To evaluate the toxicity, pharmacological and biological properties of ATN-161, a five -amino-acid peptide derived from the synergy region of fibronectin, adult patients with advanced solid tumours were enrolled in eight sequential dose cohorts (0.1 -16 mg kg À1 ), receiving ATN-161 administered as a 10-min infusion thrice weekly. Pharmacokinetic sampling of blood and urine over 7 h was performed on Day 1. Twenty-six patients received from 1 to 14 4-week cycles of treatment. The total number of cycles administered to all patients was 86, without dose-limiting toxicities. At dose levels above 0.5 mg kg À1 , mean total clearance and volume of distribution showed dose-independent pharmacokinetics (PKs). At 8.0 and 16.0 mg kg À1 , clearance of ATN-161 was reduced, suggesting saturable PKs. Dose escalation was halted at 16 mg kg À1 when drug exposure (area under the curve) exceeded that associated with efficacy in animal models. There were no objective responses. Six patients received more than four cycles of treatment (4112 days). Three patients received 10 or more cycles (X280 days). ATN-161 was well tolerated at all dose levels. Approximately, 1/3 of the patients in the study manifested prolonged stable disease. These findings suggest that ATN-161 should be investigated further as an antiangiogenic and antimetastatic cancer agent alone or with chemotherapy.

Aim of the paper:To examine current literature surrounding variables which may affect the initiation and maintenance of breastfeeding.Abstract:

Pfizer, Psioxus, Roche, and EMD Serono  Ben Markman reports reports grants, contracts, consulting fees, participation on a data safety monitoring board, advisory board, educational events, or support for attending meetings and/or travel from Merck, Amgen and Bristol Myers Squibb  Kimberley M. Heinhuis has nothing to disclose  Michael Millward reports grants, contracts, consulting fees, participation on a data safety monitoring board, advisory board, educational events, or support for attending meetings and/or travel from AstraZeneca, Bristol Myers Squibb, MSD, Novartis, Pfizer, Roche, and Takeda  Martijn Lolkema reports s grants, contracts, consulting fees, participation on a data safety monitoring board, advisory board, educational events, or support for attending meetings and/or travel from Amgen, Astellas, AstraZeneca, Bayer, Incyte, Janssen CilagResearch.

Prostate cancer treatments often affect quality of life and problems may present at any point during treatment. Measuring and identifying issues of quality of life (QoL) may create an opportunity for the patient to discuss problems and induce information transfer from health professional to patient and vice versa. Many practitioners already assess QoL in patients with prostate cancer because treatment for the disease can have a dramatic impact on lifestyle. QoL may facilitate a more holistic approach to patient care. Using a QoL assessment tool may promote and enhance the current service provision and aid identification of bothersome side-effects, for example loss of libido, gynaecomastia (i.e. abnormal over-development of the breasts in a man), and hot flushes. The Functional Assessment of Cancer Therapy-Prostate scale (FACT-P) (Cella et al, 1993) is a prostate-specific QoL assessment tool, which can be self-administered and takes little time to complete. This may be a useful tool in the ongoing management of patients with advanced prostate cancer. With the emphasis on quality of service for cancer patients (Department of Health (DH), 2000; DH, 2007a; National Health Service Improvement, 2009), it is paramount that health professionals continually examine practice and the quality of the service delivered. Addressing QoL issues for the patient with cancer should be a priority. This article will outline the significant side-effects that a patient with advanced prostate cancer may sustain and attempts to indicate how QoL assessment tools may contribute to care management and delivery.

Background: Mesothelin, a GPI-anchored cell surface protein, is highly expressed in several tumor types and can be targeted for antibody (ab)-based cancer therapy. BMS-986148 is a fully human IgG1 anti-mesothelin monoclonal ab conjugated to tubulysin to promote selective cytotoxic delivery to tumor cells. In preclinical models, combination of anti–mesothelin-tubulysin with anti–PD-1 promoted a synergistic antitumor response and influx of tumor-infiltrating lymphocytes. Here, we present initial data for BMS-986148 ± nivolumab (NIVO; anti–PD-1) from a phase 1/2a trial in a biomarker-defined population of patients (pts) with select advanced solid tumors (NCT02341625). Methods: During dose escalation (ESC), pts received BMS-986148 0.1 to 1.6 mg/kg IV Q3W, BMS-986148 0.4 or 0.8 mg/kg IV Q1W, or BMS-986148 0.8 mg/kg + NIVO 360 mg IV Q3W. During monotherapy (mono) dose expansion (EXP), pts with mesothelin-selected mesothelioma (ie, H score ≥ 100 for tumor mesothelin expression), non-small cell lung cancer (NSCLC), or ovarian cancer received BMS-986148 1.2 mg/kg mono IV Q3W, and during combination (combo) dose EXP, pts with mesothelin-selected mesothelioma or pancreatic cancer received BMS-986148 0.8 mg/kg + NIVO 360 mg combo IV Q3W. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK) and antitumor activity. Results: As of April 1, 2019, 126 pts have been treated in this trial; 96 pts received BMS-986148 mono (Q3W, n = 84; Q1W, n = 12), and 30 pts received BMS-986148 + NIVO combo. PK analysis in pts treated during ESC demonstrated that total antibody and active ADC exposures increased in a dose-proportional manner. Unconjugated tubulysin concentrations were low but sustained over the dosing interval. The maximum tolerated dose (MTD) for mono was 1.2 mg/kg Q3W, and the 0.8 mg/kg dose was determined to be tolerable for the combo. Across all cohorts, any-grade and grade 3/4 treatment-related AEs (TRAEs) were reported in 87% and 44% of all pts, respectively. Overall, the most common TRAEs (any grade; grade 3-4) reported in ≥ 15% of pts were AST increased (43%; 17%), ALT increased (41%; 16%), fatigue (37%; 5%), nausea (29%; 0%), decreased appetite (22%; 1%), and blood alkaline phosphatase increased (18%; 4%). The frequency of TRAEs and dose-limiting toxicities related to liver function tests increased with increasing dose of BMS-986148. Most TRAEs resolved with dose interruption, dose reduction, or treatment discontinuation. Serious TRAEs were reported in 18% of pts with mono and 23% of pts with combo. Fifteen percent of pts discontinued due to TRAEs, and 1 pt died due to a TRAE (pneumonitis; 1.2 mg/kg Q3W mono). The ORR was 6% (0 CR, 3 PR) with mono in EXP and 20% (0 CR, 6 PR) with the combo in ESC and EXP. Among pts with mesothelioma, the ORR was 4% with mono in EXP and 31% with combo in ESC and EXP. Among pts with ovarian carcinoma, the ORR was 9% with mono in EXP. Of note, durable responses lasting up to ≈ 20 mo in pts with ovarian cancer with mono and ≈ 9 mo in pts with mesothelioma with mono and combo were observed. Conclusions: BMS-986148 ± NIVO was tolerable and demonstrated a clinically manageable safety profile. Preliminary clinical activity was observed with BMS-986148 ± NIVO in select patient populations, including pts with mesothelioma. Citation Format: Jeffrey Clarke, Siu-Chung Chu, Lillian L Siu, Jean-Pascal Machiels, Benjamin Markman, Kimberley Heinhuis, Michael Millward, Martijn Lolkema, Sandip Pravin Patel, Paul de Souza, Giuseppe Curigliano, Armando Santoro, Michelle Brown, Ronald Fleming, Heather Vezina, Chunsheng He, Sylvie Rottey. BMS-986148, an anti-mesothelin antibody-drug conjugate (ADC), alone or in combination with nivolumab demonstrates clinical activity in patients with select advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B057. doi:10.1158/1535-7163.TARG-19-B057