Pazopanib Research Articles

Determining M2 macrophages content for the anti-tumor effects of metal-organic framework-encapsulated pazopanib nanoparticles in breast cancer

Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Neoadjuvant pazopanib with radiation therapy in patients with localized sarcoma: Experience from a sarcoma center.

e23555 Background: Tissue oxygenation is critical to the success of radiation therapy (RT) in any tumor type. However, tumor vasculature is abnormally structured and dysfunctional. Anti-angiogenic molecules have been shown to stabilize the intratumoral vascular structures and improve tissue oxygenation, which may aid in the success of RT. Pazopanib (PAZO) is a multi-kinase inhibitor targeting the Vascular Endothelial Growth Factor Receptor. Here, we report the pathologic outcome and clinical correlates of concurrent use of neoadjuvant PAZO and RT in our cohort of patients with localized soft-tissue sarcoma (STS). Methods: This is a retrospective, single institution study of patients diagnosed with localized STS between January 2019 and October 2023. Patients who received concurrent PAZO and pre-operative external beam RT (50 Gy in 25 fractions) were included. Patients with metastatic disease, unplanned resections, and those requiring excisional biopsy/curettage for diagnosis were excluded. The primary endpoint was the rate of major pathologic response (mPR) defined by > 90% necrosis on surgical pathology specimen. The secondary endpoint was local relapse-free survival (RFS), distant metastasis-free survival (DMFS), and local and distant relapse rate (RR) at 6 months. All-grade toxicities from PAZO were recorded. Results: Ten patients with a median age of 51 years (Interquartile range (IQR): 34-76) were included. Undifferentiated pleomorphic sarcoma was the most common histologic subtype (50% patients). Median follow up was 24.2 months (IQR: 11-36). Six patients tolerated the maximum dose of PAZO until RT completion (800mg PO daily). The dose of PAZO was reduced in 4 patients due to grade 3 GI toxicity and HTN. Nine patients stayed on PAZO until RT completion. The median time to surgery after RT was 42 days (IQR: 37-77). The median largest tumor dimension prior to RT was 11.65 cm (IQR: 3.8 to 18), and 10.6 cm (IQR: 5.4 to 19.7) after RT completion. Nine of 10 patients had R0 resection, and 7 (70%) had mPR. Three of 7 (43%) patients had complete necrosis. All patients with R0 resection have no local recurrence after a median follow-up of 23 months (IQR: 11-36). Median local RFS was 20 months (IQR: 5-32), and DMFS was 6 months (IQR: 1-32). The local RR at 6 months was 10%, and the distant RR at 6 months was 30%. No correlation was observed between mPR and DMFS. Conclusions: Historically, neoadjuvant RT alone induces a mPR in ~30% of patients with localized STS. In our cohort, neoadjuvant PAZO with RT achieved an mPR in 70% of patients. Although dose reduction and grade 3 toxicity were noted in the majority of patients, these were reversible after stopping PAZO. There was no correlation between mPR and DMFS. However, a short course of PAZO with RT may help achieve R0 margins, which is the strongest predictor of better local RFS. A randomized trial is warranted to help understand the true impact of neoadjuvant PAZO with RT.

Electrochemical Determination of Anti-Cancer Drug Pazopanib with High Selectivity and Sensitivity Using Molecularly Imprinted Polymer-Modified Glassy Carbon Electrode

Pazopanib (PZB) is a multiple kinase inhibitor used for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. This work focuses on achieving high selectivity and sensitivity for the determination of PZB using a molecularly imprinted polymer (MIP)-based electrochemical sensor. The MIP-based sensor was fabricated by thermal polymerization (TP) directly on a glassy carbon electrode (GCE). The electrochemical response of the 4-ABA/PZB@MIP/GCE sensor was investigated using differential pulse voltammetry (DPV). The characterization of the sensor in terms of morphology and electrochemistry was performed using scanning electron microscopy (SEM), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). The 4-ABA/PZB@MIP/GCE sensor exhibited a linear response ranging from 1.0 × 10–13 M to 1.0 × 10–12 M with a limit of detection (LOD) and limit of quantification (LOQ) of 1.04 × 10–14 M and 3.48 × 10–14 M, respectively. The applicability of the sensor was evaluated by determining commercial samples of human serum and tablets, and good recoveries were obtained. The results showed that the sensor could identify PZB, compared to structurally analogous drugs such as axitinib, nilotinib, and erlotinib. The interfering substances commonly found in biological fluids were investigated. Finally, the sensor design was validated using a non-imprinted polymer-based GCE.

Screening for Synergistic Reagents With Pazopanib Against Osteosarcoma Using a Compound Library.

Osteosarcoma (OS) is the most common malignant bone tumor. As the same agents have been in use since the mid-1970s, new therapeutic approaches are needed to improve prognosis. Pazopanib (PZP) has already demonstrated marked antitumor activity clinically and can be effective in patients with metastatic OS. We investigated the combination treatment of candidate agents with PZP and examined effects on tumor growth using an in vivo model. A library of 324 compounds was used. MG63 OS cells were treated with PZP and each compound. Cell viability was measured. The antiproliferative effects of compound combination on four OS cell lines was tested. Cell signaling was evaluated by western blot analysis. In vivo antitumor testing was performed using 143B-bearing mice. The screening process identified crizotinib (CRZ) as the most effective drug for combination with PZP. The combination of PZP and CRZ demonstrated effects compared to control or single therapy. Cell signal investigation showed that dual therapy down-regulated c-MYC, p-AKT, p-STAT3, p-cyclin D1 and survivin and up-regulated cleaved caspase-3 and cleaved PARP compared to control or single therapy. In vivo analysis showed dual therapy achieved synergic effects for tumor growth compared to control or single-treatment groups. No significant difference in the change in body weight was observed among groups. Combined use of PZP and CRZ offers synergic anti-tumor effects against OS, inducing apoptosis in vitro and in vivo by down-regulating AKT and STAT3. Our data suggest that these agents can be used for patients clinically.

Preparation of pazopanib-fumarate disodium glycyrrhizinate nanocrystalline micelles by liquid-assisted ball milling

Pazopanib (PZ) is a multikinase inhibitor, which is mainly used in the treatment of soft tissue sarcoma and advanced renal cancer. However, because of its water insolubility, oral bioavailability is poor. At the same time, photo lability and high dose oral administration lead to severe hepatotoxicity, which is limited in clinical application. In this paper, the novel pazopanib-fumarate disodium glycyrrhizinate nanocrystalline micelles are successfully prepared by liquid-assisted ball milling. The prepared cocrystals and nanocrystalline micelle structures are systematically characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier Transform Infrared Spectrometer (FTIR) analysis. In vitro solubility and dissolution experiments show that the solubility and dissolution of nanocrystalline micelles are significantly improved under different simulated physiological conditions. The accelerated stabilization experiments show that the nanocrystalline micelles have good physical and chemical stability and showed excellent stability in water (Zeta potential was 62.39 mV). In addition, the in vivo bioavailability of nanocrystalline micelles is 3 times higher than that of PZ, and the therapeutic threshold (> 20 μg/mL) is up to 30 h. This new strategy provides a feasible solution to the undesirable properties of PZ.

A phase I study of nanoparticle albumin-bound sirolimus (NAB-S) combined with pazopanib (PAZO) in patients with advanced soft tissue sarcoma (STS).

11521 Background: NAB-S (ABI-009, nab-rapamycin) is approved for treatment of adults with unresectable or metastatic perivascular epithelioid cell tumors. Albumin binding improves sirolimus solubility and may target it to tumoral cells. mTOR inhibition may enhance PAZO activity directly and by overcoming resistance. We assess feasibility and safety of the combination. Methods: Eligible patients (≥18y) had: advanced, unresectable, non-adipocytic STS progressing after 1-5 prior therapies; adequate end-organ function; ECOG performance status 0-1; measurable target lesions (RECIST v1.1); and no prior mTOR or angiogenesis inhibitor treatment. The study was conducted according to a 3+3 design. Initial cohorts received 800 or 400 mg PAZO daily and 60, 45 or 30 mg/m2 of NAB-S on days 1 and 8 on a 21-day cycle. Subsequently, NAB-S was administered only on day 1 based on preliminary analysis of adverse events (AEs) and pharmacokinetics (PK). Primary endpoint was determination of maximally tolerated dose (MTD). Dose-limiting toxicities (DLT) were grade 3-5 adverse events (AE) during the first cycle not due to PAZO. Secondary endpoints included AE characterization (CTCAE v5.0), descriptive evaluation of responses and their duration, and correlative/PK studies. Results: 19 patients were treated; initially, 13 received NAB-S on days 1 and 8. DLT included thrombocytopenia (TCP, n = 7), decreased WBC/neutrophils (n = 2), increased lipase (n = 1), and proteinuria (n = 1). Due to overlapping AEs or possible NAB-S/PAZO interaction, further cohorts received 400 mg PAZO daily and either 30 or 45 mg/m2 NAB-S (n = 6). There were no DLTs in the 30 mg/m2 cohort (n = 3). In the 45 mg/m2 cohort, 2 out of 3 patients had TCP meeting DLT definition. Grade 3-4 AEs in more than 10% included: TCP (58%), neutropenia (11%), leukopenia (11%), lymphopenia (11%), and diarrhea (11%). Any grade AEs in > 50% included: TCP (74%), mucositis (63%), fatigue (58%), and acneiform rash (53%). There was no grade 5 AEs. Of 19 treated, 11 (58%) discontinued due to disease progression, 3 (16%) due to AE (TCP-2, transaminitis-1), and 1 (5%) due to death from disease. Four (21%) remain on study as of 2/2023. 18 were evaluable for best response: 3 partial responses (PR; leiomyosarcoma, solitary fibrous tumor, spindle cell sarcoma), 13 stable disease (SD), 2 progressive disease. Clinical Benefit Rates (CBR = PR+SD) at 3 and 6 months were 72% (13/18) and 59% (10/17). Among the leiomyosarcoma subset, CBR at 3 and 6 months were 90% (9/10) and 80% (8/10). Correlative and pharmacokinetic results will be presented. Conclusions: Thrombocytopenia was the most prominent DLT when studying the NAB-S/PAZO combination. 3 patients out of 19 discontinued therapy due to AEs; the remainder continued therapy after adjustment. MTD and RP2D is NAB-S 30 mg/m2 day 1 and PAZO 400 mg days 1-21. Preliminary evidence of activity of the combination was observed. Clinical trial information: NCT03660930 .

Optimal sequencing of the first- and second-line target therapies in metastatic renal cell carcinoma: based on nationally representative data analysis from the Korean National Health Insurance System

BackgroundThe authors intend to compare the effects of each targeted therapy (TT) in the treatment of patients with metastatic renal cell carcinoma (mRCC) using big data based on the Korean National Health Insurance System (NHIS) and determine the optimal treatment sequence.MethodsData on the medical use of patients with kidney cancer were obtained from the NHIS database from January 1, 2002, to December 31, 2020. Patient variables included age, sex, income level, place of residence, prescribing department, and duration from diagnosis to the prescription date. The primary outcome was overall survival (OS) for each drug and sequencing. We performed propensity score matching (PSM) according to age, sex, and Charlson Comorbidity Index based on the primary TTs.ResultsAfter 1:1 PSM, the sunitinib (SUN) (n = 1,214) and pazopanib (PAZ) (n = 1,214) groups showed a well-matched distribution across the entire cohort. In the primary treatment group, PAZ had lower OS than SUN (HR, 1.167; p = 0.0015). In the secondary treatment group, axitinib (AXI) had more favorable OS than cabozantinib (CAB) (HR, 0.735; p = 0.0118), and everolimus had more adverse outcomes than CAB (HR, 1.544; p < 0.0001). In the first to second TT sequencing, SUN–AXI had the highest OS; however, there was no statistically significant difference when compared with PAZ–AXI, which was the second highest (HR, 0.876; p = 0.3312). The 5-year survival rate was calculated in the following order: SUN–AXI (51.44%), PAZ–AXI (47.12%), SUN–CAB (43.59%), and PAZ–CAB (34.28%). When the four sequencing methods were compared, only SUN–AXI versus PAZ–CAB (p = 0.003) and PAZ–AXI versus PAZ–CAB (p = 0.017) were statistically significant.ConclusionsIn a population-based RWD analysis of Korean patients with mRCC, SUN-AXI sequencing was shown to be the most effective among the first to second TT sequencing methods in treatment, with a relative survival advantage over other sequencing combinations. To further support the results of this study, risk-stratified analysis is needed.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

SnO2 nanoparticles/waste masks carbon hybrid materials for DNA biosensor application on voltammetric detection of anti-cancer drug pazopanib

This present study is the first investigation of pazopanib-dsDNA binding using bare and modified GCE. The interaction was mainly evaluated based on the decrease of voltammetric signal of deoxyadenosine by differential pulse voltammetry using three different ways, including the incubated solutions, dsDNA biosensor, and nanobiosensor. The nanobiosensor was fabricated with the help of SnO2 nanoparticles and carbon hybrid material. The carbon material is derived from the waste mask, the most used personal protective equipment for the ongoing COVID-19 pandemic. Both materials were synthesized via the green synthesis technique and characterized by various techniques, including BET, TEM, SEM-EDX, AFM, XPS, and XRD. Spectrophotometric and molecular docking studies also evaluated the pazopanib-dsDNA binding. All calculations showed that pazopanib (PZB) was active in the minor grove region of DNA.

Prediction for optimal dosage of pazopanib under various clinical situations using physiologically based pharmacokinetic modeling.

This study aimed to apply a physiologically based pharmacokinetic (PBPK) model to predict optimal dosing regimens of pazopanib (PAZ) for safe and effective administration when co-administered with CYP3A4 inhibitors, acid-reducing agents, food, and administered in patients with hepatic impairment. Here, we have successfully developed the population PBPK model and the predicted PK variables by this model matched well with the clinically observed data. Most ratios of prediction to observation were between 0.5 and 2.0. Suitable dosage modifications of PAZ have been identified using the PBPK simulations in various situations, i.e., 200 mg once daily (OD) or 100 mg twice daily (BID) when co-administered with the two CYP3A4 inhibitors, 200 mg BID when simultaneously administered with food or 800 mg OD when avoiding food uptake simultaneously. Additionally, the PBPK model also suggested that dosing does not need to be adjusted when co-administered with esomeprazole and administration in patients with wild hepatic impairment. Furthermore, the PBPK model also suggested that PAZ is not recommended to be administered in patients with severe hepatic impairment. In summary, the present PBPK model can determine the optimal dosing adjustment recommendations in multiple clinical uses, which cannot be achieved by only focusing on AUC linear change of PK.

In situ forming oxygen/ROS-responsive niche-like hydrogel enabling gelation-triggered chemotherapy and inhibition of metastasis.

Though the development of the diverse hypoxia-activated prodrugs (HAPs) has made great progresses in the last several decades, current cancer therapy based on HAPs still suffers many obstacles, e.g., poor therapeutic outcome owing to hard deep reaching to hypoxic region, and the occurrence of metastasis due to hypoxia. Inspired by engineered niches, a novel functional chitosan polymer (CS-FTP) is synthesized for construction of a hydrogel-based bio-niche (CS-FTP-gel) in aiming at remodeling tumor hypoxic microenvironment. The CS-FTP polymers are crosslinked to form a niche-like hydrogel via enzyme-mediated oxygen-consumable dimerization after injected into tumor, in which a HAP (i.e., AQ4N) could be physically encapsulated, resulting in enhanced tumor hypoxia to facilitate AQ4N-AQ4 toxic transformation for maximizing efficacy of chemotherapy. Furthermore, Pazopanib (PAZ) conjugated onto the CS backbone via ROS-sensitive linker undergoes a stimuli-responsive release behavior to promote antiangiogenesis for tumor starvation, eventually contributing to the inhibition of lung metastasis and synergistic action with AQ4N-based chemotherapy for an orthotopic 4T1 breast tumor model. This study provides a promising strategy for hypoxia-based chemotherapy and demonstrates an encouraging clinical potential for multifunctional hydrogel applicable for antitumor treatment.

Relation between Plasma Trough Concentration of Pazopanib and Progression-Free Survival in Metastatic Soft Tissue Sarcoma Patients.

Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor approved to treat soft tissue sarcoma (STS) but associated with a large interpatient pharmacokinetic (PK) variability and narrow therapeutic index. We aimed to define the specific threshold of PAZ trough concentration (Cmin) associated with better progression-free survival (PFS) in STS patients. Methods: In this observational study, PAZ Cmin was monitored over the treatment course. For the primary endpoint, the 3-month PFS in STS was analyzed with logistic regression. Second, we performed exposure–overall survival (OS) (Cox model plus Kaplan–Meier analysis/log-rank test) and exposure–toxicity analyses. Results: Ninety-five STS patients were eligible for pharmacokinetic/pharmacodynamic (PK/PD) assessment. In the multivariable analysis, PAZ Cmin < 27 mg/L was independently associated with a risk of progression at 3 months (odds ratio (OR) 4.21, 95% confidence interval (CI) (1.47–12.12), p = 0.008). A higher average of PAZ Cmin over the first 3 months was associated with a higher risk of grade 3–4 toxicities according to the NCI-CTCAE version 5.0 (OR 1.07 per 1 mg/L increase, CI95 (1.02–1.13), p = 0.007). Conclusion: PAZ Cmin ≥ 27 mg/L was independently associated with improved 3-month PFS in STS patients. Pharmacokinetically-guided dosing could be helpful to optimize the clinical management of STS patients in daily clinical practice.

Impact of trial-eligibility as factor for clinical outcome of patients with renal cell carcinoma treated with first-line pazopanib: Subgroup analysis from the prospective, non-interventional study PAZOREAL.

e16511 Background: In a real-world setting, a substantial number of patients (pts) with metastatic renal cell carcinoma (mRCC) do not meet all eligibility criteria for a clinical trial. Thus, data on effectiveness and safety of 1st-line (1L) treatment with pazopanib (PAZO) as well as quality of life (QoL) is underrepresented for those pts and data on treatment sequences implementing PAZO as 1L are sparse. Methods: PAZOREAL is a prospective, multi-center, non-interventional study to evaluate effectiveness, safety and QoL in pts with mRCC treated with 1L PAZO, and nivolumab (NIVO) or everolimus in second and third line. In this subgroup analysis, the clinical outcome of trial-eligible (TE) and trial-ineligible (TIE) pts with mRCC was assessed by means of overall survival (OS), time on drug (ToD), treatment-emergent adverse events (TEAE) and QoL evaluated by EQ-5D-5L. Pts were rated TIE if they met at least one of the following three ‘TIE criteria’: (i) Karnofsky Performance Status &lt; 70%, (ii) hemoglobin below the lower limit of normal, and (iii) non-clear cell carcinoma1. Results: Of 398 pts treated between December 2015 and February 2021, 376 pts received 1L treatment with PAZO. The median age was 69.7 years. 146 pts were categorized TE and 184 pts TIE, for 46 pts assessment was not applicable. Most of all pts were initially treated with PAZO 800 mg (TE: 71.9% vs TIE: 63.0%). Median ToD for PAZO was 7.7 months (95% CI 6.1-9.0) for TE and 6.0 months (95% CI 4.5-8.1) for TIE. A similar fraction of TE and TIE pts were treated with 2L NIVO (43.8% vs 44.0%). Median OS was 53.2 months (95% CI 38.9-NA) for TE and 26.0 months (95% CI 17.3-35.9) for TIE. The 12-month OS rate was 77.9% for TE and 67.1% for TIE. In patient reported outcome (PRO) measures, baseline QoL was estimated higher for TE than TIE, i.e., 63.2% TE vs 49.2% TIE pts had no limitations for mobility and 82.9% TE vs 61.7% TIE pts were independent in self-care. Frequency of related TEAEs grade 3/4 were comparable for TE and TIE (26.7% vs 25.0%), while TE tended to have less related serious TEAEs (13.0% vs 16.3%). Treatment was discontinued due to related TEAEs in 19.2% of TE and 13.0% of TIE pts. Conclusions: PAZOREAL provides real-world data for mRCC pts usually not represented in clinical trials during the study period. As it was to be expected, median OS and PRO were more favorable for TE than for the TIE pts, reflecting the difference in general condition between these groups. But more importantly, these data underline the tolerability of 1L PAZO treatment even for TIE pts, which is supported by comparable ToD for 1L PAZO and the comparable safety profile in both subgroups.1 Marschner, N. et al. Clin Genitourin Cancer 2017; 15(2):e209-215. doi:10.1016/j.clgc.2016.08.022.

Pazopanib in metastatic soft tissue sarcoma (STS): Results of a multi-institutional observational study.

e23542 Background: Soft tissue sarcomas (STS) are a heterogenous group of tumors which have limited therapeutic options and poor prognosis in advanced/metastatic settings. Herein, we present the clinical outcomes of metastatic STS patients treated with pazopanib (PAZ) in real-life. Methods: We retrospectively collected data about adult patients treated with PAZ for metastatic STS in Turkey. We described the clinical characteristics and tumor responses, and estimated the progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. The Cox proportional hazards regression model (HR, 95%CI) was used for evaluation of prognostic factors for PFS. Results: 507 patients (median age: 52 [range: 18-87]; 56.8% female) were included in the analysis. Extremities were the most common primary tumor sites (n:202; 39.8%) followed by abdomen (n:116; 22.9%) and pelvic cavity (n:102;20.1%) where 98% of STSs arose in uterus (n:100). The leading histologic subtypes were leiomyosarcoma (n:192; 37.9%), synovial sarcoma (n:58; 11.4%) and undifferentiated pleomorphic sarcoma (n:48; 9.5%). Of the reported tumor grades (n = 350), 61.4% (n:215) were grade 3. The most common metastatic sites were lungs (52.7%) and liver (20.3%). Doxorubicin plus ifosfamide (45.9%) was the preferred front-line regimen and PAZ was the treatment of choice in second (59.8%) and third-line (61.8%) settings. The median follow-up under PAZ treatment was 5.03 (0.10-84.67) months. Objective response and disease control rates were 31.4% and 42.2%, respectively. Overall, 183 (36.1%) patients were alive at last follow up, 123 of which (67.2%) did not show progression. The median PFS and OS for the study group and the most commonly observed types of STS are shown in Table. Favorable prognostic factors for PFS were low-intermediate tumor grade (HR[95% CI] for grade I and 2 vs 3:1.371[1.016-1.849]; p = 0.039) and ECOG (Eastern Cooperative Oncology Group) score (HR[95% CI] for ECOG score &lt; 2 vs ≥2: 2.698[1.923-3.787]; p = 0.0001). Weakness/asthenia (10.8%), impaired liver function tests (4.7%) and diarrhea (3.6%) were the most common adverse events, no grade 4 or 5 events were observed. Conclusions: This large scale real-life study confirms that PAZ, with its positive impact on clinical outcomes and acceptable tolerability and safety profile is a valuable treatment option for metastatic STS.[Table: see text]

Activity of regorafenib in patients with non-adipocytic soft tissue sarcoma (NASTS): Evaluation of heterogeneity of treatment effect on the updated analysis of pooled cohorts.

11555 Background: Results of the double-blind randomized phase 2 trial (NCT01900743), showed that regorafenib (REG) is an active treatment in patients (pts) previously treated with chemotherapy for an NASTS (cohorts B-leiomyosarcoma, C-synovial sarcoma, D-other sarcoma, Mir 2016), and in pts previously treated with pazopanib (PAZ) (cohort E, Penel 2019). We now present an updated analysis of progression-free survival (PFS) in all NASTS pts to assess the heterogeneity of treatment effect according to histological subtype and prior exposure to PAZ. Methods: Pts received REG 160 mg/d, 21/28 d, or placebo (PB). Pts receiving PB were offered optional cross over in case of centrally confirmed disease progression. The primary endpoint was PFS, according to RECIST-1.1, based on full blinded central review of imaging (including a re-review for cohorts B, C and D, because first analysis was based on a partial central review in these cohorts). Overall survival (OS) was a secondary endpoint. We performed a pooled analysis of cohorts B, C, D and E, on the intent-to-treat dataset, including a multivariate analysis with interaction terms to assess the heterogeneity of treatment effect according to covariates. Results: From 06/2013 to 10/2017, 175 pts were randomized (87 REG vs 88 PB; 56, 27, 55, 37 pts in cohorts B, C, D and E, respectively). The median age was 59 yrs (range, 20-81). There were 101 women (58%). Histological subtype was leiomyosarcoma in 80 pts (LMS; 41 REG vs 39 PB; 56 in cohort B and 24 in cohort E), synovial sarcoma in 28 (SS; 13 REG vs 15 PB; 27 in cohort C and 1 in cohort E), and other sarcoma in 67 (33 REG vs 34 PB; 55 in cohort D and 12 in cohort E). The median number of prior lines of systemic treatment was 2 (range, 1-6). Overall, 43 pts had received prior PAZ (21 REG vs 22 PB). Out of 88 pts assigned to PB, 69 switched to REG after progression (79%). We confirmed a significant PFS-benefit associated with REG in multivariate analysis of the pooled study population, with a HR = 0.48 (95%CI, 0.35–0.66, p &lt; 0.001); median PFS = 2.1 vs 1.0 months, respectively. This benefit appears significant in each histological subtype. However, we observed a borderline interaction between histological subtype and treatment effect (p = 0.09): PFS benefit appears larger in pts with SS (HR = 0.21, 0.10-0.48, p &lt; 0.001) and other sarcoma (HR = 0.49, 0.30-0.81, p = 0.006) than in LMS (HR = 0.59, 0.37-0.93, p = 0.022). PFS benefit appears rather homogeneous across strata of pts with vs without prior exposure to PAZ (interaction test, p = 0.26). Overall, in this study, regorafenib does not show any statistically significant OS-benefit (HR = 0.77, 0.57–1.05, p = 0.10), likely due to the fact that 79% of PB pts crossed over to REG at progression. Conclusions: The present study confirms the clinical PFS benefit associated with regorafenib in all NASTS pts, regardless of prior treatment with pazopanib. Clinical trial information: NCT01900743.

Investigation of Pazopanib and Human Serum Albumin Interaction Using Spectroscopic and Molecular Docking Approaches

Pazopanib (PAZ), a tyrosine kinase inhibitor, is used to treat advanced renal cell carcinoma (RCC) and advanced soft tissue sarcoma (STS). The FDA approved PAZ for RCC in 2009 and for STS in 2012. The antitumor activity of pazopanib, according to the degree of inhibition, shows different results depending on the dose. Renal cell carcinoma is the most sensitive carcinoma to pazopanib, with 77% inhibition at the 10 mg/kg dose. Clinical studies have shown 53% to 65% inhibition in carcinomas such as breast carcinoma, prostate carcinoma, and melanoma. Plasma proteins such as human serum albumin (HSA) have a critical role in transporting and storing bioactive components. This feature of HSA is very important for the development of cancer therapy. Here, we investigated the interaction between PAZ and HSA to evaluate their binding strength, binding types, and conformational change in HSA. We used spectroscopic methods to assess the drug–protein interaction. Fluorescence measurements revealed that the interaction of PAZ with HSA occurred via the static quenching mechanism. The calculated binding number and binding constants were 1.041 and 1.436 × 106 M−1, respectively, at 298.15 K based on fluorescence screening. The high binding constant and calculated Gibbs free energy at different temperatures showed spontaneous and strong binding. Circular dichroism measurements showed that the α-helix structure of HSA was retained as the secondary structure, with a slight reduction in its percentage after adding PAZ. Furthermore, molecular modeling studies suggested that the docking score of PAZ is higher than those of bicalutamide and ibuprofen, the drugs that were chosen as model competitors against PAZ. Accordingly, PAZ was found to replace bicalutamide and ibuprofen on the HSA binding site, which was also confirmed by UV absorption spectroscopy.

Real-word evidence in patients treated with pazopanib for advanced/metastatic renal cell carcinoma (mRCC): The APOLON study.

299 Background: The efficacy and safety of pazopanib (PZP) have been evaluated in pivotal randomized, clinical trials Real-world evidence (RWE) is required to further assess its use, effectiveness and safety in mRCC in clinical routine practices. Methods: APOLON is a non-interventional, multicentric prospective study with mRCC patients who receive frontline PZP treatment. The study is designed to assess PZP Progression-Free Survival (PFS) (under treatment), Overall Survival (OS), Objective Response Rate (ORR) assessed by investigators, tolerability and subsequent post-pazopanib therapy sequences. Impact of COVID-19 on patient’s care was also assessed. Eligible patients were recruited from Nov 2017 to Jan 2019 in 55 participant sites in France. This interim analysis presents results 30 months (mo) after last patient was enrolled in the study. Results: The 217 patients were 71.1% males, with a median age of 69.6 years and had mRCC with a favourable (27.1%), intermediate (52.1%) or poor (20.8%) IMDC risk score according to physician. ECOG-PS was 0, 1 and ≥2 in respectively 43.3%, 39% and 17.6% of patients. Metastases were mainly located in lungs (64.1%), bones (28.6%), mediastinal (18%)/abdominal (17.1%). Patients had an history of partial/total nephrectomy in 54.8% of cases and previous local treatments for metastases in 27.6%. Median PFS, assessed by investigator, was 10.5 mo (95%CI: 9-12.4), similarly in patients &lt; 65-year-old (YO) with 11.3 mo (95%CI: 7-16.3) and in those ≥ 65 YO with 9.9 mo (95%CI: 8.9-12). When assessed according to the IMDC risk score, mPFS was 18.1 mo (95%CI: 9.9-23.3) in favourable, 11.5 mo (95%CI: 8.7-14.4) in intermediate and 6.2 mo (95%CI: 3.5-9.5) in poor mRCC. The median OS was 27.3 mo (95%CI: 24.3 - ND). Investigator-assessed ORR was 48.3% with a CR in 6 patients (3.5%) and a PR in 77 (44.8%). After a median treatment duration of 10.1 mo, 190 patients (87.6%) discontinued PZP and 67.9% received at least one post-PZP line. Second line post-PZP consisted in nivolumab (71.3%), cabozantinib (14.7%), sunitinib (7%) or other (7%). Adverse Event (AE) leading to PZP dose reduction and discontinuation were reported in 42% and 40.9% of patients and treatment-related serious AE in 22.2% of patients. No safety signal was newly identified. The impact of the Covid 19 pandemic was limited on patients’ cares and study follow-up. Visits during the pandemic included 84.1% of tumour evaluation. For 29 patients (14.1%), follow-up visits were carried out as a teleconsultation. Few patients (5,7%) had no visits during the pandemic. Conclusions: The APOLON study confirms PZP effectiveness and safety in patients with mRCC in real-life setting. The efficacy of pazopanib remains significant in patients aged 65 years and older. It is highly associated with risk score. The COVID pandemics had limited impact on patients’ cares.

VEGFa/VEGFR2 autocrine and paracrine signaling promotes cervical carcinogenesis via β-catenin and snail.

VEGF secretion into the tumor microenvironment by cancer cells regulates several oncogenic signaling pathways and cancer-regulated angiogenesis. VEGFR receptors are exclusively present on endothelial cells to maintain their biological homeostasis. The acquisition of unique VEGFR2 receptor and VEGFa in cervical cancer (CC) cells reflects VEGFa/VEGFR2 autocrine machinery. Given the critical role of VEGFR2 in endothelial cell proliferation, migration, and angiogenesis, we explored its function in CC epithelial-mesenchymal transition (EMT) and stemness. Here we report that VEGFR2 regulates cancer-induced angiogenesis and EMT-linked stemness in CC cells via AKT/GSK3β/β-catenin and Snail pathway. Receptor tyrosine kinase inhibitor (RTKi) of VEGFR, Pazopanib (PAZ), shows potential anti-VEGFR2 activity and inhibits VEGFa induced metastatic events such as migration, invasion, and anoikis resistance in CC cells. Similarly, PAZ also attenuates cancer-regulated angiogenesis by inhibiting VE-cadherin internalization in endothelial cells followed by inhibition of endothelial cell migration. Selective depletion of VEGFR2 ligand VEGFa in CC cells also attenuates EMT, metastatic events, and inhibition of cancer-induced angiogenesis. In addition, blocking of VEGFR2 signaling in CC cells via PAZ or shRNA alters the formation of cervical tumorspheres (TS) and their successive generation. Collectively, inhibition of functional VEGFa/VEGFR2 autocrine and paracrine axis ceases the cancer-promoting events in cervical cancer cells. Based on the finding in this study, this oncogenic pathways could be used as a potential therapeutic target in a clinical setting with conventional radio-chemotherapy to achieve synergistic killing of CC cells.

1549P Pazopanib exposure in advanced soft tissue and bone sarcoma: A pharmacokinetic/pharmacodynamic analysis

Pazopanib (PAZ) is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma (RCC) and soft tissue sarcoma (STS). A relationship was reported between PAZ trough concentration (Cmin) and progression free survival (PFS) in RCC (Suttle A.B. 2015; Verheijen R.B. 2017). However, information on the exposure-efficacy relationship in sarcoma remains sparse. A PAZ Cmin threshold of 27 mg/L was determined in an exploratory study (Bellesoeur A. 2017).

Low-dose metronomic topotecan and pazopanib in children with recurrent or refractory solid tumors: A C17 Canadian phase I trial (TOPAZ).

10020 Background: Low-dose metronomic topotecan (mTP) represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib (PZ) in targeting angiogenesis. This study was designed to determine the recommended phase 2 dose (RP2D) of mTP/PZ in pediatric patients with solid tumors, while describing the safety and toxicity of this regimen. Methods: A phase I dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) study of mTP/PZ was conducted at ten sites across Canada, enrolling pediatric patients aged 2-21 years with relapsed/refractory solid tumors. Patients were treated with oral mTP and PZ suspension daily without interruption in 28-day cycles, with dose escalation in accordance with the rolling-six design. Five dose levels (0.12/125, 0.16/125, 0.22/125, 0.22/160, and 0.3/160 mg/m2/day of mTP/PZ) were evaluated. PK studies were performed on day 1 and at steady state, and PD studies included circulating angiogenic factors VEGFR1, VEGFR2, VEGF, endoglin and placental growth factor. Results: Thirty patients (pts) were enrolled, of whom 26 were evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). The most common diagnoses included osteosarcoma (8), neuroblastoma (NB, 7), Ewing sarcoma/PNET (4), and rhabdomyosarcoma (4). The most common grade 3/4 adverse events (AEs) related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphocytopenia (11%), AST elevation (11%), and lipase elevation (11%). Only 2 cycle-1 DLTs were observed on study, both at the 0.3/160 mg/m2 mTP/PZ dose level (2/5 pts) comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle-1 required treatment discontinuation. Best response was stable disease in 10/25 pts (40%) for a median duration of 6.4 months (1.7-45.1). One patient with refractory NB achieved stable disease for 45 months and continued on mTP/PZ via compassionate access after study closure. PK and PD results are pending at this time. Conclusions: The combination of oral mTP and PZ is safe and tolerable in pediatric patients with solid tumors, with a RP2D of mTP 0.22 mg/m2/day and PZ suspension 160 mg/m2/day. Ten patients achieved stable disease for a median of 6 months. The lack of objective responses suggests that this combination is likely of limited benefit for relapsed disease, but may play a role as maintenance therapy. Clinical trial information: NCT02303028.