Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy.

Introduction: Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities. Methods: We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This "PD1/IL15" selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials. Results: The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0-4.1 days) compared to wild-type IL-15 (half-life ∼1.1 h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003 mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data. Conclusion: This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

A phase I, randomized study to evaluate the safety, tolerability, and pharmacokinetics of mefunidone in healthy subjects.

Background: Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects. Methods: Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, bis in die) on days 1-6 and once in the morning on day 7. Results: Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg-600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in Tmax by approximately 1 h and a slight reduction of approximately 20% in Cmax compared to that in fasting conditions, but it did not significantly affect systemic exposure. Conclusion: Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone. Clinical Trial Registration: clinicaltrials.gov, identifier CXHL1900206.

[64Cu]Cu-FAP-NOX, a N-oxalyl modified cyclic peptide for FAP PET imaging with a flexible imaging time window.

BACKGROUND: The aim of the present study was to develop a novel 64Cu-labeled cyclic peptide ([64Cu]Cu-FAP-NOX) that targets fibroblast activation protein (FAP) and may offer advantages in terms of image contrast, imaging time window, and low uptake in normal tissues. METHODS: The novel cyclic peptide featuring with a N-oxalyl modified tail was constructed and conjugated to NOTA for 64Cu labeling. Biochemical and cellular assays were performed with A549.hFAP cells. The performance of [64Cu]Cu-FAP-NOX was compared to that of two established tracers ([64Cu]Cu-FAPI-04 and [68Ga]Ga-FAP-2286) and three different NOTA-conjugates in HEK-293T.hFAP xenograft mice using micro-PET imaging. Ex vivo biodistribution studies were performed to confirm the FAP specificity and to validate the PET data. Furthermore, a first-in-human study of this novel tracer was conducted on one patient with lung cancer. RESULTS: Compared to [64Cu]Cu-FAPI-04, [64Cu]Cu-FAP-NOX demonstrated faster and higher rates of cellular uptake and internalization in A549.hFAP cells, but lower rates of cellular efflux. All six radiotracers were rapidly taken up by the tumor within the first 4 h post-injection. However, [64Cu]Cu-FAP-NOX had more intense tumor accumulation and slower washout from the target. The ratios of the tumor to normal tissue (including kidneys and muscles) increased significantly over time, with [64Cu]Cu-FAP-NOX reaching the highest ratio among all tracers. In the patient, [64Cu]Cu-FAP-NOX PET showed a comparable result to FDG PET in the primary malignant lesion while exhibiting higher uptake in pleural metastases, consistent with elevated FAP expression as confirmed by immunohistochemistry. CONCLUSION: [64Cu]Cu-FAP-NOX is a promising FAP-targeted tracer with a highly flexible imaging time window, as evidenced by preclinical evaluation encompassing biodistribution and micro-PET studies, along with a successful patient application. Furthermore, [64Cu]Cu-FAP-NOX showed enhanced image contrast and favorable pharmacokinetic properties for FAP PET imaging, warranting translation into large cohort studies.

Organizational aspects of tissue engineering clinical translation: insights from a qualitative case study.

Background: Tissue engineering is a multidisciplinary field that combines principles from cell biology, bioengineering, material sciences, medicine and surgery to create functional and viable bioproducts that can be used to repair or replace damaged or diseased tissues in the human body. The complexity of tissue engineering can affect the prospects of efficiently translating scientific discoveries in the field into scalable clinical approaches that could benefit patients. Organizational challenges may play a key role in the clinical translation of tissue engineering for the benefit of patients. Methods: To gain insight into the organizational aspects of tissue engineering that may create impediments to efficient clinical translation, we conducted a retrospective qualitative case study of one tissue engineering multi-site translational project on knee cartilage engineered tissue grafts. We collected qualitative data using a set of different methods: semi-structured interviews, documentary research and audio-visual content analysis. Results: Our study identified various challenges associated to first-in-human trials in tissue engineering particularly related to: logistics and communication; research participant recruitment; clinician and medical student participation; study management; and regulation. Conclusions: While not directly generalizable to other types of advanced therapies or to regenerative medicine in general, our results offer valuable insights into organizational barriers that may prevent efficient clinical translation in the field of tissue engineering.

A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas.

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted.

A Minimal PBPK/PD Model with Expansion-Enhanced Target-Mediated Drug Disposition to Support a First-in-Human Clinical Study Design for a FLT3L-Fc Molecule.

FLT3L-Fc is a half-life extended, effectorless Fc-fusion of the native human FLT3-ligand. In cynomolgus monkeys, treatment with FLT3L-Fc leads to a complex pharmacokinetic/pharmacodynamic (PK/PD) relationship, with observed nonlinear PK and expansion of different immune cell types across different dose levels. A minimal physiologically based PK/PD model with expansion-enhanced target-mediated drug disposition (TMDD) was developed to integrate the molecule's mechanism of action, as well as the complex preclinical and clinical PK/PD data, to support the preclinical-to-clinical translation of FLT3L-Fc. In addition to the preclinical PK data of FLT3L-Fc in cynomolgus monkeys, clinical PK and PD data from other FLT3-agonist molecules (GS-3583 and CDX-301) were used to inform the model and project the expansion profiles of conventional DC1s (cDC1s) and total DCs in peripheral blood. This work constitutes an essential part of our model-informed drug development (MIDD) strategy for clinical development of FLT3L-Fc by projecting PK/PD in healthy volunteers, determining the first-in-human (FIH) dose, and informing the efficacious dose in clinical settings. Model-generated results were incorporated in regulatory filings to support the rationale for the FIH dose selection.

Clinical pharmacology considerations for first-in-human clinical trials for enzyme replacement therapy.

Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are conditions caused by deficiency of one or more key enzymes, cofactors, or transporters involved in a specific metabolic pathway. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme and is one of the most effective treatment options for IEMs. In this paper, we review the first-in-human (FIH) protocols for ERT drug development programs supporting 20 Biologic License Applications (BLA) approved by the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) in the period of May 1994 to September 2023. We surveyed study design elements across these FIH protocols including study population, dosage form, dose selection, treatment duration, immunogenicity, biomarkers, and study follow-up. A total of 18 FIH trials from 20 BLAs were identified and of those, 72% (13/18) used single ascending dose (SAD) and/or multiple ascending dose (MAD) study design, 83% (15/18) had a primary objective of assessing the safety and tolerability, 72% (13/18) included clinical endpoint assessments, and 94% (17/18) included biomarker assessments as secondary or exploratory endpoints. Notably, the majority of ERT products tested the approved route of administration and the approved dose was tested in 83% (15/18) of FIH trials. At last, we offer considerations for the design of FIH studies.

Pharmacokinetic models for first-in-human dose selection of immune-activating products in oncology.

Pharmacokinetic (PK) models are increasingly submitted to the FDA to support first-in-human (FIH) dose selection of immune-oncology products. To examine whether a simple PK modeling (SPM) using clearance for scaling was acceptable for dose estimation, FIH(SPM) doses were computed and compared to doses that were safely administered to patients. We concluded that the SPM approach is acceptable in FIH dose estimation, but the variables should be carefully selected for CD3 constructs. For CD3 constructs, use of 60 kg BWh, a clearance exponent of 0.75, and a targeted plasma concentration based on relevant and/or sensitive activity assays was an acceptable approach for FIH dose selection; use of 0.85 as the scaling factor is questionable at this time as it resulted in a FIH dose that was too close to the AHD for one product (7%). Immune activating mAbs were not sensitive to changes in the clearance exponent (0.75-0.85) or body weight (60-70 kg). For PD-1/PD-L1 mAbs, using products' in vitro EC50 in the model resulted in suboptimal FIH doses and clinical data of closely related products informed FIH dose selection. PK models submitted by sponsors were diverse in methods, assumptions, and variables, and the resulting FIH doses were not always optimal.

One-year initial efficacy and safety outcomes of the premounted dry-pericardium Vienna self-expandable transcatheter aortic valve system: A first-in-human VIVA feasibility study.

BACKGROUND: The dry-pericardium Vienna transcatheter aortic valve system is repositionable and retrievable, already premounted on the delivery system, eliminating the need for assembly and crimping of the device before valve implantation. METHODS: The VIVA first-in-human feasibility study, a prospective, nonrandomized, single-center trial, evaluated the Vienna aortic valve in 10 patients with severe symptomatic aortic stenosis, who were at intermediate or high surgical risk. This study, registered at ClinicalTrials.gov (NCT04861805), focused on the safety, feasibility, clinical and hemodynamic performance of the Vienna system up to 1-year follow-up. RESULTS: The mean patient age was 79 ± 5 years, 60% male. Valve sizes used: 26 mm (10%), 29 mm (30%), 31 mm (60%). Key hemodynamic improvements were significant: mean aortic valve pressure gradient (mmHg) decreased from 48.7 to 8.1, aortic valve area (cm2) increased from 0.75 to 1.91, and maximum jet velocity through the aortic valve (m/s) decreased from 4.41 to 1.95 (p < 0.0001). No moderate/severe paravalvular leakage was observed, and computed tomography scans revealed no evidence of hypo-attenuated leaflet thickening. The study recorded one life-threatening bleeding event, two cases requiring postprocedural pacemaker implantation, and three ischemic events, with only one causing lasting neurological impairment. Importantly, there were no cases of cardiovascular mortality and only one noncardiovascular death, which was confirmed as unrelated to the device. CONCLUSIONS: The study indicates the Vienna valve as a potential option for severe symptomatic aortic stenosis, designed to streamline the procedure and potentially lower healthcare costs by reducing resource and equipment needs, also procedural errors. Further research is essential to thoroughly evaluate its safety and efficacy.

A review of dose escalation for FDA-approved products treating solid tumors and hematological malignancies in first-in-human trials.

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.

Safety and pharmacokinetics of antifungal agent VT-1598 and its primary metabolite, VT-11134, in healthy adult subjects: phase 1, first-in-human, randomized, double-blind, placebo-controlled study of single-ascending oral doses of VT-1598.

VT-1598 is a novel fungal CYP51 inhibitor and 1-tetrazole-based antifungal drug candidate with improved selectivity minimizing off-target binding to and inhibition of human CYP450 enzymes. Data are presented from this first clinical study in the evaluation of the safety and pharmacokinetic (PK) of single ascending doses of 40, 80, 160, 320, and 640 mg VT-1598, comprising a 160 mg cohort in both fasting and fed states. Eight healthy adults per dose were randomized to receive either oral VT-1598 or placebo (3:1). Over the dose range, exposures were with relatively high variation. The maximum plasma concentrations (Cmax) for VT-1598 were 31.00-279.4 ng/ml and for its primary metabolite, VT-11134, were 27.80-108.8 ng/ml. The plasma area under the concentration-time curve to the last measurable concentration (AUC0-last) for VT-1598 were 116.1-4507 ng*h/ml, and for VT-11134 were 1140-7156 ng*h/ml. The dose proportionality was inconclusive based on the results of the power model. The peak concentration time (Tmax) was 4-5 h for VT-1598 and for VT-11134. Half-life was 103-126 h for VT-11134. After food intake, Cmax of VT-1598 increased by 44% (geometric mean ratio (GMR), 1.44; 90%CI [0.691, 2.19]) and AUC0-last by 126% (GMR, 2.26; 90%CI [1.09, 3.44]), while exposure of VT-11134 was decreased 23% for Cmax (GMR, 0.77; 90%CI [0.239, 1.31]) and unchanged for AUC0-last (GMR, 1.02; 90%CI [0.701, 1.33]). Neither VT-1598 nor VT-11134 were detected in urine. No serious adverse events (AEs) or AEs leading to early termination were observed. The safety and PK profiles of VT-1598 support its further clinical development.

VT-1598 is a tetrazole antifungal with improved selectivity and demonstrated a high survival rate when murine infected with invasive aspergillosis, coccidiodomycosis, cryptococcosis, and candidiasis. We report a first-in-human study to evaluate safety and pharmacokinetics after an oral dose of VT-1598.

Coronary bypass surgery guided by computed tomography in a low-risk population.

BACKGROUND AND AIMS: In patients with three-vessel disease and/or left main disease, selecting revascularization strategy based on coronary computed tomography angiography (CCTA) has a high level of virtual agreement with treatment decisions based on invasive coronary angiography (ICA). METHODS: In this study, coronary artery bypass grafting (CABG) procedures were planned based on CCTA without knowledge of ICA. The CABG strategy was recommended by a central core laboratory assessing the anatomy and functionality of the coronary circulation. The primary feasibility endpoint was the percentage of operations performed without access to the ICA. The primary safety endpoint was graft patency on 30-day follow-up CCTA. Secondary endpoints included topographical adequacy of grafting, major adverse cardiac and cerebrovascular (MACCE), and major bleeding events at 30 days. The study was considered positive if the lower boundary of confidence intervals (CI) for feasibility was ≥75% (NCT04142021). RESULTS: The study enrolled 114 patients with a mean (standard deviation) anatomical SYNTAX score and Society of Thoracic Surgery score of 43.6 (15.3) and 0.81 (0.63), respectively. Unblinding ICA was required in one case yielding a feasibility of 99.1% (95% CI 95.2%-100%). The concordance and agreement in revascularization planning between the ICA- and CCTA-Heart Teams was 82.9% with a moderate kappa of 0.58 (95% CI 0.50-0.66) and between the CCTA-Heart Team and actual treatment was 83.7% with a substantial kappa of 0.61 (95% CI 0.53-0.68). The 30-day follow-up CCTA in 102 patients (91.9%) showed an anastomosis patency rate of 92.6%, whilst MACCE was 7.2% and major bleeding 2.7%. CONCLUSIONS: CABG guided by CCTA is feasible and has an acceptable safety profile in a selected population of complex coronary artery disease.

First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

A phase I study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer.

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics, tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients. Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles. Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks. Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea (85.7%), vomiting (28.6%), nausea (25.0%) and decreased appetite (17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response (CR), and three achieved partial response (PR). The objective response rate (ORR) and disease control rate (DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival (PFS) was 3.98 months. Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase III trial (No. NCT05122494).

Preclinical and translational pharmacology of afucosylated anti-CCR8 antibody for depletion of tumour-infiltrating regulatory T cells.

BACKGROUND AND PURPOSE: RO7502175 is an afucosylated antibody designed to eliminate C-C motif chemokine receptor 8 (CCR8)+ Treg cells in the tumour microenvironment through enhanced antibody-dependent cellular cytotoxicity (ADCC). EXPERIMENTAL APPROACH: We report findings from preclinical studies characterizing pharmacology, pharmacokinetics (PK)/pharmacodynamics (PD) and safety profile of RO7502175 and discuss the translational PK/PD approach used to inform first-in-human (FiH) dosing strategy and clinical development in solid tumour indications. KEY RESULTS: RO7502175 demonstrated selective ADCC against human CCR8+ Treg cells from dissociated tumours in vitro. In cynomolgus monkeys, RO7502175 exhibited a biphasic concentration-time profile consistent with immunoglobulin G1 (IgG1) antibodies, reduced CCR8+ Treg cells in the blood, induced minimal and transient cytokine secretion, and was well tolerated with a no-observed-adverse-effect level (NOAEL) of 100 mg·kg-1. Moreover, RO7502175 caused minimal cytokine release from peripheral blood mononuclear cells (PBMCs) in vitro. A quantitative model was developed to capture surrogate anti-murine CCR8 antibody PK/PD and tumour dynamics in mice and RO7502175 PK/PD in cynomolgus monkeys. Subsequently, the model was used to project RO7502175 human PK and receptor occupancy (RO) in patients. Because traditional approaches resulted in a low FiH dose for this molecule, even with its superior preclinical safety profile, an integrated approach based on the totality of preclinical data and modelling insights was used for starting dose selection. CONCLUSION AND IMPLICATIONS: This work demonstrates a translational research strategy for collecting and utilizing relevant nonclinical data, developing a mechanistic PK/PD model and using a comprehensive approach to inform clinical study design for RO7502175.

A first-in-human phase I study of the PD-1 inhibitor, retifanlimab (INCMGA00012), in patients with advanced solid tumors (POD1UM-101).

BACKGROUND: Retifanlimab is a humanized, hinge-stabilized immunoglobulin G4κ monoclonal antibody against human programmed cell death protein 1 (PD-1). This first-in-human, phase I study assessed the safety and efficacy of retifanlimab in patients with advanced solid tumors and identified optimal dosing. PATIENTS AND METHODS: POD1UM-101 was conducted in two parts: (i) dose escalation-evaluated retifanlimab [1 mg/kg every 2 weeks (q2w), 3 or 10 mg/kg q2w or every 4 weeks (q4w)] in patients with relapsed/refractory, unresectable, locally advanced or metastatic solid tumors; (ii) cohort expansion-biomarker-unselected tumor-specific cohorts [endometrial, cervical, sarcoma, non-small-cell lung cancer (NSCLC)] received retifanlimab 3 mg/kg q2w, and tumor-agnostic cohorts received flat dosing [375 mg every 3 weeks (q3w), or 500 and 750 mg q4w]. Primary objectives were safety and tolerability; secondary objective was efficacy in selected tumor types. RESULTS: Thirty-seven patients were enrolled in dose escalation, 134 in PD-1 therapy-naïve tumor-specific cohort expansion (endometrial, n = 29; cervical, NSCLC, soft tissue sarcoma, each n = 35), and 45 in flat dosing (375 mg q3w, 500 and 750 mg q4w, each n = 15). No dose-limiting toxicities occurred during dose escalation; maximum tolerated dose was not reached and 3-mg/kg q2w expansion dose was selected based on safety and pharmacokinetic data. Immune-related adverse events were experienced by 40 patients (30%) in tumor-specific cohorts (most frequently hypothyroidism, hyperthyroidism, colitis, nephritis) and 6 (13%) in flat dosing (most frequently hypothyroidism, hyperthyroidism). Objective response rate (95% confidence interval) was 14% (4.8 to 30.3), 14% (3.9 to 31.7), 20% (8.4 to 36.9), and 3% (0.1 to 14.9) in advanced NSCLC, endometrial, cervical, and sarcoma tumor-specific cohorts that progressed after multiple prior systemic therapies. CONCLUSIONS: Retifanlimab demonstrated clinical pharmacology, safety, and antitumor activity consistent with the programmed death (ligand)-1 inhibitor class. POD1UM-101 results support further exploration of retifanlimab as monotherapy and backbone immunotherapy in combination treatments, with recommended doses of 500 mg q4w and 375 mg q3w.

EANM guidance document: dosimetry for first-in-human studies and early phase clinical trials.

The numbers of diagnostic and therapeutic nuclear medicine agents under investigation are rapidly increasing. Both novel emitters and novel carrier molecules require careful selection of measurement procedures. This document provides guidance relevant to dosimetry for first-in human and early phase clinical trials of such novel agents. The guideline includes a short introduction to different emitters and carrier molecules, followed by recommendations on the methods for activity measurement, pharmacokinetic analyses, as well as absorbed dose calculations and uncertainty analyses. The optimal use of preclinical information and studies involving diagnostic analogues is discussed. Good practice reporting is emphasised, and relevant dosimetry parameters and method descriptions to be included are listed. Three examples of first-in-human dosimetry studies, both for diagnostic tracers and radionuclide therapies, are given.

Development of an extemporaneous preparation formulation using a simple and non-solubilizing matrix for first in human clinical study.

Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.

A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors.

PURPOSE: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated. METHODS: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity. RESULTS: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response. CONCLUSION: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition. TRIAL REGISTRATION: jRCT2080222728 (January 29, 2015).