Clinical trial NCT01261429: Study of Nilotinib Efficacy in Pigmented Villo-Nodular Synovitis/ Tenosynovial Giant Cell Tumour (PVNS/TGCT)
Official title: Phase II Study of Nilotinib Efficacy in Pigmented Villo-Nodular Synovitis/ Tenosynovial Giant Cell Tumour (PVNS/TGCT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pigmented Villonodular Synovitis
Keywords: Pigmented villonodular synovitis
tenosynovial giant cell tumour
nilotinib
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2010-12-16
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to explore the efficacy of nilotinib as a treatment of patients with progressive or relapsing pigmented villo-nodular synovitis / tenosynovial giant cell tumour (PVNS/TGCT) who cannot be treated by surgery.

The primary objective of the study will be to determine the efficacy of 12 weeks (3 months) of nilotinib treatment as measured by the non progression rate (Complete response + Partial Response + Stable disease according to Response Evaluation Criteria In Solid Tumours - RECIST version 1.1) in patients with progressive or relapsing PVNS/TGCT who cannot be treated by surgery.

this study is an international, multicentre, non-randomized, open-label phase II clinical trial with a Bayesian design.

A maximum sample size of 50 patients will be included in the study

Detailed description: A key secondary objective of the study will be to determine the efficacy of 24 weeks (6 months) of nilotinib treatment as measured by the non progression rate (Complete response + Partial Response + Stable disease according to Response Evaluation Criteria In Solid Tumours - RECIST version 1.1) in patients with progressive or relapsing PVNS/TGCT who cannot be treated by surgery.

This key secondary objective was defined for the purpose of a further analysis (not described in this protocol) which will pool the data of the PVNS study with those of a similar concomitant study conducted in the US and Australia.

The other secondary objectives will be:

To evaluate the efficacy of nilotinib according to:

* The objective tumour response rate (Complete response + Partial Response according to RECIST version 1.1) after 12 weeks of treatment
* The duration of treatment response
* The best overall response obtained during the study
* The progression-free survival (PFS)
* The time to progression (TTP)
* The time to treatment failure (TTF)
* The proportion of patients with an operable tumour after nilotinib exposure according to investigator evaluation
* The description of concomitant treatments use
* The correlation between trough levels of nilotinib and objective tumour response To assess the safety of nilotinib for PVNS/TGCT patients

An exploratory objective of the study will be to study the relationship between the objective tumour response and the following tumour characteristics (tissues collected in a prior surgery, or by biopsy, upon specific acceptance by the patient; if no tissue is available in the prior surgery, a biopsy will be done at visit 2):

Presence of COL6A3/CSF1 fusion gene Presence of M-CSF, CSF1R, KIT, PDGFRA and B on immunohistochemistry Presence of phosphorylated c-fms on tumour samples Activation of the PI3K/Akt/mTor pathway, presence of activating mutations of ras, and other potential molecular alterations

Eligibility criteria: Inclusion Criteria:

* Age \> 18 years
* Histologically confirmed diagnosis of inoperable progressive or relapsing PVNS/TGCT OR resectable tumour requesting mutilating surgery
* Demonstrated progressive disease in the last 12 months
* At least one measurable site of disease on MRI/CT scan according to RECIST criteria (RECIST version 1.1) based on investigator's assessment
* WHO Performance status of 0, 1 or 2
* Adequate organ, electrolyte and marrow function, defined as the following: serum bilirubin \> or =1.5 x ULN, ALT and AST \< or = 2.5 x ULN, serum creatinine \< or = 1.5 x ULN or creatinine clearance \> or = 50 mL/min, absolute neutrophil count (ANC) \> or = 1.5x109/L, platelets \> or = 100x109/L, serum lipase \< or =1.5 x ULN, magnesium ≥ lower limit of normal (LLN) and potassium ≥ LLN
* Prior adequate physical examination including weight, height, ECOG PS and vital signs (systolic and diastolic blood pressure, heart rate after at least 5 minutes in supine position)
* Signed written informed consent form
* Covered by a medical insurance (in countries where applicable)

Exclusion Criteria:

* Pregnant or lactating female or female of child-bearing potential not employing adequate contraception during the study and for up to three months following termination of the study
* Known hypersensitivity to nilotinib or to any of the excipients, galactose intolerance, lactase deficiency or glucose-galactose malabsorption prior to enrollment
* Acute or chronic uncontrolled liver disease, or severe renal disease
* Impaired cardiac function, including:
* LVEF\<50% or below the institutional lower limit of the normal range (whichever is higher) as determined by echocardiogram or MUGA scan
* History or signs of prior myocardial infarction
* History of unstable angina
* Congenital long QT prolongation
* Personal history of unexplained syncope
* QTc interval ≥ 450 msec on screening ECG
* Other clinically significant heart disease (e.g. bradycardia, congestive heart failure or uncontrolled hypertension)
* Patient with family history of long QT syndrome, of unexplained syncope or of unexplained sudden death
* Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol e.g. uncontrolled diabetes, active or uncontrolled infection, history of pancreatitis
* History of non-compliance to medical regimens
* Concomitant treatment with medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John's Wort), or that inhibit the CYP3A4 activity (e.g. ketoconazole, itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin)
* Concomitant treatment with warfarin
* Concomitant treatment with anti-arrhythmic drug (e. g. amiodarone, sotalol, disopyramide, quinidine, procainamide) or medication that prolongs the QT interval (e.g. chloroquine, chlorpromazine, domperidone, droperidol, halofantrine, haloperidol, methadone, pentamidine, pimozide, thioridazine)
* Prior treatment with imatinib except if no progression was demonstrated

Primary outcomes:
measure: the non progression rate after 12 weeks (3 months) of treatment, based on the response evaluated by CT scan or MRI according to RECIST criteria (RECIST version 1.1) and validated by a central review committee.
timeFrame: after 12 weeks (3 months) of treatment
Secondary outcomes:
measure: Non progression rate after 24 weeks (6 months) of treatment, based on the response evaluated by CT scan or MRI according to RECIST criteria (RECIST version 1.1).
timeFrame: after 24 weeks (6 months) of treatment
measure: Objective tumour response according to RECIST version 1.1 (CR and PR) after 12 weeks of treatment
timeFrame: after 12 weeks of treatment
measure: Duration of response
timeFrame: during the study
measure: Best overall response
timeFrame: during the study
measure: Progression-free survival
timeFrame: during the study
measure: Time to progression
timeFrame: during the study
measure: Time to treatment failure
timeFrame: during the study
measure: Non progression rate after 12 weeks of treatment, based on the response evaluated locally by the investigator in charge using CT scan or MRI and according to RECIST criteria (RECIST version 1.1)
timeFrame: after 12 weeks of treatment
measure: Proportion of patients with an operable tumour after nilotinib exposure according to investigator evaluation
timeFrame: at the end of the study (last visit)
measure: Concomitant treatment use during the study
timeFrame: during the study
measure: Correlation between trough level of nilotinib at 6 weeks and 12 weeks and objective tumour response
timeFrame: at the end of the study
measure: Safety evaluation will be based on overall safety profile characterized by type, frequency and severity (as graded using NCI-CTCAE V3.0) of adverse events.
timeFrame: at the end of the study
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonié
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hôpital La Timone
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Paris
country: France
facility: Institut Curie
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Milano
country: Italy
facility: Istituto Nazionale dei Tumori
city: Roma
country: Italy
facility: Regina Elena National Cancer Institute
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Warsaw
country: Poland
facility: Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
city: London
country: United Kingdom
facility: University College Hospital UCL Hospitals NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford Cancer Centre
Study officials:
affiliation: Centre Léon Bérard, Lyon
name: Jean Yves Blay, PR
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Blay JY, El Sayadi H, Thiesse P, Garret J, Ray-Coquard I. Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol. 2008 Apr;19(4):821-2. doi: 10.1093/annonc/mdn033. Epub 2008 Feb 21. No abstract available.
citation: Brownlow N, Russell AE, Saravanapavan H, Wiesmann M, Murray JM, Manley PW, Dibb NJ. Comparison of nilotinib and imatinib inhibition of FMS receptor signaling, macrophage production and osteoclastogenesis. Leukemia. 2008 Mar;22(3):649-52. doi: 10.1038/sj.leu.2404944. Epub 2007 Sep 13. No abstract available.
citation: P. A. Cassier, S. Stacchiotti, H. Gelderblom, D. M. Thomas, W. Van Der Graaf, B. M. Seddon, D. Julien, A. J. Wagner, J. Blay. Imatinib mesylate for the treatment of locally advanced and/or metastatic pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). J Clin Oncol. 2010 (suppl; abstr 10012); 28:15s. Meeting: 2010 ASCO Annual Meeting Abstract No: 10012
citation: V. Ravi, W. Wang, D. M. Araujo, J. A. Ludwig, R. J. Luke, V. O. Lewis, J. C. Trent, R. S. Benjamin, S. Patel. Imatinib in the treatment of tenosynovial giant-cell tumor and pigmented villonodular synovitis. J Clin Oncol. 2010 (suppl; abstr 10011); 28:15s. Meeting: 2010 ASCO Annual Meeting Abstract No: 10011
citation: Spierenburg G, Grimison P, Chevreau C, Stacchiotti S, Piperno-Neumann S, Le Cesne A, Ferraresi V, Italiano A, Duffaud F, Penel N, Metzger S, Chabaud S, van der Heijden L, Perol D, van de Sande MAJ, Blay JY, Gelderblom H. Long-term follow-up of nilotinib in patients with advanced tenosynovial giant cell tumours: Long-term follow-up of nilotinib in TGCT. Eur J Cancer. 2022 Sep;173:219-228. doi: 10.1016/j.ejca.2022.06.028. Epub 2022 Aug 3.
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