f Relebactam (REL [MK-7655]) is a novel class A/C ␤-lactamase inhibitor intended for use with imipenem for the treatment ofGram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas. In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were >18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains.

P ediatric drug development is challenging and fairly unique in several aspects. 1 Most of the development programs have just one chance to perform an informative set of trials. After that, industry does not have any financial incentive. Pharmacokinetic (PK) information is useful in (1) selecting dose range for future studies; (2) assessing drug exposure for efficacy and safety purposes, especially by matching exposures to adults, and ultimately (3) supporting dosing approval. Different guidances were published to explain the role of pediatric studies under various conditions and the growth and developmental changes in factors influencing absorption, distribution, metabolism, and elimination of drugs in the pediatric population. 2,3 Even though sample size justification is provided for pediatric efficacy studies, the sample size selection for pediatric PK and safety studies has been vastly different without clear justification. As a consequence, either the pediatric exclusivity determination or the approval decision was affected. Hence, there is a need for a uniform definition of study quality for PK studies.One of the important goals of the pediatric PK study is to ensure the precise estimate of important PK parameters, such as clearance and volume of distribution, to justify the choice of a safe and effective dose from a PK perspective. To achieve this goal, a standard regulatory requirement has been drafted and communicated to the sponsors, where applicable, as follows:The study must be prospectively powered to target a 95% CI [confidence interval] within 60% and 140% of the geometric mean estimates of clearance and volume of distribution for DRUG NAME in each pediatric sub-group with at least 80% power. This report describes methodological details and expectations to fulfill this requirement based on either a noncompartment analysis (NCA) or a population PK (popPK) modeling approach. In the case of NCA analysis, we assume PK parameters have been robustly evaluated with an appropriate blood sampling strategy at the individual patient level. In some cases, the requirement for sample size is primarily driven by safety objectives where a minimum number of participants are required for safety evaluation, and this number may be more than that for PK objectives. Nevertheless, the same language will be communicated to the sponsors even if the planned sample size for safety objectives is more than that for PK objectives. A review of 3 pediatric clinical trials is presented to illustrate the feasibility of complying with the proposed quality standard. Finally, the potential impact of the quality standard on pediatric drug development is discussed. MethodIn this section, detailed steps to achieve the target, 95% CI within 60% and 140% of the geometric

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BackgroundMetastatic triple-negative breast cancer (mTNBC), an aggressive histological subtype, has poor prognosis. Chemotherapy remains standard of care for mTNBC, although no agent has been specifically approved for this breast cancer subtype. Instead, chemotherapies approved for metastatic breast cancer (MBC) are used for mTNBC (National Comprehensive Cancer Network Guidelines [NCCN] v1.2019). Atezolizumab in combination with nab-paclitaxel was recently approved for programmed death-ligand 1 (PD-L1)–positive locally advanced or metastatic TNBC. Published historical data were reviewed to characterize the efficacy of NCCN-recommended (v1.2016) agents as first-line (1L) and second-line or later (2L+) treatment for patients with locally recurrent inoperable or metastatic TNBC (collectively termed mTNBC herein).MethodsA systematic literature review was performed, examining clinical efficacy of therapies for mTNBC based on NCCN v1.2016 guideline recommendations. Data from 13 studies, either published retrospective mTNBC subgroup analyses based on phase III trials in MBC or phase II trials in mTNBC, were included.ResultsA meta-analysis of mTNBC subgroups from three phase III trials in 1L MBC reported pooled objective response rate (ORR) of 23%, median overall survival (OS) of 17.5 months, and median progression-free survival (PFS) of 5.4 months with single-agent chemotherapy. In two subgroup analyses from a phase III study and a phase II trial (n = 40 each), median duration of response (DOR) to 1L chemotherapy for mTNBC was 4.4–6.6 months; therefore, responses were not durable. A meta-analysis of seven cohorts showed the pooled ORR for 2L+ chemotherapy was 11% (95% CI, 9–14%). Median DOR to 2L+ chemotherapy in mTNBC was also limited (4.2–5.9 months) per two subgroup analyses from a phase III study. No combination chemotherapy regimens recommended by NCCN v1.2016 for treatment of MBC showed superior OS to single agents.ConclusionsChemotherapies have limited effectiveness and are associated with unfavorable toxicity profiles, highlighting a considerable unmet medical need for improved therapeutic options in mTNBC. In addition to the recently approved combination of atezolizumab and nab-paclitaxel for PD-L1–positive mTNBC, new treatments resulting in durable clinical responses, prolonged survival, and manageable safety profile would greatly benefit patients with mTNBC.

Background: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. Patients and methods: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with nonsmall-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. Results: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatmentrelated adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEsethe most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEsethe most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. Conclusions: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Relebactam is a small-molecule β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin. The pharmacokinetics of relebactam and imipenem across 10 clinical studies were analyzed using data from adult healthy volunteers and patients with bacterial infections. Renal function estimated by creatinine clearance significantly affected the clearance of both compounds, whereas weight and health status were of less clinical significance. Simulations were used to calculate probability of joint target attainment (ratio of free drug area under the curve from 0 to 24 hours to minimum inhibitory concentration (MIC) for relebactam and percentage of time the free drug concentration exceeded the MIC for imipenem) for the proposed imipenem/relebactam dose of 500/250 mg, with adjustments for patients with renal impairment, administered as a 30-minute intravenous infusion four times daily. These dosing regimens provide sufficient antibacterial coverage (MIC ≤ 4 μg/mL) for all renal groups.Relebactam is a small-molecule β-lactamase inhibitor active against classes A and C β-lactamases that is being developed as a fixed-dose combination with imipenem/cilastatin (PRIMAXIN, Whitehouse Station, NJ). 1,2 Imipenem is an approved carbapenem β-lactam antibacterial agent that covers many gram-negative organisms and certain gram-positive organisms and anaerobes. 2 Cilastatin alone has no antibacterial activity, but prevents the metabolism of imipenem by renal dehydropeptidase produced in vivo.In vitro susceptibility and hollow fiber (HF) time-kill studies found that relebactam restored the activity of subinhibitory concentrations of imipenem against imipenem-resistant isolates. [3][4][5] Animal studies further confirmed the activity of relebactam, and integrated translational pharmacokinetic/ pharmacodynamic (PK/PD) modeling suggested that the combination of imipenem/relebactam would be efficacious against the majority of imipenem-resistant strains at clinically achievable doses and concentrations. 6,7 From these

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Background Pembrolizumab is a potent, humanized, monoclonal anti–programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study. Patients and methods Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non–small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately. Results Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA–positive; none had neutralizing antibodies. Conclusions The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab. Trial registration ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015). ...