Infusion Of Bevacizumab Research Articles

Reflections on the changes in ascites and serum VEGF1 levels before and after intraperitoneal infusion of bevacizumab.

e17539 Background: This study analyzes the levels of VEGF1 in ascites and serum before and after intraperitoneal infusion of bevacizumab, aiming to explore the optimal administration route for treating recurrent ovarian cancer accompanied by ascites. Methods: Sixty-seven patients with advanced recurrent ovarian cancer and significant ascites were treated with intraperitoneal infusion of bevacizumab combined with chemotherapy. Under ultrasound guidance, a peritoneal drainage tube was placed, and the volume of ascites was measured before the infusion. The effects of the treatment were assessed by measuring the ascites volume during the 2nd to 3rd treatment (final ascites drainage) and by analyzing and comparing the levels of Vascular Endothelial Growth Factor 1 (VEGF1) in both ascites and serum. Results: The average volumes of ascites before and after treatment were 4229.97 ml and 5.42 ml, respectively (P<0.0001), with an overall response rate (ORR) of 89.6% (60/67). Before and after treatment, the levels of VEGF1 in ascites were 283.86 pg/mL and 18.76 pg/mL, respectively (P<0.0001). Before and after treatment, serum levels of VEGF1 were 80.67 pg/mL and 61.25 pg/mL, respectively (P<0.0001). Before treatment, the level of VEGF1 in ascites at 283.86 pg/mL was significantly higher than in serum, which was 80.67 pg/mL (P<0.0001). The reduction in VEGF1 levels following intraperitoneal infusion was over tenfold greater in serum compared to ascites. When the cutoff value for VEGF1 in ascites was set at 37.12 pg/mL, the sensitivity was 80.28%, and the specificity was 91.55%. Conclusions: The combined treatment of intraperitoneal infusion of bevacizumab with chemotherapy is an effective strategy for controlling ascites in recurrent ovarian cancer. Keywords: Bevacizumab, Intraperitoneal Infusion, Recurrent Ovarian Cancer, Ascites, Vascular Endothelial Growth Factor 1 (VEGF1).

Unleashing the potential: transarterial chemoembolization combined with intra-arterial infusion of bevacizumab for unresectable hepatocellular carcinoma.

The purpose of this study is to compare the efficacy and safety of transarterial chemoembolization (TACE) alone with transarterial chemoembolization combined with the arterial infusion of bevacizumab (TACE + Bev) in patients with unresectable hepatocellular carcinoma (uHCC). A retrospective analysis was conducted on 446 uHCC patients treated with TACE or TACE + Bev between January 2021 and March 2023. The study evaluated objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events in both treatment groups. Finally, the TACE group comprised 295 patients, and the TACE + Bev group comprised 151 patients. Patients in the TACE + Bev group exhibited significantly prolonged median PFS (7.9months vs. 10.3months, P = 0.013) and median OS (16.1months vs. 21.4months, P = 0.041), improved ORR (26.8% vs. 37.7%, P = 0.017) and DCR (71.5% vs. 80.8%, P = 0.033) compared to the TACE group. Multifactorial Cox analysis identified alpha-fetoprotein (AFP) > 400ng/ml as an independent prognostic factor for PFS and OS. Meanwhile, portal vein cancer thrombosis and distant metastasis are poor prognostic factors for OS. The overall incidence of adverse events was similar between the two groups. In comparison with the TACE group, the TACE + Bev group demonstrated efficacy in improving outcomes for patients with uHCC with a manageable safety profile.

Incidence of port site complications in relation to timing of bevacizumab infusion.

Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor, with a serious complication of wound healing complications. The package insert currently does not have recommendations on the management of bevacizumab administration around minor procedures, including port placements. Currently, there are only two trials that have examined the optimal timing of bevacizumab after port placement. This is a single-center retrospective trial aiming to evaluate the rate of wound dehiscence and other port site complications depending on the time between port placement and bevacizumab infusion. Eligible patients who have had at least one port place and have received bevacizumab for an oncologic indication were identified in a study period of 1/1/2016-3/31/2021. The primary outcome of this study was the incidence of wound dehiscence in relation to the timing of bevacizumab infusion. A total of 243 patients met the inclusion criteria, and 116 port placements had a port site complication. For wound dehiscence, 6% was observed 0 days from port placement, 10% was observed 1 day from port placement, 0% was observed 2 days from port placement, 0% was observed 3-7 days from port placement, 3% was observed 8-14 days from port placement, and 3% was observed 15-30 days from port placement. The results of this study show an inverse relationship between the risk of wound dehiscence and port site complication and the timing of bevacizumab infusion to port placement, with an increase in absolute risk of wound dehiscence when bevacizumab is given within 2 days of port placement.

Efficacy of bevacizumab through an indwelling pleural catheter in non-small cell lung cancer patients with symptomatic malignant pleural effusion

BackgroundSeveral studies have indicated that intrapleural infusion of bevacizumab is an effective treatment for non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE). However, the impact of bevacizumab administered through an indwelling pleural catheter (IPC) on the prognosis of these patients is unknown.MethodsConsecutive advanced NSCLC patients with symptomatic MPE receiving an IPC alone or bevacizumab through an IPC were identified in a tertiary hospital. The patient characteristics and clinical outcomes were collected.ResultsA total of 149 patients were included, and the median age was 60.3 years. Males and nonsmokers accounted for 48.3% and 65.8%, respectively. A total of 69.8% (104/149) of patients harbored actionable mutations, including 92 EGFR-activating mutations, 11 ALK fusions, and 1 ROS1 fusion. A total of 81.9% (122/149) of patients received IPC alone, and 18.1% (27/149) received bevacizumab through an IPC. The incidence of spontaneous pleurodesis during the first 6 months was greater in the bevacizumab-treated group than in the IPC-treated group in the subgroup with actionable mutations (64.3% vs. 46.9%, P = 0.28). The median overall survival (OS) in patients with actionable mutations treated with bevacizumab through an IPC was 42.2 months, which was significantly longer than the 26.7 months in patients who received an IPC alone (P = 0.045). However, the median OS did not differ between the two arms in the subgroup without actionable mutations (10.8 vs. 41.0 months, P = 0.24). No significant difference between the bevacizumab through an IPC group and the IPC group was detected in the number of participants who had adverse events, either in patients with actionable mutations (14.3% vs. 8.4%; P = 0.42) or in patients without actionable mutations (16.7% vs. 12.8%; P = 1.00).ConclusionsBevacizumab through an IPC resulted in a significantly improved prognosis for NSCLC patients with MPE and actionable mutations. However, patients without actionable mutations do not benefit from bevacizumab through IPC.

IMMU-32. CAN PEMBROLIZUMAB TREAT RECURRENT GLIOBLASTOMA AND REVERSE HIV LATENCY?

Abstract Immunotherapy revolutionized treatment for many solid tumors. Early studies show that immunotherapy may be effective for recurrent glioblastoma. The ongoing Phase 2 LEEP-005 clinical trial (pembrolizumab+lenvima) is currently enrolling glioblastoma patients, but excludes patients with HIV. However, there is a strong need to treat this special patient population. One of the barriers to achieving cure in HIV patients is HIV latency within infect CD4+ T cells. Recently published data suggests that pembrolizumab can reverse HIV latency by forcing the HIV out of intracellular hiding into the plasma where anti-retroviral therapy can be effective. We present a case of a 39 year-old male with HIV and a Left Parietal Glioblastoma who had progressive disease following a subtotal resection and radiation alone due persistent neutropenia. Post-radiation MR brain wwo showed progressive disease in the left parietal lobe and new dural-based lesions in the left frontal and temporal lobes. HIV viral load was < 20 and CD4 count was 406 on HAART. The patient declined lenvima, but was amenable to bevacizumab. At 1 month follow-up, after 1 infusion of pembrolizumab 200mg and 2 infusions of bevacizumab, he achieved CR in the original site of disease and stable disease in the left frontal and temporal lobes. HIV viral load was 52. CD4 count was 660. Though it is too early to draw any firm conclusions, in our patient, pembrolizumab appears to induce HIV reversal, which is supported by an increase in the increase in his HIV viral load. The combination of pembrolizumab and bevacizumab appears to be effective at short-term follow-up. Our study is significant because there is limited evidence on the use of PD-L1 inhibitors in active HIV patients with cancer. To our knowledge, our case is the first reported case of the use of pembrolizumab in a patient with HIV and glioblastoma.

CTNI-62. INTERIM DATA ON DUAL INHIBITION OF POST-RADIOGENIC ANGIO-VASCULOGENESIS BY OLAPTESED PEGOL (NOX-A12) AND BEVACIZUMAB IN GLIOBLASTOMA FROM THE FIRST EXPANSION ARM OF THE PHASE 1/2 GLORIA TRIAL

Abstract BACKGROUND We recently reported favorable safety and preliminary efficacy signals for treatment with radiotherapy (RT), the CXCL12 neutralizing L-RNA aptamer olaptesed pegol (NOX-A12) and bevacizumab for glioblastoma (GBM) in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report updated outcomes on dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab). METHODS Six patients with incompletely resected, MGMT-unmethylated GBM, ECOG≤ 2 were enrolled, receiving standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response according to modified RANO criteria (mRANO) as well as perfusion/diffusion imaging. RESULTS Combination treatment was well-tolerated and safe. Of all G≥2 AEs (n = 79), two G2 events (2.5%) were deemed related to NOX-A12 only. There were no dose-limiting toxicities and no treatment-related deaths. At a median follow-up of 14.6 months, one patient deceased due to distant leptomeningeal spread. Median overall survival (OS) has not yet been reached. With an overall response rate (ORR) of 83.3% under treatment, one patient achieved confirmed complete response (CR), four patients partial response (PR) and one patient stable disease (SD). The median best response under treatment was -68.9% (-53,8% to -100%) for target lesion sums and -100% (-99.9% to -100%) for non-target lesion (NTL) sums. In all three patients with NTLs at least one lesion disappeared. The median best change from baseline of the highly perfused-tumor fraction was -98.2% (-61.3% to -100%) and the median best change of the apparent diffusion coefficient was 24.9% (7.3% to 59.1%). CONCLUSIONS Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 for combinatory treatment with bevacizumab while demonstrating improved efficacy with deeper and longer-lasting responses and a higher ORR compared to treatment with RT and NOX-A12 only.

Case Report: Implication of antiangiogenic therapy (bevacizumab) along with dichloroacetate therapy on endometriosis patient seeking infertility treatment

Endometriosis is a pervasive gynecological ailment which usually results in unease and infertility and is signified by an accumulation of endometrial-like tissue outside the uterus. Current endometriosis medications, which often entail surgical intervention and hormone therapy, are geared around easing discomfort as well as improving fertility. However, alternative approaches targeting angiogenesis have shown promise in managing endometriosis-associated infertility. This case report highlights the implications of combining antiangiogenic therapy (bevacizumab) with dichloroacetate (DCA) therapy in a patient with endometriosis seeking infertility treatment. A 34-year-old woman presented with a five-year history of severe pelvic pain and primary infertility due to stage IV endometriosis. The patient sought other possibilities after repeated unsuccessful attempts using assisted reproductive technology. A revolutionary therapy strategy combining bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, and DCA, a metabolic modulator, has been proposed considering the potential significance of angiogenesis in endometriosis-related infertility. The patient underwent a six-month treatment regimen consisting of intravenous bevacizumab infusions combined with oral DCA administration. The theory behind this combination was to target the metabolic reprogramming typically associated with the disease in addition to altering the abnormal angiogenic signaling pathways that contribute to the pathogenesis of endometriosis. Given the scores on the visual analogue scale, the patient's pelvic pain substantially decreased during the time frame of treatment. Additionally, a notable improvement in ovarian reserve markers was observed, including an increase in anti-Müllerian hormone levels and the number of antral follicles. This case report suggests that the combination of bevacizumab and DCA may have a synergistic effect in managing endometriosis-associated infertility. This form of therapy may provide patients who have failed typical infertility treatment options with an innovative therapeutic approach since it targets both angiogenesis and metabolic changes.

NEIM-14 PET/MRI DETECTS A RAPID DECREASE IN CEREBRAL BLOOD FLOW IN GLIOBLASTOMA FOLLOWING BEVACIZUMAB INFUSION

Abstract BACKGROUND The impacts of bevacizumab on the vasculature and metabolism of glioblastoma have been understudied. Previous work has shown that perfusion measurements of lesions decrease weeks after infusion. Metabolic consequences, either direct or as sequelae of vascular changes, have also been proposed. The timing of both processes in humans, however, is unclear. We aimed to study changes to the vasculature and metabolism of glioblastoma after the administration of bevacizumab. METHODS Patients (n = 8) diagnosed with recurrent glioblastoma requiring bevacizumab were enrolled. Baseline scans were acquired with a GE Healthcare SIGNA PET/MRI scanner. Following the first infusion of bevacizumab (7.5 mg/kg), repeat scans were obtained within two days and two weeks. All scans were co-registered and analyzed using 3D Slicer. Cerebral blood flow (CBF) and standard uptake value (SUV) measures were normalized by taking the ratio of the mean tumor and contralateral region values, and the ratios at different time points were compared using Wilcoxon signed-rank tests. RESULTS A statistically significant decrease in tumor CBF was detected within two days of infusion (0.88 ± 0.36 vs. 0.79 ± 0.29, p = 0.01), but no significant decrease in SUV was detected within the same timeframe (0.89 ± 0.36 vs. 0.88 ± 0.39, p = 0.26). No statistically significant drop was detected at two weeks in our sample. CONCLUSIONS Our results provide evidence that bevacizumab decreases glioblastoma blood flow within two days of the infusion. The measure of tumor metabolism also trended downward, though not significantly. Taken together, these data support a model by which bevacizumab rapidly affects VEGF-mediated vascular changes within the tumor, withpotential effects on tumor metabolism over a longer timeframe. These findings enrich our understanding of the impacts on glioblastoma of bevacizumab, which has a continued high clinical utility that is underscored by its ubiquity in the neuro-oncology clinic.

Efficacy of Systemic Bevacizumab for Recurrent Respiratory Papillomatosis with Pulmonary Involvement.

Pulmonary papillomatosis is a rare but severe manifestation of recurrent respiratory papillomatosis (RRP). Efficacy data of systemic bevacizumab for pulmonary RRP are limited. This study's objective was to characterize disease response of pulmonary RRP to systemic bevacizumab. A retrospective review was performed to identify patients with pulmonary RRP seen at three medical institutions. Clinical symptoms, CT findings, and disease response were compared before and after initiation of systemic bevacizumab therapy. Disease response was categorized as complete response, partial response, stabilization, or progression for each subsite involved by papilloma. Of the 12 pulmonary RRP patients treated with systemic bevacizumab, 4 (33.3%) were male, and 11 (91.7%) were juvenile-onset RRP patients. All presented with laryngeal, tracheal, and pulmonary RRP. The median (range) age at first bevacizumab infusion was 48.1 (19.5-70.2) years. Progression to pulmonary malignancy was identified in 3 (25.0%) patients, 2 before initiation of and 1 after complete cessation of bevacizumab therapy. Clinical symptoms such as dyspnea (75.0% vs. 25.0%; p = 0.01) and dysphagia and/or odynophagia (33.3 vs. 0.0%; p = 0.03) were significantly decreased following bevacizumab therapy. Compared with pre-treatment baseline, 9 (75.0%) patients experienced a stable-to-partial response in the lungs to systemic bevacizumab, and 10 (83.3%) experienced partial-to-complete responses in the larynx and trachea. Systemic bevacizumab is effective in stabilizing progression in even the most severe cases of RRP, with both a dramatic reduction in laryngeal and tracheal disease as well as a stable-to-partial response of pulmonary involvement in a majority of patients. 4 Laryngoscope, 134:577-581, 2024.

TACE combined with the intra-arterial infusion of sintilimab and bevacizumab for advanced hepatocellular carcinoma: A prospective, single-arm, phase II study.

e16133 Background: Combination treatment with an immune checkpoint inhibitor and an anti-VEGF antibody is recommended as the standard care for advanced hepatocellular carcinoma (HCC). However, the efficacy of systemic therapy is less than satisfactory in BCLC stage C. Transarterial chemoembolization (TACE) combined with systemic therapy may synergistically improve patients’ clinical outcomes and obtain survival benefits. Intra-arterial infusion of Sintilimab and Bevacizumab has not been assessed previously. This study aimed to evaluate the safety and efficacy of TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab in patients with BCLC stage C HCC. Methods: This prospective, single-arm phase II study recruited 16 patients with advanced HCC. Main inclusion criteria: aged ≥ 18 years; a confirmed HCC (BCLC stage C) based on the ALSLD with either pathological or imaging findings; no previous systemic/locoregional anticancer treatment; Child-Pugh score ≤7; ECOG performance status: 0-1. Patients were treated with TACE (30-40mg of pirarubicin, 30-40mg of lobaplatin, and lipiodol) plus Sintilimab (200mg, intra-arterial infusion, d1, Q3W) and Bevacizumab (7.5mg/kg, intra-arterial infusion, d1, Q3W) for four cycles, followed by maintenance therapy with Sintilimab (200mg, intravenously, d1, Q3W) and Bevacizumab (15mg/kg, intravenously, d1, Q3W) to a maximum total cycle of eighteen unless any evidence of disease progression or unacceptable side effects. The primary endpoint was objective response rate (ORR) (assessed with mRECIST v1.1) and the secondary endpoints included disease control rate (DCR), time to progress (TTP), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Drug safety was investigated according to CTCAE (version 5.0). Results: From September 2021 to December 2022, 16 patients with a median age of 52 years (range:38 -73) were enrolled. 12 (75%) patients with HBV infection and 6 (38%) with extrahepatic metastasis. 14 (88%) patients were classified as Child-Pugh A class. With a median follow-up of 5.4 months (range 3.9-14.3), the ORR was 63% (95%CI, 36.4%- 84.8%) with 3 CR and 7 PR per mRECIST v1.1, and the DCR was 69% (95%CI, 41.3%-89.0%). The median PFS was not reached. Adverse events in 31% of 16 patients were hypertension (3, 19%), fatigue (1, 6%), and proteinuria (1, 6%). The most common adverse event of grade 3 was hypertension (2, 13%). There were no treatment-related serious adverse events. Conclusions: TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab as the first-line strategy for advanced HCC patients (BCLC stage C) demonstrated a promising value by improving ORR, with acceptable side effects. Clinical trial information: NCT04796025 .

A Randomized, Double-Blind, Parallel-Controlled Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of SCT510 to Bevacizumab (Avastin®) in Healthy Chinese Males.

SCT510 is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), which is intended as a candidate biosimilar of bevacizumab that is approved for various metastatic cancers.Please confirm change in wording to match definition for VEGF belowYes. This study aimed to compare the pharmacokinetics profiles, safety, and immunogenicity of SCT510 to bevacizumab (Avastin®) in healthy Chinese males. This was a single-center, double-blind, parallel-group phase I study. A total of 84 participants were randomly assigned (1:1) to receive a single 3mg/kg infusion of either SCT510 or bevacizumab and followed up for 99days. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC0-∞), area under the serum concentration-time curve from time 0 to last quantifiable concentration (AUC0-t), and the maximum observed concentration (Cmax). Secondary endpoints included safety and immunogenicity.Kindly check and confirm the edit made in the article title.Yes. A total of 82 subjects completed the study. Geometric means ratios (GMR) for AUC0-∞, AUC0-t, and Cmax were 0.88, 0.89, and 0.97, respectively, for SCT510 versus bevacizumab (USA). The 90% confidence intervals for GMRs of AUC0-∞, AUC0-t, and Cmax were all within the prespecified criteria (80-125%). No adverse events (AEs) led to study termination, and no serious adverse events (SAEs) were reported. None of the anti-drug antibodies (ADAs) identified were found to be neutralizing antibodies (NAbs), and only one subject from the SCT510 group tested positive for the ADA at the day99 visit. This study demonstrated that the pharmacokinetics, safety, and immunogenicity of SCT510 were equivalent to bevacizumab (Avastin®). As a proposed biosimilar drug to bevacizumab, SCT510 was well tolerated in healthy Chinese males. NCT05113511.

An exploratory study on the effect of mechanical stress on particle formation in monoclonal antibody infusions.

Monoclonal antibody infusions (mAb-i) are administered for the treatment of various diseases. They are often transported over long distances from the compounding site to the site of administration. However, transport studies are typically carried out with the original drug product but not with compounded mAb-i. To address this gap, the impact of mechanical stress on the formation of subvisible/nanoparticles in mAb-i was investigated by dynamic light scattering and flow imaging microscopy. Different mAb-i concentrations were subjected to vibrational orbital shaking and stored at 2-8°C up to 35 days. The screening revealed that pembrolizumab and bevacizumab infusions show the highest propensity for particle formation. Especially bevacizumab at low concentrations exhibited an increase in particle formation. Because of the unknown health risks associated with the long-term application of subvisible particles (SVPs)/nanoparticles in infusion bags, stability studies carried out in the frame of licensing application procedures should also focus on SVP formation in mAb-i. In general, pharmacists should minimize the time of storage and mechanical stress during transport, especially in the case of low-concentrated mAb-i. Moreover, if siliconized syringes are used, they should be washed once with saline solution to minimize particle entry.

Intra-arterial hepatic bevacizumab and systemic chemotherapy in hepatic metastasis of colorectal cancer: A phase II multicentric trial in second-line treatment

IntroductionIntra-arterial hepatic (IAH) treatment has shown promising results in the management of patients with unresectable colorectal liver metastases (CRLM) the prognosis of which is poor. Bevacizumab adjunction to standard chemotherapy has been shown to improve survival of this patient population. This prospective study was conducted to assess the efficacy and safety of IAH bevacizumab combined to systemic chemotherapy after first-line treatment failure in patients with CRLM. MethodsIncluded patients had dominant or isolated unresectable CRLM progressing after standard first-line treatment for metastases of colorectal cancer. Three patients had less than 30% liver invasion, three patients between 30 and 50%, two more than 50% and data was missing in two patients. An intra-hepatic catheter was implanted surgically or percutaneously. Bevacizumab 7.5 mg/kg was administered once every 3 weeks in combination with capecitabine 2000 mg/m² per day for 2 weeks and oxaliplatin 130 mg/m² or irinotecan 200 mg/m² once every 3 weeks. The primary end-point was the objective response rate. ResultsBetween June 2013 and February 2015, 10 patients were included. The trial was prematurely closed because of the lack of financial support and poor accrual. The patients had a median of 6 [1–9] cycles of treatment. Partial response was achieved in 2 patients (20%) and a R0 liver metastases resection in one another. All patients died of disease progression. The median overall and progression-free survival rates were respectively 14.0 (95% IC [4.8 – 25.8] and 5.4 months (95% IC [1.6 – 6.2]). Four patients had severe side effects but no toxic death occurred. ConclusionIAH bevacizumab combined to systemic chemotherapy is feasible and safe in patients with unresectable isolated or dominant CRLM progressing after a first-line systemic treatment. Based on the low number of patients included in our study, our results suggest that this treatment does not increase dramatically the response rate versus an adapted systemic treatment. However, considering the safety data provided in this study, arterial infusion of bevacizumab in adjunction to chemotherapeutic agents could be evaluated in the future.

CTNI-67. DUAL INHIBITION OF POST-RADIOGENIC ANGIO-VASCULOGENESIS BY OLAPTESED PEGOL (NOX-A12) AND BEVACIZUMAB IN GLIOBLASTOMA – INTERIM DATA FROM THE FIRST EXPANSION ARM OF THE GERMAN PHASE 1/2 GLORIA TRIAL

Abstract BACKGROUND We recently reported favorable safety, promising clinical efficacy and immunohistochemical indicators of response after radiotherapy (RT) plus escalating doses of the CXCL12-neutralizing RNA-Spiegelmer olaptesed pegol (NOX-A12) for glioblastoma in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report outcomes after RT plus dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab). METHODS After establishing safety in the monotherapy arm, we enrolled six patients with incompletely resected GBM, ECOG ≤ 2, age ≥ 18 and without MGMT promoter hypermethylation into a pre-planned expansion arm. Patients received standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response, perfusion/diffusion imaging and neurologic performance. RESULTS Dual treatment was well-tolerated and safe. Of all G ≥ 2 AEs (n = 37), two G2 events (5.4%) were deemed related to NOX-A12. There were no dose-limiting toxicities and no treatment-related deaths. Longitudinal NANO assessment revealed stable neurologic functioning in all patients. Five out of six patients achieved partial responses (PRs) as per mRANO in week 9. All PRs remained durable at a median follow up of 5.6 months (range 3.6 to 9.3 months). No progression occurred. The mean best response was -65.9% (-13.3% to -99.9%) for target lesion sums and -92.1% (-76.2% to -100%) for non-target lesion (NTL) sums. In all three patients with NTL at least one lesion disappeared. The mean best change from baseline of the highly perfused-tumor fraction was -84.5% (-51.9% to -100%) and the mean best change of the apparent diffusion coefficient was 20.1% (-24.5% to 59.1%). CONCLUSION Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 and suggest improved efficacy of dual inhibition of post-radiogenic angio- and vasculogenesis by the addition of bevacizumab.

P11.42.A Short course of Bevacizumab for differential diagnosis of tumor progression and radionecrosis or pseudoprogression after brain metastasis SRS

Abstract Background Despite use of modern MRI techniques (perfusion, spectroscopy, TRAMs, radiomics), PET and SPECT the differential diagnosis of radio-necrosis and tumor progression is still difficult in malignant gliomas and brain metastasis after radiotherapy or radiosurgery. For patients who have enlargement of brain metastasis after radiosurgery we suggest a new strategy to discriminate pseudoprogression and true progression - two intravenous infusions Bevacizumab in 5-7 mg/kg with 2-3 week interval and new contrast MR. Material and Methods We present 3 relevant clinical cases, all after LINAC-based SRS for brain metastasis.1st case - 49 y.o. female with ovarian cancer underwent SRS for two small closely seated metastases in temporal lobe, both metastasis had shrunk and remained stable until 34 months after radiosurgery a new asymptomatic contrasting lesion with edema developed on MRI adjacent to one of metastasis. Patient developed no other new brain or extracranial mets, so we proposed radionecrosis, but MR-perfusion data was ambiguous. 2nd case - 67 y.o. female with lung adenocarcinoma underwent SRS (27 Gy in 3 fractions) for solitary brain metastasis. 4 months after SRS metastasis partially regressed, but 4 months later a new contrast enhancement zone appeared on its periphery with edema. 18F-FET PET failed to differentiate recurrence and pseudoprogression. 3d case - 48 y.o. female with breast cancer underwent SRS (27 Gy in 3 fractions) for 3 brain metastases. All mets regressed during the next 7 months, but 3 months later one of them showed significant symptomatic enlargement with edema on MRI. All patients received two intravenous infusions Bevacizumab in 5-7 mg/kg with 2-3 week interval and new contrast MRI (1-2 week after second infusion). Results 1st case - after two infusions of 6 mg/kg with a 3-week interval new contrasting zone disappeared and did not develop again for at least 6 months (with no chemotherapy), so we confirmed necrosis. 2nd case - substantial regression of pathological MRI changes was noted, which was stable for 3 months, diagnostic for pseudoprogression. 3d case - MRI showed substantial regress of contrasting lesion (diagnostic for necrosis), symptoms also regressed and 1 month later methionine PET showed no active tumor. Conclusion Our preliminary data suggest that use of two infusions of Bevacizumab and routine contrast MRI have very promising diagnostic value to rule out tumor growth after SRS of brain metastasis.

Retrospective Study of the Efficacy and Safety of Chemoembolization with Drug-Eluting Microspheres Combined with Intra-Arterial Infusion of Bevacizumab for Unresectable Hepatocellular Carcinoma.

PurposeTo evaluate the efficacy and safety of chemoembolization with drug-eluting microspheres (DEM-TACE) combined with intra-arterial infusion of bevacizumab in patients with unresectable hepatocellular carcinoma (uHCC) and to identify possible prognostic factors.Patients and MethodsBetween November 2014 and December 2020, 34 patients underwent DEM-TACE combined with intra-arterial infusion of bevacizumab for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) beyond the Up-to-seven criteria or BCLC stage C HCC. Patients with extrahepatic metastasis or inferior vena cava invasion were excluded. The primary endpoint was overall survival (OS). The secondary endpoints were safety (assessed using Common Terminology Criteria for Adverse Events v5.0), the response rate at 1 month, and the identification of prognostic factors. The median OS was calculated using the Kaplan–Meier method. The response rate was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. Prognostic factors were investigated by univariate and multivariable analysis using the Cox proportional hazards model.ResultsThe median OS was 13 months. BCLC stage and presence of portal vein invasion were not significantly associated with OS. There were no grade ≥3 adverse events. The Child–Pugh class did not decline after treatment in 31 of 34 patients. The overall response rate was 14.2% and the disease control rate was 100%. Significant prognostic factors were alcoholic liver disease, Child–Pugh score of ≥8, and microsphere size of 50–100 μm.ConclusionDEM-TACE combined with intra-arterial infusion of bevacizumab is safe and effective, and it could be a treatment option for unresectable HCCs.

Short bevacizumab infusion as an effective and safe treatment for colorectal cancer.

Bevacizumab is a humanized monoclonal antibody that contains <10% murine protein. To prevent infusion-related hypersensitivity reactions (HSRs), the initial bevacizumab infusion is delivered for 90 min, the second for 60 min and subsequent doses for 30 min. Several previous studies have shown that short bevacizumab infusions are safe and do not result in severe HSRs in patients with colorectal, lung, ovarian and brain cancer. However, the efficacy of short bevacizumab infusions for colorectal cancer management remains unclear. Therefore, to investigate this issue, a prospective multicenter study was conducted using 23 patients enrolled between June 2017 and March 2019. The initial infusion of bevacizumab was for 30 min followed by a second infusion rate of 0.5 mg/kg/min (5 mg/kg over 10 min and 7.5 mg/kg over 15 min. The primary endpoint was progression-free survival (PFS). The overall response and disease control rates were 57 and 87%, respectively. The median PFS time was 306 days (interquartile range, 204-743 days). No HSRs were noted. Adverse events associated with bevacizumab included grade 4 small intestinal perforation and grade 3 stroke in 1 patient each. These results suggest that a short bevacizumab infusion regime comprising an initial infusion for 30 min followed by a second infusion at 0.5 mg/kg/min is safe and efficacious for the management of colorectal cancer.

Albumin Paclitaxel Combined with Intrapleural Infusion of Bevacizumab + Lobaplatin for the Second-Line Treatment of Patients with Non-Squamous Non-Small Cell Lung Cancer.

Objective To investigate the clinical efficacy and safety of albumin paclitaxel combined with intrapleural bevacizumab + lobaplatin for patients with non-squamous non-small cell lung cancer (NS-NSCLC) with malignant pleural effusion (MPE) and analyze prognostic factors. Methods A total of 126 NS-NSCLC patients were included in the study. Control group with 64 cases received intrapleural infusion of lobaplatin + intravenous albumin paclitaxel, and treatment group with 62 cases received additional intrapleural bevacizumab perfusion. Analysis was performed by collecting data about MPE, progression-free survival (PFS), overall survival (OS), and scores of quality of life. Results In the treatment and control groups, objective response rate (ORR) was 51.6% and 31.3% (χ2 = 5.39, P=0.02), and disease control rate (DCR) was 91.9% and 71.9% (χ2 = 8.49, P=0.004), respectively. The main adverse reactions (≥grade 3) in the treatment group were thrombocytopenia, peripheral neurotoxicity, proteinuria, neutropenia, and nausea/vomiting, and in the control group, they were weakness, nausea/vomiting, anemia, and peripheral neurotoxicity. In the control and treatment groups, the median PFS was 6.2 (95% confidence interval (CI): 5.86–6.56) and 5.1 (95% CI: 4.956–5.191), and the median OS was 14.4 (95% CI: 12.681–16.113) and 10.6 months (95% CI: 8.759–12.391). The score of quality of life for treated patients was significantly higher than those before treatment and the control group, and the parameters included general health status (GH), role physical (RP), body pain (BP), social function (SF), and vitality (VT); pH, CD4+/CD8+ values, and vascular endothelial growth factor (VEGF) in the pleural effusion significantly affected the PFS and OS (P < 0.05). Bevacizumab administration in patients with bloody pleural effusion did not increase the risk of pleural hemorrhage. Conclusion The combination of albumin paclitaxel and intrapleural bevacizumab + lobaplatin is effective and may reverse the adverse events in patients with NS-NSCLC and MPE. The change of CD4+/CD8+ ratio before and after treatment is an independent and prognostic factor for patients with NS-NSCLC and MPE.

P143 EDOXABAN EFFECT IN A BREAST CANCER PATIENT WITH LIVER ARTERIAL INFUSION CHEMOTHERAPY (LAIC) AND BOTH JUGULAR VEIN AND HEPATIC ARTERY THROMBOSIS. A UNIQUE CLINICAL CASE

Abstract 41 y–o woman, without cardiovascular risk factors, was diagnosed with breast cancer (pT2N1aMx, G3, ER:70%, PgR:30%, HER–2/NEU:2+, Ki67:60%). Treated (2010) with adjuvant antracyclines, taxanes and hormonal therapy. Subsequently, developed (2012) bone lesions treated with radiotherapy and hepatic metastases (2016) treated with systemic infusions of bevacizumab and taxanes. Started (2017) chemoembolization (CE), due to further liver severe progression configuring a main hepatic disease. Started LIVER ARTERIAL INFUSION CHEMOTHERAPY (LAIC) with 5fluoruracil and concomitant venous systemic chemotherapy (CT) with taxanes and bevacizumab. Developed (2020) arterial catheter–related thrombosis (ACRT) recurrent after urokinase, clopidogrel and enoxaparin, in spite of thromboprohylaxis with aspirin/clopidogrel. LAIC was discontinued and CT with taxanes and trastuzumab was administrated by systemic route. Left jugular deep vein thrombosis (DVT) occured (2021), treated for 8 months with low–molecular–weight heparin (LMWH): firstly with enoxaparin 100 IU/kg twice a day and secondly, because of lack of efficacy and patient’s request for a more manageable therapy, with parnaparin 6400 IU once a day. After 8 months the patient refused any more injectable anticoagulant drugs, asking for oral root of administration. LMWH were replaced by direct oral anticoagulant (DOAC), edoxaban 30 mg/die (weight: 43 kg). After 3 months of edoxaban a duplex ultrasound showed an almost total DVT regression; neither bleedings nor dru–drug interactions with the ongoing CT were detected. Instead, the 3 months follow–up CT–scan revealed persistence of the ACRT, despite of edoxaban. Conclusions Thromboembolism is the second leading cause of death in malignancy. Venous thromboembolic events are prevalent compared to the arterial ones. However, in active cancer hypercoagulable burden is common to both kind of thrombosis and sometimes occur simultaneously. In this case, a young woman with advanced breast cancer treated with CE and LAIC developed both DVT and ACRT. According to inefficacy and patient’s preference, we replaced LMWH with edoxaban. Arterial thrombosis was persistent although treated with several antithrombotic agents, whereas edoxaban resulted effective in the DVT regression. The take home message of this case report is that DOACs could be a feasible, efficient and safe anticoagulant choice for venous cancer related thrombosis.

Direct Observation of Retinal Microvessels in Cancer Patients After Systemic Administration of Bevacizumab and Oxaliplatin.

Antiangiogenic chemotherapy is the backbone of the various anticancer therapies. To date no practical biomarker predicting their antitumor effects and toxicity has been reported. We aimed to determine the feasibility of direct retinal observation as a practical biomarker in antiangiogenic chemotherapy. By direct retinal observation using a nonmydriatic retinal camera, we measured retinal microvessel diameters in 10 patients with colorectal cancer before and after intravenous infusion of bevacizumab and oxaliplatin. All patients also received oral capecitabine during their therapy. Retinal microvessel diameters were decreased from baseline temporarily by 14.5±6.5% after infusion of bevacizumab and oxaliplatin in five patients who responded to treatment and 8.8±6.2% in the other five patients (p=0.008). Measurement of retinal microvessel diameters by direct observation appears to be feasible in patients receiving systemic chemotherapy. The decrease of retinal microvessel diameters might indicate improved tumor response to treatment with bevacizumab-containing systemic chemotherapy.