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

This study has been completed.
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by:
Centre Leon Berard
ClinicalTrials.gov Identifier:
NCT01261429
First received: December 15, 2010
Last updated: April 15, 2013
Last verified: April 2013
  Purpose

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


Condition Intervention Phase
Pigmented Villonodular Synovitis
Drug: Tasigna
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Nilotinib Efficacy in Pigmented Villo-Nodular Synovitis/ Tenosynovial Giant Cell Tumour (PVNS/TGCT)

Resource links provided by NLM:


Further study details as provided by Centre Leon Berard:

Primary Outcome Measures:
  • 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. [ Time Frame: after 12 weeks (3 months) of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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). [ Time Frame: after 24 weeks (6 months) of treatment ] [ Designated as safety issue: No ]
  • Objective tumour response according to RECIST version 1.1 (CR and PR) after 12 weeks of treatment [ Time Frame: after 12 weeks of treatment ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • Best overall response [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • Time to progression [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • Time to treatment failure [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • 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) [ Time Frame: after 12 weeks of treatment ] [ Designated as safety issue: No ]
  • Proportion of patients with an operable tumour after nilotinib exposure according to investigator evaluation [ Time Frame: at the end of the study (last visit) ] [ Designated as safety issue: No ]
  • Concomitant treatment use during the study [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • Correlation between trough level of nilotinib at 6 weeks and 12 weeks and objective tumour response [ Time Frame: at the end of the study ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: at the end of the study ] [ Designated as safety issue: Yes ]

Enrollment: 50
Study Start Date: December 2010
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nilotinib Drug: Tasigna

The study drug is nilotinib (Tasigna®). All patients will be administered with nilotinib 400 mg twice a day for one year. The patient will begin the treatment the day of inclusion.

The prescribed dose should be swallowed whole with a glass of water. Doses of 400 mg should be administered twice daily approximately 12 hours apart. Patients should not eat within two hours before and one hour after taking nilotinib and need to avoid foods such as grapefruit juice which may inhibit CYP3A4 enzymes.


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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01261429

Locations
France
Institut Bergonié
Bordeaux, France
Centre Oscar Lambret
Lille, France
Centre Léon Bérard
Lyon, France
Hôpital La Timone
Marseille, France
Institut Paoli Calmettes
Marseille, France
Institut Curie
Paris, France
Institut Claudius Regaud
Toulouse, France
Institut Gustave Roussy
Villejuif, France
Italy
Istituto Nazionale dei Tumori
Milano, Italy
Regina Elena National Cancer Institute
Roma, Italy
Netherlands
Leiden University Medical Center
Leiden, Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Netherlands
Poland
Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Warsaw, Poland
United Kingdom
University College Hospital UCL Hospitals NHS Foundation Trust
London, United Kingdom
Oxford Cancer Centre
Oxford, United Kingdom
Sponsors and Collaborators
Centre Leon Berard
Ministry of Health, France
Investigators
Principal Investigator: Jean Yves Blay, PR Centre Léon Bérard, Lyon
  More Information

Publications:
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
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

Responsible Party: David Pérol, Centre Léon Bérard, 28 rue Laënnec, 69373, Lyon
ClinicalTrials.gov Identifier: NCT01261429     History of Changes
Other Study ID Numbers: PVNS, 2010-018869-29
Study First Received: December 15, 2010
Last Updated: April 15, 2013
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Centre Leon Berard:
Pigmented villonodular synovitis
tenosynovial giant cell tumour
nilotinib

Additional relevant MeSH terms:
Giant Cell Tumors
Synovitis
Synovitis, Pigmented Villonodular
Joint Diseases
Musculoskeletal Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue

ClinicalTrials.gov processed this record on November 20, 2014