Efficacy Threshold Research Articles

NET-02: A multicenter, randomized, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).

4005 Background: The prognosis for pts with PD-EP-NEC is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy; there is no standard second-line (2L) treatment (area of unmet need). Methods: This was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI (70mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m2), Q21 days (ARM B), as 2L therapy in a planned 102 pts with progressive PD-EP-NEC, aimed at selecting a treatment for continuation to a phase III trial. Pts with histologically-confirmed PD-EP-NEC (Ki-67>20%; Grade 3, WHO 2019), who had prior 1L platinum-based chemotherapy and radiological disease progression or discontinuation of 1L therapy due to intolerance, with an ECOG performance status ≤2 were eligible. Randomisation was stratified by Ki-67, ECOG PS, presence of liver metastases, and response to previous platinum-based therapy. Primary endpoint was 6 month (mo) progression-free survival (PFS) rate; 80% power to demonstrate the one-sided 95% confidence interval (CI) of the 6 mo PFS rate excluded 15%, if the true rate was at least 30%, where 30% was the required level of efficacy; a rate of <15% would give grounds for rejection. Intention was to show that the regimens were sufficiently active, but not to assess superiority of one regimen over the other. Secondary endpoints included objective response rate (ORR), PFS, overall survival (OS), and toxicity. Based on futility analysis, the DSMB recommended closure of recruitment in Dec 21. Results: Of 58 patients in 15 UK centres (Nov 18-Dec 21), 29 in ARM A, 29 in ARM B, 57% were male, median age (range): 63.5 years (22-85), 90% ECOG PS 0/1, 10% PS 2, 90% Ki-67≥55%, 33%/38%/29% small/large cell/unknown morphology, primary site: 69% gastrointestinal, 12% unknown, 9% genitourinary, 5% head & neck, 3% gynae, 2% breast, 60% had liver mets, 91%/7%/2% were resistant/sensitive/intolerant to 1L platinum-based treatment. At a median follow up of 6.6 mo, the primary end-point of 6-mo PFS rate was met in ARM A; ORR, median PFS and OS are also presented (Table). Adverse events ≥ grade 3 occurred in 51.7% and 55.2% in ARM A and B and there were 1 and 6 discontinuations due to toxicity in ARM A and B, respectively. Data cleaning is on-going. Conclusions: nal-IRI/5-FU, but not docetaxel, met the primary endpoint (exceeding the threshold for efficacy), with manageable toxicity, and warrants evaluation in a phase III trial. Clinical trial information: 03837977. [Table: see text]

Results of a phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response pathway deficient neoplasms.

3122 Background: BRCA1-Associated Protein 1 (BAP1) acts as a tumor suppressor and critical regulator of the cell cycle and DNA damage response (DDR). PARP inhibitors (PARPi) demonstrate synthetic lethality in BAP1 mutant (mBAP1) preclinical models, independent of underlying germline BRCA status. mBAP1 leads to a loss of functional protein in several solid tumors. This study aimed to explore the clinical activity of niraparib in patients (pts) with advanced tumors likely to harbor mBAP1. Methods: Eligible adult pts with measurable metastatic solid tumors having exhausted approved therapies, adequate organ function, and ECOG PS 0-1 were assigned to Cohort A (histology-specific): tumors likely to harbor mBAP1 (i.e., cholangiocarcinoma, uveal melanoma, mesothelioma, or clear cell renal cell carcinoma) with tissue available for mBAP1 confirmation; or Cohort B (histology-agnostic): tumors with other known non-BRCA confirmed DDR mutations. Known BRCA1 or 2 mutations or prior PARPi exposure were excluded. All pts received niraparib 200-300mg daily, depending on weight and/or platelet count. Radiographic response was assessed by RECIST v1.1 measured every 8 weeks while on treatment. The primary endpoint was ORR with secondary endpoints of PFS, OS, clinical benefit (CR+PR+SD), toxicity, and exploratory biomarker determinations. Cohort A employed Simon's optimal two-stage design to assess a 30% ORR increase (a = 0.05; power = 90%). Cohort B aimed to assess a 40% ORR increase for this molecularly selected/enriched patient population. Results: From 08/13/2018 to 12/21/2021, 37 pts enrolled from two different centers, with 32 evaluable for response (Cohort A n = 18; Cohort B n = 14). In Cohort A, best ORR was 1 PR (6%), 8 SD (44%; median 5.7 mo; range 2 - 9.4 mo), and 9 PD (50%). Cohort A was stopped at the first stage following the pre-specified Simon’s design. mBAP1 was confirmed in 7/9 pts (78%) with PR or SD but in only 2/9 (22%) in those with PD. In Cohort B, best ORR was 6 SD (43%; median 7.5 mo; range 3.3 - 8.6 mo) and 8 PD (57%). Mutations in those with SD included ATM, CHEK2, PTEN, RAD50, and ARID1A. Common grade 3/4 AEs observed were anemia (16%), thrombocytopenia (16%), nausea (11%), and vomiting (8%). There were no unexpected nor grade 5 toxicities. Conclusions: The use of niraparib was well tolerated in pts with advanced treatment refractory solid tumors but failed to meet pre-specified efficacy threshold of ORR. However, clinical benefit was identified in 78% of patients in cohort A who had a confirmed mBAP1 tumor. Further correlative analyses are ongoing and additional clinical development restricted to mBAP1 tumors may be justified. Clinical trial information: NCT03207347.

High threshold efficacy responses in moderate-to-severe atopic dermatitis are associated with additional quality of life benefits: pooled analyses of abrocitinib monotherapy studies in adults and adolescents.

BackgroundOnce‐daily abrocitinib treatment provided meaningful improvements in signs and symptoms of moderate‐to‐severe atopic dermatitis (AD) in randomized controlled studies.ObjectiveTo evaluate proportions of patients with responses meeting higher threshold efficacy responses than commonly used efficacy end points and to determine if these responses were associated with quality‐of‐life (QoL) benefits.MethodsData from a phase 2b (NCT02780167) and two phase 3 studies (NCT03349060/JADE MONO‐1; NCT03575871/JADE MONO‐2) in adult and adolescent patients (N = 942) with moderate‐to‐severe AD receiving once‐daily abrocitinib 200 mg, abrocitinib 100 mg or placebo were pooled. Commonly used (Eczema Area and Severity Index [EASI]‐75 and ≥4‐point improvement in Pruritus Numerical Rating Scale [PP‐NRS4]) and higher threshold efficacy end points (EASI‐90 to <EASI‐100, EASI‐100 or PP‐NRS0/1 response) were evaluated. Proportions of patients across Children's Dermatology Life Quality Index/Dermatology Life Quality Index (CDLQI/DLQI) band descriptors who achieved various efficacy end points were analysed.ResultsMore abrocitinib‐treated patients achieved commonly used or higher threshold efficacy end points at week 12 vs. placebo. More abrocitinib‐treated patients who achieved higher threshold efficacy end points reported ‘no effect’ of AD on QoL (by CDLQI/DLQI) at week 12 vs. those who achieved commonly used but not higher threshold efficacy end points (PP‐NRS0/1 vs. PP‐NRS4 but not PP‐NRS0/1 responders [200 mg: 66.3% vs. 17.5%; 100 mg: 62.1% vs. 20.0%]; EASI‐100, EASI‐90 to <EASI‐100 vs. EASI‐75 to <EASI‐90 responders [200 mg: 67.6%, 48.9% vs. 28.8%; 100 mg: 63.2%, 48.1% vs. 36.7%]).ConclusionsSubstantial proportions of patients with moderate‐to‐severe AD receiving abrocitinib met higher threshold efficacy end points, and this was associated with meaningful additional QoL benefits compared with those who did not meet these higher efficacy thresholds. Not only do a substantial proportion of abrocitinib‐treated patients achieve higher threshold efficacy end points but they also do so in a similar timeframe as the more commonly used thresholds for efficacy end points.Clinical trialsNCT02780167, NCT03349060 and NCT03575871.

Evaluation of the Effectiveness of New Phytosanitary Protection Programs in Cotton Crops Adapted to Jassids

In recent years, jassids have become a problem for cotton and the current control program for this pest seems ineffective. This study was therefore initiated with the objective of evaluating the effectiveness of three new phytosanitary protection programs against jassids. Trials were conducted at the Nambingué observation post. The study designs were Fisher blocks with 5 objects and 4 replications. Each elemental plot had a length of 10 m and a width covering 10 lines, 8 of which were treated. The spacing between rows was 0.8 m. The distance between patches on a line was 0.4 m. The distance between blocks was 2 m. Six insecticide treatments were carried out. Treatments were started on the 45th day after cotton emergence, at 14-day intervals. These three new programs, which differ according to the composition and positioning of the active substances, were tested during two years in a fisher block design with four repetitions. Two programs, labelled programs B and C, had an efficacy threshold greater than 80%. Program B was characterized by a positioning spiromesifen or chlorantraniliprole in T1 and T2, cypermethrin + abamectin in T2 and T3 and spinetoram + sulfoxaflor in T5 and T6 respectively. And program C was characterized by a positioning spinetoram + sulfoxaflor in T1 and T2, Deltamethrin + chlorpyrifos ethyl in T3 and T4 and dinotefuran 14% + alphacypermethrin 22% in T5 and T6 respectively. They both contributed to a significant reduction in jassid outbreaks during the two years of experimentation. Programs B and C can be used as an alternative to the extension program to manage resistance.

Comparing the relative and absolute effect of erenumab: is a 50% response enough? Results from the ESTEEMen study

BackgroundMonoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab.MethodsESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women.ResultsOut of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs.ConclusionsThe present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.

Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants.

ObjectivesThe objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg/kg) or intravenous (IV, 0.05 mg/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for optimized dosing and timing of painful interventions in infants 1–3 months old.MethodsPPK analysis of nalbuphine serum concentrations, prospectively collected 15, 30, and between 120 and 180 min post-dose, utilizing the software package Monolix. The final PPK model was applied to derive individual time-matched concentration predictions for each pain assessment (Neonatal Infant Pain Score, NIPS) after establishment of venous access and urinary catheterization or lumbar puncture. Drug exposure-pain response simulations were performed to evaluate potential benefits of higher doses with respect to a previously proposed target concentration of 12 mcg/L (efficacy threshold).ResultsThirty-eight of 52 study subjects receiving nalbuphine had at least one concentration measurement and were included in the pharmacometric analysis. A two-compartment model with allometric scaling was applied to describe population PK data, with intranasal bioavailability estimated to be 41% (95%CI: 26–56%). Model-based simulations showed that the proposed efficacy threshold (12 mcg/L) is expected to be exceeded with an IV dose of 0.05 mg/kg for 6 min, with 0.1 mg/kg for 30 min and with 0.2 mg/kg for 80 min. This efficacy threshold is not achieved with intranasal doses of 0.1 and 0.2 mg/kg, whereas an intranasal dose of 0.4 mg/kg is expected to exceed such threshold for 30 to 100 min.ConclusionThis PMX study confirmed that bioavailability of intranasal nalbuphine is close to 50%. Exposure-pain response simulations indicated that an intranasal dose of 0.4 mg/kg is required to provide a comparable pain control as achieved with an IV dose of 0.1–0.2 mg/kg. The optimal time window for painful procedures appears to be within the first 30 min after IV administration of 0.1 mg/kg nalbuphine, whereas such procedures should be scheduled 30 min after an intranasal dose of 0.4 mg/kg nalbuphine. Additional clinical studies are warranted to confirm these PMX based recommendations and to further optimize pain management in this vulnerable infant population.

A phase II study of talazoparib and avelumab in VHL deficient clear cell renal cell carcinoma.

347 Background: VHL inactivation may lead to impairments in the DNA damage response pathway and increased replication stress, which consequently can increase the genomic instability of clear cell renal cell carcinoma (RCC). Other molecularly driven RCC subtypes including FH and SDH deficient RCC show impaired DNA repair through oncometabolite accumulation. Synthetic lethality with PARP inhibitors (PARPi) has been suggested in preclinical models, and PARPi may potentiate the effects of immune checkpoint blockade (ICB) therapy. Methods: We conducted a single center, investigator-initiated phase II trial to evaluate combined PARPi + PD-L1 inhibition in two genomically selected advanced RCC cohorts: 1) VHL altered RCC; 2) FH, SDH-RCC and renal medullary carcinoma. For Cohort 1, patients had to have previously been treated with VEGFR TKI and ICB therapy with maximum 3 prior lines of therapy. Patients received talazoparib 1mg daily plus avelumab 800mg IV every 14 days. The primary endpoint was objective response rate (ORR) by iRECIST, and secondary endpoints included progression-free survival (PFS), safety and tolerability. Results from Cohort 1 are reported here. Results: From 2019-2021, 10 advanced RCC patients were enrolled per the first stage of a Simon 2-stage design for cohort 1. The median age was 63 years (R: 42-71), and median number of prior therapies was 2 (R: 1-3). All patients had VHL loss detected by tissue NGS sequencing via MSK-IMPACT, and 3/10 (30%) of patients had co-occurring somatic or germline alterations in DDR specific genes. No objective tumor responses were seen, and the disease control rate was 60% (6/10) with those patients achieving stable disease as best response. All patients experienced disease progression and the median PFS was 3.6 months (95% CI 1.4-4.9). Adverse events were in keeping with reported toxicities for individual agents without emerging safety signals. Conclusions: This is the first clinical study of combination PARPi and ICB therapy in advanced clear cell RCC. In our cohort of VHL deficient TKI/ICB refractory RCC, the study did not meet its pre-defined efficacy threshold to continue enrollment, and our results do not support further study of this regimen in this population. Exploratory efforts to evaluate this treatment approach in other biomarker selected populations of RCC, including cohort 2 of this study, are ongoing. Clinical trial information: NCT04068831.

Pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC): Final outcomes of a phase 2 trial.

444 Background: Immune checkpoint inhibitors (ICI) have limited activity as monotherapy in unselected patients with ABC; the objective response rate (ORR) of PEM was 5.8% in the multicenter phase 2 KEYNOTE-158 trial. GM-CSF modulates immune cells including monocytes and the innate immune response and has demonstrated safety and prolonged survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial was designed to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Single-center, phase 2 trial with Simon’s 2-stage design and expansion cohort (EC) (NCT02703714). Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior ICI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 and EC) or in cycles 1 and 2 (Stage 2). Primary endpoint was objective response rate (ORR) by RECIST 1.1, H0 5% vs. H1 20%. Key secondary endpoints were safety, progression-free survival (PFS), OS, PD-L1 expression. Exploratory endpoints included relationship between efficacy outcomes and anatomic subsite, risk factors, and tumor genotype. Results: Overall, 42 patients enrolled between 5/2016-12/2019: n = 9 in Stage 1, n = 18 in Stage 2, and n = 15 in EC. Overall: median age 61; female 67%; intrahepatic (ICC) 67%, extrahepatic (ECC) 26%, gallbladder (GBC) 7%; stage IV 90%; hepatitis B/C virus positive (HBV/HCV+) 24%; microsatellite instability (MSI-H)/stable (MSS)/unknown n = 1/35/6. Immune-related (ir)AE occurred in 69%, grade 3/4 treatment-related (tr)AE in 10%, all-cause serious (S)AE in 36%, and trSAE in 7%. ORR was 12% (95% CI: 4, 26), with median PFS of 63 days (95% CI: 55, 125), PFS at 6 months in 27% (95% CI: 14, 43), and median OS 3of 93 days (95% CI: 243, 573). There was no significant difference in ORR, PFS, or OS by anatomic subsite or tumor PD-L1 expression; HBV/HCV+ showed trends toward higher ORR (30% vs 6%, p = 0.08) and longer median PFS (276 vs 63 days, p = 0.06) and OS (1033 vs 323 days, p = 0.052). Conclusions: The combination of PEM plus GM-CSF was safe and well-tolerated with higher ORR than expected for PEM monotherapy in a predominantly MSS ABC population but did not meet target ORR threshold for efficacy. ORR and median PFS and OS were highest in patients with underlying HBV or HCV infection. Immune profiling of on-treatment biopsies and peripheral blood are ongoing to ascertain influence of both PEM and GM-CSF on circulating and tumor immune microenvironment. Clinical trial information: NCT02703714.

Impact of Area Under the Concentration-Time Curve-Guided Monitoring on Vancomycin Nephrotoxicity and Treatment Outcomes in Methicillin-Resistant Staphylococcus Aureus Bacteremia in Korean Patients

Current guidelines for the therapeutic monitoring of vancomycin recommend dosing based on the area under the concentration-time curve (AUC) to achieve clinical efficacy while reducing nephrotoxicity. Although a wide range of nephrotoxicity thresholds have been reported, few studies have documented clinical outcomes based on AUC-guided vancomycin dosing in Korea. The aim of the study was to evaluate whether a relationship exists between AUC and treatment outcomes in vancomycin treated patients in methicillin-resistant Staphylococcus aureus bacteremia. Furthermore, this study tries to estimate AUC threshold for treatment failure and nephrotoxicity. The records of adult patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin for ≥72 hours without dialysis between April 2013 and April 2021, were reviewed retrospectively. Treatment success was defined as defervescence and blood culture sterilization by day 7. Nephrotoxicity was defined as an increase in serum creatinine levels ≥0.3 mg/dL or a 50% increase from baseline on 2 consecutive days. Bayesian estimation was used to predict individual vancomycin AUC. Both classification and regression tree and receiver operating characteristic curve analyses were performed to estimate the optimal AUC thresholds for vancomycin efficacy and nephrotoxicity. Of 118 patients, 61 (51.7%) experienced treatment failure and 42 (35.6%) developed acute kidney injury. The vancomycin AUC threshold for predicting acute kidney injury was 615.0 mg· hr/L. In the multivariate analysis, AUC ≥615.0 mg· hr/L was a significant risk factor for nephrotoxicity (adjusted odds ratio [aOR] = 5.24; 95% CI, 1.8-14.65). The lower threshold for treatment failure was not defined because it was not statistically significant. Risk factors for treatment failure included low body mass index (aOR = 0.82; 95% CI, 0.70-0.96), severity of acute illness represented by complicated infection (aOR = 77.56; 95% CI, 16.7-359.4) and comorbidities, such as solid organ tumors (aOR = 6.61; 95% CI, 1.19-36.81) and cerebrovascular disease (aOR = 6.05; 95% CI, 1.17-31.23). Although AUC-guided vancomycin dosing was associated with a reduced risk of acute kidney injury, its ability to predict clinical outcomes was modest. Further studies are needed to define the AUC therapeutic range to maximize efficacy and minimize nephrotoxicity. (Curr Ther Res Clin Exp. 2023; 83:XXX-XXX).

Probiotics for Antibiotic-Associated Diarrhea: What, When, and How Long?

Probiotics have been formally defined as “live microorganisms that confer a health benefit on the host when administered in adequate amounts.” Although a range of applications has been explored for probiotics, their utility in antibiotic-associated diarrhea (AAD) is both biologically plausible and supported by abundant clinical evidence. However, the strength of evidence underlying the efficacy of specific strains and formulations for AAD varies widely. This review leverages recent meta-analyses and systematic reviews to clarify some outstanding issues on the utility of probiotics for AAD, including which strains have evidence for efficacy in AAD, what doses have been demonstrated to be effective, and the optimal duration of probiotic therapy, and provides practical guidance on how to select an appropriate product. Some trends emerged in this analysis of recent meta-analyses and systematic reviews, including: 1) Certain probiotics, such as Saccharomyces boulardii and some Lactobacilli-containing products, are consistently found to be effective for the management of AAD; 2) Dosing thresholds for efficacy exist that must be achieved through the administration of probiotics that reliably contain the labeled amounts of probiotic constituents; 3) Most effective probiotics are initiated at the same time as antibiotic therapy and continued for between 1 and 3 weeks after the cessation of therapy. These data suggest that attention must be paid to species, dose, and duration when selecting an appropriate product for patients initiating antibiotic therapy; further considerations may include the antibiotic used and the patient’s baseline risk for AAD.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h)/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.

Pharmacokinetics and therapeutic drug monitoring of anticancer protein/kinase inhibitors

Over the past two decades, protein/kinase inhibitors, as targeted therapies, raised in number and have become increasingly mainstream in the treatment of malignant diseases, thanks to the ease of oral administration and the minimal adverse drug reactions. These drugs have similar pharmacokinetic properties: a relatively good absorption and distribution, a strong hepatic metabolism, and a mainly biliary excretion. However, this pharmacokinetic and route of administration has the disadvantage of resulting in a large inter- and intra-individual variability. Despite this significant variability, these drugs are largely prescribed at the same initial dose for quite all patients (flat dose), even though this variability would require individualized adaptation for each patient and/or each new circumstance. Promptly after their commercialization, scientific teams have performed concentration measurements of several drugs and showed the existence of efficacy or toxicity thresholds. This has contributed to the development of therapeutic drug monitoring as one of the strategies to improve the response and reduce the adverse reactions of these drugs. There is still a need to determine precise thresholds for the remaining drugs and to evaluate the impact of TDM in therapeutic management. In order to determine the current state of the art, this article reviews indications, pharmacokinetics and TDM data for 49 marketed PKIs.

Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: results from a pharmacokinetics/pharmacodynamics study

BackgroundCabozantinib is a tyrosine kinase inhibitor with a substantial efficacy in metastatic renal cell carcinoma, and is associated with a challenging toxicity profile leading to frequent drug discontinuations. Whereas an exposure/safety relationship was demonstrated for this drug, an exposure/efficacy relationship is still unknown.Patients and methodsWe carried out a monocentric, observational, pharmacokinetics/pharmacodynamics (PK/PD) study in patients with metastatic renal cell carcinoma (INDS MR 5612140520). We used measured blood concentrations of cabozantinib (Cmeas) to determine the area under the curve (AUC), apparent clearance (Cl/F) and residual blood concentration (Ctrough). Best overall response according to RECIST 1.1 and relevant toxicity (adverse event grade 3-4 or grade 2 requiring dose reduction or discontinuation) were assessed according to Cmeas, Ctrough, AUC and Cl/F.ResultsWe enrolled 76 patients, including 35 who experienced disease progression and 30 with grade 3-4 toxicity. Patients with progressive disease had a significantly lower median Ctrough (406 versus 634 ng/ml, P = 0.001), Cl/F (2 versus 2.9 l/h, P = 0.002) and AUC (16 versus 20 μg h/ml, P = 0.037) compared with patients who had disease control as best response. Patients with relevant toxicity had a significantly higher Cmeas (732 versus 531 ng/ml, P = 0.006), Ctrough (693 versus 521 ng/ml, P = 0.005) and AUC (21 versus 16 μg h/ml, P = 0.046) compared with patients who did not experience any grade relevant toxicity. Receiver operating characteristic curves obtained from our study defined a threshold for drug efficacy of 536.8 ng/ml and of 617.7 ng/ml for toxicity.ConclusionWe first demonstrate the PK/PD relationship for cabozantinib. Severe toxicities are associated with a higher drug exposure, whereas inefficacy is associated with a lower drug exposure. Cabozantinib plasma drug monitoring may be useful to optimize clinical practice.

Abstract P032: Berzosertib plus irinotecan in patients with TP53 mutant gastric/gastroesophageal junction adenocarcinoma: A phase II study

Abstract Background: Nearly 50% of patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma possess somatic TP53 mutations, with most mutations falling within exons 2 or 4-11. Though the presence of TP53 mutations has historically been considered a poor prognostic factor in advanced gastric/GEJ adenocarcinoma, cancer cells with mutations in TP53 tend to depend on ataxia telangiectasia and Rad3-related protein kinase (ATR) as a primary mediator of DNA damage repair (DDR). In preclinical studies, topoisomerase 1 inhibitors and ATR inhibitors demonstrate synergy in TP53 mutant gastrointestinal cancer cell lines. Based on the dearth of active later-line treatments in patients with advanced gastric/GEJ adenocarcinoma, we initiated a combinatorial study of the highly selective ATR inhibitor berzosertib (formerly VX-970/M6620) with irinotecan in this disease population. Methods: The study is a single arm phase II trial of berzosertib plus irinotecan in patients with advanced (progressive on at least one prior line of therapy) TP53 mutant (with mutations in exons 2 or 4-11) gastric/GEJ adenocarcinoma and is sponsored by the National Cancer Institute [NCT03641313]. The primary endpoint of the study is objective response rate (ORR) with key secondary endpoints of overall survival (OS), progression-free survival (PFS), duration of response (DOR) and measuring pharmacodynamic biomarkers of DNA damage induction (γ-H2AX, KAP1 p-Ser 824 and p-ATR) from on-treatment biopsies in select patients. Exploratory aims of the study are to assess ORR, OS, PFS and DOR in patients based upon the presence of other tumor DDR mutations (e.g. BRCA1, BRCA2, MRE11, RAD50, RAD51, NBN, ATM). The study utilizes a Simon's Optimal two-stage design to assess ORR. If 2 or more responses are not observed in the first 9 response-eligible patients on the study, it will close for futility. If the interim efficacy threshold is achieved, 14 more response-eligible patients will be enrolled for a total of 23. A safety lead-in is being utilized for the initial 6 patients as the RP2D of the experimental combination had not yet been fully defined from its preceding phase I study. Results: The initial 6 patients have been treated with irinotecan (180 mg/m2 D1,D15 every 28 days) and berzosertib (270 mg/m2 D1,D15 every 28 days). No dose limiting toxicities were observed during cycle 1 in these patients and thus this dose was established as a safe dose for the remainder of the study patients. Patients have experienced grade 3/4 adverse events in 7 instances (most have been hematologic with 1 case of grade 4 neutropenia and 1 case each of grade 3 anemia, neutropenia and thrombocytopenia). Of the initial 6 patients, 1 has demonstrated a partial response while 3 others have demonstrated stable disease on initial response assessment (by RECIST 1.1). Conclusion: Berzosertib plus irinotecan appears to be safe in patients with TP53 mutated gastric/GEJ adenocarcinoma. The interim efficacy analysis, along with pharmacodynamic assessments of DNA damage induction, remain pending. Citation Format: Satya Das, G. Dan Ayers, Jennifer Whisenant, Anwaar Saeed, Edward Kim, Vaia Florou, George Yacoub, Percy Ivy, Charles Kunos, Jordan Berlin. Berzosertib plus irinotecan in patients with TP53 mutant gastric/gastroesophageal junction adenocarcinoma: A phase II study [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 P032.

Short-cycle therapy in HIV-infected adults: rilpivirine combination 4 days on/3 days off therapy.

Short-cycle therapy (SCT) is the administration of ART for 4 or 5 consecutive days a week, followed by 3 or 2 days off therapy. Its benefits include improving patient satisfaction and reducing ART toxicity and costs. In this observational study we included HIV-infected adults with a three-drug ART containing rilpivirine, a history of long-term virological suppression and no evidence of resistance to previous drug regimens. Patients switched to a SCT of 4 days on/3 days off and were followed for 48 weeks with regular check-ups. The primary outcome was virological suppression; secondary outcomes were changes in CD4+ cells and rilpivirine plasma concentration, the occurrence of adverse events and resistance in the case of failure, and patient satisfaction. At week 48 no virological failure was observed, with a virological suppression rate of 30/30 (100%). Three patients switched back to continuous therapy for other reasons, with an overall success rate of SCT of 30/33 (90.9%, 95% CI = 81.24% to 100%). The CD4+ mean value increased by +64 cells/mm3 (95% CI = -59 to +187 cells/mm3; P = 0.052). No adverse events were observed and the mean total score in the satisfaction questionnaire was 57.7/60 (96.22%). Rilpivirine plasma concentration was below the efficacy threshold in 71.3% of the samples, suggesting that the patients' characteristics, more than the drug's pharmacokinetics, played a role in maintaining virological suppression. SCT with rilpivirine-containing regimens could be an effective alternative to continuous therapy in selected HIV-infected patients with previous long-term virological suppression.

The Blueprint for Successful Device Development: Disruptive Innovation and Co-Opetition, Then Randomized Trials

• Novel devices must meet rigorous thresholds for clinical efficacy and safety. Some innovations succeed more than others. • Variations in the success trajectory of innovations cannot be easily explained by device efficacy alone. • The key to successful device development lies in 2 concepts of business theory: disruptive innovation and co-opetition. • We propose that initial randomized clinical trials of newer devices be conducted on these 2 building blocks. • Our construct places interventions in a Venn diagram depicting disruptive innovation, co-opetition and randomized trials. • Our construct has significant implications for industry, regulatory bodies and clinical trialists.

Abstract 10920: Cost-Effectiveness of Pulmonary Vein Isolation with Epicardial Left Atrial Appendage Ligation for the Treatment of Non-Paroxysmal Atrial Fibrillation

Introduction: Electrical isolation of the left atrial appendage (LAA) using percutaneous epicardial ligation may improve catheter ablation outcomes for non-paroxysmal atrial fibrillation (AF) patients. Little is known regarding the cost effectiveness of this procedure. Hypothesis: We hypothesized that cost-effectiveness between pulmonary vein isolation (PVI) + LAA epicardial ligation using a percutaneous LARIAT ® Suture Delivery Device would be cost effective (CE) compared to PVI alone over 5 years. Methods: A Markov model simulated outcomes for a population with annual stroke risk of 4.6% (CHA 2 DS 2 -VASc score 3). Model inputs for procedure efficacy, stroke and bleed events, health utility, and event costs were estimated from literature. Procedure costs from Medicare rates were used. The model had a 5-year time-horizon and US payer perspective. Univariate and probabilistic sensitivity analyses (PSA) were performed. Outcomes were health care costs and quality-adjusted life-years (QALYs). In the base case, PVI + LAA ligation efficacy from published studies was 67% after 1-year, with an estimated 25% oral anticoagulant (OAC) utilization in PVI + LAA ligation patients in normal sinus rhythm 13-60 months after the index procedure. Cost effectiveness thresholds were evaluated with alternative PVI + LAA ligation efficacy and OAC utilization rates, including 1-year PVI + LAA ligation efficacies of 67%, 70%, 75%, and 80% and OAC utilization of 20-60%. Results: In the base case, PVI + LAA ligation had a mean 5-year cost of $72,865 with 3.25 QALYs and PVI alone had mean cost of $69,936 with 3.19 QALYs. The incremental cost-effectiveness ratio was $46,716; PVI + LAA ligation was CE at $50,000 per QALY gained. In PSA, 64% and 82% of simulations were CE at $50,000 and $100,000 per QALY gained, respectively. In various scenarios, procedure efficacy of 75% combined with OAC utilization of 50% or below yielded CE at $50,000 per QALY gained. Reduction of OAC utilization to 30% yielded CE at $50,000 per QALY gained, regardless of efficacy. Conclusions: In the base case, PVI + LAA ligation was CE at $50,000 per QALY gained when compared to PVI alone. The CE threshold for efficacy was 75% and OAC utilization was 30%. Cost savings were driven by reductions in OAC use and increased efficacy.

Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta-Analysis Approach.

Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug-drug interactions (DDIs) and obesity (women with body mass index (BMI)≥30kg/m2 ) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically-based pharmacokinetic modeling and model-based meta-analysis approach to determine LNG's efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG-containing hormonal contraceptives (HCs). Based on this approach, co-administration of strong CYP3A4 inducers and LNG-containing HCs (LNG150: LNG 150µg+EE 30µg and LNG100: LNG 100µg+EE 20µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI<25kg/m2 : 50-65%; obese women: 70-75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2-1.30 and 1.80-2.10, respectively, in women with BMI<25kg/m2 (incidence rate ratios (IRRs): 1.7-2.2), whereas it ranged from 1.6-1.80 and 2.40-2.85 in obese women (IRR: 2.2-3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG+EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.

Emitting area limitation via scattering control in phosphor film realizing high-luminance laser lighting

One major benefit of laser lighting is the possibility to achieve very high luminance. In phosphor-converted laser lighting systems, a blue (pump) laser can be focused into a very small spot. However, after excitation of the phosphor, the white-light-emitting area usually increases considerably, which reduces the luminance parameter substantially. Herein, we design and investigate a highly scattering YAG:Ce/glass composite film with a porous microstructure. Both the glass/phosphor interfaces and the introduced pores act as scattering centers, which can confine the emission area effectively. The relationship between the spot size and the microstructure (porosity, phosphor-particle size, thickness) is elucidated. Under excitation with blue laser, the composite film shows a uniform white-light emission with high luminous efficacy (230 lm/W) and high saturation threshold (> 40 W/mm2), thus achieving a high luminous exitance of ∼1239 lm/mm2. With above excellent properties, the designed composite films show great potential for use in high-luminance laser lighting.

MP31-16 GONADOTROPIN CONCENTRATION THRESHOLDS TO PREDICT IMPROVEMENTS IN TESTOSTERONE AND SEMEN PARAMETERS WITH CLOMIPHENE CITRATE

You have accessJournal of UrologyInfertility: Therapy (MP31)1 Sep 2021MP31-16 GONADOTROPIN CONCENTRATION THRESHOLDS TO PREDICT IMPROVEMENTS IN TESTOSTERONE AND SEMEN PARAMETERS WITH CLOMIPHENE CITRATE Tommy Jiang, Alvaro Santamaria, Neilufar Modiri, Michael Zheng, Vadim Osadchiy, John Sigalos, Jesse Mills, and Sriram Eleswarapu Tommy JiangTommy Jiang More articles by this author , Alvaro SantamariaAlvaro Santamaria More articles by this author , Neilufar ModiriNeilufar Modiri More articles by this author , Michael ZhengMichael Zheng More articles by this author , Vadim OsadchiyVadim Osadchiy More articles by this author , John SigalosJohn Sigalos More articles by this author , Jesse MillsJesse Mills More articles by this author , and Sriram EleswarapuSriram Eleswarapu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002035.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Due to its indirect ability to increase pituitary gonadotropins, clomiphene citrate is prescribed off-label to men with hypogonadism or impaired sperm counts. However, threshold values for pre-treatment LH and FSH that predict response remain unknown. We sought to identify pre-treatment thresholds to guide clomiphene use in men with hypogonadism or subfertility. METHODS: Using an IRB approved database, we retrospectively extracted LH, FSH, testosterone (T), and semen analysis (SA) data in men pre- and 3 months post-treatment with clomiphene (25 mg daily). Patients with prior hormone therapy or genitourinary surgery were excluded. We determined efficacy thresholds by identifying the highest LH or FSH level at which a significant difference in initial and final values for each outcome (T and each SA parameter) could be observed, based on Student t-tests with α=0.05. A representative FSH threshold curve measuring fluctuation in P-value for effect on sperm concentration is provided in Figure 1. Men whose partners achieved pregnancy while taking clomiphene were used to contextualize the computed LH and FSH thresholds. RESULTS: Threshold determinations were made from data on 137 men; 28 had partners achieve pregnancy; 25 of these had pre-treatment LH and FSH levels. Table 1 reports thresholds for either LH or FSH for each outcome. For each given threshold, pregnancy rates are listed. For example, the highest FSH at which to achieve a significant improvement in sperm concentration with clomiphene is a level of 9.9 miU/mL, and this translated to a pregnancy rate of 80% in our cohort. Similar data are presented in Table 1 for each outcome. CONCLUSIONS: Threshold values of gonadotropins were identified, below which statistically significant improvements in testosterone, sperm concentration, total sperm count, and total motile sperm count occurred. These thresholds may be useful in guiding clomiphene use in men contending with hypogonadism or subfertility. Further prospective evaluation is needed to validate these thresholds. Source of Funding: N/A © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e561-e561 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tommy Jiang More articles by this author Alvaro Santamaria More articles by this author Neilufar Modiri More articles by this author Michael Zheng More articles by this author Vadim Osadchiy More articles by this author John Sigalos More articles by this author Jesse Mills More articles by this author Sriram Eleswarapu More articles by this author Expand All Advertisement Loading ...