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, K
(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.
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.
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).
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, K
, 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).
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, K
, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundMalignant bowel obstruction (MBO) is a common cause of morbidity and mortality in women diagnosed with ovarian cancer. Earlier detection of MBO may improve patient outcomes. There are ...currently no screening tools to assist detection.AimWe report a screening questionnaire that can be used to detect MBO, and how the severity score for key clinical symptoms correlate with radiological evidence of MBO from ovarian cancer.DesignA case–control study in which patients with relapsed, metastatic ovarian cancer were asked to answer 10 questions related to key clinical symptoms associated with intestinal obstruction. The study group included women with CT-confirmed MBO, whereas the control group had no evidence of MBO. Patients scored each question according to severity from 1 (least severe) to 5 (most severe).Setting/participantsBetween 1 June and 31 December 2016, 37 women completed the screening questionnaire.ResultsPatients in the study group (n=17) reported significantly higher (ie, more severe) scores for abdominal pain, nausea, vomiting and constipation. In contrast, differences in severity scores between groups did not differ significantly in response to questions regarding abdominal swelling, borborygmi, diarrhoea or loss of appetite. All patients in the study group more frequently stated that their symptoms had deteriorated within the 2 months prior to completing the questionnaire.ConclusionHere we report the key clinical symptoms associated with radiologically-confirmed MBO in relapsed, metastatic ovarian cancer. We recommend healthcare practitioners focus on these specific symptoms during patient consultations in order to improve risk stratification of MBO.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.
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.
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.
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background: Integrins promote cell survival, metastasis, and angiogenesis, with integrins ανβ3 and ανβ5 promoting neovascularization. Abituzumab (EMD 525797) is a humanized monoclonal IgG2 ...antibody that specifically binds to the αν integrin subunit to inhibit αν integrin-mediated functions. It has shown antitumor activity in preclinical models and clinical trials. We investigated the tolerability and potential anti-angiogenic activity of abituzumab using DCE-MRI.
Methods: This phase I study recruited patients (pts) ≥18 years with liver metastases (3-10 cm in diameter) of either colorectal (CRC) or ovarian cancer (OC) who had failed standard therapy. Pts received abituzumab 250, 500, 1,000, or 1,500 mg IV q2w, with ≥6 pts per dose. The decision to escalate the dose was based on the occurrence of dose-limiting toxicity (DLT). DCE-MRI scans were performed 24 and 96 hours after the first abituzumab dose, 1 week after first dose, and immediately prior to the second dose to identify changes in parameters including Ktrans, extracellular/extravascular volume, and blood plasma volume during one cycle of therapy. DCE-MRI scan data were analyzed centrally. Tumor response was evaluated every 6 weeks. Primary objectives were to assess the tolerability of abituzumab and to investigate vascular and volumetric responses to abituzumab using DCE-MRI. Secondary objectives included characterization of the pharmacokinetics of abituzumab and its effect on exploratory pharmacodynamic markers, including tumor markers.
Results: 41 pts were enrolled (CRC, n = 30; OC, n = 11). All pts had received ≥1 prior anticancer treatment. Four of 31 pts included in the dose-escalation analysis set had DLTs: myocardial ischemia (250 mg, n = 1/6), intracranial hemorrhage (500 mg, n = 1/12), and drug hypersensitivity (1,500 mg, n = 2/7). With the exception of drug hypersensitivity, the nature and incidence of adverse events (AEs) were similar between the dose levels. The most frequently reported treatment-related AEs were fatigue (12.2%) and headache (12.2%). Of 32 patients with available response information, 3 with OC had a best overall response of stable disease (SD) lasting ≥6 weeks (2 treated with abituzumab 500 mg, 1 with abituzumab 1,000 mg); one 73-year-old pt with high-grade serous OC who received abituzumab as 5th-line therapy had SD for 33 weeks and a CA-125 response. No complete or partial responses were observed. No trends in differences in mean DCE-MRI parameters between abituzumab doses and no vascular or volumetric responses to abituzumab were observed, although alterations in DCE-MRI parameters were noted in individual patients. Small changes in IAUC60, Ktrans, and blood plasma volume were observed between Week 1 Day 5 and Week 2 Day 1 that may have been due to abituzumab-induced effects, but did not correlate with clinical activity (SD).
Conclusions: This phase I trial has confirmed the tolerability of abituzumab, although hypersensitivity reactions represent a new event that warrants further investigation. The occurrence of SD in pts with OC with large liver metastases suggests that abituzumab has activity. However, there was little evidence of a clear effect of abituzumab on tumor vasculature, suggesting limited dependence on neovascularization in advanced tumors.
Citation Format: Josep Tabernero, Geoffrey Parker, Andrew Clamp, Elena Elez, Nerissa Mescallado, Rodrigo Dienstmann, Tamara Sauri, Jurjees Hasan, Jose J. Mateos, Rolf Bruns, Claude Gimmi, Gordon C. Jayson. Investigation of the anti-angiogenic effects of abituzumab in patients with colorectal or ovarian cancer and liver metastases using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C119.
Advanced-stage, platinum-resistant, ovarian cancer can be treated with dose-intense chemotherapy; one such regimen includes intravenous cisplatin and oral etoposide. To minimize the toxicity ...associated with weekly cisplatin, pretreatment and posttreatment hydration is required, often necessitating inpatient, overnight admission. We report a shorter, within-day regimen for delivering weekly cisplatin.
This was a retrospective study to assess the use of standard (inpatient; treatment time of 12 hours) versus modified (outpatient; treatment time of 4 hours) regimens. The primary outcome included all-grade and grade 3/4 adverse events. Secondary outcomes included clinical benefit response and, median progression-free survival and overall survival.
Between January 2012 and December 2014, 66 women with metastatic ovarian cancer received dose-intense weekly cisplatin and oral etoposide (n = 45 standard, n = 21 modified). The commonest all-grade adverse events were anemia (96% vs 90%, standard and modified, respectively), fatigue (73% vs 67%), neutropenia (71% vs 76%), hypocalcemia (51% vs 43%), and thrombocytopenia (49% vs 57%). There were no statistically significant differences in the incidence or grades of adverse events. The clinical benefit response was 53% in the standard group and 62% in the modified group (P = 0.9). The median progression-free survival was 4.2 and 6.5 months (incidence rate ratio, 1.22; 95% confidence interval, 0.71-2.15; P = 0.29), and median overall survival was 6.6 and 8.4 months (incidence rate ratio, 1.83; 95% confidence interval, 1.04-3.35; P = 0.03), in favor of the modified regimen.
Our shorter, within-day regimen for delivering dose-intense weekly cisplatin and oral etoposide to treat platinum-resistant metastatic ovarian cancer is safe and efficacious.
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Background: VEGF inhibitor (VEGFi) use is compromised by lack of predictive/ response biomarkers. Previously, we identified plasma Tie2 (pTie2) as a vascular response biomarker ...(VRB) for bevacizumab (bev) in ovarian cancer (OC). Here, we applied dynamic contrast-enhanced MRI (DCE-MRI) and circulating biomarkers in colorectal cancer (CRC), to validate pTie2 as the first tumor VRB. Methods: Seventy patients were recruited, with untreated, mCRC and ≥1 lesion of 3-10cm diameter for DCE-MRI. Patients received bev 10mg/kg for 2 weeks to elicit a biomarker response and then FOLFOX6/bev until progressive disease (PD) Thirteen circulating and 6 imaging biomarkers were measured before and during treatment and at PD. Unsupervised correlation analysis identified bev-induced biomarker correlations. Biomarkers were evaluated by clustered parameter-time course studies to determine their epithelial or vascular origin. Clinical significance was determined by relating the biomarker data to tumor 3D volumetric change assessed by MRI and PFS. The emergent vascular biomarker signal was modelled with epithelial biomarkers to assess the independent contribution of the vascular compartment to PD. Results: Bev induced significant correlations between pTie2, Ang2 and K
trans
. Cluster analysis of Tie2 concentration-time course curves showed that pTie2 reflected tumor K
trans
but not CK18, an epithelial antigen, i.e. changes in pTie2 reflected tumor vascular biology Patients who had the greatest area under the pTie2-time curve had tumors with high K
trans
and/or low pVEGFR2, pre-treatment. They also had the greatest reduction in tumor volume and longest PFS. Fusion of pTie2 and CK18 data significantly improved modelling of PD. Conclusions: Bev impacts tumor vasculature causing proportional changes in pTie2. Information from pTie2 adds clinical value to that derived from the epithelial compartment. Thus (i) pTie2 is the first vascular response biomarker for bev and probably all VEGFi and (ii) demonstration of separate vascular and epithelial compartments in ovarian and CRC validates the vascular compartment as a target. This work identifies the first assay that could optimise use of VEGFi. Clinical trial information: 2009-011377-33.
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