Efficacy and Safety of PF-07038124 in Patients With Atopic Dermatitis and Plaque Psoriasis: A Randomized Clinical Trial.

Importance: Atopic dermatitis (AD) and plaque psoriasis are inflammatory skin diseases with unmet need for effective topical treatments with few application site reactions.

Objective: To assess the efficacy and safety of the topical phosphodiesterase 4 inhibitor PF-07038124 in patients with AD and plaque psoriasis.

Design, Setting, And Participants: This phase 2a, randomized, double-blind clinical trial was conducted from December 21, 2020, to August 18, 2021, at 34 sites across 4 countries.

Efficacy and safety of topical brepocitinib cream for mild-to-moderate chronic plaque psoriasis: a phase IIb randomized double-blind vehicle-controlled parallel-group study.

Background: Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways.

Objectives: To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO.

Methods: This phase IIb multicentre randomized double-blind study was conducted in two stages.

A phase Ib dose escalation study of oral monotherapy with KX2-391 in elderly patients with acute myeloid leukemia.

Poor tolerance to standard therapies and multi-drug resistance complicate treatment of elderly patients with acute myeloid leukemia (AML). It is therefore imperative to explore novel tolerable agents and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization.

Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells.

The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in vivo experiments were performed with low and high doses of sorafenib using human T cells and spontaneous developed woodchuck HCC models.

A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib With Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients.

Objectives: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies.

Materials And Methods: Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8, capecitabine 1300 mg/m² oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle.

A phase 1, open-label, dose escalation study of intravenous paricalcitol in combination with gemcitabine in patients with advanced malignancies.

Background: Calcitriol, the active analogue of vitamin D, is antiproliferative and enhances the cytotoxicity of several anticancer agents, including gemcitabine. The vitamin D receptor (VDR) is expressed in the tumor stroma and treatment with VDR ligands results in stromal remodeling and increased intratumoral gemcitabine delivery. Furthermore, calcitriol can decrease the activity of the gemcitabine deactivating enzyme cytidine deaminase (CDD).

Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361).

The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy.

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study.

To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI). Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2* signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve.

Development and verification of a pharmacokinetic model to optimize physiologic replacement of rhIGF-1/rhIGFBP-3 in preterm infants.

Background: rhIGF-1/rhIGFBP-3 is being investigated for prevention of retinopathy of prematurity in extremely preterm infants.

Methods: A population pharmacokinetic model was developed using data from phase I/II (Sections A-C) trials of rhIGF-1/rhIGFBP-3 and additional studies in preterm infants to predict optimal dosing to establish/maintain serum IGF-1 within physiological intrauterine levels. In Section D of the phase II study, infants (gestational age (GA) (wk+d) 23+0 to 27+6) were randomized to rhIGF-1/rhIGFBP-3, administered at the model-predicted dose of 250 µg/kg/d continuous i.

Efficacy, Safety, and Potential Biomarkers of Sunitinib and Transarterial Chemoembolization (TACE) Combination in Advanced Hepatocellular Carcinoma (HCC): Phase II Trial.

Objectives: To evaluate the safety/efficacy and explore biomarkers for a rationally designed combination of sunitinib and transarterial chemoembolization (TACE) in a prospective phase 2 study of advanced hepatocellular carcinoma (HCC).

Methods: Inoperable HCC patients with Child-Pugh A disease received 37.5 mg sunitinib from days 1 to 7 followed by TACE on day 8.

Tumor priming by Apo2L/TRAIL reduces interstitial fluid pressure and enhances efficacy of liposomal gemcitabine in a patient derived xenograft tumor model.

Interstitial fluid pressure (IFP) is elevated in tumors and high IFP, a negative cancer prognosticator, is known to limit the uptake and efficacy of anti-tumor therapeutics. Approaches that alter the tumor microenvironment and enhance uptake of therapeutics are collectively referred to as tumor "priming". Here we show that the cytotoxic biological therapy Apo2L/TRAIL can prime the tumor microenvironment and significantly lower IFP in three different human tumor xenograft models (Colo205, MiaPaca-2 and a patient gastrointestinal adenocarcinoma tumor xenograft).

Phase 1b study of the oral gemcitabine 'Pro-drug' LY2334737 in combination with capecitabine in patients with advanced solid tumors.

Background This Phase 1b study aimed to determine the recommended Phase 2 dose of LY2334737, an oral pro-drug of gemcitabine, in combination with capecitabine, an oral pro-drug of 5-fluorouracil, in patients with advanced solid tumors. In addition, pharmacokinetics (PK) and tumor response were evaluated. Patients and methods Patients with advanced/metastatic solid tumors received 650 mg/m(2) capecitabine twice daily (BID) and escalating doses of LY2334737 once daily (QD; initial dose 10 mg/day), both for 14 days followed by 7-day drug holiday.

Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients.

Background And Objectives: No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus

Methods: The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed.

Pharmacokinetic analysis of the FAK scaffold inhibitor C4 in dogs.

Inhibition of focal adhesion kinase-vascular endothelial growth factor receptor 3 complex by C4 was previously shown to reduce tumor growth alone and synergistically with other chemotherapeutic agents in animal tumor models. Single and multiple dose IV and oral dosing studies were performed in dogs to determine C4 pharmacokinetics. C4 was administered to 4 dogs at 1.

A phase I study of the histone deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors.

Based on preclinical data demonstrating cytotoxic synergy between sorafenib and entinostat, a phase I study of this combination was conducted in patients with advanced solid tumors. Enrollment followed the traditional "3 + 3" dose escalation scheme. Entinostat was given orally once every 2 weeks, starting at a dose of 4 mg and escalating to 6 and 10 mg every 2 weeks.

Sequential use of the androgen synthesis inhibitors ketoconazole and abiraterone acetate in castration-resistant prostate cancer and the predictive value of circulating androgens.

Purpose: Patients previously treated with ketoconazole were excluded from phase III trials of abiraterone acetate due to potential overlapping mechanism of action. The purpose of this study was to determine the clinical utility of abiraterone and its impact on circulating androgens following ketoconazole.

Experimental Design: Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and prior ketoconazole therapy ≥28 days received abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily.

Androgenic biomarker prof|ling in human matrices and cell culture samples using high throughput, electrospray tandem mass spectrometry.

Unlabelled: BACKGROUND. A high throughput, high pressure liquid chromatographic (HPLC) method with triple quadrupole mass spectral detection (LC/MS/MS) was validated for the measurement of 5 endogenous androgens in human plasma and serum and applied to various in vivo and in vitro study samples to pursue a better understanding of the interrelationship of the androgen axis, intracrine metabolism, and castration-recurrent prostate cancer (CaP).

Methods: A Shimadzu HPLC system interfaced with a Sciex QTRAP 5500 mass spectrometer with electrospray ionization was used with in line column-switching.

A pilot study comparing the effect of flaxseed, aromatase inhibitor, and the combination on breast tumor biomarkers.

Use of complementary approaches is common among breast cancer survivors. Potential interactions between aromatase inhibitors (AI) and high phytoestrogen foods, such as flaxseed (FS), are not often described. We conducted a pilot 2 × 2 factorial, randomized intervention study between tumor biopsy and resection, in 24 postmenopausal women with estrogen receptor positive (ER+) breast cancer, to assess the effects of FS and anastrozole, and possible interactions between them, on serum steroid hormone and tumor-related characteristics associated with long-term survival (Roswell Park Cancer Institute, 2007-2010).

Carboplatin pharmacokinetics in a patient receiving hemodialysis.

With refinements and advances in hemodialysis techniques, survival for patients with end-stage renal disease has improved significantly. To our knowledge, however, no prospective trials have been performed in patients receiving hemodialysis who are also diagnosed with cancer and are candidates for chemotherapy. We describe a 73-year-old man who was diagnosed with high-grade neuroendocrine carcinoma, metastatic to the bone and lymph nodes, and was undergoing hemodialysis.

Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data.

The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed.

Development of a preclinical PK/PD model to assess antitumor response of a sequential aflibercept and doxorubicin-dosing strategy in acute myeloid leukemia.

Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.

Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice.

Purpose: Molecular targeting of cellular signaling pathways is a promising approach in cancer therapy, but often fails to achieve sustained benefit because of the activation of collateral cancer cell survival and proliferation pathways. We tested the hypothesis that a combination of targeted agents that inhibit compensatory pathways would be more effective than single agents in controlling pancreatic cancer cell growth. We investigated whether everolimus, an mTOR inhibitor, and sorafenib, a multi-kinase inhibitor, would together inhibit growth of low-passage, patient-derived pancreatic cancer xenografts in mice more efficaciously than either agent alone.

Physiologically based pharmacokinetic models for everolimus and sorafenib in mice.

Purpose: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions.

A phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies.

Background: Src kinase is central to tumor cell proliferation, apoptosis, and metastasis. KX2-391 is a synthetic, orally bioavailable small molecule inhibitor of Src tyrosine kinase (TK) signaling and tubulin polymerization. This compound is distinct from other Src kinase inhibitors by targeting the peptide substrate rather than the ATP binding site; the binding site on hetero-dimeric tubulin is novel and distinct from the taxanes and other known tubulin inhibitors.