Dose Of Pazopanib Research Articles

Therapeutic drug monitoring to personalize dosing of imatinib, sunitinib, and pazopanib: A mixed methods study on barriers and facilitators.

Personalized dosing based on measurement of individual drug levels and adjusting the dose accordingly can improve efficacy and decrease unnecessary toxicity of oncological treatment. For imatinib, sunitinib, and pazopanib, this therapeutic drug monitoring (TDM)-guided dosing is, however, not routinely used, despite accumulating evidence favoring individualized dosing. Therefore, we aimed to identify and quantify (potential) barriers and facilitators in TDM-guided dosing for imatinib, sunitinib, and pazopanib. We performed a mixed methods study among all stakeholders involved: patients, healthcare professionals (HCPs), pharmaceutical companies, and health insurance companies. During the first qualitative part of this study, we performed semi-structured individual interviews and one focus group interview to identify all (potential) barriers and facilitators, and during the second quantitative part of this study, we used a web-based survey to quantify these findings. The interviews addressed the six domains of the implementation of change model of Grol and Wensing: (1) the innovation itself; (2) the HCP; (3) the patient; (4) social context; (5) organizational context; and (6) finances, law, and governance. In the qualitative study, we interviewed 20 patients, 18 HCPs and 10 representatives of pharmaceutical and health insurance companies and identified 72 barriers and 90 facilitators. In the quantitative study, the survey was responded by 66 HCPs and 58 patients. Important barriers were on the domain of the HCP, such as a lack of experience with TDM (36.4%), on the domain of the patient, such as lack of awareness of TDM (39.7%), and the processing time for measurement and interpretation of the TDM result (40.9%) (organizational domain). Important facilitators were education of HCPs (95.5%), education of patients (87.9%) and facilitating an overview of when and where TDM measurements are being performed (86.4%). We identified and quantified important barriers and facilitators for the implementation of TDM-guided dosing for imatinib, sunitinib, and pazopanib. Based on our results, the implementation strategy should mainly focus on educating both HCPs and patients and on the organizational aspect of TDM.

Pazopanib with Topotecan weekly for patients with platinum-resistant or intermediate-sensitive recurrent ovarian cancer: results of a multicentre, open label phase I/II study (TOPAZ)

PurposePazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC).MethodsPatients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m2 (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT 01600573.ResultsBetween June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3–4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0—5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment.ConclusionThe combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit.

Prolonged disease control with pazopanib following radiation of primary tumor for locally advanced and metastatic soft tissue sarcoma.

e23563 Background: Pazopanib is approved for second or later line therapy for advanced soft tissue sarcoma (STS). Whether or not Pazopanib and radiation have cooperative effect remains unclear. Methods: We retrospectively reviewed 10 patients with locally advanced or metastatic soft tissue sarcoma treated with pazopanib either at the start of radiation or within 4 weeks after the start of radiation. Results: Seven patients were females and age ranged 39-80. Four patients had undifferentiated pleomorphic sarcoma (UPS), two leiomyosarcoma (LMS), two synovial sarcoma (SS), and two dedifferentiated liposarcoma (DDLS). All patients had a large primary tumor that was unresectable with or without distant metastasis. The disease burden with the distant metastasis was low for patients with metastatic disease. Radiation was delivered to the large primary tumor with dose ranging from 15 to 50 Gy (median dose 30 Gy). Pazopanib dose ranged from 400 to 800 mg (majority received 600-800 mg). Eight patients had received one to two lines of chemotherapy previously. Three patients whose pazopanib treatment is still ongoing with stable disease (SD) at 4 (UPS), 25 (LMS), and 26 (DDLS) months respectively. One patient (UPS) with SD discontinued Pazopanib after 3.5 months due to liver toxicities. One patient with SS obtained PR that lasted for 11 months and one patient with SS had SD for 12 months. One patient with relapsed abdominal DDLS obtained a PR followed by resection of residual tumor 8 months after the start of Pazopanib, however, disease relapsed again 3 months after the resection. Three other patients had SD for 8, 8 and 13 months respectively. Conclusions: Our results suggest that Pazopanib at the start or within 4 weeks of radiation in palliative dose can achieve prolonged disease control for patients with locally advanced or metastatic STS. This approach can be considered for selective STS patients with large primary tumor and low distant disease burden.

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 < 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.

Discrimination of hand-foot skin reaction caused by tyrosine kinase inhibitors based on direct keratinocyte toxicity and vascular endothelial growth factor receptor-2 inhibition

Tyrosine kinase inhibitors (TKIs) are molecular-targeted anticancer drugs. Their benefits are limited by dermal toxicities, including hand-foot skin reaction (HFSR), which is commonly found in skin areas subjected to friction. The present study aimed to explain the incidence of HFSR in patients treated with TKIs by focusing on keratinocyte toxicity and inhibition of vascular endothelial growth factor receptor (VEGFR), which plays an essential role in angiogenesis. Mice with gene knockout for the immunosuppressive cytokine interleukin-10 exhibited HFSR-like phenotypes, such as cytotoxicity in keratinocytes and increased number and size of blood vessels after repeated doses of regorafenib, sorafenib, and pazopanib, all of which cause high incidence of HFSR, in combination with tape-stripping mimicking skin damage at the friction site. Comprehensive examination of the direct cytotoxic effects of 21 TKIs on primary cultured human keratinocytes revealed that 18 of them reduced the cell viability dose-dependently. Importantly, the ratio of the trough concentration in patients (Ctrough) to the LC50 values of cell viability reduction was higher than unity for four HFSR-inducing TKIs, suggesting that these TKIs cause keratinocyte toxicity at clinically relevant concentrations. In addition, eight HFSR-inducing TKIs caused inhibition of VEGFR-2 kinase activity, which was validated by their ratios of Ctrough to the obtained IC50,VEGFR-2 of more than unity. All 12 TKIs with no reported incidence of HFSR exhibited less than unity values for both Ctrough/LC50,keratinocytes and Ctrough/IC50,VEGFR-2. These results suggested that a combination of keratinocyte toxicity and VEGFR-2 inhibition may explain the incidence of HFSR upon TKI usage in humans.

Research Highlights

Research Highlights

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation.

Simple SummaryThe use of multi-gene testing platforms to individualize treatment is rapidly expanding into routine oncology practice. UGT1A1, which encodes for the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme, is commonly included on multi-gene molecular testing assays. UGT1A1 polymorphisms may influence drug-induced toxicities of numerous medications used in oncology. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is sparse and can differ depending on the referenced resource. We summarize the literature describing associations between UGT1A1 polymorphisms and toxicity risk with irinotecan, belinostat, pazopanib, and nilotinib. Resources that provide recommendations for UGT1A1-guided drug prescribing are reviewed, and considerations for implementation into patient care are provided.Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.

Outcomes of starting low-dose pazopanib in patients with metastatic renal cell carcinoma who do not meet eligibility criteria for clinical trials

Purpose: Eligibility for clinical trials is very strict and only patients who satisfy various criteria can enter trials. The individual use of pazopanib has not been adequately investigated. An optimal administration regimen for pazopanib in “real-world” patients with metastatic renal cell carcinoma (mRCC) is required. Our purpose was to determine the tolerability and efficacy of first-line pazopanib with a low starting dose in patients with mRCC who were ineligible for clinical trials. Materials and Methods: This study included patients with mRCC who underwent treatment with first-line pazopanib and were previously excluded from clinical trials because they did not meet the inclusion criteria. A 400 mg pazopanib starting dose is used routinely in patients with mRCC; if tolerated, dose escalation up to 800 mg may occur. Results: We identified 18 patients with mRCC who received first-line pazopanib and were previously determined ineligible for clinical trials. Pazopanib dose was escalated in 12 patients (66.6%), to 600 mg/day in 8 patients (44.4%) and to 800 mg/day in 4 patients (22.2%), and was not escalated in 6 patients (33.3%). In 3 patients (16.7%), pazopanib was discontinued owing to intolerability. The most common frequent adverse event was elevated alanine aminotransferase levels in 6 patients (33.3%), followed by a decreased platelet count in 5 patients (27.8%) and anorexia in 5 patients (27.8%). Partial response was seen in 5 patients (27.8%) and stable disease in 10 patients (55.6%); median progression-free survival was 11.9 months (95% confidence interval: 6.3–28.7 months). Conclusion: Our data indicated that a low starting dose of 400 mg pazopanib did not negatively affect treatment tolerability and efficacy in patients with mRCC ineligible for clinical trials. We found that lower starting doses may lead to better results. Additional studies are needed in a larger cohort and longer follow-up to attain authentic outcomes.

Outcomes based on age in patients with metastatic renal cell carcinoma treated with first line targeted therapy or checkpoint immunotherapy: Older patients more prone to toxicity

ObjectivesOlder patients with metastatic renal cell carcinoma (mRCC) were underrepresented in pivotal trials. Materials and methodsConsecutive patients with mRCC treated at Aarhus University Hospital with first line tyrosine kinase inhibitors (TKI), mTOR inhibitors, or checkpoint immunotherapy (CPI) were retrospectively analyzed in age-subgroups; ≥ 75, 65–74, and < 65 years, with overall survival (OS), time-to-treatment discontinuation (TTD), and progression-free survival (PFS) as endpoints. Hazards ratios were adjusted (aHR) for International Metastatic RCC Database Consortium (IMDC) risk factors, histology, and age. ResultsOf 838 patients, 159 (19%) were ≥ 75 years, 324 (39%) 65–74 years, and 355 (42%) < 65 years. Treatments were TKI in 729 (87%) patients, mTOR in 43 (5%) and CPI in 67 (8%). Older patients ≥ 75 years compared with 65–74 years and < 65 years had lower toxicity-adjusted median doses of pazopanib, 300 mg vs. 400 mg vs. 600 mg, respectively, (p < 0.001), and sunitinib, 25 mg vs. 37.5 mg vs. 50 mg, respectively (p < 0.001); numerically fewer doses of CPI, median 2 vs. 5 vs. 5, respectively, (p = 0.2); a higher proportion had dose reduction/interruption, 76% vs. 55% vs. 41%, respectively, (p < 0.001); and shorter mean time to dose reduction/interruption, 0.5 months vs. 1.9 months vs. 3.4 months, respectively, (p < 0.001). After adjusting IMDC prognostic factors and histology in multivariate analyses, age did not impact OS (aHR 1.0; 95% CI 0.99–1.02, p = 0.2), TTD (aHR 1.0; 95% CI 0.99–1.01, p = 0.4) or PFS (aHR 1.0, 95% CI 0.99–1.01; p = 0.9). ConclusionOlder patients with mRCC were more prone to toxicity; but age did not impact outcomes. Proactive dose modification/interruption and awareness may help to reduce toxicity while maintaining efficacy.

SP4 Medicines optimisation in action: the development of a dosing schedule and an extemporaneous formulation of pazopanib to treat a child with a recurrent desmoid tumour of the head and neck

BackgroundInternational experts recommended pazopanib to treat a 9 year old boy with a recurrent desmoid tumour. The tumour had progressed, leading to blockage of the airway and dysphagia. The child had previously received three lines of intravenous chemotherapy as well as surgery and local radiotherapy. Treatment intent was to give an effective oral therapy with minimal side effects aiming to maintain a reasonable quality of life and prevent further life threatening respiratory compromise. As the child had an unsafe swallow, the drug would need to be given via a gastrostomy tube.Pharmacy InputA literature review was completed to establish the evidence to support the use and dose of pazopanib to treat desmoid type tumours in children.1 2 Attempts made to find a commercial supply of pazopanib liquid yielded no results. In the absence of any data or experience from other principal children’s cancer centres in the UK, first principles were used to review the physico-chemical properties of the molecule. Given the highly insoluble nature of pazopanib, an extemporaneous formulation for a pazopanib suspension was developed using Orasweet®, by adapting a formula suggested by the University of Oklahoma.3 A risk assessment for the preparation process was completed and a mini isolator was re-commissioned for this purpose following appropriate testing by Quality Control. The Department of Pharmacology at Newcastle University were contacted to establish if therapeutic drug level analysis might be possible. Local approval for pazopanib use was obtained from the Drug and Therapeutic Group and an IFR was submitted to NHS England.ChallengesIt was challenging to establish a dose regimen since the recommended paediatric dose from Phase I studies of pazopanib were dependent on the formulation used.1 4 Pharmacokinetic sampling was not possible as no assay had been developed in the UK. The lack of availability of any commercial or compassionate use liquid preparation meant that the only way of giving the drug to this child was to prepare an extemporaneous preparation, despite paucity of evidence to support the stability of the preparation. Funding was not approved by NHS England; local funding was agreed.Outcome and DiscussionThe child commenced treatment with the suspension in October 2018, administered via the gastrostomy tube. By July 2019 the patient had completed 10 cycles of therapy. Treatment was well tolerated. Minor side effects included abdominal and leg pain, vomiting, and a change in hair colour. The patient has had a good clinical response and a recent scan has shown substantial improvements in morphological appearance and size of the tumour.These results indicate that a locally prepared extemporaneous oral chemotherapy suspension can be successfully used to deliver treatment for a rare type of children’s cancer. Pharmacy colleagues from across the department collaborated to facilitate this novel treatment option.ReferencesGlade Bender J, Lee A, Reid J, et al. Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children’s oncology group phase I consortium report. JCO 2011;31:3034–3043.Agresta L, Lee H, Turpin B, et al. Pazopanib therapy for desmoid tumors in adolescent and young adult patients. Pediatr Blood Cancer 2018;65:e26968.Allen L Jr. Pazopanib 50 mg/ml oral suspension. US Pharm 2015;40:61–62.Heath E, Forman K, Malburg L, et al. A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors. Invest New Drugs 2012;30:1566–1574.

Pazopanib for metastatic soft-tissue sarcoma: A multicenter retrospective study

Soft tissue sarcomas are associated with a poor prognosis and low chemotherapeutic efficiency. Pazopanib is an orally available multi-tyrosine kinase inhibitor that was explored in patients with non-adipocytic advanced soft tissue sarcomas. The aim of this retrospective study was to evaluate the real life data of single-agent pazopanib efficacy and safety for soft tissue sarcomas in the Turkish population. We evaluated a total of 103 patients (41 males, 62 females) who received pazopanib for advanced non-adipocytic soft tissue sarcomas diagnosis in eight centers of Turkey, retrospectively. The pazopanib dose was 800 mg once daily. Progression-free survival, overall survival, and adverse events were analyzed. The median age was 50 years (range, 38-58). Majority of the patients had leimyosarcoma (41%). Median progression-free survival was 4.3 months, and the median overall survival was 10.1 months. The main common toxicities were fatigue, anorexia, weight loss, nausea, hypertension, and grade ≥3 toxicities were fatigue, anorexia, weight loss, and liver disorder. Pazopanib is an efficient and tolerable agent and is well tolerated in good performance status patients with relapsed, advanced non-adipocytic soft tissue sarcomas.

Possibility for Dose Optimization of Pazopanib from Its Plasma Concentration in Japanese Patients with Cancer.

The currently approved dose of pazopanib (800 mg) is being re-examined owing to its adverse effects. The aim of this study was to evaluate the relationships among starting or maintenance doses of pazopanib, estimated pazopanib Cmin, and other clinical factors, including albumin and α-1 acid glycoprotein levels, in soft-tissue sarcoma and renal cell carcinoma. We also determined whether therapeutic drug monitoring of pazopanib concentrations may be used to improve its therapeutic efficacy and prevent adverse effects. Forty patients who received pazopanib for renal cancer or soft-tissue sarcoma at the Hokkaido Cancer Center were evaluated prospectively. Cmin for pazopanib was calculated based on the measured values from the plasma samples. The efficacy and time to treatment failure were then assessed. The pazopanib maintenance doses were 200 (n = 4), 400 (n = 34), 600 (n = 4), and 800 mg (n = 1). Most patients (65%) who received a 400 mg dose had an effective pazopanib concentration (≧20 µg/mL), whereas 35% of patients who received the 400 mg dose had ineffective concentrations (<20 µg/mL). Logistic regression analysis revealed that only the albumin level was significantly associated with effective pazopanib concentrations (odds ratio: 1.37, p = 0.0234). In conclusion, a dose of 400 mg had been effective and well tolerated in more than half of patients in this study. However, therapeutic drug monitoring is necessary during pazopanib therapy.

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Tyrosine kinase inhibitors (TKIs) are anti‐cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure‐treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs.In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.

Pazopanib in the Treatment of Bone Sarcomas: Clinical Experience

BACKGROUND: The effect of chemotherapy in metastatic bone sarcomas is poor and the condition is invariably fatal. Therefore, new treatment modalities are intensely needed. Pazopanib is a selective multitargeted tyrosine kinase inhibitor that has proven to be effective in the treatment of metastatic soft tissue sarcomas. The objective of this study was to evaluate the off-label use of pazopanib in patients with metastatic bone sarcomas who failed standard chemotherapy. METHODS: All patients with metastatic bone sarcomas treated with pazopanib between October 1st, 2011 and October 1st, 2017 at the Department of Oncology, Aarhus University Hospital were evaluated. Demographics, treatment, and survival outcomes were collected and analyzed. RESULTS: Nineteen patients were identified. The median age was 38 years (range 18–62). Most of the patients (50%) were diagnosed with osteosarcoma. All patients had documented disease progression at the time of initiating pazopanib treatment. The median overall survival was 11 months. Median progression free survival was 5.4 months. Out of 19 patients, 13 (68%) had either partial response or stable disease. In five patients, the dose of pazopanib was reduced because of toxicity. CONCLUSION: Off-label use of pazopanib is effective in the treatment of metastatic bone sarcomas of different histologies. Pazopanib was well tolerated in the treatment of patients with refractory bone sarcomas. Studies examining the effect of pazopanib alone or in combination with chemotherapy or other targeted therapies are needed.

Real-World Effectiveness and Tolerability of Pazopanib as First Targeted Therapy in Metastatic Renal Cell Carcinoma: A Retrospective Chart Review in Latin America

Pazopanib is approved in Latin America as first targeted therapy for patients with metastatic renal cell carcinoma (mRCC). A retrospective chart review of adult patients with mRCC who initiated pazopanib as first targeted therapy between January 2011 and March 2016 was conducted among oncology care centers in Argentina, Brazil, Chile, Colombia, and Mexico. Patient characteristics, treatment patterns, overall survival (OS), progression-free survival (PFS), and adverse events were summarized. A total of 156 charts of patients with mRCC receiving first-line pazopanib were reviewed (29, 54, 27, 28, and 18 patients from Argentina, Brazil, Chile, Colombia, and Mexico, respectively). The mean age at initial mRCC diagnosis was 61.6years, 73.7% were male, and 51.3% were Hispanic. The median dose of pazopanib was 800mg and the median time from initial mRCC diagnosis to pazopanib start was 2.2months. The median time on treatment was 10.0months. At the time of data extraction, 16.7% of patients remained on pazopanib, with clinical progression listed as the main reason for discontinuation. Subsequent therapy was received by 25.6% of patients; the most common were everolimus (9.6%) and axitinib (5.8%). Overall, median PFS and OS were 10.8 and 16.9months, respectively, and varied across countries. The most common all-grade adverse events were diarrhea (44.9%), asthenia/fatigue (43.6%), and nausea (28.8%). Pazopanib was used for first-line mRCC treatment in a clinically diverse patient population across Latin America. Real-world PFS and tolerability were similar to clinical studies of pazopanib. Novartis Pharmaceuticals Corporation, Inc.

1677PD - A phase II study of pazopanib as front-line therapy in patients with non-resectable or metastatic soft tissue sarcomas who are not candidates for chemotherapy

BackgroundAnthracycline based chemotherapy remains the standard of care for first-line treatment for advanced and metastatic soft tissue sarcoma. In some instances, patients may not be a candidate for chemotherapy based on age or other comorbidities leaving no viable treatment option. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA approved as a second-line and beyond treatment for metastatic soft tissue sarcoma. We proposed a phase II study to evaluate pazopanib as a first-line agent in patients with non-resectable or metastatic disease who are not candidates for cytotoxic chemotherapy. MethodsEligible patients were at least 18 years old, not a candidate for chemotherapy, and had not received prior systemic therapy for sarcoma. Initial starting dose of pazopanib was 200mg BID titrated to 800mg daily. The primary endpoint was clinical benefit rate (CBR) (CR + PR + SD per RECIST 1.1) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesized CBR of≥35% against an unfavorable CBR of≤20%. If≥17 patients achieved benefit, the null CBR of 20% would be rejected would be rejected at a nominal 5% alpha level (actual alpha=0.043). Secondary endpoints included PFS rate, OS, quality of life, and serum biomarkers. Results56 patients are included in the intention-to-treat analysis. Currently 52 patients are evaluable for CBR. Data from the final 4 patients will be added at the time of presentation. Median PFS was 12 (8.29∼24.14) weeks and PFS rate at 16 weeks was 40% (CI 0.2893-0.5617). Median OS was 8.6 months, CBR=36.5% (19/52), 95% CI=0.2362∼0.5104, 2-sided exact binomial test p=0.00507. No new or unexpected adverse events were seen. The most common Grade I-II adverse events were diarrhea, nausea, and anemia. The most common grade III-IV adverse events were hypertension and liver function test (LFT) abnormalities. Longitudinal quality of life analysis will be added at the time of presentation as well. ConclusionsGiven that the primary endpoint was met, these data suggest that there is a benefit to front-line pazopanib in patients who are not candidates for cytotoxic chemotherapy. Clinical trial identificationNCT02300545. Legal entity responsible for the studyWashington University in St Louis. FundingNovartis/GSK. DisclosureM. Agulnik: Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Bayer. M. Varun: Travel / Accommodation / Expenses: Deciphera; Research grant / Funding (institution): Immunocellular; Research grant / Funding (institution): Orbus Therapeutics. M. Milhem: Advisory / Consultancy: Amgen; Advisory / Consultancy: Trieza; Advisory / Consultancy: Biontech; Advisory / Consultancy: Blueprint medicine cooperation; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Array BioPharma, Inc. S. Robinson: Research grant / Funding (institution): TRACON; Honoraria (institution), Advisory / Consultancy: BTG International; Honoraria (institution), Advisory / Consultancy: Society of Interventional Radiology Foundation. S. Attia: Research grant / Funding (institution): AB Science; Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (institution): CytRX Corporation; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Immune Design; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): BluePrint Medicine; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): CBA Pharma; Research grant / Funding (institution): Desmoid Tumor Research Foundation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Philogen; Research grant / Funding (institution): Laboratories; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): BTG; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): FORMA Therapeutics. B.A. Van Tine: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Tracon; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Adaptimmune; Speaker Bureau / Expert testimony: Caris; Advisory / Consultancy: Bayer. All other authors have declared no conflicts of interest.

Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction, Safety, and Patient Outcomes.

Pazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes. Patients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods. Of 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P= .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P= .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism. UGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanib-induced liver toxicity in patients with mRCC.

Results of the dose-finding phase of ARST 1321 from the Children's Oncology Group and NRG Oncology: Neoadjuvant chemoradiation or radiation therapy +/- pazopanib in non-rhabdomyosarcoma soft tissue sarcomas.

11070 Background: Pazopanib is a tyrosine kinase inhibitor approved globally for advanced soft tissue sarcomas. The dose finding phase of this cooperative group trial assessed the dose limiting toxicities (DLT) and the maximally tolerated dose (MTD) of adding pazopanib to neoadjuvant chemoradiation or radiation therapy in children and adults with unresected intermediate/high-risk trunk and extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Methods: ARST1321, a jointly designed intergroup study lead by Children's Oncology Group and NRG Oncology opened for enrollment in July 2014. Eligible adult and pediatric patients with newly diagnosed, unresected trunk/extremity NRSTS with plans for primary tumor resection were enrolled into either the Chemotherapy Cohort (those with chemosensitive NRSTS &gt; 5 cm, grade 3, including all synovial sarcoma) or the Non-Chemotherapy Cohort (those with chemotherapy insensitive NRSTS of any size, grade 2/3, or any chemosensitive NRSTS for whom no chemotherapy was planned per discretion of patients and treatment teams). In the Chemotherapy Cohort, pazopanib was given with ifosfamide (7.5 grams/m2) and doxorubicin (75 mg/m2) plus 45 Gy preoperative RT starting after cycle 2. Primary tumor was resected at week 13, followed by chemotherapy and pazopanib to week 25. In the Non-Chemotherapy Cohort, pazopanib was given with 50 Gy preoperative RT, primary tumor was resected at week 10, and pazopanib continued to week 25. Feasibility was assessed through week 6 of therapy to determine pazopanib dose escalation/de-escalation based on DLT, total doses of pazopanib, and overall adverse event profile. Results: In the Chemotherapy Cohort, MTD was reached at Dose Level 1 (350 mg/m2 peds; 600 mg adults) with two DLTs (1 grade 3 ALT rise, 1 intolerability to therapy) in 10 patients. In the Non-Chemotherapy Cohort, 11 patients enrolled at Dose Level 1 (350 mg/m2 peds; 600 mg adults) without any observed DLTs and all received ≥75% of prescribed total pazopanib dose; MTD was reached at Dose Level 2 (450 mg/m2 peds; 800 mg adults) with 2 DLTs in ten patients enrolled (1 grade 3 dermatitis and 1 intolerability to therapy) and 9/10 receiving ≥75% of full dose. Conclusions: Pazopanib in combination with chemoradiation or radiation therapy alone was found to be safe in children and adults with NRSTS. Following this finding, ARST1321 opened in both arms using the newly determined pazopanib MTDs. Clinical trial information: NCT02180867.

A reduced pazopanib dose with food: Is it more patient-friendly and does it reduce drug costs?

4564 Background: Pazopanib has been licensed for advanced soft tissue sarcoma and metastatic renal cell carcinoma in a fixed oral daily dose of 800mg taken fasted. We hypothesized that ingesting pazopanib with food may improve patients’ comfort and reduce gastro-intestinal adverse events. Moreover, a food intervention, resulting in a better absorption, can lead to a lower dose, which could significantly reduce treatment costs. Methods: Part 1 of the study was performed to determine whether 600mg pazopanib taken with a continental breakfast was bioequivalent to 800mg pazopanib taken fasted. In part 2, differences in GI-toxicity and patient satisfaction were assessed by the cancer-therapy-satisfaction-questionnaire after both intake regimens. Finally, patient’s preference for either intake regimen was asked. Results: 16 patients were included in the bioequivalence study. The geometric mean ratio (fed/fasted) of the area under the plasma concentration time curve was 1.10 (90% CI 1.00-1.19), maximum peak concentration was 1.12 (90% CI 1.02-1.22) and pazopanib trough concentration was 1.10 (90% CI 1.02-1.18). In part 2, 60 patients were included. No differences were seen in the occurrence of GI-toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects (72.3(95% CI 68.1-76.5) vs 68·2 (62.7-73.6); p=.092) and satisfaction with therapy scores were higher (84.7(95% CI 81.4-87.9) vs 81.9 (78.7-85.2); p= .059) when pazopanib was taken with food. 41 (68%) of the patients preferred the intake with continental breakfast. Conclusions: Intake of 600mg pazopanib with food results in bioequivalent exposure and was preferred over a standard pazopanib dose without food. Moreover, with this simple food intervention a large cost reduction can be realized in patients treated with pazopanib. Clinical trial information: NCT02138526.

Efficacy of low dose pazopanib in advanced soft tissue sarcoma (STS): Experience from a dedicated sarcoma medical oncology clinic in India.

e22555 Background: The approved dose of pazopanib in advanced STS is 800 mg/day and is not weight based. After initial patients who couldn’t tolerate pazopanib we started pazopanib at lower doses escalating to higher doses. There is already preliminary data about low dose pazopanib in asian patients. Methods: We retrospectively analysed the prospectively kept data base of patients with advanced non adipocytic STS who were treated with pazopanib at AIIMS sarcoma medical oncology clinic between September 2015 and February 2019. After start of pazopanib we get CT scan done every 3 monthly as institutional protocol. Statistical analysis was done by SPSS 23. Results: There were total of 66 patients with median age 40 yrs (17 – 81)and majority were males who (60). ECOG Performance status (PS) was PS 1 in 63% and PS 2 in 23%. Most common diagnosis was synovial sarcoma (22%), leiomyosarcoma (18 %), angiosarcoma (9%), MPNST(8%) and others (43%). Most of the patients received pazopanib as second line (59%) and third line (31%). 90% of patients received dose of 400 mg and remaining 10% of the patients received 600 mg of dose (in which it could be escalated after 1 month). Median weight was 63kg and median height in our patients was 160cm while the median BSA was 1.6. Dose escalation was attempted, but was not feasible due to toxicities. Out of total 66 patients, 57 were available for response assessment. RECIST responses were complete response (CR) was present in 2.9%, partial response (PR) in 17% , stable disease (SD) in 28%. The median progression free survival (PFS) was 5 months and median overall survival was 18 months after a median duration of follow up of 20 months. Grade 3 and grade 4 toxicities were present in 31% of the patients. Grade 3 hand foot syndrome (HFS) was present in 12% of patients.4.5% had hypertension. Other grade 3 and 4 toxicities were oral mucositis (6%) , transaminitis (4%) Cardiomyopathy (3%) and cholestasis jaundice (1.5%) with bilirubin elevated to the level on 19.1 mg/dl. This resolved after stoppage of Pazopanib. Conclusions: Pazopanib at low doses in our series was as efficacious and with similar toxicity as previous literature The option of lower dose pazopanib needs to be explored in Asian population who have lower body weight.