Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein.

Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The mFc-mIL-10 EC for the IL-18 induction was estimated to be 2.

Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO-Friends of Cancer Research Joint Research Statement.

Purpose: Restrictive clinical trial eligibility criteria (EC) limit the number of patients who can enroll and potentially benefit from protocol-driven, investigational treatment plans and reduce the generalizability of trial results to the broader population. Following publication of expert stakeholder recommendations for broadening EC in 2017, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research () convened working groups to produce additional recommendations and analyze the potential impact on clinical trials using real-world data.

Experimental Design: Multistakeholder working groups were appointed by an ASCO- leadership group to propose recommendations for more inclusive EC related to: washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status.

The effect of sonidegib (LDE225) on the pharmacokinetics of bupropion and warfarin in patients with advanced solid tumours.

Aims: We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6).

Methods: This was a multicentre, open-label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15-mg dose on Day 1 of the run-in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration.

Correction to: A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer.

An amendment to this paper has been published and can be accessed via the original article.

A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer.

Background: Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice.

Evaluation of pharmacokinetics and safety of cetuximab with cisplatin/carboplatin in patients with advanced solid tumor: Result from phase II studies.

The pharmacokinetics and potential drug-drug interactions between cetuximab and cisplatin or carboplatin from two studies (JXBA and JXBB) were evaluated. These studies were multicenter, open-label phase II trials designed to evaluate the drug-drug interactions between cetuximab (400 mg m initial dose) and cisplatin (JXBA; 100 mg m) or carboplatin (JXBB; area under the curve [AUC] = 5 mg × min mL) with or without 5-fluorouracil (5FU) in patients with advanced solid tumors. Concentrations of cetuximab, cisplatin and carboplatin were determined using analytical methods.

A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib Plus Dexamethasone in Relapsed Multiple Myeloma.

Purpose: Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12.

Patients And Methods: This phase Ib/II study aimed to determine the safety and tolerability of ulocuplumab alone and in combination with lenalidomide and dexamethasone (Arm A), or bortezomib and dexamethasone (Arm B), in patients with relapsed/refractory multiple myeloma.

Results: Forty-six patients were evaluated (median age, 60 years; range, 53-67).

Assessing an ASCO Decision Aid for Improving the Accuracy and Attribution of Serious Adverse Event Reporting From Investigators to Sponsors.

Purpose: Investigators often send reports to sponsors that incorrectly categorize adverse event (AE)s as serious or attribute AEs to investigational drugs. Such errors can contribute to high volumes of uninformative investigational new drug safety reports that sponsors submit to the US Food and Drug Administration and participating investigators, which strain resources and impede the detection of valid safety signals. To improve the quality of serious AE (SAE) reporting by physician-investigators and research staff, ASCO developed and tested a Decision Aid.

Drug screening to target nuclear orphan receptor NR4A2 for cancer therapeutics.

Background: Our previous study suggested NR4A2, a subfamily member of orphan nuclear receptors, is essential for survival of human cancer cells such as mucoepidermoid carcinoma (MEC).

Methods: We conducted high throughput drug screening for NR4A2 inhibitors as a novel therapeutic modality. Positive screening was performed using a luciferase reporter vector containing NR4A2 binding sequence, and a CRE-reporter control vector was used to eliminate false positives.

Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer.

Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974).

Clinical Trial Electronic Portals for Expedited Safety Reporting: Recommendations from the Clinical Trials Transformation Initiative Investigational New Drug Safety Advancement Project.

Background: Use of electronic clinical trial portals has increased in recent years to assist with sponsor-investigator communication, safety reporting, and clinical trial management. Electronic portals can help reduce time and costs associated with processing paperwork and add security measures; however, there is a lack of information on clinical trial investigative staff's perceived challenges and benefits of using portals.

Objective: The Clinical Trials Transformation Initiative (CTTI) sought to (1) identify challenges to investigator receipt and management of investigational new drug (IND) safety reports at oncologic investigative sites and coordinating centers and (2) facilitate adoption of best practices for communicating and managing IND safety reports using electronic portals.

Sponsors' and investigative staffs' perceptions of the current investigational new drug safety reporting process in oncology trials.

Background/aims: The Food and Drug Administration's final rule on investigational new drug application safety reporting, effective from 28 March 2011, clarified the reporting requirements for serious and unexpected suspected adverse reactions occurring in clinical trials. The Clinical Trials Transformation Initiative released recommendations in 2013 to assist implementation of the final rule; however, anecdotal reports and data from a Food and Drug Administration audit indicated that a majority of reports being submitted were still uninformative and did not result in actionable changes. Clinical Trials Transformation Initiative investigated remaining barriers and potential solutions to full implementation of the final rule by polling and interviewing investigators, clinical research staff, and sponsors.

Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment.

Aim: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations.

Methods: Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.

Systematic analysis of design and stratification for phase III trials in first-line advanced non-small cell lung cancer.

Background: A recent study reviewed phase III trials of first-line advanced non-small cell lung cancer (NSCLC) conducted from 1981 to 2010, and provided trends in the study outcome. However, such trials have never been analyzed in detail for design and stratification factors.

Methods: Phase III studies of systemic treatment for first-line advanced or metastatic NSCLC published in English literature between 1981 and 2010 were identified.

Primary lung mucoepidermoid carcinoma: analysis of prognostic factors using surveillance, epidemiology and end results program.

Introduction: Mucoepidermoid carcinoma (MEC) primarily occurs in salivary glands, but can also arise in other organs; however, the impact of primary location on patient prognosis is largely unknown.

Methods: Using Surveillance, Epidemiology and End Results Program (SEER) data we investigated whether the clinical and prognostic features of MEC differed among multiple organ sites. The SEER-18 dataset from 18 cancer registries in the US between 1972 and 2012 was chosen.

Infrequent chemoradiation-induced acute esophagitis in the Asian population: A meta-analysis of published clinical trials for unresectable stage III non-small cell lung cancer.

Severe (grade 3 or higher) esophagitis is one of the major toxicities for chemoradiation in the treatment of stage III non-small cell lung cancer (NSCLC). The difference among ethnic groups has never been investigated in detail. Prospective trials with concurrent platinum-containing chemoradiation in unresectable disease were investigated, and a total of 116 treatment arms with 7520 patients were identified.

Extracellular Membrane Vesicles Derived from 143B Osteosarcoma Cells Contain Pro-Osteoclastogenic Cargo: A Novel Communication Mechanism in Osteosarcoma Bone Microenvironment.

The bone microenvironment (BME) is the main hub of all skeletal related pathological events in osteosarcoma leading to tumor induced bone destruction, and decreasing overall bone quality and bone strength. The role of extra-cellular membrane vesicles (EMVs) as mediators of intercellular communication in modulating osteosarcoma-BME is unknown, and needs to be investigated. It is our hypothesis that osteosarcoma-EMVs contain pro-osteoclastogenic cargo which increases osteoclastic activity, and dysregulated bone remodeling in the osteosarcoma-BME.

Phase I and pharmacokinetic study of AI-850, a novel microparticle hydrophobic drug delivery system for paclitaxel.

Purpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a <30-min i.v.