Phase II study of trifluridine/tipiracil (TAS-102) therapy in elderly patients with colorectal cancer (T-CORE1401): geriatric assessment tools and plasma drug concentrations as possible predictive biomarkers

Purpose The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. Methods This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1–5 and 8–12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. Results A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9–4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7–8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). Discussion The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. Trial registration number UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network)

327 Study of anti-PD-1 antibody multimodal combination as first-line treatment on time window of advanced solid tumor

BackgroundImmune checkpoint inhibitors (ICIs) targeting the programmed cell death-1(PD-1) has dramatically shifted the therapeutic paradigm of advanced tumor. However, a large proportion of patients do not achieve durable responses with anti-PD-1 monotherapy. Strategically combining immunotherapies with other systemic therapies to harness potential synergies is critical for maximizing their clinical activity and realizing the greatest benefits for patients with cancer. Chemotherapy drugs induce a form of tumor cell death that is immunologically active, thereby inducing an adaptive immune response specific for the tumor. Apatinib (VEGFR2 inhibitor) in combination with an anti-PD-1 has demonstrated synergistic antitumor effects. In our previous research, steady-state of apatinib (250 mg qd) plasma drug concentration was achieved by day 3. Camrelizumab and sintilimab are humanized anti-PD-1 antibody. We aim to assess time window, efficacy and safety of patients who receive anti-PD-1 antibody multimodal combination as first-line treatment of advanced solid tumor.MethodsThis multicentre, open-label, exploratory cohort study. Eligible patients were aged 18–70 years, and had histologically or cytologically confirmed advanced solid tumors, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous anti-tumor treatment for advanced disease. 180 patients were assigned to three group: Camrelizumab/sintilimab (200 mg,iv,d4,q3w,24 months) plus standard chemotherapy (d1-3), Camrelizumab/sintilimab (200 mg,iv,d4,q3w,24 months) plus apatinib (250 mg, po, d1,qd), Camrelizumab/sintilimab (200 mg,iv,d7,q3w,24 months) plus standard chemotherapy(d1-3) and apatinib (250 mg,po, d1,qd). Tumor tissue and matched blood of all patients will be collected for NGS-based 727 genes panel assay, and the blood samples will be collected until disease progression. Meanwhile, plasma drug concentrations were detected by daily measurement of trough and peak concentrations(d0, 1, 2, 3, 21, 42, 63). The primary endpoint of this study is progression free survival (PFS), and the secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. In addition, exploratory analysis was performed to comprehensively assess the relationship between gene status and efficacy, plasma drug concentrations and biological effects. This study is registered with ClinicalTrials.gov, number NCT04282278.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov, number NCT04282278.Ethics ApprovalThe study was approved by the Fourth Hospital of Hebei Medical University Institution’s Ethics Board, approval number 2020012.

Pharmacovirological analyses of blood and male genital compartment in patients receiving dolutegravir + lamivudine dual therapy as a switch strategy (ANRS 167 LAMIDOL trial)

Objectives To describe plasma residual HIV viraemia, cellular HIV reservoir size, blood plasma drug concentrations and their male genital tract penetration during the maintenance dual therapy dolutegravir + lamivudine. Patients and methods ANRS167 LAMIDOL enrolled 104 virologically suppressed patients to switch to dolutegravir + lamivudine. In this pharmacovirological substudy, ultrasensitive plasma viral load (USpVL) and plasma drug concentrations were measured at Day 0 (D0), Week 24 (W24) and W48 of dolutegravir + lamivudine, and HIV-DNA was measured at W−8 and W48. Semen samples were collected at D0 and W24 from 18 participants. Total and unbound blood and seminal plasma drug concentrations were measured using UPLC–MS/MS. Results Median HIV-DNA was 2.5 log10 copies/106 PBMC (IQR = 2.2–3.0, n = 100) at W−8 and 2.4 log10 copies/106 PBMC (IQR = 2.1–2.9, n = 100) at W48 (P = 0.17). The proportion of patients with undetected USpVL was 38% (n = 98), 43% (n = 98) and 49% (n = 97) at D0, W24 and W48, respectively (P = 0.08). Total and unbound plasma dolutegravir concentrations were stable between timepoints (P = 0.13) and all total plasma dolutegravir concentrations except one were adequate. Median free fraction of dolutegravir in plasma was 0.21%. Median blood plasma and seminal plasma concentrations of total dolutegravir at 24 h were 1812 ng/mL and 206 ng/mL, respectively. Median seminal plasma/blood plasma total concentration ratios were 11.6% and 2478% for dolutegravir and lamivudine, respectively. HIV-RNA (365 to 475 copies/mL) was detected in seminal plasma of one patient at D0 (5.9%) and of two patients at W24 (11.8%). Conclusions These findings add further important information regarding the effectiveness of dolutegravir + lamivudine maintenance dual therapy in terms of plasma residual viraemia, cellular reservoir size and drug penetration in the male genital tract.

Drug plasma trough concentrations during treatment with daclatasvir and sofosbuvir are associated respectively with liver impairment and with renal dysfunction in HIV/HCV co-infected patients

Background Sofosbuvir (SOF) plus daclatasvir (DCV) achieved high rates of sustained virologic response (SVR) with no difference according to HIV serostatus. Only limited information is available on the pharmacokinetics variability of SOF and DCV in HIV/HCV co-infected patients. Aim was to evaluate the association of plasma drug concentrations (Ctrough) of SOF and of DCV with patient-, treatment-, and disease-related factors in the real-world setting of HIV/HCV co-infected persons. Methods HIV/HCV co-infected patients, undergoing SOF plus DCV treatment, were prospectively enrolled. At baseline, week4 (W4), end of treatment (EOT), and after-EOT, biochemical and viro-immunological parameters were assessed. FIB-4 score and CKD-EPI equation were used for estimation of liver disease and glomerular filtration rate (eGFR), respectively. SOF, SOF metabolite (GS-331007), and DCV Ctrough were measured at W4 and week8 (W8), and the mean value (mean-Ctrough) was calculated Results Thirty-five patients were included (SVR 94%). Increasing GS-331007 mean-Ctrough significantly correlated with decreasing eGFR at W4 (rho=-0.36; p=0.037) and EOT (rho=-0.34; p=0.048). Between DCV mean-Ctrough and FIB-4, a significant correlation was observed at all time-points: baseline (rho=-0.35; p=0.037), W4 (rho=-0.44; p=0.008), EOT (rho=-0.40; p=0.023), after-EOT (rho=-0.39; p=0.028). Conclusion In HIV/HCV co-infected patients receiving SOF plus DCV, plasma drug concentrations are associated with renal dysfunction for GS-331007 and with liver impairment for DCV. Though clinical and therapeutically relevance of these findings may apparently be limited, growth of clinicians’ knowledge on DAA exposure in difficult-to-treat patients, as cirrhotic and renal impaired subjects, can be relevant in single cases.