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Indian Journal of Cancer 2019There is no study till date determining the spectrum of adverse events of pazopanib in Indian patients with advanced sarcoma. (Clinical Trial)
Clinical Trial
PURPOSE
There is no study till date determining the spectrum of adverse events of pazopanib in Indian patients with advanced sarcoma.
MATERIALS AND METHODS
We conducted a retrospective study by analyzing the case records of metastatic sarcoma patients treated with pazopanib from January 2016 to July 2017 in sarcoma medical oncology clinic. Toxicity was assessed according to CTCAE v.4.03 criteria. SPSS version 23 was used for statistical evaluation.
RESULTS
A total of 33 patients received pazopanib. The median age was 41 years (range, 19-75 years), with a male predominance (54.5%). Twenty-six patients (78.8%) had ECOG performance status 1 at the time of pazopanib initiation. The most common type of sarcoma was synovial sarcoma, and the mean duration of pazopanib intake in patients was 4.12 months. The median follow-up was 13 months. Median progression-free survival was 5 months, and median overall survival was 18 months. Overall response rate was 6.0%. Out of the 33 patients, 42.4% (n = 14) received it after first line of therapy. Six patients (18.2%) required dose reductions due to toxicity. Thirteen (39.4%) patients experienced CTCAE grade 3 or 4 toxicities. Most common grade 3 and 4 toxicities experienced among patients were hand-foot skin reaction (18.2%) and proteinuria (9.1%). No significant difference was seen when analyzed for variables such as age, sex, ECOG performance status, comorbidities, and number of previous lines received in patients experiencing grade 3 and 4 toxicities.
CONCLUSIONS
The spectrum of adverse events in Indian patients at doses lower than the recommended dose is distinctly different from the western population. However, this unique toxicity profile needs to be validated in prospective studies.
Topics: Adult; Aged; Angiogenesis Inhibitors; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Indazoles; Male; Middle Aged; Prognosis; Pyrimidines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Survival Rate; Young Adult
PubMed: 31389382
DOI: 10.4103/ijc.IJC_105_18 -
Clinical Pathology (Thousand Oaks,... 2019Cardiac sarcoma treatment is challenging for surgeons because of frequent tumor recurrence and poor prognosis. In addition, optimal management of recurrences is not well...
Cardiac sarcoma treatment is challenging for surgeons because of frequent tumor recurrence and poor prognosis. In addition, optimal management of recurrences is not well established. The multi-targeted tyrosine kinase inhibitor, pazopanib, was recently approved for soft-tissue sarcoma. Herein, we present a case involving recurrent cardiac angiosarcoma where the patient survived for 2 years with complete remission of disease after repeated surgical resection and treatment with oral pazopanib. Based on our experience, aggressive surgical resection combined with pazopanib may be a valid treatment for recurrent cardiac angiosarcoma to improve patient survival.
PubMed: 31211293
DOI: 10.1177/2632010X19831261 -
British Journal of Cancer Aug 2021Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have...
BACKGROUND
Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma.
METHODS
This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort.
RESULTS
57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients.
CONCLUSIONS
In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Prospective Studies; Pyrimidines; Sarcoma; Sulfonamides; Topotecan; Treatment Outcome; Young Adult
PubMed: 34050255
DOI: 10.1038/s41416-021-01448-0 -
Advances in Therapy Jul 2017Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past... (Review)
Review
UNLABELLED
Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past few decades owing to the adoption of a multidisciplinary approach, patients with advanced disease have a poor prognosis. The development of anticancer drugs has been directed toward improving overall survival (OS). Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. However, there is no standard therapy for second-line and later treatment at present. Since 2012, three anticancer drugs-pazopanib, trabectedin, and eribulin-have been approved in Japan for the second-line or later treatment of patients with advanced STS of any histologic subtype. However, the chemosensitivity of STS to each of these drugs varies by histologic subtype and their safety profiles differ; thus, histologic subtype and patient characteristics must be considered when determining optimal treatment. In this article, we review data from clinical studies related to the efficacy of all three drugs, including their effect on OS, and propose optimal treatment strategies for advanced STS by histologic subtype. In addition, with regard to the safety profiles, we highlight the key issues to be considered when selecting patients for treatment with pazopanib, trabectedin, or eribulin and ensuring their appropriate use, based on our combined clinical experience as specialists in the treatment of patients with STS. The proposed treatment strategies as well as treatment precautions based on clinical experience would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs.
FUNDING
Eisai Co., Ltd.
Topics: Antineoplastic Agents, Alkylating; Dioxoles; Furans; Humans; Indazoles; Japan; Ketones; Pyrimidines; Sarcoma; Sulfonamides; Tetrahydroisoquinolines; Trabectedin
PubMed: 28547734
DOI: 10.1007/s12325-017-0561-4 -
Clinical Cancer Research : An Official... Jul 2018PROTECT, a phase III, randomized, placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant renal cell carcinoma setting. The relationship... (Randomized Controlled Trial)
Randomized Controlled Trial
PROTECT, a phase III, randomized, placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant renal cell carcinoma setting. The relationship between pazopanib exposure (C) and efficacy and safety was evaluated. Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early C) and 250 patients at week 16 or 20 (late C). Pazopanib pharmacokinetic (PK) data were analyzed via a population model approach. Relationship between C or dose intensity and disease-free survival (DFS) was explored via Kaplan-Meier and multivariate analysis. Adverse events (AE) and AE-related treatment discontinuation proportions were summarized by C quartiles. Most (>90%) patients with early or late C data started on 600 mg. Mean early and late C overlapped across dose levels. Patients with higher early C quartiles achieved longer DFS (adjusted HR, 0.58; 95% confidence interval, 0.42-0.82; = 0.002). Patients achieving early or late C >20.5 μg/mL had significantly longer DFS: not estimable (NE) versus 29.5 months, = 0.006, and NE versus 29.9 months, = 0.008, respectively. Dose intensity up to week 8 did not correlate with DFS, consistent with population PK model-based simulations showing overlapping pazopanib exposure with 600 and 800 mg doses. The proportion of AE-related treatment discontinuation and grade 3/4 AEs, with the exception of hypertension, was not correlated to C In the adjuvant setting, higher pazopanib C was associated with improved DFS and did not increase treatment discontinuations or grade 3/4 AEs, with the exception of hypertension. .
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Female; Humans; Indazoles; Kidney Neoplasms; Male; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Treatment Outcome
PubMed: 29330204
DOI: 10.1158/1078-0432.CCR-17-2652 -
BMC Cancer Aug 2019PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to...
BACKGROUND
PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS.
METHODS
PALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory.
RESULTS
A total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities.
CONCLUSIONS
Longer mPFS was observed in patients receiving pazopanib following only 1 line of therapy. Additionally, mPFS with pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity.
TRIAL REGISTRATION
NCT00753688 , first posted September 16, 2008 (registered prospectively).
Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Sarcoma; Sulfonamides; Survival Analysis; Treatment Outcome
PubMed: 31409302
DOI: 10.1186/s12885-019-5988-3 -
Annals of Oncology : Official Journal... Jan 2019Major challenges in clinical trials of ultra-orphan oncology diseases include limited patient availability and paucity of reliable prior data for estimating the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Major challenges in clinical trials of ultra-orphan oncology diseases include limited patient availability and paucity of reliable prior data for estimating the treatment effect and, therefore, determining optimal sample size. Angiosarcoma (AS), a particularly aggressive form of soft tissue sarcoma with an incidence of about 2000 cases per year in the United States and Europe is poorly addressed by current systemic therapies. Pazopanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) is approved for the treatment of AS, with modest benefit. TRC105 (carotuximab) is a monoclonal antibody to endoglin, an essential angiogenic target highly expressed on proliferating endothelium and both tumor vessels and tumor cells in AS, that has the potential to complement VEGFR tyrosine kinase inhibitors. In a phase I/II study of soft tissue sarcoma, TRC105 combined safely with pazopanib and the combination demonstrated durable complete responses and encouraging progression-free survival (PFS). In addition, there was a suggestion of superior benefit in patients with cutaneous lesions versus those with the non-cutaneous lesions.
PATIENTS AND METHODS
This article describes the design of a recently initiated phase III trial of TRC105 And Pazopanib versus Pazopanib alone in patients with advanced AngioSarcoma (TAPPAS trial). Given the ultra-orphan status of the disease and the paucity of reliable prior data on PFS or overall survival (end points required for regulatory approval as a pivotal trial), an adaptive design incorporating population enrichment and sample size re-estimation was implemented. The design incorporated regulatory input from the Food and Drug Administration (FDA) and European Medicines Agency and proceeded following special protocol assessment designation by the FDA.
CONCLUSIONS
It is shown that the benefit of the adaptive design as compared with a conventional single-look design arises from the learning and subsequent improvements in power that occur after an unblinded analysis of interim data.
REGISTERED ON CLINICALTRIALS.GOV
NCT02979899.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Epidemiologic Research Design; Follow-Up Studies; Hemangiosarcoma; Humans; Indazoles; Patient Selection; Prognosis; Pyrimidines; Sulfonamides; Survival Rate
PubMed: 30357394
DOI: 10.1093/annonc/mdy464 -
Journal of the National Cancer Institute Nov 2014Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular... (Review)
Review
Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Cell Cycle; Cell Survival; Chemotherapy, Adjuvant; Cyclin-Dependent Kinase 4; Humans; Indazoles; Indoles; Ipilimumab; Molecular Targeted Therapy; Niacinamide; Nivolumab; Phenylurea Compounds; Proto-Oncogene Proteins c-mdm2; Pyrimidines; Pyrroles; Radiotherapy, Adjuvant; Sarcoma; Signal Transduction; Sorafenib; Sulfonamides; Sunitinib; Tumor Microenvironment
PubMed: 25326640
DOI: 10.1093/jnci/dju329 -
JAMA Oncology Feb 2021Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma: Final Results of the PAPAGEMO Phase 2 Randomized Clinical Trial.
IMPORTANCE
Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required.
OBJECTIVE
To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020.
INTERVENTIONS
Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B).
MAIN OUTCOMES AND MEASURES
The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates.
RESULTS
A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological.
CONCLUSIONS AND RELEVANCE
This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma).
TRIAL REGISTRATION
German Clinical Trials Identifier: DRKS00003139.
Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Humans; Ifosfamide; Indazoles; Middle Aged; Pyrimidines; Quality of Life; Sarcoma; Sulfonamides; Treatment Outcome; Young Adult; Gemcitabine
PubMed: 33355646
DOI: 10.1001/jamaoncol.2020.6564 -
Anti-cancer Drugs Jan 2023Tyrosine kinase inhibitors (TKIs) are the backbone of the systemic treatment for patients with metastatic renal cell carcinoma (mRCC). TKIs such as pazopanib and...
Tyrosine kinase inhibitors (TKIs) are the backbone of the systemic treatment for patients with metastatic renal cell carcinoma (mRCC). TKIs such as pazopanib and cabozantinib can interact with other drugs concomitantly administered, particularly with proton-pump inhibitors (PPIs), possibly impacting the effectiveness of the anticancer treatment and patients outcome. Few data are available about this interaction. We conducted a multicenter retrospective observational data collection of patients with mRCC treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Univariate and multivariate analyses were performed. The aim was to describe the impact of baseline concomitant PPIs on the outcome of patients to pazopanib and cabozantinib in terms of response, progression-free survival (PFS) and overall survival (OS), toxicity, and treatment compliance. The use of PPI in our study population (301 patients) significantly influenced the effectiveness of TKIs with worse PFS (16.3 vs. 9.9 months; P < 0.001) and OS (30.6 vs. 18.4 months; P = 0.013) in patients taking PPI at TKI initiation. This detrimental effect was maintained both in the pazopanib and cabozantinib groups. The use of PPI influenced the toxicity and TKI treatment compliance with a reduction of dose or schedule modifications, and treatment interruptions in the population taking PPIs. Our study demonstrates that the use of PPIs can significantly influence the outcome and compliance of patients with mRCC to TKI treatment, suggesting the importance of a more careful selection of patients who need a gastroprotective therapy, avoiding indiscriminate use of PPIs.
Topics: Humans; Carcinoma, Renal Cell; Proton Pump Inhibitors; Tyrosine Kinase Inhibitors; Kidney Neoplasms; Retrospective Studies; Protein Kinase Inhibitors
PubMed: 36539370
DOI: 10.1097/CAD.0000000000001356