Study of Nilotinib Efficacy in Pigmented Villo-Nodular Synovitis/ Tenosynovial Giant Cell Tumour (PVNS/TGCT)

Phase II Study of Nilotinib Efficacy in Pigmented Villo-Nodular Synovitis/ Tenosynovial Giant Cell Tumour (PVNS/TGCT)

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

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

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