Q2W Regimen Research Articles

154. Pharmacokinetics and Safety of GS-1720 Following Multiple Ascending Doses in a Phase 1a Study in People Without HIV-1

Abstract Background Long-acting antiretrovirals for HIV-1 treatment may improve adherence by reducing treatment fatigue. GS-1720 is an oral integrase strand transfer inhibitor (INSTI) with potent anti-HIV-1 activity. Pharmacokinetics (PK) and safety of single ascending GS-1720 doses in participants without HIV-1 have been previously reported. Here, we report preliminary PK and safety of multiple ascending doses (MAD). Methods In this Phase 1a, randomized, blinded, placebo-controlled, multicohort study, oral GS-1720 or placebo (6:3/cohort) was administered under fasting conditions in 3 once-weekly (QW) and 2 once-daily (QD) MAD cohorts. Participants received 150, 450, or 1350 mg of GS-1720, or placebo, for 6 weeks or 450 or 900 mg of GS-1720, or placebo, for 7 or 14 days, respectively. Primary endpoints were plasma PK parameters (including AUC, Cmax, and accumulation ratios) and incidence of adverse events (AEs) and laboratory abnormalities. Participants were followed up to Day (D) 105. Results Overall, 45 participants were enrolled: median age, 29–40 years; 47% female. For QW doses of 150, 450, or 1350 mg at Week 6, respectively, mean (coefficient of variation [CV]%) Cmax was 19.9 (21.3), 39.6 (23.3), and 60.6 (25.8) μg/mL, and median (range) Tmax was 6 (4–8), 4 (3–4), and 4 (2–6) hours. Accumulation ratios ranged from 2.4–2.9 for AUC and 2.0–2.2 for Cmax. For QD doses of 450 and 900 mg at D7 and D14, respectively, mean (CV%) Cmax was 64.5 (13.6) and 126 (13.6) μg/mL, and median (range) Tmax was 4 (2–8) hours. Accumulation ratios were 5.3 and 6.8 for AUC and 4.2 and 5.4 for Cmax at D7 and D14, respectively. AEs related to GS-1720/placebo (blinded data) were reported in 12/45 participants (27%); most AEs (16/20; 80%) were Grade 1. One AE in the 450 mg QW cohort led to GS-1720/placebo discontinuation. Conclusion GS-1720 exhibits a PK and safety profile supportive of oral QW dosing. The data support the development of GS-1720 as part of a first INSTI-containing oral QW regimen. Disclosures Haeyoung Zhang, PharmD, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Ines Mendes, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Eva Mortensen, MD, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Hui Wang, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Aaron Share, B.Sc, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Monika Sobczyk, M.Sc, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Ramesh Palaparthy, PhD, Gilead Sciences, Inc.: 1475-US-PSP, 1475-WO-PCT, 1474-US-PSP, 1515-US-PSP, 1515-WO-PCT|Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Dhananjay Marathe, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

OP35 Low remission recapture after ustekinumab dose optimization in Crohn’s disease: results of the randomized placebo-controlled double-blind REScUE study.

Abstract Background In Crohn’s disease (CD), an exposure-response relationship exists for ustekinumab, with higher serum levels associated with better outcomes. Although several retrospective and observational studies demonstrate dose-escalation of ustekinumab can be effective in case of secondary loss of response (LOR), prospective placebo-controlled data are lacking. The aim of the REScUE study (NCT04245215) was to investigate the effect of 2 different re-induction regimens with ustekinumab on clinical, endoscopic, biological and pharmacological outcomes in patients with CD. Methods This Belgian multicentre prospective double-blind randomized placebo-controlled trial included adult patients with CD treated with ustekinumab who presented with secondary LOR to ustekinumab after documented primary response. Secondary LOR was defined by PRO-2 (AP> 1 AND SF> 3) and confirmed by either an elevated biomarker (CRP >5 mg/L or faecal calprotectin >250 µg/mg) or endoscopic signs of inflammation. All patients received a single IV re-induction with ustekinumab (≈6mg/kg) and were then randomized 1:1 to blinded maintenance ustekinumab 90 mg SC Q4W (intervention) or 90 mg SC Q8W (control) for 48 weeks. Primary endpoint was proportion of patients with steroid-free clinical remission (definition in fig 1) at week 48, with missing data were handled using non-responder imputation. Results In total, 132 patients were screened, and 108 patients were included: 67% female, median [IQR] age 41 [32-54] year, median disease duration 14 [7-22] years. Prior anti-TNF exposure was reported in 92% of patients, while ustekinumab was the first-line advanced treatment in 7% of patients. The primary endpoint of steroid-free clinical remission at week 48 was achieved by 9/54 (17%) patients in the q4w regimen vs 8/54 (16%) in the q8w regimen (p=0.96) (fig 1). Endoscopic remission (SES-CD <3) was achieved in 5/54 (10%) vs 3/54 (6%) (p=0.52), endoscopic response (≥50% decrease in SES-CD from baseline) was achieved in 11/54 (22%) vs 6/54 (12%) (p=0.23) and 0.52biomarker remission was achieved in 20/54 (38%) vs 13/54 (26%) (p=0.19) in the q4w regimen vs the q8w regimen, respectively. Time to first clinical remission was similar between groups (fig 2). Association with ustekinumab serum levels will be reported. No new safety signals were observed. Conclusion In patients with CD experiencing secondary LOR to ustekinumab, dose optimization with a single IV re-induction followed by intensified maintenance dosing (90 mg SC q4W) was not superior to a single IV re-induction followed by conventional maintenance dosing (90 mg SC q8W) in achieving steroid-free clinical remission. The secondary endpoints were numerically higher but not significant in the intensified regimen.

Symptomatic Improvement in Adults and Adolescents with Eosinophilic Esophagitis Requires Higher Systemic Dupilumab Exposure than Histologic Response.

We assessed potential mechanisms behind the requirement for more frequent dupilumab dosing in eosinophilic esophagitis (EoE) compared with other approved indications. Results for the phase 3 LIBERTY EoE TREET study co-primary endpoints (proportion of patients achieving a peak intraepithelial eosinophil count of ≤6 eosinophils per high-power field and absolute change from baseline in Dysphagia Symptom Questionnaire total score) were pooled in exposure-response analyses. A steep initial relationship then plateau was observed between higher dupilumab steady state trough concentrations (Ctrough) and decreased eosinophilic infiltration at Week 24, while a graded exposure-response relationship was observed for symptomatic improvement at Week 24. Patients with the highest exposures were more likely to achieve greater symptomatic benefit, independent of strictures or history of dilation. The dupilumab 300 mg qw regimen approved for adults and adolescents with EoE weighing ≥40 kg is supported by dose- and exposure-response relationships.

Four-weekly dosing intervals with subcutaneous spesolimab appear to be required for optimal prevention of generalized pustular psoriasis flares: Data from the EFFISAYIL® 2 and EFFISAYIL® ON trials

Generalized pustular psoriasis (GPP) is a rare chronic skin disease characterized by recurrent, acute, and often life-threatening flares of widespread neutrophilic sterile pustules and systemic inflammation. Spesolimab, an anti-interleukin-36 receptor antibody, is approved in adults and adults and pediatric patients 12 years of age and older and weighing at least 40 kg, as a subcutaneous dosage for treatment of GPP when not experiencing a flare, and as an intravenous dosage for GPP flare treatment. In Effisayil 2, a randomized, placebo-controlled trial (NCT04399837), subcutaneous spesolimab was superior to placebo and well tolerated for flare prevention when administered as a 600-mg subcutaneous loading dose followed by 300 mg every 4 weeks (q4w) over 48 weeks. In Effisayil 2, 3/30 (10.0%) patients receiving subcutaneous spesolimab 300 mg q4w had flares, and there were no flares after Week 4 until the end of the study. We assessed the effect on flare recurrence of a longer (q12w) interval between subcutaneous spesolimab doses in Effisayil 2 and Effisayil ON (NCT03886246), an ongoing open-label extension trial. Flares were defined as a ≥2-point increase in GPP Physician Global Assessment total score with pustulation subscore of ≥2, or intravenous spesolimab or standard of care treatment due to GPP worsening. In Effisayil 2, 9/31 (29.0%) patients who received subcutaneous spesolimab 300 mg q12w had a flare; of those, 7/9 (77.8%) experienced a flare before their second subcutaneous dose (Week 12), and 5/7 (71.4%) flares occurred during Weeks 4–12, indicating the need for q4w dosing. In Effisayil ON, 36/108 (33.3%) patients who started q12w dosing were either escalated to a q4w regimen (n=24) or experienced a flare (n=12). These observations suggest that subcutaneous spesolimab 300 mg q4w is the optimal dosing regimen for prevention of GPP flares.

Phase 2 study of the antitumour activity and safety of simlukafusp alfa (FAP-IL2v) combined with atezolizumab in patients with recurrent and/or metastatic cervical squamous cell carcinoma

Simlukafusp alfa (FAP-IL2v) is an immune cytokine engineered to selectively promote immune responses in the tumour microenvironment. We evaluated the antitumour activity and safety of FAP-IL2v plus atezolizumab in recurrent and/or metastatic cervical squamous cell carcinoma (SCC) in a phase 2 basket study (NCT03386721). Patients with confirmed metastatic, persistent or recurrent cervical SCC who had progressed on ≥1 anti-cancer therapy and had measurable disease were enrolled. FAP-IL2v 10mg was administered once every 3 weeks (Q3W) or once weekly (QW) for 4 weeks then once every 2 weeks (Q2W) with the corresponding Q3W or Q2W atezolizumab regimens. The primary endpoint was objective response rate by investigator assessment. Forty-eight patients were enrolled (Q3W: n=47; QW/Q2W: n=1). Among 45 response evaluable patients, objective responses occurred in 12 patients (27%; CI 16.0-41.0), including 3 complete and 9 partial responses. Responses occurred in 6/19 PD-L1 positive patients (32%; 95% CI 15.4-54.0) and 5/24 PD-L1 negative patients (21%; 95% CI 9.2-35.6). Median duration of response was 13.3 months (95% CI 7.6-NE). Median progression-free survival was 3.7 months (95% CI 3.3-9.0). Adverse events (AEs) were consistent with the known safety profile of each drug. AEs leading to withdrawal of either agent occurred in 6 patients (13%). Pronounced expansion and activation of natural killer and CD8 T cells in peripheral blood and increased tumour infiltration and inflammation were observed. FAP-IL2v plus atezolizumab is clinically active and has manageable safety in patients with recurrent and/or metastatic cervical SCC. F. Hoffmann-La Roche Ltd.

A phase III study to access the safety and efficacy of prolgolimab 250 mg fixed dose administered every 3 weeks versus prolgolimab 1 mg/kg every 2 weeks in patients with metastatic melanoma (FLAT).

Prolgolimab is the first Russian PD-1 inhibitor approved for the first-line treatment of unresectable or metastatic melanoma and advanced non-small cell lung cancer. It was approved in two weight-based regimens of 1 mg/kg Q2W and 3 mg/kg Q3W, but because of re-evaluation of weight-based dosing paradigm, studying of a fixed-dose regimen was considered perspective. We conducted a multicenter, single-arm, open-label efficacy, pharmacokinetics, and safety study to obtain data that would allow the approval of the new flat dosing regimen of prolgolimab in patients with previously untreated unresectable or metastatic melanoma (BCD-100-8/FLAT, NCT05783882). The primary objective was to prove the non-inferiority of prolgolimab 250 mg Q3W versus prolgolimab 1 mg/kg Q2W for the treatment of patients with unresectable or metastatic melanoma in terms of ORR according to RECIST 1.1. Patients from the MIRACULUM study (BCD-100-2/MIRACULUM, NCT03269565) comprised a historical control group. One hundred fourteen patients received prolgolimab 250 mg Q3W, and 61 patients received prolgolimab (Prolgo) 1 mg/kg Q2W (historical control). Objective response was achieved by 33.3% [95% confidence interval (CI): 24.8, 42.8] of patients in the Prolgo 250 mg group compared with 32.8% (95% CI: 21.3, 46.0) of patients in the Prolgo 1 mg/kg group. Risk difference was 0.00, 95% CI (-0.12; NA), p = 0.0082. Both regimens were well tolerated, and safety profiles were comparable. The pharmacokinetic analysis (PK) showed that the regimen with the fixed dose of 250 mg Q3W was characterized by higher PK parameters. The immunogenicity study did not detect binding antibodies to prolgolimab in any of the subjects. The obtained results showed that the selected fixed dosing regimen of prolgolimab 250 mg Q3W is characterized by efficacy and safety parameters comparable to that observed for the 1 mg/kg Q2W regimen.

Efficacy and Safety of Levilimab in Combination with Methotrexate in Patients with Active Rheumatoid Arthritis: 56-Week Results of Phase III Randomized Double-Blind Placebo-Controlled Trial SOLAR.

. To evaluate the efficacy and safety of levilimab in combination with methotrexate (MTX) in subjects with MTX resistant active RA. : The study was conducted at 21 clinical sites in Russia and Belarus. All randomized subjects have completed the study between November 2019 and October 2021. Adult subjects (154) aged ≥18years with confirmed diagnosis of RA1 were randomly assigned (2 : 1) to receive either levilimab (162 mg, SC, QW) + MTX (n = 102) or placebo + MTX (n = 52). After W24 of the study all subjects continued toreceive open label levilimab. Subjects who have achieved DAS28-CRP ≤ 2.6 at W24 were switched to maintenance (Q2W) regimen of levilimab at W28 (LVL QW/Q2W and PBO/LVL Q2W arms). Those with DAS28-CRP > 2.6 at W28 continued with QW regimen (LVL QW and PBO/LVL QW arm). The PBO/LVL Q2W arm contained only one subject, thus not included in the analysis. The efficacy analysis was performed in a population of all randomized subjects. Those with missing data due to study discontinuation or rescue therapy prescription were considered non-responders. Otherwise, the analysis was performed on complete cases. Safety was assessed through monitoring of adverse events (AEs) in a population of those, who received at least on dose of LVL (n = 152). : Better response to treatment was observed in LVL QW/Q2W as it composed of those who reach DAS28-CRP ≤ 2.6 at W24. At this time point 15/27 (55.6%) of them achieved ACR70; 23/27 (85.2%) achieved DAS28-CRP remission (<2.6) and 7/27 (25.9%) achieved ACR/EULAR2011 remission of RA. After switching to LVL Q2W, rates of ACR70 and DAS28-CRP<2.6 did not significantly changed until W52: 17/27 (63.0%) and 21/27 (77.8%), respectively, yet the proportion of subject with ACR/EULAR 2011 remission further increased and reached 12/27 (44.4%). LVL QW arm was diminished by subjects who achieved high response to treatment at W24 and composed LVL QW/Q2W arm. Thus, ACR70, and remissions rate in this arm was close to zero at W24. However, continuation of LVL QW in those who not achieved DAS28-CRP ≤ 2.6 at W24 induced ACR70 response in 37/75 (36.0%), DAS28-CRP remission in 35/75 (46.7%) and ACR/EULAR 2011 remission in 8/75 (10.7%) at W52. The most common adverse events (reported in ≥5% of subjects) were blood cholesterol increase (30.3%), ALT increase (23.0%), lymphocyte count decrease (17.1%), ANC decrease (16.4%), blood triglycerides increase (13.8%), bilirubin increase (11.2%), AST increase (9.9%), WBC decrease (9.9%), IGRA with Mycobacterium tuberculosis antigen positive (7.2%), and injection site reactions (5.9%). No deaths occurred. : Open label period confirmed the lasting efficacy and safety of levilimab in combination with MTX in subjects with MTX resistant active RA and suggested the possibility of switching to levilimab maintenance regimen (once every 2 weeks) (Q2W) in those who achieved remission of RA at week 24.

Population pharmacokinetic modeling of sotatercept in healthy participants and patients with pulmonary arterial hypertension.

Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studiesand one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH.

Evaluation of safety outcomes between nivolumab regimens with differing dosing patterns.

Real-world safety outcomes between the two flat-dose nivolumab regimens demonstrated to be similar in a study of adjuvant nivolumab recipients for melanoma. However, this study was limited by a single oncology patient population, a small sample size, and insufficient study power. The primary objective of this study was to evaluate the incidence of immunotherapy-related adverse effects (irAEs) between nivolumab regimens with differing dosing patterns in various solid tumor patient populations. Single-center retrospective cohort study of adult patients with solid tumor malignancies who received nivolumab 240 mg Q2W or 480 mg Q4W, or who were transitioned from 240 mg Q2W to 480 mg Q4W from March 1, 2018 to March 31, 2022 were selected for analysis from an electronic health record generated report. The primary endpoint evaluated was the incidence of irAEs. Secondary endpoints included the incidence of significant irAEs and reasons for treatment discontinuation. These endpoints were compared by univariate analysis between all three cohorts. A multivariate analysis was then conducted for the primary endpoint. Nivolumab 240 mg Q2W was associated with a statistically significant increase in the incidence of colitis whereas the 480 mg Q4W regimen was associated with a statistically significant increase in the incidence of pruritis. The incidence of irAEs was not different between the three cohorts, while the incidence of significant irAEs was higher in the 240 mg Q2W and 240 mg Q2W to 480 mg Q4W cohorts. Clinicians ought to be aware of differences in the irAE profiles between nivolumab regimens with differing dosing patterns.

Abstract PO2-04-03: BL-M07D1, an antibody-drug conjugate directed to HER2 in patients with locally advanced or metastatic Breast Cancer with HER2-positive/low-expression and other solid tumors: Results from a first-in-human phase 1 study

Abstract Background: BL-M07D1 is an anti-HER2 antibody-drug conjugate (ADC) comprised of a humanized anti-HER2 antibody, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor (Ed-04). Methods: This study included subjects with locally advanced or metastatic HER2 expressing (positive/low) breast cancer (BC) and other solid tumors. BL-M07D1 would be administered at doses of 1.0mg/kg Day 1 &amp; Day 8 every 3 weeks (D1D8 Q3W) or 2.6, 3.2, 3.8, 4.4, 5.0, 5.6, 6.2, 6.8 and 7.4 mg/kg Day 1 every 3 weeks (D1Q3W) during dose escalation (D-ESC). A subset of patients (pts) will be enrolled in the dose-expansion phase (D-EXP) at D1 Q3W regimens. Results: As of June 25, a total of 75 pts have been treated with at least one dose of BL-M07D1, with 22 pts in the D-ESC phase and 53 in the D-EXP phase. Among the 75 pts, 1 received 1.0 mg/kg D1D8Q3W and 74 were treated on the D1Q3W schedule. Dose-limiting toxicity (DLT) was observed at 6.2mg/kg (febrile neutropenia and G3 thrombocytopenia lasting &amp;gt;7 days in one patient). The maximum tolerated dose (MTD) has not been reached yet. D-EXP dose levels included 3.8, 4.4, 5.0 and 5.6mg/kg D1 Q3W. This study enrolled 62 patients with BC, 6 with gastric cancer, 4 with colorectal cancer and 3 with non-small cell lung cancer. The most common TEAEs ( &amp;gt;10%, all grade/≥G3) were leukopenia (79%/24%), neutropenia (69%/39%), anemia (63%/11%), nausea (47%/0%), thrombocytopenia (37%/9%), vomiting (37%/1%), decreased appetite (27%/0%), lymphopenia (24%/8%), alopecia (23%/0%), asthenia (19%/0), gamma-glutamyl transferase increased (17%/0%), aspartate aminotransferase increased (17%/0%), constipation (13%/0%), diarrhea (12%/0%), hypertriglyceridemia (12%/0%), urinary tract infection (11%/1%), COVID-19 (11%/0%), occult blood positive (11%/0%), pyrexia (11%/0%). No ILD was observed. Forty-five pts with BC were evaluated for efficacy (i.e., had at least one post-baseline tumor assessment). Updated efficacy and pharmacokinetic (PK) results will be presented at the meeting. Conclusions: BL-M07D1 demonstrated encouraging efficacy in heavily pretreated HER2 expressing cancers, especially in HER2+ BC. The safety profile showed adequate safety and tolerability. Clinical trial identification: NCT05461768. Efficacy in Patients with Breast Cancer a. 8/9 pts received prior HER2-ADC with microtubule inhibitor. 1/9 pts received prior HER2-ADC with TOPI inhibitor. b. 6 pts with tumor shrinkage are still on-going. c. All pts with tumor shrinkage are still on-going. Citation Format: Erwei Song, Herui Yao, Meili Sun, Hong Zong, Rongbo Lin, Wen Zou, Muran Ding, Jing Yu, Sa Xiao, Hongwei Wang, Hai Zhu, Martin Olivo, Yi Zhu. BL-M07D1, an antibody-drug conjugate directed to HER2 in patients with locally advanced or metastatic Breast Cancer with HER2-positive/low-expression and other solid tumors: Results from a first-in-human phase 1 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-03.

Glycemic control of once-weekly and other administration frequencies for DPP-4 inhibitor in patients with type 2 diabetes: a real-world retrospective cohort study.

To assess the glycemic control of once-weekly (QW) and other administration frequencies for dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with type 2 diabetes in a real-world setting. A retrospective cohort study used Japanese medical claims data and medical check-up data between December 2015 and February 2020. Patients with type 2 diabetes had been newly prescribed a DPP-4i regimen of once-daily (QD), twice-daily (BID), or QW administration and had hemoglobin A1c (HbA1c) values from regular medical check-ups. HbA1c values and proportion of patients achieving their HbA1c target were assessed. Multivariable analyses were conducted to examine the association between DPP-4i regimen and achievement of HbA1c target. Of the analysis population (N = 7229), 6098 patients were prescribed the QD regimen, 772 BID, and 359 QW. Mean HbA1c before exposure to DPP-4i was 7.31 ± 1.20% (mean ± standard deviation) for QD, 7.64 ± 1.47% for BID, and 7.06 ± 0.96% for QW, decreasing after DPP-4i exposure to 6.71 ± 0.78%, 6.77 ± 0.84%, and 6.59 ± 0.67%, respectively. HbA1c < 7% was achieved in 72.1% of patients for QD, 69.0% for BID, and 79.1% for QW. On multivariable analysis, the odds ratio (95% confidence interval) for HbA1c < 7.0% in patients < 65years of age was 0.97 (0.73-1.30) for BID and 0.90 (0.57-1.42) for QW compared to QD. Similar achievement of HbA1c target was noted in each regimen for patients age ≥ 65years and for age ≥ 65years with multimorbidity. In this study under real-world conditions, glycemic control for the DPP-4i QW regimen was similar to that for QD and BID. The online version contains supplementary material available at 10.1007/s13340-024-00718-5.

Abstract CT059: Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas

Abstract Background: AXL is a cell surface receptor tyrosine kinase widely expressed in solid tumors (ST), including sarcomas. ADCT-601 (Mipasetamab uzoptirine; Mipa) is an antibody-drug conjugate comprising a humanized anti-AXL antibody conjugated via a cleavable linker to SG3199 (pyrrolobenzodiazepine dimer cytotoxin). Mipa demonstrated antitumor activity in pre-clinical mice models of sarcoma, adrenocortical carcinoma and pancreatic cancer, and clinical activity in ST patients (pts) in its first-in-human trial. Here, we report initial clinical data in pts with advanced bone and soft tissue sarcomas treated in dose escalation with Mipa. Objective: To characterize the safety and tolerability of Mipa in pts with sarcoma indications who exhausted standard of care therapy. Method: This is a phase 1b, open-label, dose-escalation, dose expansion study of Mipa (NCT05389462; EudraCT: 2021-00566-18). Pts received Mipa every 3 weeks (Q3W) at escalating dose levels, in a 3+3 dose escalation design. Results: As of 04 December 2023, 18 sarcoma patients (15 [83%], soft tissue sarcoma [STS] and 3 [17%] bone sarcoma), unselected for AXL expression, with a median number of 3 prior lines of therapy (1-10), were enrolled in 4 different dose cohorts: 7.5mg, 11mg, 13mg and 15mg. Reasons for treatment discontinuation were disease progression (10 pts [55.6%]), adverse events (3 pts [16.7%]) and consent withdrawal (2 pts [11.1%]). Treatment emergent adverse events (TEAE) were seen in 17 pts (94.4%). Most common TEAE (all grades and relationship [≥20%]) were palmar-plantar erythrodysesthesia syndrome (7 pts [38.9%]); anemia (6 pts [33.3%]); rash maculopapular (5 pts [27.8%]); cheilitis and constipation (4 pts each [22.2%]). TEAE≥grade 3 were seen in 9 pts (50%). Most common TEAE≥grade 3 (≥10%) were GGT increase (2 pts [11.1%]). Two dose limiting toxicities were seen: cheilitis grade 2 and grade 3 at 15mg and 13mg respectively. Cutaneous reactions, all grades, are more prominent in higher doses. Maximum tolerated dose (MTD) has not been established. In 17 sarcoma pts evaluable per RECISTv1.1, best overall response was partial response (PR) (2 pts [11.8%]), including a confirmed PR; stable disease (SD) (8 pts [47.1%]); progressive disease (7 pts [41.2%]). Tumor reductions was observed at 7.5mg, 11mg and 13mg. By week 12, 6/17 pts (35.3%) did not demonstrate PD . Initial IHC staining showed AXL expression in all sarcoma baseline biopsies tested so far. Initial pharmacokinetic (PK) data indicate exposures with moderate to marked interpatient variability; rapid clearance with no accumulation by Cycle 2. Updated biomarkers and PK data will be presented. Conclusion: The MTD was not established. Due to the incidence of TEAE judged related to Mipa and the preliminary activity observed, 15mg was selected as the highest dose to be tested in a fixed dose Q3W regimen. The study continues to enroll to further optimize Mipa dosing regimen and in dose escalation with gemcitabine. Citation Format: Brian Andrew Van Tine, Christopher T. Chen, Victor Moreno, Elizabeth J. Davis, Maria J. de Miguel, Antoine Italiano, Esma Saada-Bouzid, Mohammed Milhem, Claudia Valverde, Sant P. Chawla, Abdul Rafeh Naqash, Louise Carter, Robin Jones, Ilaria Conti, Joe Boni, Karin Havenith, Yvan LeBruchec, Serafino Pantano, Jean-Yves Blay. Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT059.

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.

Clinical pharmacology profile of the claudin 18.2 antibody zolbetuximab.

316 Background: Zolbetuximab is an investigational first-in-class chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2 (CLDN18.2). Zolbetuximab is currently being developed as first-line treatment of patients with locally advanced unresectable or metastatic HER2 – gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, in combination with fluoropyrimidine- and platinum-containing chemotherapy. Methods: The clinical pharmacology of zolbetuximab (pharmacokinetics [PK] and impact of covariates, potential for drug-drug interactions and QTc prolongation, exposure-response [E-R] for efficacy and safety, immunogenicity [antidrug antibodies; ADAs]) was characterized from 9 studies in adults with advanced CLDN18.2-positive adenocarcinoma of the stomach, esophagus, or GEJ. Results: Zolbetuximab exhibited dose-proportional PK at doses of 33 to 1000 mg/m 2 . Based on population PK modeling using data from 714 participants, zolbetuximab exposure (Table) was not meaningfully affected by sex, race/ethnicity, age, mild/moderate renal impairment, or mild hepatic impairment. Gastrectomy was predicted to increase C ave by 36%. Coadministration of zolbetuximab with chemotherapy did not show clinically meaningful changes in drug exposures of zolbetuximab or chemotherapy. At therapeutic doses, zolbetuximab had no clinically meaningful effect on QTc prolongation. In phase 3 studies, zolbetuximab (800 mg/m 2 loading dose/600 mg/m 2 Q3W) had a manageable safety profile and was associated with significant prolongation of progression-free survival (PFS) and overall survival (OS). E-R analyses suggested that higher zolbetuximab exposure may further prolong PFS and OS but with increased probability of gastrointestinal events and infusion-related reactions. E-R model simulations suggested comparable zolbetuximab efficacy and safety between the 800/600 mg/m 2 Q3W regimen and an alternative 800/400 mg/m 2 Q2W regimen for use in combination with chemotherapy. ADAs were detected in 4.4% of patients in phase 3 studies with no apparent impact on zolbetuximab PK, efficacy, or safety. Conclusions: The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m 2 Q3W regimen as well as an 800/400 mg/m 2 Q2W regimen in combination with chemotherapy. Clinical trial information: NCT00909025 , NCT01671774 , NCT03528629 , NCT04086758 , NCT01197885 , NCT01630083 , NCT03505320 , NCT03504397 , NCT03653507 . Model-estimated exposure metrics of zolbetuximab. Mean (SD) First Dose(800 mg/m 2 ) Steady State(600 mg/m 2 Q3W) C max (µg/mL) 434 (96) 425 (91) AUC 21d (day·µg/mL) 2164 (589) 3359 (1254) C trough (µg/mL) 43.9 (25.1) 101 (51) C ave (µg/mL) – 140 (50) First dose simulation was for a 3-week interval after the first dose. For steady state, simulation was for a 3-week interval from Weeks 28–31. Estimated terminal elimination half-life was 43.6 days. Q3W, every 3 weeks.

Abstract B130: Phase 1 study of Zanidatamab Zovodotin (ZW49): Safety Profile and Recommended Dose (RD) in patients with Human Epidermal Growth Factor 2 (HER2)-positive solid cancers

Abstract Background ZW49 is a novel, humanized, antibody-drug conjugate comprised of a bispecific antibody directed against 2 non-overlapping HER2 epitopes and attached to a proprietary auristatin toxin with a protease-cleavable linker. Here we present data supporting the selection of the ZW49 RD in an ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233).1 Methods The 3+3 DE phase evaluated safety and tolerability of ZW49 IV (1-1.75 mg/kg QW; 1-2 mg/kg Q2W; and 2-3 mg/kg Q3W) in pts with HER2+ cancers. The DX phase further evaluated safety and antitumor activity of ZW49 IV (1.25 and 1.5 mg/kg QW; 2.5 mg/kg Q3W) in pts with centrally confirmed HER2+ (IHC 3+ or IHC 2+/FISH+) cancers. Primary endpoints are safety, tolerability, and maximum tolerated dose/RD. Secondary endpoints are pharmacokinetics (PK) parameters and response per RECIST1.1. Analyses of data for 66 pts treated with ZW49 at select cohorts/regimens in DE and DX are herein presented. Results As of 19 Dec 2022, 66 pts (n = 18, 1.25 mg/kg QW; n = 18, 1.5 mg/kg QW; and n = 30, 2.5 mg/kg Q3W; male, 52%; median age, 60.5 years [range, 32 – 83]) were treated with ZW49 in the selected population. The most common cancer types were gastric (35%) and breast (15%); 67% of pts had received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range, 1 – 13). The overall incidence of treatment-related adverse events (TRAEs) was 91% (100% [18/18 pts] in 1.5 mg/kg QW, 93% [28/30 pts] in 2.5 mg/kg Q3W, and 78% [14/18 pts] in 1.25 mg/kg QW regimens). Overall, the most common (≥ 20%) TRAEs were keratitis (44%), alopecia (26%), and diarrhea (24%); the majority were Grade (Gr) 1 or 2 in severity; Gr 3 or 4 TRAEs occurred in 14 (21%) pts. Serious TRAEs occurred in 4 (6%) pts. Eight pts discontinued (D/C) due to TRAEs, including 1 pt D/C due to a serious TRAE (Gr 4 infusion-related reaction [IRR]; 2.5 mg/kg Q3W). No interstitial lung disease or TR-deaths were reported. Seven dose-limiting toxicities (DLTs) occurred, including 4 DLTs in 1.5 mg/kg QW (3 Gr 2 keratitis events and 1 Gr 3 diarrhea), 2 DLTs in 1.25 mg/kg QW (Gr 3 blurred vision and Gr 3 IRR), and 1 DLT in 2.5 mg/kg Q3W (Gr 2 keratitis) regimens. The 1.5 mg/kg QW regimen was closed due to the frequency of DLTs and dose modifications observed. The safety profile was comparable between the 1.25 mg/kg QW and 2.5 mg/kg Q3W regimens. Preliminary PK analyses indicated that the half-life was similar across these dose/regimens. The confirmed objective response rate and disease control rate in HER2+ response-evaluable pts were 6% (1/17 pt) and 53% (9/17 pts) in 1.25 mg/kg QW regimen; and 31% (9/29 pts) and 72% (21/29 pts) in 2.5 mg/kg Q3W regimen, respectively. Based on these results, 2.5 mg/kg Q3W regimen was chosen as the RD. Conclusions ZW49 2.5 mg/kg Q3W IV was well tolerated, showed encouraging antitumor activity in heavily pretreated pts with advanced HER2+ cancers, and has been identified as the RD for further clinical development. References 1 Jhaveri K, et al.; ESMO; Sep 09 -13 2022 Citation Format: Do-Youn Oh, Philippe L Bedard, Keun-Wook Lee, Hyo Sook Han, Yoon-Koo Kang, Wilson H Miller, Sun Young Rha, Jwa Hoon Kim, Efrat Dotan, Chih-Yi Liao, Anthony Tolcher, Alexander Spira, Erika Hamilton, Christos Karapetis, Lisa Boyken, Charles Chen, Joseph Woolery, Komal Jhaveri. Phase 1 study of Zanidatamab Zovodotin (ZW49): Safety Profile and Recommended Dose (RD) in patients with Human Epidermal Growth Factor 2 (HER2)-positive solid cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B130.

Abstract C063: OSE279, a PD-1 blocking monoclonal antibody, as future backbone of a bifunctional checkpoint inhibitor platform: Preclinical characterization and early clinical results of a First-In-Human (FIH) study in subjects with advanced malignancies

Abstract Background: Anti-PD-1 antibodies have shown significant clinical activity with favorable safety. Bispecific anti-PD-1 antibodies are being developed. OSE279 is a humanized S228P-immunoglobulin (Ig)G4 monoclonal bivalent antibody directed against PD-1 which will be further used as the anti-PD-1 backbone component of a bifunctional checkpoint inhibitor BiCKI® platform. Methods: We performed preclinical assessments of OSE279 that support development in humans. A FIH study investigating OSE279 is ongoing, evaluating 2 Dose Levels (DLs) of 100 and 300 mg given q3w and 1 DL of 600 mg q6w, according to BOIN design, in subjects with refractory malignancies, with no standard treatments, for which anti-PD1/PDL1 have shown efficacy but are not locally available, or rare tumors with reported activity of anti-PD1, or PDL1 positive tumors. Primary objective is to determine the MTD and/or Recommended Phase 2 Doses (RP2D). Secondary objectives are efficacy, safety, PK and PD profiles. DLT period is 21 days. Results: Preclinical investigations showed that OSE279 has antagonist activity against PD1, blocking the binding of PD1 ligands (IC50 308 ± 170 ng/mL). OSE279 blocked PDL1-induced SHP1 phosphorylation in a cell-based assay (IC50=14.19 ng/mL) and promoted reactivation of primary T cell effector functions leading to interleukin 2 and Interferon γ secretion in MLR assay. OSE279 showed potent antitumor activity in syngeneic models of colon cancer, hepatocarcinoma and mesothelioma implanted in immunocompetent Human PD1 Knock-in mice, with long-term response and survival. OSE279 showed good affinity to hFcRn receptor predicting good half-life in humans. Simulations showed that trough Receptor Occupancy (RO) would be 94.1±36.9% and 98.3±36.8% at 100 mg and 300 mg, respectively. NOAEL was determined in monkey at 100 mg/kg for 1 month. In the FIH study as of June 2023, 9 subjects were treated, with 8 tumor types. Median age was 60y (range 43-70), 6/9 patients (67%) were female, median number of prior metastatic lines was 2 (range 1-6). 300 mg was declared RP2D for a q3w regimen; a new cohort is exploring 600 mg q6w. One (with HCC) of seven patients in DL2 (300 mg) had a DLT of gr3 hepatitis. Treatment-Related Adverse Events (TRAEs) occurred in 8 patients (88.9%). Serious TRAEs (pneumonitis gr2, hepatitis gr3) occurred in 2 patients (22.2%). A confirmed PR was observed in HCC after one dose of OSE279 300mg. SD was reported in 3 patients. PK profile showed good exposure and dose-proportionality. RO was maintained and within the boundaries of simulation. Conclusions: OSE279 preclinical data showed comparable efficacy and safety profiles to the EMA/FDA approved anti-PD1 antibodies. In FIH study, OSE279 showed a manageable safety profile with preliminary signs of efficacy in the first 9 patients treated. A RP2D of 300 mg q3w was selected. 600 mg q6w is being evaluated (data available by October 2023). PK and PD profiles were according to modelling. Expansion cohorts are planned. Clinical trial information: NCT 05751798. Research Sponsor: OSE Immunotherapeutics. Citation Format: Philippe Cassier, Carlos Gomez-Roca, Nuria Kotecki, Christophe Massard, Sophie Postel-Vinay, Aurore Morello, Mylène Déramé, Caroline Chevalier, Laurie Cordonnier, Constant Josse, Silvia Comis, Nicolas Poirier, Marie Robert. OSE279, a PD-1 blocking monoclonal antibody, as future backbone of a bifunctional checkpoint inhibitor platform: Preclinical characterization and early clinical results of a First-In-Human (FIH) study in subjects with advanced malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C063.

Emicizumab prophylaxis for people with hemophilia A: Waste estimation and the Brazilian perspective

Costs of hemophilia A treatment are increasing. Waste of clotting products should be avoided. To estimate the first-year waste of emicizumab prophylaxis for people with hemophilia A and inhibitors (PwHAi) who failed immune tolerance induction (ITI), in Brazil. We evaluated the manufacturer and the Brazilian Ministry of Health (MoH) protocol-recommended regimens in a budget impact model. The loading dose consisted of 3.0 mg/kg/Q1W for 4 weeks, for both recommendations. The manufacturer maintenance regimens comprised 1.5 mg/kg/Q1W, 3.0 mg/kg/Q2W, and 6.0 mg/kg/Q4W. The MoH protocol maintenance regimen encompassed a hybrid Q1W/Q2W administration, depending on the body weight. The Q4W regimen was not recommended by the MoH protocol. Analyses were performed to estimate waste given its expense based on the World Health Organization body weight range (percentiles [P] 15, 50, and 85). The first-year emicizumab waste was estimated individually and for the disclosed PwHAi who failed ITI (n = 114). The highest emicizumab waste was estimated for the lowest body weights and the Q1W regimen. The Q4W regimen resulted in the lowest emicizumab waste, followed by the MoH protocol regimen. The total reconstituted costs estimated for the PwHAi who failed ITI according to the hybrid MoH protocol ranged from US$32,858,777 (P15) to US$47,186,858 (P85), with emicizumab waste ranging from 7.9 % (US$2,594,515) to 3.7 % (US$1,738,750), respectively. Lost resources due to current protocols for emicizumab prophylaxis for PwHAi who failed ITI in Brazil are considerable. Waste was more pronounced due to lower body weight and shorter administration intervals.

Pharmacokinetics and Immunogenicity of Abbv-383, a B-Cell Maturation Antigen (BCMA) × CD3 Bispecific T-Cell-Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction ABBV-383 is a fully human, silenced Fc region IgG4 monoclonal, BCMA × CD3 T-cell-engaging bispecific antibody with 2 BCMA-binding domains and a low-affinity CD3-binding domain. ABBV-383 has shown promising activity following intravenous (IV) infusion every three weeks (Q3W) as monotherapy in patients (pts) with RRMM in an ongoing phase 1 study (D'Souza A, et al. J Clin Oncol. 2022 Nov 1;40(31):3576-3586; Voorhees et al. Blood 2022;140[suppl 1]:4401). Herein, preliminary pharmacokinetic (PK) and immunogenicity results from Q3W regimens of this study and impact of soluble BCMA (sBCMA) on ABBV-383 PK are reported. Methods In the phase 1 study (NCT03933735), adult pts with RRMM, who were previously exposed to ≥3 prior multiple myeloma agents including ≥1 proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody, received Q3W IV infusion at doses 0.025 - 120 mg in escalation (ESC) phase, and at 20 mg, 40 mg, and 60 mg in expansion (EXP) phase. Serial blood samples for PK characterization were collected in cycles 1, 3, and 6 along with sparse/periodic samples throughout the study. Blood samples were also collected throughout the study to detect anti-drug antibodies (ADAs) for immunogenicity characterization and to determine sBCMA concentrations. Appropriate validated assays were used to determine ‘total’ (unbound and bound to sBCMA) and ‘free’ (unbound and partially bound to sBCMA) ABBV-383 serum concentrations, to detect/determine ADAs/titers, and to determine total sBCMA concentrations. ‘Total’ and ‘free’ ABBV-383 serum concentrations from cycles 1, 3, and 6 were used to calculate individual PK parameters (peak concentration [C max], trough concentration [C trough], area under the concentration-time curve [AUC], terminal phase elimination half-life [t 1/2], clearance [CL], and steady state volume of distribution [V ss]) using non-compartmental analysis in Phoenix WinNonlin Version 8.2. Immunogenicity was summarized using ADA/titer data. Impact of baseline/pre-dose sBCMA concentrations on ‘total’ and ‘free’ ABBV-383 PK parameters from cycles 1, 3, and 6 was explored. Results ‘Total’ and ‘free’ ABBV-383 intensive PK data (cycles 1, 3, and 6) were available from 169 and 157 pts, respectively, representing Q3W regimens in ESC and EXP cohorts and ADA data were available from 186 evaluable subjects. Preliminary PK results suggest that ‘total’ and ‘free’ ABBV-383 exhibited approximately dose-proportional PK between 5.4-120 mg Q3W. Estimated t 1/2 for ‘total’ and ‘free’ ABBV-383 ranged between 11-12 days and 8-11 days, respectively, with steady state achieved by cycle 4 in Q3W EXP cohorts. Estimated CL and V ss were consistent with those of a typical IgG4 antibody in humans. Across EXP Q3W regimens, accumulation (cycle 3 vs. cycle 1) was 30%-60% in C max and 60%-177% in C trough for ‘free’ and ‘total’ ABBV-383. ABBV-383 exposures (AUC tau and C trough) of ‘total’ ABBV-383 were 28-74% higher than those representing ‘free’ ABBV-383 among the EXP Q3W regimens with no/minimal observed differences in C max (≤21%). Higher sBCMA levels prior to treatment appeared to reduce ‘free’ ABBV-383 PK exposures with pronounced reduction at lower doses (e.g., 20 mg) and in cycle 1, however the effect diminished in later cycles (cycles 3 and 5). Preliminary assessment of immunogenicity indicated an ADA incidence of 3.8% (7/186) with low titers ranging between 11.7 and 187 titer units and no impact on PK. Conclusions ABBV-383 exhibited a PK profile with relatively long half-life and low incidence of immunogenicity. Overall, sBCMA impacted (reduced) the ‘free’ ABBV-383 (pharmacologically active component) PK exposures only, with pronounced effect at lower doses and the effect is consistent with understanding of treatment dependent sBCMA dynamics over time. Determination of both ‘total’ and ‘free’ ABBV-383 serum concentrations allowed to demonstrate such underlying impact of sBCMA on PK.

In vitro to clinical translation of combinatorial effects of doxorubicin and dexrazoxane in breast cancer: a mechanism-based pharmacokinetic/pharmacodynamic modeling approach.

Dexrazoxane (DEX) is the only drug clinically approved to treat Doxorubicin-induced cardiotoxicity (DIC), however its impact on the anticancer efficacy of DOX is not extensively studied. In this manuscript, a proof-of-concept in vitro study is carried out to quantitatively characterize the anticancer effects of DOX and DEX and determine their nature of drug-drug interactions in cancer cells by combining experimental data with modeling approaches. First, we determined the static concentration-response of DOX and DEX in breast cancer cell lines, JIMT-1 and MDA-MB-468. With a three-dimensional (3D) response surface analysis using a competitive interaction model, we characterized their interaction to be modestly synergistic in MDA-MB-468 or modestly antagonistic in JIMT-1 cells. Second, a cellular-level, pharmacodynamic (PD) model was developed to capture the time-course effects of the two drugs which determined additive and antagonistic interactions for DOX and DEX in MDA-MB-468 and JIMT-1, respectively. Finally, we performed in vitro to in vivo translation by utilizing DOX and DEX clinical dosing regimen that was previously identified to be maximally cardioprotective, to drive tumor cell PD models. The resulting simulations showed that a 10:1 DEX:DOX dose ratio over three cycles of Q3W regimen of DOX results in comparable efficacy based on MDA-MB-468 (additive effect) estimates and lower efficacy based on JIMT-1 (antagonistic effect) estimates for DOX + DEX combination as compared to DOX alone. Thus, our developed cell-based PD models can be used to simulate different scenarios and better design preclinical in vivo studies to further optimize DOX and DEX combinations.

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer

BackgroundWe assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC).MethodsThis phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1–21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D.ResultsIn phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses.ConclusionsNofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC.Clinical trial registr ationClinicaltrials.gov (NCT03475251).