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Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).

Background This review aims to synthesise evidence on the economic impact of psychological interventions and therapies when applied to a broad range of physical health conditions. Methods The following bibliographic databases were searched for relevant articles: MEDLINE (Ovid), EMBASE (Ovid) and PsycINFO (Ebsco). As this review was intended to update an earlier review, the date range for the search was restricted to between January 2012 and September 2018. Reference lists from the review articles were also searched for relevant articles. Study quality was evaluated using the Scottish Intercollegiate Network Guidelines (SIGN) appraisal checklists for both economic studies and Randomised Controlled Trials (RCTs). When the economic analyses did not provide sufficient detail for quality evaluation, the original RCT papers were sought and these were also evaluated. Half of the papers were quality rated by a second author. Initial agreement was high and all disagreements were resolved by discussion. Results This yielded 1408 unique articles, reduced to 134 following screening of the title and abstract. The full texts of the remaining articles were reviewed by at least one team member and all exclusions were discussed and agreed by the team. This left 46 original research articles, alongside five systematic reviews. Fifty-seven per cent of the articles were deemed to be of high quality, with the remainder of acceptable quality. Fifteen different medical conditions were covered, with chronic pain (10 articles) and cancer (9 articles) being the two most investigated health conditions. Three quarters of the papers reviewed showed evidence for the cost-effectiveness of psychological interventions in physical health, with the clearest evidence being in the field of chronic pain and cancer. Conclusions This paper provides a comprehensive integration of the research on the cost-effectiveness of psychological therapies in physical health. Whilst the evidence for cost-effectiveness in chronic pain and cancer is encouraging, some health conditions require further study. Clearly, as the primary research is international, and was therefore conducted across varying health care systems, caution must be exercised when applying the results to counties outside of those covered. Despite this, the results are of potential relevance to service providers and funders.

Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood-brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10-300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9-13.5) and for the breast cancer subgroup was 7.7 mo (2.8-15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3-3.8) and 4.9 mo (4.2-5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.