pexidartinib and Giant-Cell-Tumor-of-Tendon-Sheath

For drugs with enhanced serious safety risks, Risk Evaluation and Mitigation Strategy (REMS) may be required. Pexidartinib is approved for treatment of adult symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Its approval was conditional on its prescription via a mandatory REMS due to serious and potentially fatal liver injury seen in clinical trials. Turalio. For drugs with serious side effects, specific safety measures may be put in place to manage these serious side effects in the form of Risk Evaluation and Mitigation Strategy (REMS) programs. Pexidartinib (Turalio

Topics: Adult; Aminopyridines; Giant Cell Tumor of Tendon Sheath; Humans; Pyrroles; Risk Evaluation and Mitigation; United States; United States Food and Drug Administration

Tenosynovial giant cell tumor refers to a group of rarely occurring tumors that are formed in the joints, which are characterized by pain, swelling, and limitation of movement of the joint. Surgery is the main treatment strategy, but the tumor is likely to recur, especially in pigmented villonodular synovitis, which is the diffuse-type giant cell tumor. Pexidartinib was approved in August 2019 by the Food and Drug Administration (FDA) with a brand name TURALIO as the first systemic approved therapy for patients having Tenosynovial Giant Cell Tumors (TGCT).. In this review, different aspects pertaining to pexidartinib have been summarized, including the pathophysiology of TGCT, chemistry, pharmacokinetics and pharmacodynamics of pexidartinib. Special attention is given to various reported clinical trials of pexidartinib.. A comprehensive literature search was conducted in the relevant databases to identify studies published in this field during recent years.. Pexidartinib acts by inhibiting the Colony-Stimulating Factor (CSF1)/CSF1 receptor pathway, which leads to the inhibition of the cell lines proliferation and promotes the autophosphorylation process of the ligand-induced CSF1 receptor. Pexidartinib emerged as a potential drug candidate for the treatment of TGCT.

Topics: Aminopyridines; Antineoplastic Agents; Giant Cell Tumor of Tendon Sheath; Humans; Macrophage Colony-Stimulating Factor; Pyrroles; Receptor, Macrophage Colony-Stimulating Factor; United States; United States Food and Drug Administration

Tenosynovial giant cell tumor (TGCT) is a benign clonal neoplastic proliferation arising from the synovium often causing pain, swelling, joint stiffness, and reduced quality of life. The optimal treatment strategy in patients with diffuse-type TGCT (dt-TGCT) is evolving. Surgery is the main treatment, with a high recurrence rate and surgery-related morbidity. Radiotherapy is associated with important side effects. TGCT cells overexpress colony-stimulating factor 1 (CSF1). Pexidartinib (Turalio™) is a selective CSF1 R inhibitor, which was recently approved by the FDA for the treatment of TGCT.. This article reviews the pharmacological properties, clinical efficacy, and safety of pexidartinib.. Pexidartinib was effective with an acceptable safety profile for advanced TGCT in phase I-III studies. The phase III trial (ENLIVEN) in unresectable TGCT met its primary endpoints of overall response rate. These results led to FDA approval for this TGCT population. Mixed or cholestatic hepatotoxicity was observed in rare cases. For this reason, pexidartinib is currently available only through a Risk Evaluation and Mitigation Strategy (REMS) Program in the USA. TGCT significantly impairs patients' quality of life. The approval of pexidartinib has changed the therapeutic armamentarium for this condition. However, strict monitoring of liver function is warranted.

Topics: Adult; Aminopyridines; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Giant Cell Tumor of Tendon Sheath; Humans; Macrophage Colony-Stimulating Factor; Neoplasm Recurrence, Local; Pyrroles; Quality of Life

Tenosynovial giant cell tumor (TGCT) is a rare benign tumor that involves the synovium, bursa, and tendon sheath, resulting in reduced mobility of the affected joint or limb. The current standard of care for TGCT is surgical resection. However, some patients have tumor recurrence, present with unresectable tumors, or have tumors that are in locations where resection could result in amputations or significant debility. Therefore, the development of systemic agents with activity against TGCT to expand treatment options is a highly unmet medical need. Pathologically, TGCT is characterized by the overexpression of colony-stimulating factor 1 (CSF-1), which leads to the recruitment of colony-stimulating factor-1 receptor (CSF-1R) expressing macrophages that make up the primary cell type within these giant cell tumors. The binding of CSF-1 and CSF-1R controls cell survival and proliferation of monocytes and the switch from a monocytic to macrophage phenotype contributing to the growth and inflammation within these tumors. Therefore, molecules that target CSF-1/CSF-1R have emerged as potential systemic agents for the treatment of TGCT. Given the role of macrophages in regulating tumorigenesis, CSF1/CSF1R-targeting agents have emerged as attractive therapeutic targets for solid tumors. Pexidartinib is an orally bioavailable and potent inhibitor of CSF-1R which is one of the most clinically used agents. In this review, we discuss the biology of TGCT and review the pre-clinical and clinical development of pexidartinib which ultimately led to the FDA approval of this agent for the treatment of TGCT as well as ongoing clinical studies utilizing pexidartinib in the setting of cancer.

Topics: Aminopyridines; Antineoplastic Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Giant Cell Tumor of Tendon Sheath; Humans; Molecular Structure; Pyrroles; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Structure-Activity Relationship

Tenosynovial giant cell tumor (TGCT) is a benign mesenchymal tumor arising from the synovium of tendon sheats and joints, driven by colony-stimulating factor 1 (CSF1) over-expression. Standard treatment is surgery, but local recurrences are frequent, especially in diffuse TGCT subtype, rarely cured with surgery. When TGCT becomes a chronic condition, which may severely compromise joint function and quality of life, patients may need a systemic therapy. Areas covered: We reviewed the drugs on clinical development in TGCT, focusing on the pharmacodynamics, pharmacokinetics, efficacy, and toxicity profile of pexidartinib, the first drug approved in the US for TGCT, and on the open questions about its optimal use in clinical practice.. CSFR1 inhibitors have opened a new avenue for treatment of TGCT patients. Pexidartinib is the first-in-class FDA approved agent for symptomatic locally advanced TGCT, based on a phase III study where pexidartinib showed high anti-tumor activity, improved patient symptoms, and functional outcome. A few cases of potentially life-threatening hepatic toxicity were observed. TGCT patients candidate to pexidartinib need to be carefully selected by the multidisciplinary board of center of expertise, balancing the expected risk-benefit ratio. Close monitoring of liver function and adequate education on the approved indication is warranted.

Topics: Adult; Aminopyridines; Antineoplastic Agents; Giant Cell Tumor of Tendon Sheath; Humans; Macrophage Colony-Stimulating Factor; Neoplasm Recurrence, Local; Pyrroles; Quality of Life; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

Tenosynovial giant cell tumor is a rare proliferative tumor that arises from the synovium, bursae, or tendon sheaths due to an overproduction of colony-stimulating factor 1. Historically, treatment options for patients with local or diffuse tenosynovial giant cell tumor have been limited to surgical interventions. However, for some patients, surgical resection could worsen functional limitations and/or morbidity. In August 2019, the FDA approved pexidartinib (TURALIO™, Daiichi Sankyo), the first systemic treatment option for adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations that were not amenable to improvement with surgery. Pexidartinib is an oral tyrosine kinase inhibitor with selective inhibition of colony-stimulating factor 1 receptor and is the first systemic therapy to show significant improvement in overall response rates when compared with placebo. Clinicians using pexidartinib should monitor for liver-related adverse events, which may require treatment interruption, dose reduction, or treatment discontinuation. Pexidartinib provides a novel non-surgical treatment option for patients with tenosynovial giant cell tumor that may significantly improve patients' overall response, range of motion, physical function, tumor volume, and stiffness.

Topics: Administration, Oral; Adult; Aminopyridines; Antineoplastic Agents; Clinical Trials as Topic; Contraindications, Drug; Drug Approval; Drug Interactions; Female; Giant Cell Tumor of Tendon Sheath; Humans; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Protein Kinase Inhibitors; Pyrroles; United States; United States Food and Drug Administration

Pexidartinib is an orally administered small molecule tyrosine kinase inhibitor. Phase III ENLIVEN study results provided clinical evidence for US FDA approval for treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Recommended dosage is 400 mg orally twice daily on an empty stomach. Long-term follow-up in pooled analyses showed increased response rates compared with those observed in ENLIVEN. Patients on pexidartinib also experience meaningful improvements in range of motion. Side effects associated with pexidartinib are generally manageable; however, there is a risk of potentially life-threatening mixed or cholestatic hepatotoxicity and pexidartinib has a Risk Evaluation and Mitigation Strategy (REMS) program to ensure appropriate monitoring.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Diagnostic Imaging; Disease Management; Giant Cell Tumor of Tendon Sheath; Humans; Molecular Targeted Therapy; Neoplasm Staging; Protein Kinase Inhibitors; Pyrroles; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Structure-Activity Relationship; Treatment Outcome

Pexidartinib (TURALIO™) is an orally administered small molecule tyrosine kinase inhibitor with selective activity against the colony-stimulating factor 1 (CSF1) receptor, KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD). In August 2019, the US FDA approved pexidartinib capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. This approval was based on positive results from the phase III ENLIVEN trial. Pexidartinib is being investigated in various malignancies as monotherapy or combination therapy. This article summarizes the milestones in the development of pexidartinib leading to its first approval for TGCT.

Topics: Aminopyridines; Antineoplastic Agents; Drug Approval; fms-Like Tyrosine Kinase 3; Giant Cell Tumor of Tendon Sheath; Humans; Macrophage Colony-Stimulating Factor; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins c-kit; Pyrroles; United States; United States Food and Drug Administration

The double-blind, randomized, placebo-controlled phase 3 study of orally administered PLX3397 in patients with pigmented villonodular synovitis or giant cell tumor of the tendon sheath (ENLIVEN) showed that pexidartinib provides a robust objective tumor response in adults with tenosynovial giant cell tumors (TGCT) not amenable to improvement with surgery. Based on these results, in 2019, pexidartinib received accelerated approval in the United States in this population as a breakthrough therapy under an orphan drug designation. However, the ability of pexidartinib to relieve pain in ENLIVEN was not fully detailed, and the relationship between pain relief and objective tumor response was not described.. (1) What level of pain relief was achieved by pexidartinib treatment in ENLIVEN? (2) How was pain relief related to objective tumor responses? (3) How durable was pain relief?. The current study included planned primary and exploratory assessments of patient-assessed worst pain at the site of the tumor in the ENLIVEN trial. ENLIVEN was a phase 3 randomized, placebo-controlled clinical trial in which adults with TGCT not amenable to improvement with surgery received pexidartinib or placebo for 24 weeks, after which eligible patients could receive open-label pexidartinib. Of 174 patients assessed for eligibility, 121 were randomized (50% [60] to placebo, 50% [61] to pexidartinib), and 120 were given either placebo or pexidartinib (59 received placebo and 61 received pexidartinib) and were included in an intent-to-treat analysis. Fifty-nine percent (71 of 120) of the overall treated population was female, and 88% (106 of 120) were White. Mean age was 45 ± 13 years. Tumors were mostly in the lower extremities (92% [110 of 120]), most commonly in the knee (61% [73 of 120]) and ankle (18% [21 of 120]). As a secondary outcome, patients scored worst pain at the site of the tumor in the past 24 hours on an 11-point numeric rating scale (NRS). The primary definition of a pain response was a decrease of at least 30% in the weekly mean worst-pain NRS score and increase of less than 30% in narcotic analgesic use between baseline and week 25. Planned exploratory assessments of pain included the frequency of a pain response using alternative thresholds, including a decrease in worst-pain NRS score of 50% or more and a decrease of at least 2 points (minimum clinically important difference [MCID]), the magnitude of pain reduction between baseline and week 25, correlation between worst-pain NRS score and tumor shrinkage by RECIST 1.1 criteria, and the durability of the pain response during the open-label extension. Pain responses during the randomized portion of the trial were compared according to intention-to-treat analysis, with a one-sided threshold of p < 0.025 to reduce the risk of false-positive results. Pain assessment was complete for 59% (35 of 59) of patients in the placebo group and 54% (33 of 61) of patients in the pexidartinib group. Demographic and disease characteristics did not differ between the two treatment groups.. A difference in the primary assessment of a pain response was not detected between pexidartinib and placebo (response percentage 31% [19 of 61] [95% CI 21% to 44%] versus 15% [9 of 59] [95% CI 8% to 27%]; one-sided p = 0.03). In the exploratory analyses, pexidartinib provided a modest improvement in pain (response percentage 26% [16 of 61] [95% CI 17% to 38%] versus 10% [6 of 59] [95% CI 5% to 20%]; one-sided p = 0.02 using the 50% threshold and 31% [19 of 61] [95% CI 21% to 44%] versus 14% [8 of 59] [95% CI 7% to 25%]; one-sided p = 0.02 using the MCID threshold). The least-squares mean change in the weekly mean worst-pain NRS score between baseline and week 25 was larger in patients treated with pexidartinib than placebo (-2.5 [95% CI -3.0 to -1.9] versus -0.3 [95% CI -0.9 to 0.3]; p < 0.001), although the mean difference between the two groups (-2.2 [95% CI -3.0 to -1.4]) was just over the MCID. Improvement in the weekly mean worst-pain NRS score correlated with the reduction in tumor size (r = 0.44; p < 0.001) and tumor volume score (r = 0.61; p < 0.001). For patients in the open-label extension, the change in the worst-pain NRS score from baseline was similar to the change at the end of the randomized portion and just above the MCID (mean -2.7 ± 2.2 after 25 weeks and -3.3 ± 1.7 after 50 weeks of receiving pexidartinib).. Based on the current study, a modest reduction in pain, just larger than the MCID, may be an added benefit of pexidartinib in these patients, although the findings are insufficient to justify the routine use of pexidartinib for pain relief.. Level II, therapeutic study.

Topics: Adult; Aminopyridines; Double-Blind Method; Female; Giant Cell Tumor of Tendon Sheath; Humans; Middle Aged; Pain; Treatment Outcome

Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N = 159) and 2 studies in patients with TGCT or other solid tumors (N = 216). A structural 2-compartment model with sequential zero- and first-order absorption and lag time, and linear elimination from the central compartment adequately described pexidartinib and ZAAD PKs. Clearance of pexidartinib was estimated at 5.83 L/h in a typical patient with reference covariates (male, non-Asian, weight = 80 kg, creatinine clearance ≥90 mL/min, aspartate aminotransferase ≤80 U/L, and total bilirubin ≤20.5 μmol/L). In the covariate analysis, Asians and healthy subjects had modestly lower pexidartinib exposure (21% decrease each) in terms of steady-state area under the curve values from 0 to 24 hours (AUC

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Agents; Area Under Curve; Asian People; Bacterial Proteins; Body Weight; Creatinine; Female; Giant Cell Tumor of Tendon Sheath; Humans; Kidney Function Tests; Liver Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Pyrroles; Racial Groups; Sex Factors; Sociodemographic Factors; Tumor Burden; Young Adult

Background and purpose - The ENLIVEN trial showed that, after 25 weeks, pexidartinib statistically significantly reduced tumor size more than placebo in patients with symptomatic, advanced tenosynovial giant cell tumor (TGCT) for whom surgery was not recommended. Here, we detail the effect of pexidartinib on patient-reported physical function and stiffness in ENLIVEN.Patients and methods - This was a planned analysis of patient-reported outcome data from ENLIVEN, a double-blinded, randomized phase 3 trial of adults with symptomatic, advanced TGCT treated with pexidartinib or placebo. Physical function was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS)-physical function (PF), and worst stiffness was assessed using a numerical rating scale (NRS). A mixed model for repeated measures was used to compare changes in PROMIS-PF and worst stiffness NRS scores from baseline to week 25 between treatment groups. Response rates for the PROMIS-PF and worst stiffness NRS at week 25 were calculated based on threshold estimates from reliable change index and anchor-based methods.Results - Between baseline and week 25, greater improvements in physical function and stiffness were experienced by patients receiving pexidartinib than patients receiving placebo (change in PROMIS-PF = 4.1 [95% confidence interval (CI) 1.8-6.3] vs. -0.9 [CI -3.0 to 1.2]; change in worst stiffness NRS = -2.5 [CI -3.0 to -1.9] vs. -0.3 [CI -0.9 to 0.3]). Patients receiving pexidartinib had higher response rates than patients receiving placebo for meaningful improvements in physical function and stiffness. Improvements were sustained after 50 weeks of pexidartinib treatment.Interpretation - Pexidartinib treatment provided sustained, meaningful improvements in physical function and stiffness for patients with symptomatic, advanced TGCT.

Topics: Adult; Aminopyridines; Double-Blind Method; Female; Giant Cell Tumor of Tendon Sheath; Humans; Lower Extremity; Male; Middle Aged; Patient Reported Outcome Measures; Pyrroles

Topics: Aminopyridines; Giant Cell Tumor of Tendon Sheath; Humans; Pain; Pyrroles

Tenosynovial giant cell tumor (TGCT) is a mesenchymal tumor derived from the synovium of the tendon sheath and joints, most frequently in the large joints. The standard of care for TGCTs is surgical resection. A new targeting approach for treating TGCTs has emerged from studies on the role of the CSF1/CSF1 receptor (CSF1R) in controlling cell survival and proliferation during the pathogenesis of TGCTs. We established four novel cell lines isolated from the primary tumor tissues of patients with TGCTs. The cell lines were designated Si-TGCT-1, Si-TGCT-2, Si-TGCT-3, and Si-TGCT-4, and the TGCT cells were characterized by CSF1R and CD68. These TGCT cells were then checked for cell proliferation using an MTT assay and three-dimensional spheroid. The responses to pexidartinib (PLX3397) and sotuletinib (BLZ945) were evaluated by two-dimensional MTT assays. All cells were positive for α‑smooth muscle actin (α‑SMA), fibroblast activation protein (FAP), CSF1R, and CD68. Except for Si-TGCT-4, all TGCT cells had high CSF1R expressions. The cells exhibited continuous growth as three-dimensional spheroids formed. Treatment with pexidartinib and sotuletinib inhibited TGCT cell growth and induced cell apoptosis correlated with the CSF1R level. Only Si-TGCT-4 cells demonstrated resistance to the drugs. In addition, the BAX/BCL-2 ratio increased in cells treated with pexidartinib and sotuletinib. With the four novel TGCT cell lines, we have an excellent model for further in vitro and in vivo studies.

Topics: Cell Line; Giant Cell Tumor of Tendon Sheath; Humans; Receptor, Macrophage Colony-Stimulating Factor

Pexidartinib is a colony-stimulating factor-1 receptor inhibitor approved in the United States for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Because of the risk of severe and potentially fatal hepatotoxicity, pexidartinib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. Pexidartinib pharmacokinetics are influenced by the fat content of meals: compared with the fasted state, consuming a high-fat meal with pexidartinib increases pexidartinib absorption by 100%; a low-fat meal increases absorption by approximately 60%. Pexidartinib was initially authorized to be taken at 800 mg/day on an empty stomach; therefore, if this same dose of pexidartinib is taken with food, there is a risk of overexposure and potential toxicity. To reduce the risk of hepatotoxicity and improve patient compliance, pexidartinib has undergone a revised dosing regimen, from 800 mg/day (400 mg twice daily) fasted to 500 mg/day (250 mg twice daily) with a low-fat meal (approximately 11-14 g of total fat). The objective of this report is to educate clinical and allied health professionals on the revised dosing regimen and the importance of patient compliance with a low-fat meal. Healthcare professionals need to understand the rationale for the switch from pexidartinib dosing on an empty stomach to dosing with a low-fat meal and how meal composition and timing influence pharmacokinetics. Finally, we provide guidance for the healthcare team of prescribing providers, nurses, pharmacists, and dietitians who are caring for patients with TGCT on pexidartinib. It is important for healthcare providers to deliver consistent messaging on the low-fat meal requirement and help patients fit pexidartinib into their regular meal schedules. Consulting a dietitian may be helpful for patients, especially those with complex dietary needs. We provide an overview of the roles and responsibilities of each healthcare professional and outline steps to best support patients, including key questions and answers related to the revised dosing regimen. This report provides the information necessary to guide the multidisciplinary team caring for patients with TGCT and to support them through the pexidartinib dosing regimen change.

Topics: Adult; Allied Health Personnel; Aminopyridines; Chemical and Drug Induced Liver Injury; Giant Cell Tumor of Tendon Sheath; Humans; United States

Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd. All rights reserved.

Topics: Antineoplastic Agents; DCC Receptor; Giant Cell Tumor of Tendon Sheath; Humans; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Receptor, Macrophage Colony-Stimulating Factor

Tenosynovial giant cell tumor-diffuse type (diffuse TSGCT) is a benign but locally aggressive proliferative disorder of the synovium. Treatment is usually surgical, although in cases of extensive disease complete synovectomy is not possible and local recurrence rates are high. Pexidartinib (trade name Turalio®), a colony-stimulating factor-1 (CSF-1) inhibitor, was shown in a recent phase III trial to effectively treat diffuse TSGCT and is FDA approved for the treatment of adult patients with symptomatic diffuse TSGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) because of the risk of hepatotoxicity. Magnetic resonance imaging (MRI) is the preferred imaging modality for the diagnosis and surveillance of TSGCT. Here we present three patients with diffuse TSGCT of the knee who underwent multiple MRIs over several years while on pexidartinib. We describe the disease burden and signal characteristics on MRI and correlate with the response reported in the patients' medical records. Given that the use of pexidartinib and other CSF inhibitors is likely to increase, musculoskeletal radiologists should be aware of this novel non-operative treatment and the MRI appearance of diffuse TSGCT during therapy.

Topics: Adult; Aminopyridines; Colony-Stimulating Factors; Giant Cell Tumor of Tendon Sheath; Humans; Magnetic Resonance Imaging; Pyrroles; Synovitis, Pigmented Villonodular

To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.. From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO). CSF1 transcripts and gene expression were explored in TGCT biopsies.. These results offer insight into outcome patterns in cancers whose biology suggests use of a CSF1R inhibitor. Pexidartinib results in tumor regression in TGCT patients, providing prolonged control with an acceptable safety profile.

Topics: Adult; Aminopyridines; Giant Cell Tumor of Tendon Sheath; Humans; Protein Kinase Inhibitors; Pyrroles

Topics: Aminopyridines; Giant Cell Tumor of Tendon Sheath; Humans; Pyrroles; Response Evaluation Criteria in Solid Tumors

The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT).. This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019.. One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months).. This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Female; Giant Cell Tumor of Tendon Sheath; Humans; Male; Middle Aged; Pyrroles; Young Adult

Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib.. Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288.. In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases.. This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury.. This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.

Topics: Aminopyridines; Chemical and Drug Induced Liver Injury; Giant Cell Tumor of Tendon Sheath; Humans; Liver; Pyrroles

Pexidartinib is the first approved medication in the USA for people with tenosynovial giant cell tumor (TGCT). The drug was approved based on the ENLIVEN study, which looked at pexidartinib (brand name, Turalio™), a medication taken by mouth (orally) for people with TGCT (also known as giant cell tumor of the tendon sheath [GCTTS] and pigmented villonodular synovitis [PVNS]) who are not able to have surgery because of the location and/or the size of the tumor. The study showed that pexidartinib is effective in treating people with TGCT because it shrunk the size of their tumors and improved their symptoms and their ability to function. In general, people treated with pexidartinib had side effects that were mostly mild that went away after treatment with pexidartinib was stopped. The most common side effects were hair color changes and tiredness (fatigue). Pexidartinib was also associated with liver problems (or hepatotoxicity), which started within the first 2 months of treatment. Due to the risk of liver problems, which may be severe and potentially life threatening, the researchers closely monitored participants' blood liver function tests before, during, and after participants in the study took pexidartinib.

Topics: Aminopyridines; Giant Cell Tumor of Tendon Sheath; Humans; Protein Kinase Inhibitors; Pyrroles; Synovitis, Pigmented Villonodular