Pharmacokinetics of Tarlatamab, a Delta-Like Ligand-3 (DLL3) Targeted Half-Life Extended Bispecific T-Cell Engager (BiTE) Immunotherapy in Adult Patients with Previously Treated Small-Cell Lung Cancer: Results from DeLLphi-300, a Phase I Multiple-Dose-Escalation Study.

Background: Tarlatamab binds to delta-like ligand 3 on cancer cells and cluster of differentiation-3 on T cells, leading to T-cell-mediated tumor lysis, and has demonstrated a promising safety and efficacy profile in patients with previously treated small-cell lung cancer (SCLC). Here, we present pharmacokinetic results from DeLLphi-300 (NCT03319940), an ongoing international, open-label, first-in-human study in previously treated adult patients with SCLC.

Methods: Multiple escalating doses of tarlatamab were administered every 2 weeks (Q2W; 0.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp Alfa, a Bispecific Inhibitor of BAFF and ICOSL: Analyses of Phase I Clinical Trials.

Rozibafusp alfa (AMG 570) is a first-in-class bispecific IgG2-peptide fusion designed to inhibit inducible T-cell costimulator ligand (ICOSL) and B-cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo-controlled clinical studies: a phase Ia single ascending-dose study (7-700 mg subcutaneously (s.c.

Impact of Sotorasib on the Pharmacokinetics and Pharmacodynamics of Metformin, a MATE1/2K Substrate, in Healthy Subjects.

Background And Objective: The objectives of this study were to evaluate the effect of sotorasib on metformin pharmacokinetics and pharmacodynamics and the effect of metformin on sotorasib pharmacokinetics in healthy subjects. Sotorasib is an oral, small molecule inhibitor of the Kirsten rat sarcoma oncogene homolog (KRAS) G12C mutant protein (KRASG12C) protein approved by the U.S.

KRAS Inhibition with Sotorasib in Advanced Solid Tumors.

Background: No therapies for targeting mutations in cancer have been approved. The p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers.

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity.

Distribution, Metabolism, and Excretion of Gedatolisib in Healthy Male Volunteers After a Single Intravenous Infusion.

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion.

Modeling and simulations relating overall survival to tumor growth inhibition in renal cell carcinoma patients.

Purpose: To assess the link between tumor growth inhibition (TGI) and overall survival (OS) based on historical renal cell carcinoma (RCC) data. To illustrate how simulations can help to identify TGI thresholds based on target OS benefit [i.e.

Effect of axitinib on the QT interval in healthy volunteers.

Purpose: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization.

Methods: The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily).

Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer.

Purpose: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity of the PI3K/mTOR inhibitor PF-04691502, administered orally once daily.

Methods: Escalating doses of PF-04691502 were administered to 23 patients with advanced solid tumors in sequential cohorts across the following dose levels: 2 mg, 4 mg, 8 mg, and 11 mg. 14 additional patients were enrolled in an expansion cohort at the MTD to ensure at least five matched pre- and post-treatment biopsies for biomarkers of PI3K activity.

Phase I trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies.

Background: Heat shock protein (HSP)90 regulates the function of proteins responsible for cell growth and survival, is overexpressed in many cancers and is an attractive therapeutic target. We undertook a phase 1 trial of PF-04929113 (SNX-5422), a novel oral HSP90 inhibitor, to estimate the maximum tolerated dose and describe the pharmacokinetic and toxicity profiles.

Patients And Methods: Patients with relapsed, refractory, hematologic malignancies and adequate organ function were eligible.

Standard Error of Empirical Bayes Estimate in NONMEM® VI.

The pharmacokinetics/pharmacodynamics analysis software NONMEM® output provides model parameter estimates and associated standard errors. However, the standard error of empirical Bayes estimates of inter-subject variability is not available. A simple and direct method for estimating standard error of the empirical Bayes estimates of inter-subject variability using the NONMEM® VI internal matrix POSTV is developed and applied to several pharmacokinetic models using intensively or sparsely sampled data for demonstration and to evaluate performance.

A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas.

Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas.

Methods: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response.

Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors.

The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.

Determination of PF-04928473 in human plasma using liquid chromatography with tandem mass spectrometry.

A simple, rapid and sensitive liquid chromatography/tandem mass spectrometric (LC/MS/MS) analytical method was developed for quantification of Hsp90 inhibitor PF-04928473 in human plasma, following administration of its prodrug, PF-04929113. Sample processing involved protein precipitation by addition of 0.4 mL of methanol containing internal standard (PF-04972487) to 50 μL volume of plasma sample.

Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis.

Purpose: In this pharmacokinetic/pharmacodynamic meta-analysis, we investigated relationships between clinical endpoints and sunitinib exposure in patients with advanced solid tumors, including patients with gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC).

Methods: Pharmacodynamic data were available for 639 patients of whom 443 had pharmacokinetic data. Sunitinib doses ranged from 25 to 150 mg QD or QOD.

A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients.

Purpose: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor. Following administration, sunitinib is metabolized by cytochrome P450 3A4 to an active metabolite (SU12662). The objective of this analysis was to assess sunitinib and SU12662 pharmacokinetics and to identify covariates that might explain variability in exposure following oral administration.