Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial

Gelderblom, Hans; Cropet, Claire; Chevreau, Christine; Boyle, Richard; Tattersall, Martin H. N.; Stacchiotti, Silvia; Italiano, Antoîne; Piperno‐Neumann, Sophie; Cesne, Axel Le; Ferraresi, Virginia; Penel, Nicolas; Duffaud, Florence; Cassier, Philippe; Toulmonde, Maud; Casali, Paolo; Taïeb, S.; Guillemaut, S.; Metzger, Séverine; Pérol, David; Blay, Jean‐Yves

doi:10.1016/s1470-2045(18)30143-8

Cited by 85 publications

(84 citation statements)

References 24 publications

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“…Response rates with other TKI agents have been inferior to the rate observed with pexidartinib. In a retrospective study of advanced TGCT patients treated with imatinib (n = 29), ORR was 19% (phase II) [15], whereas in a single-arm study of nilotinib (n = 56), ORR at week 12 was 0% (phase II) [16].…”

Section: Discussionmentioning

confidence: 99%

A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors

et al. 2019

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Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colonystimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC 0-8h ), and maximum observed plasma concentration (C max ) increased on days 1 and 15 with increasing pexidartinib doses, and time at C max (T max ) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).

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Section: Discussionmentioning

confidence: 99%

A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors

et al. 2019

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“…Detection of H3.3 p.G34W expression by immunohistochemistry would exclude diagnosis of tenosynovial giant cell tumour as this is restricted to GCT. Tyrosine kinase inhibitors targeting the colony‐stimulating factor 1 receptor can induce a response in affected patients, therefore making an accurate diagnosis even more important …”

Section: Tenosynovial Gctmentioning

confidence: 99%

“…Tyrosine kinase inhibitors targeting the colonystimulating factor 1 receptor can induce a response in affected patients, therefore making an accurate diagnosis even more important. 46…”

Section: Aneurysmal Bone Cyst (Abc)mentioning

confidence: 99%

An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

Baumhoer

Amary

Flanagan

2018

Genes Chromosomes & Cancer

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The last decade has seen the majority of primary bone tumor subtypes become defined by molecular genetic alteration. Examples include giant cell tumour of bone (H3F3A p.G34W), chondroblastoma (H3F3B p.K36M), mesenchymal chondrosarcoma (HEY1‐NCOA2), chondromyxoid fibroma (GRM1 rearrangements), aneurysmal bone cyst (USP6 rearrangements), osteoblastoma/osteoid osteoma (FOS/FOSB rearrangements), and synovial chondromatosis (FN1‐ACVR2A and ACVR2A‐FN1). All such alterations are mutually exclusive. Many of these have been translated into clinical service using immunohistochemistry or FISH. 60% of central chondrosarcoma is characterised by either isocitrate dehydrogenase (IDH) 1 or IDH2 mutations distinguishing them from other cartilaginous tumours. In contrast, recurrent alterations which are clinically helpful have not been found in high grade osteosarcoma. High throughput next generation sequencing has also proved valuable in identifying germ line alterations in a significant proportion of young patients with primary malignant bone tumors. These findings will play an increasing role in reaching a diagnosis and in patient management.

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“…TOPP represents the largest prospective, international, multi-center disease registry for dt-TGCT, being able to include 166 patients in slightly more than 2 years, and shows that conducting collaborative observational studies for rare tumor is feasible. Current literature is largely focused on the oncological outcomes of this often chronic disease [15,16,17,18,19,20,21,22]. Data derived from this registry made it possible for the rst time to describe the dt-TGCT patient journey and treatment decisions around disease onset and diagnosis of dt-TGCT patients.…”

Section: Discussionmentioning

confidence: 99%

“…Multimodality treatments (e.g., external beam radiotherapy and radiosynoviorthesis) have been performed in an attempt to reduce the recurrence rate in dt-TGCT, leading to varied reported outcomes [17,18,19]. In addition to surgery, several CSF1receptor inhibitors including TKIs showed promising results in tumor volume decrease and reduction of debilitating symptoms [20,21,22,30,31]. Of the TKIs, pexidartinib is an approved systemic therapy, recently added as a category 1 recommendation for the treatment of adult patients with symptomatic TGCT/pigmented villonodular synovitis (PVNS) associated with severe morbidity or functional limitations that is not amenable to improvement with surgery.…”

Section: Discussionmentioning

confidence: 99%

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective real-world study

Bernthal¹,

Spierenburg²,

Healey³

et al. 2020

Preprint

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Background: Tenosynovial giant cell tumor (TGCT) is a rare locally aggressive neoplasm arising from the synovium of joints, bursae, and tendon sheaths affecting small and large joints. It represents a wide spectrum ranging from minimally symptomatic to massively debilitating. The majority of findings to date are mainly from small, retrospective case series, and thus the morbidity and actual impact of this rare disease remain to be elucidated. This study explores prospectively the real-world management of TGCT.Methods: The TGCT Observational Platform Project (TOPP) registry was a multinational, multicenter, prospective observational study involving 12 tertiary sarcoma centers in 7 European countries, and 2 US sites. This study enrolled for 2 years all consecutive ≥ 18 years old patients, with histologically diagnosed primary or recurrent cases of diffuse-type TGCT. Patient demographic and clinical characteristics were collected at baseline and every 6 months for 24 months. Quality of life questionnaires (PROMIS-PF and EQ-5D) were also administered at the same time-points. Here we report baseline patient characteristics.Results: 166 patients were enrolled between November 2016 and March 2019. Baseline characteristics were: mean age 44 years (mean age at disease onset: 39 years), 139/166 (83.7%) had prior treatment, 71/166 patients (42.8%) had ≥ 1 recurrence after treatment of their primary tumor, 76/136 (55.9%) visited a medical specialist ≥ 5 times, and 66/116 (56.9%) missed work in the 24 months prior to baseline, and 17/166 (11.6%) changed employment status or retired prematurely due to disease burden. Prior treatment consisted of surgery (i.e., arthroscopic, open synovectomy) (128/166; 77.1%), and systemic treatments (52/166; 31.3%) with imatinib (19/52; 36.5%) or pexidartinib (27/52; 51.9%). Treatment strategies at baseline visits consisted mainly of watchful waiting (81/166; 48.8%), surgery (41/166; 24.7%), or targeted systemic therapy (37/166; 22.3%). Patients indicated for treatment reported more impairment compared to patients indicated for watchful waiting: worst stiffness NRS 5.16/3.44, worst pain NRS 6.13/5.03, PROMIS-PF 39.48/43.85, and EQ-5D VAS 66.54/71.85.Conclusion: This study confirms that diffuse-type TGCT can highly impact quality of life. A prospective observational registry in rare disease is feasible and can be a tool to collect curated-population reflective data in orphan diseases.

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Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial

Cited by 85 publications

References 24 publications

A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors

A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors

An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective real-world study

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