 days, and PET signal was recorded at baseline and at end of day 3. In vitro study demonstrated that RA123 was able to induce cell killing of RPMI8226 after 72 hours of treatment. These data translated in vivo by a dose-dependent effect on cell growth. In a terminal PK/PD study, RA123 confirmed a dose-dependent impact on glutamine and glutamate tumor levels which correlated with both plasma and tumor exposure. Further confirmation of target engagement was observed with reduced PET uptake post- RA123 treatment at the three doses tested. In conclusion, this study demonstrated that RA123, a new specific GLS1 allosteric inhibitor was able to impact multiple myeloma tumor cell growth both in vitro and in vivo. This effect was associated with reduced glutamate pools and accumulation of glutamine levels within the tumor cells. Citation Format: Christophe Henry, Dimitri Gorge-Bernat, Pascal Pannier, Isabelle Meaux, Jane Cheng, Fangxian Sun, Olivier Pasquier, Philippe Lienard, Erwan Jouannot, Thierry Gouyon, Geneviève Estenne-Bouhtou, Bailin Zhang, Bérangère Thiers, Laurent Debussche, David Machnik. RA123, a new GLS1 allosteric inhibitor demonstrates in vitro and in vivo activity in multiple myeloma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6033.

Machine Learning for Pharmacokinetic/Pharmacodynamic Modeling

A variety of new recurrent neural networks (RNNs) including the ODE-LSTM, Phased LSTM, CTGRU and GRU-D, were evaluated on modeling irregularly sampled PK/PD data with 6 or 12 time points/day and predicting PD data of unseen dosing regimens and dosing levels. The one-compartment absorption PK model and the Indirect PK/PD model I was used to simulate the PK/PD with inter-individual variabilities in volume of distribution and residual errors in PD measurement. The four RNNs were able to successfully model daily dose (QD) PK/PD and extrapolate to twice daily (BID) dose PD based on BID PK. The RNNs not only captured the additional fluctuations in the BID regimen but also the return phase to the baseline PD. However, extrapolating to unseen dose levels outside of the dose range for training proved to be challenging for all the RNNs tested. Only the GRUD demonstrated reasonable prediction results when extrapolating to unseen doses that were 3 or 10-fold outside the training doses. Overall, these new RNNs were able to overcome some limitations of previous RNNs evaluated and showed promise of integrating neural networks in PK/PD.

Aspirin in essential thrombocythemia. For whom? What formulation? What regimen?

Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm, the most common clinical manifestations of which include arterial and venous thrombosis, bleeding and vasomotor/microvascular disturbances. Low-dose (81-100 mg) aspirin once daily, which irreversibly inhibits platelet thromboxane A2 (TxA2) production by acetylating cyclo-oxygenase-1, is the recommended treatment for the control of vascular events in all ET risk categories, except patients at very low risk, who need aspirin for treatment of vasomotor/microvascular disturbances only. Simple observation should be preferred over aspirin prophylaxis in low-risk patients with platelet counts >1,000x109/L or harboring CALR mutations. Plain aspirin should be preferred over enteric coated aspirin because some ET patients display poor responsiveness ("resistance") to the latter. When treated with a once daily aspirin regimen, adequate inhibition of platelet TxA2 production (measured as serum thromboxane B2 level) does not persist for 24 h in most patients. This phenomenon is associated with the patients' platelet count and the number (but not the fraction) of circulating immature reticulated platelets with non-acetylated cyclo-oxygenase-1 and is therefore consequent to high platelet production (the hallmark of ET), rather than increased platelet turnover (which is normal in ET). Twice daily aspirin administration overcame this problem and proved safe in small studies. Although additional data on gastrointestinal tolerability will be useful, the twice daily regimen could already be implemented in clinical practice, considering its favorable risk/benefit profile. However, patients whose platelet count has been normalized could still be treated with the once daily regimen, because they would otherwise be unnecessarily exposed to a potential small risk of gastrointestinal discomfort.

Anagliptin twice-daily regimen improves glycaemic variability in subjects with type 2 diabetes: A double-blind, randomized controlled trial.

To determine whether the twice-daily (BID) regimen is superior to the once-daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD. A double-blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase-4 (DPP-4) inhibitor treatment to compare glycaemic variability. The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P < .05); -30.4 ± 25.6 mg/dl (P < .001) in the anagliptin group versus -9.5 ± 38.0 mg/dl (P=.215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P < .001) in the anagliptin group and by 14.6% ± 28.2% (P=.014) in the sitagliptin group, with a statistically significant difference (P=.009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG). The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG.

Justification for Asciminib Dosing in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (Ph+ CML-CP) with and without the T315I Mutation

Introduction: Asciminib (ASC), a first-in-class BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), is approved by the FDA for adult patients (pts) with Ph+ CML-CP previously treated with ≥2 tyrosine kinase inhibitors (TKIs) and for pts with the T315I mutation. Approval was based on the results of the pivotal phase III ASCEMBL trial (NCT03106779), where ASC 40 mg twice daily (BID) demonstrated superior efficacy and better safety and tolerability vs bosutinib 500 mg once daily (QD), and an ongoing phase I study (NCT02081378), which evaluates ASC in doses of 20‒200 mg BID and 10‒200 mg BID in pts with and without the T315I mutation, respectively; doses of 80‒200 QD are also evaluated. Population pharmacokinetics (PopPK) has previously shown that total systemic exposure of ASC over 24 h was comparable between 80 mg QD and 40 mg BID (AUC0-24h 12,646 vs 12,638 ng*h/mL) and exposure-response (ER) models have quantified the longitudinal effect of ASC on BCR:ABL1IS levels. Here, we illustrate the similarity in efficacy and safety of ASC at 80 mg QD and 40 mg BID in pts with Ph+ CML-CP without the T315I mutation, and further support the ASC 200 mg BID dose in pts with the T315I mutation. Methods: Two ER-efficacy analyses, assessing the association between ASC exposure and efficacy endpoint were performed: 1) for pts without the T315I mutation on either 40 mg BID or 80 mg QD, and 2) for pts with the T315I mutation. The efficacy endpoint was based on longitudinal BCR::ABL1IS and summarized as major molecular response (MMR) rates at weeks (wks) 24 and 48. The ER-safety analysis assessed the association between ASC exposure and the probability of safety event based on laboratory abnormalities, vital signs for hypertension and adverse events (AEs) of fatigue/asthenia at any time during treatment. Results: Similar efficacy was predicted for ASC 80 mg QD vs 40 mg BID in pts without the T315I mutation (predicted MMR rate [mean ± SE] at Wk 24: 24.8 ± 4.2% vs 27.6 ± 4.5%; Wk 48: 30.6 ± 4.7% vs 32.3 ± 4.8%, respectively); rates were similar to those observed in ASCEMBL. Predicted efficacy did not differ significantly between the two regimens regardless of the different ASC minimum and maximum plasma concentrations. Stratified time-course simulations using both 80 mg QD and 40 mg BID regimens showed clinically relevant decreases in BCR::ABL1IS levels regardless of regimen, baseline (BL) BCR::ABL1IS levels or number of prior TKIs received. Predicted BCR::ABL1IS values continued to decrease after 48 wks of treatment for all BL BCR::ABL1IS levels. In pts with the T315I mutation, a dose of 200 mg BID was the most efficacious, as BCR::ABL1IS decreases were more likely than with lower dose regimens. The ER-safety analysis showed that increasing ASC exposure was not associated with increased probability of experiencing fatigue/asthenia or hypertension, the most common AEs reported in clinical trials. Additionally, there was no clinically relevant association between ASC exposure at doses up to 200 mg BID and risk of laboratory abnormalities, including amylase increase and lipase increase (any grade and Grade ≥3); ALT increase, AST increase and bilirubin increase (Grade ≥2); platelet decrease, neutrophil decrease and hemoglobin decrease (Grade ≥3); and triglyceride increase (any grade). Conclusions: Both the ASC 80 mg QD and 40 mg BID regimens demonstrated substantial efficacy in pts with Ph+ CML-CP without the T315I mutation, regardless of BL BCR::ABL1IS levels or number of prior TKIs received. While ASC showed efficacy across subgroups, pts who are heavily pre-treated and those with high BL BCR::ABL1IS levels may benefit from continuous, long-term ASC treatment as BCR::ABL1IS was predicted to decrease beyond 48 wks of treatment. The 80 mg QD dose regimen is likely to support better treatment adherence, potentially improving benefit from therapy. For pts with the T315I mutation, modelling validated the 200 mg BID dose as both effective and safe. ASC had a similar safety profile across all dose regimens evaluated (up to 200 mg BID), with ER-safety analyses suggesting that increased exposure had no clinically relevant association with increased risk of assessed toxicities. More data on asciminib at the 80 mg QD dose in both first and later lines will be available from ongoing clinical trials: ASC4FIRST (NCT04971226), AIM4CML (NCT04666259), ASC4OPT (NCT04948333). Sponsor: Novartis.

Low Toxicity and Excellent Cosmesis with Highly Conformal Accelerated Partial Breast Irradiation Delivered Either Twice Daily or Every Other Day

<h3>Purpose/Objective(s)</h3> Two landmark randomized controlled trials (RCT) of external beam accelerated partial breast irradiation (EB-APBI) using 38.5 Gy/10 fractions (F) BID demonstrated excellent cancer control outcomes in appropriately selected patients but conflicting results regarding cosmesis. A recent RCT reported high rates of acceptable cosmesis using 30 Gy/5F QOD, making the most appropriate schedule for EB-APBI unclear. We utilized the BID regimen largely until the COVID-19 pandemic with strict contouring, dosimetric, and planning guidelines for gross/clinical/planning target volumes (GTV/CTV/PTV) and organs-at-risk (OAR). We report our experience with BID and QOD EB-APBI with a hypothesis that our treatment planning approach would result in acceptable acute toxicity and cosmesis. <h3>Materials/Methods</h3> We identified patients that received EB-APBI from 4/2017 through 12/2021. Clinical, pathologic, acute toxicity, cosmesis and dosimetric data for the lumpectomy (Lump) GTV/CTV/PTV and key OARs (ipsilateral breast [IB V50%, V80% and V100% of the Rx dose] heart (mean dose, V5% Rx dose; V3 Gy], ipsilateral lung [IL V30% Rx dose] and mean total lung dose [TLD]) were collected. Cosmesis was physician-reported using the 4-point NRG Oncology/RTOG Global Cosmetic Score (GCS): Excellent (E)/Good (G)/Fair (F)/Poor (P). We report descriptive statistics to summarize our results. <h3>Results</h3> 245 patients were included with median follow-up 19 months (IQR, 9-30 months): median age, 66 y (IQR, 59-71 y); 51% left-sided; 82% invasive; 100% invasive tumors HR+/HER2-; 95% of DCIS HR+; median invasive tumor size 9.5 mm (IQR, 6-13 mm) and DCIS size 8mm (IQR, 4-12 mm); 96% nodal surgery in invasive disease. Fractionation was BID in 55%, QOD in 45%. 3DCRT was used in 88% with median 6 fields (IQR, 5-7) and 96% were treated prone. Median Lump PTV eval volume was 176 mL and median breast volume 1335 mL resulting in median breast V50%Rx Dose=40.3% (IQR, 34.5-45.8%) and median breast V100=15.6% (IQR, 10.2-18.6%). Lump PTV coverage was high (median V95=100%). The mean heart dose was 35 cGy (IQR, 15-59 cGy), heart V5%=1.1% (IQR, 0-8.1%), and median heart V3Gy=0% (0-0.5%). The IL V30% (median 0%, IQR 0-0.4%) and TLD (median 49 cGy, IQR 26-93.1 cGy) were also low. The majority of patient had no acute toxicity (55% grade 0 dermatitis; 57% grade 0 fatigue; 97% grade 0 pruritis). The rate of E/G cosmesis was 97.1% (N=238) and F/P 2.9% (N=7). In patients with at least 2 years follow-up, rates were 96% E/G (N=95) and 4% F/P (N=4). The IB V100 was marginally associated with increased odds of F/P cosmesis (OR=1.18, 95% CI 0.99-1.42, p=0.07). <h3>Conclusion</h3> With multiple-field 3DCRT in the prone position, EB-APBI can be delivered with low toxicity and great cosmetic results with BID or QOD treatment. Given the low rate of F/P cosmesis, longer follow-up is needed to confirm stability of these results and to help identify optimal dose-volume parameters to minimize the rate of F/P cosmesis.

Twice- or once-daily dosing of direct oral anticoagulants and gastrointestinal bleeding in patient with atrial fibrillation

AimsDirect oral anticoagulant (DOAC) is widely used for the prevention of embolic stroke in non-valvular atrial fibrillation (NVAF) patients. However, the gastrointestinal bleeding risk in several DOAC regimens was higher than warfarin, especially in once-daily regimens. Methods and resultsWe conducted a single-center prospective registry of patients with NVAF treated with DOACs: the DIRECT registry (N = 2216; follow-up duration 650 [IQR 103–1574] days, UMIN000033283). All patients were divided into 2 groups: the twice-daily (BID) regimen group (dabigatran and apixaban) versus the once-daily (QD) regimen group (rivaroxaban and edoxaban). Out of 2216 patients, we successfully matched 904 patients in the QD group and 904 patients in the BID group using propensity score. The primary endpoint was gastrointestinal bleeding defined as any bleeding in the gastrointestinal tract that was identified through medical records regardless of bleeding site or severity. The BID group showed a significantly lower gastrointestinal bleeding rate than the QD group (3.5/100 person-year vs. 6.2/100 person-year, log-rank P < 0.0001). The secondary endpoints were all death, stroke, major bleeding, and any bleeding. The rate of major bleeding was significantly lower in patients with BID regimen group (log-rank P = 0.040). In contrast, all death, stroke, and any bleeding did not differ between both groups (log-rank P = 0.280, 0.520 and 0.066, respectively). ConclusionsThe BID regimen as compared with the QD regimen was associated with reduced risk of gastrointestinal bleeding.

Twice Daily Compared to Three Times Daily Hydrocortisone in Prepubertal Children with Congenital Adrenal Hyperplasia

Introduction: Glucocorticoid therapy in children with congenital adrenal hyperplasia (CAH) must be finely balanced between optimizing adrenal control and minimizing side effects. Twice (BID) rather than three times daily (TID) hydrocortisone may provide similar adrenal control and reduce metabolic risk. We compared BID and TID regimens with respect to adrenal control, growth, and metabolic effects. Methods: A retrospective chart review (n = 128 visits, 36 individual patients) of prepubertal children with classical CAH was conducted at a tertiary care center between March 2007 and February 2020. Adrenal control, growth, and metabolic data were extracted in those taking hydrocortisone BID versus TID. Univariate generalized estimating equations models were performed to analyze the effect of dose frequency on outcomes of interest. Results: Overall, we found no difference in adrenal control (8% vs. 18% poor control) or testosterone levels (9.65 ng/dL vs. 7.62 ng/dL) between the BID versus TID groups. We detected no difference in growth velocity (6.86 vs. 6.32 cm/year) or bone age advancement (11.3 vs. 5.91 months) between the groups. There was no difference in daily steroid dose (12.1 vs. 11.7 mg/m²/day), BMI Z-score (0.43 vs. 0.31), or systolic blood pressure percentile (65.5 vs. 61.7). Conclusion: BID dosing provides similar adrenal control and does not appear to impact growth or bone age advancement. On the other hand, TID dosing does not appear to increase the metabolic side effect profile in this age-group. Dosing should be patient-centered with individualized consideration.

Limited-Stage Small-Cell Lung Cancer: Current Progress and the Next Frontier

Limited-stage (LS) small-cell lung cancer (SCLC) is defined as disease confined to a tolerable radiation portal without extrathoracic metastases. Despite clinical research over two decades, the prognosis of LS-SCLC patients remains poor. The current standard of care for LS-SCLC patients is concurrent platinum-based chemotherapy with thoracic radiotherapy (RT). Widespread heterogeneity on the optimal radiation dose and fractionation regimen among physicians highlights the logistical challenges of administering BID regimens. Prophylactic cranial irradiation (PCI) is recommended to patients following a good initial response to chemoradiation due to improved overall survival from historical trials and the propensity for LS-SCLC to recur with brain metastases. However, PCI utilization is being debated due to the greater availability of magnetic resonance imaging (MRI) and data in extensive-stage SCLC regarding close MRI surveillance in lieu of PCI while spurring novel RT techniques, such as hippocampal-avoidance PCI. Additionally, novel treatment combinations incorporating targeted small molecule therapies and immunotherapies with or following radiation for LS-SCLC have seen recent interest and some concepts are being investigated in clinical trials. Here, we review the landscape of progress, limitations, and challenges for LS-SCLC including current standard of care, novel radiation techniques, and the integration of novel therapeutic strategies for LS-SCLC.

Abstract P223: Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors

Abstract Background: Elevated expression of PIM kinases in various solid and hematologic malignancies is correlated with increased cell survival and reduced apoptosis, implicating inhibition of PIM kinases as attractive targets for disruptive therapy. TP-3654 is an oral, small molecule, investigational PIM kinase inhibitor with favorable selectivity against PIM-1 over other kinases. TP-3654 is currently being evaluated in a phase 1 first-in-human study in patients (pts) with advance solid tumors (NCT03715504). Methods: Pts with advanced metastatic, progressive, or unresectable solid tumors refractory or intolerant of established therapies were treated with TP-3654. Pts took TP-3645 orally once (QD) or twice (BID) daily in a 28-day dosing cycle until unacceptable toxicity or disease progression. Escalating dose levels of TP-3654 were evaluated using a 3+3 design. The primary objective was to determine maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included establishing the pharmacokinetic (PK) profile of oral TP-3654 and any evidence of antitumor activity. An exploratory objective was to study predictive biomarkers in tumor tissues and mechanism-based pharmacodynamic activity in peripheral blood mononuclear cells (PBMCs). Results: As of 31 May 2021, 22 pts were treated with TP-3654 at 480 mg QD (n=3), 720 mg QD (n=3), 1080 mg QD (n=4), 1440 mg QD (n=3), 720 mg BID (n=3), and 960 mg BID (n=6). Median age of 58 years (range: 20–72), 59% (13/22) pts male, and 86% (19/22) pts received ≥3 lines of prior therapy. Median treatment duration is 2 cycles (range: 0.1–24) and 6 pts received treatment for ≥4 cycles. Two pts remain on active study treatment. No DLT was observed. The most common treatment-emergent adverse events (TEAEs) reported in ≥20% of pts were vomiting, diarrhea, nausea, and abdominal pain. No related myelosuppressive AEs were reported. Fifty percent (11/22) of pts reported 18 Grade ≥3 TEAEs, of which only one (alanine aminotransferase increased) was considered related to TP-3654. No related, serious AEs were reported. Two TEAEs resulted in a fatal outcome (acute kidney injury, completed suicide); neither were related to TP-3654. Best response is stable disease (SD) in 67% (10/15) evaluable pts, SD for ≥ 16 weeks in 5 pts, best reduction of tumor size from baseline is -22%. TP-3654 plasma exposure increased with doses up to 1080 mg QD; the BID regimen at the 720 mg dose achieved greater plasma exposure than the 1440 mg QD dosing regimen. Reduced phosphorylation of PIM-1 downstream signal protein pBAD was observed in isolated PBMCs, predominantly in pts with prolonged clinical benefit. Conclusions: Preliminary data suggest that TP-3654 is tolerated as a monotherapy up to 960 mg BID in pts with heavily pretreated, relapsed, and refractory solid tumors. No DLT was observed and MTD was not reached. PK data indicate that the BID dose regimen achieved better plasma exposure than the QD regimen at higher doses. TP-3654 has shown target-specific inhibition of PIM-1 in pts. Updated data will be presented. Citation Format: Ignacio Garrido-Laguna, Patrick M. Dillon, Sujan Kabir, Jian Mei, Mark L. Wade, Huyuan Yang, Carl Stapinski, Jason M. Foulks, Steven L. Warner, Clifford Whatcott, Claudia Lebedinsky, Siqing Fu. Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P223.

Exposure-Response of Entospletinib (ENTO) for the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia

Background: Entospletinib (ENTO) is a selective spleen tyrosine kinase (SYK) inhibitor that has demonstrated evidence of efficacy and tolerability in chronic lymphocytic leukemia (CLL). The relationship between ENTO plasma exposures and clinical efficacy and safety were evaluated in relapsed/refractory (R/R) CLL subjects, following administration of 100, 200, and 400 mg twice daily (BID) in a Phase 2 Study (NCT01799889; study -0102).Methods: ENTO pharmacokinetics (PK) and plasma exposures (Cmax, AUCtau, and Ctau) were characterized in 60 R/R CLL subjects using a population PK model developed from data collected in phase 1/2 clinical studies. ENTO plasma samples were collected on day 1, and day 8 (pre-dose,1.5 hours, and 4 hours post-dose), day 15, and day 22 (pre- and 1.5 hours post-dose) of cycle 1 and on day 1 (pre- and 1.5 hours post-dose) of subsequent 28 day cycles. Data for efficacy and safety endpoints were collected every 8 weeks (for cycles 1-6) followed by every 12 weeks (for cycles 7-18). Efficacy endpoints, including best overall response rate (BOR), progression-free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, maximum change from baseline in lymphocytes, platelets, and hemoglobin were evaluated against ENTO plasma exposure (AUCtau and Ctau). Safety endpoints, including adverse events (all grades) of skin rash, infection, diarrhea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin (total), and neutrophils (maximum change from baseline) versus ENTO plasma exposure (AUCtau and Cmax) were evaluated.Results: A dose proportional increase in ENTO exposures was observed across 100, 200, and 400 mg BID regimen. A greater reduction in SPD and lymphocytes and an increase in platelets were associated with higher ENTO exposures. No exposure-response relationship was observed for PFS at Week 24 (i.e., there was an overlap in survival curves across quartiles of ENTO exposures) or hemoglobin. No association between ENTO exposures vs incidence of skin rash, infection, diarrhea, AST, ALT and neutrophils was observed. There was a slight trend toward elevated total bilirubin with higher ENTO exposures.Conclusions:In R/R CLL subjects, following ENTO 100, 200, and 400 mg BID regimen, higher exposures corresponding to 400 mg BID are associated with greater efficacy (reduction in SPD lymphocytes and an increase in platelets). No clinically relevant relationship between ENTO exposures and safety, except total bilirubin, was observed. Overall, the analyses support ENTO 400 mg BID regimen as a starting dose for future phase 2 trials in CLL patients. [Display omitted] DisclosuresGupta:Gilead Sciences, Inc.: Employment, Equity Ownership. Meng:Gilead Sciences, Inc.: Employment, Equity Ownership. Sharma:Gilead Sciences, Inc.: Employment, Equity Ownership. Ye:Gilead Sciences, Inc: Employment, Equity Ownership. Silverman:Gilead Sciences, Inc.: Employment, Equity Ownership. Abella:Gilead Sciences, Inc.: Employment, Equity Ownership. Mathias:Gilead Sciences, Inc.: Employment, Equity Ownership.

PHARMACOKINETIC SIMULATION AND OPTIMIZING GENTAMICIN DOSING IN PEDIATRICS

Aim: This study was conducted to optimize gentamicin (genta) use in paediatrics incorporating the estimation of serum drug concentrations and customized pharmacokinetic (PK) simulations. Method: 66 patients (age 1-144 month) were enrolled in the study. They received gentamicin 2-2.5 mg/kg every 8 hr. (TID regimen). Serum genta concentrations within one dosing interval of dose 3 and dose 4 were determined using an immunoassay; blood samples were collected at 30 minutes after the end of infusion while a trough level sample was collected just before the next dose. Customized PK simulation analysis was based on the following assumptions: Single-compartment model, first-order elimination, and repeated short time IV infusion. PK parameters and simulation of genta peak/trough levels after various regimens were estimated and compared statistically. Results: About 65% of the patients showed subtherapeutic peak genta levels (less than 6 ug/ml) during the dosing intervals. Potentially toxic trough levels (>1 ug/ml) were observed in two patients. Neonates (1-12 months) showed a relatively higher mean genta volume of distribution (Vd), 0.51±0.18 L/Kg, vs 0.37±0.13 (p 1-12 y). Half-life in both groups was comparable (about 3 h). Simulation suggests BID regimens will provide the best theoretically overall peak/trough targets. Discussion: In children, a higher volume of distribution of genta could be associated with the lower serum peak levels due to the conventional dosing regimen (TID). Conclusion: Optimal dosing regimen in pediatric patients can be designed to achieve target high peak, low trough levels based on simplified customized PK simulations.