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Background: We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.Methods: We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours.Results: Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10-300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1-2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3-18) weeks. Four of 18 evaluable patients (22%) had stable disease.Conclusions: Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers. [ABSTRACT FROM AUTHOR]

Objective: The optimum sequencing of adjuvant treatment in patients with high-risk endometrial cancer remains contentious. Here, we report the outcomes of women treated in Manchester, United Kingdom, where sequential chemotherapy-radiotherapy is the standard adjuvant treatment approach for these patients. Methods: A retrospective analysis was carried out on 106 consecutive patients referred for adjuvant treatment of high-risk endometrial cancer in 2014 and 2015. High-risk endometrial cancer was defined as: International Federation of Gynaecology and Obstetrics (2009) stage I grade 3 endometrioid carcinoma with deep myometrial invasion and/or lymphovascular space invasion, stage II-III endometrioid carcinoma, or any other histological subtype with stage I-III disease. Adjuvant treatment included carboplatin (AUC5) and paclitaxel (175 mg/m2) every 21 days for 4/6 cycles, followed by external beam pelvic radiotherapy (40 Gy in 20 fractions#) or vaginal brachytherapy (28 Gy in 2 fractions#) or both. Primary outcome measures were recurrence free survival (RFS), overall survival (OS) and treatment-related toxicity. Results: Seventy-nine percent of patients were treated with sequential chemotherapy-radiotherapy. After a median follow-up of 64.4 months, 5-year RFS was 70% (95% CI 60.8-80.6%) and 5-year OS was 71.4% (95% CI 62.3-81.7%). Single modality adjuvant therapy was given for patient choice or contra-indications to treatment. Patients tolerated sequential treatment well; 96% of patients completed all treatment and 20% of patients had=grade 3 adverse events. Conclusions: Sequential chemotherapy-radiotherapy as adjuvant treatment for high-risk endometrial cancer was tolerable and was associated with survival outcomes consistent with recent international phase III clinical trials. [ABSTRACT FROM AUTHOR]

Background: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers.Methods: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS).Results: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025).Conclusions: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents. [ABSTRACT FROM AUTHOR]

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:−0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi. Identification of response biomarkers is a key step towards the development of personalised care. Here, Jayson et al. identify plasma Tie2 as a biomarker for the response of the tumor vasculature to anti-angiogenics in patients with metastatic colorectal cancer, suggesting that monitoring Tie2 levels may help guide therapy in the clinics. [ABSTRACT FROM AUTHOR]