Phase II study of nilotinib efficacy in pigmented villo-nodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT)

Pigmented villonodular synovitis (PVNS), also known as tenosynovial giant cell
tumor (TGCT), is a rare pathological entity affecting the synovium in young
adults. Initially considered as an inflammatory reactive process, recent
observations have shown that this disease may actually be a benign neoplastic
process with specific genetic alterations. Indeed, a specific t (1;2)
translocation, involving the collagen 6A3 gene (on 2q35) and the M-CSF (also
known as CSF1) gene (on 1p13), is present in a fraction of tumor cells in
PVNS/TGCT. This fusion gene expressed by a fraction of the cells encodes for a
fusion protein which attracts non-neoplastic cells expressing M-CSF receptor
(macrophages and monocytes), through a paracrine - *landscape*- effect (1-4).
Imatinib is a treatment indicated for chronic myeloid leukaemia (CML) and
gastrointestinal stromal tumor which block M-CSF receptor activation at
therapeutic concentration (5). PVNS/TGCT is usually treated by surgery alone
(1). However, relapses may occur, and re-excision may be needed, sometimes with
possible important functional impairment. Blay et al. recently reported the
case of a patient with recurrent and symptomatic PVNS/TGCT following surgery,
in whom surgical re-excision would have had important functional consequences
(6). In the case report, the patient was treated with imatinib, providing rapid
tumor response. A relapse was observed at discontinuation of imatinib, and a
secondary response was obtained at imatinib reintroduction. This is the first
report of the activity of imatinib in a M-CSF/M-CSF receptor dependent solid
tumor.
Although a potential contribution of the blockade of other tyrosine kinases by
imatinib can not be ruled out, the frequency at which the col6A3/CSF1 fusion
gene is observed in PVNS/TGCT (4) as compared to other pathological synovial
process strongly suggests that imatinib activity involves M-CSF receptor
blockade in this disease, despite recent observation showing limited biological
activity of the product of the fusion gene.
As a consequence, imatinib is a good candidate to induce complete responses in
relapsing PVNS/TGCT and may offer an option in patients in whom surgery is not
feasible or implies to much risks. In the first 4 patients treated with
imatinib in Lyon, 2 patients interrupted treatment because of poor tolerance (1
interruption at patient request, 1 interruption because of grade 4 liver
toxicity).
Another phenylaminopyrimidine commercialized by Novartis called nilotinib
(Tasigna®) has inhibitory properties similar to imatinib on M-CSF receptor
pathway (7). Nilotinib is indicated for the treatment of adults with chronic
phase and accelerated phase Philadelphia chromosome positive chronic
myelogenous leukaemia (CML) with resistance or intolerance to prior therapy
including imatinib.
The reason for selecting nilotinib as compared to imatinib came out from
different considerations
1) In the limited experience with imatinib in PVNS reported so far the toxicity
experienced by some patients was substantial.
2) Nilotinib has a more favourable toxicity profile in particular regarding
soft tissue and facial oedema. This may favour a better compliance to the
treatment.
In this context, it is interesting to set up a clinical study designed to
explore the efficacy of nilotinib as a treatment of patients with inoperable
PVNS/TGCT. This disease being rare, this clinical trial is a non-randomised
open-label and international study. Nilotinib will be administered to patients
with progressive or relapsing PVNS/TGCT who cannot be treated by surgery.
Patients will receive the medication according to the posology recommended by
the summary of product characteristics and used in the treatment of CML (400 mg
twice a day).
The main benefit anticipated for the patients included in the protocol will be
the tumor reduction and the consequent functional improvements. The main risk
will be the non-response to the treatment and the known adverse effects of
nilotinib. In case of secondary effects, doses of nilotinib will be adjusted
according to the system showing the greatest degree of toxicity.
Also, upon specific acceptance of the patients, a biological analysis of the
tumor will be conducted by a centralised laboratory to explore the relationship
between the tumor response to the treatment and some characteristics of tumors
(presence of COL6A3/CSF1 fusion gene, M-CSF and M-CSF receptor and
phosphorylated c-fms/M-CSFR).
Patients will be treated by nilotinib for 1 year. In case of treatment efficacy
as assessed by intermediary analyses, maintenance of the treatment upon
patients* acceptance will be considered.
This study will be conducted following local legal requirements and according
to Good Clinical Practices.

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

SECONDARY OBJECTIVES
The secondary objectives will be:
• To evaluate the efficacy of nilotinib according to:
- The objective tumor response rate (Complete response + Partial Response
according to RECIST) after 12 weeks of treatment
- The duration of treatment response
- The best overall reponse obtained during the study
- The progression-free survival (PFS)
- The time to progression
- The time to treatment failure
- The non-progression rate
- The proportion of patients with an operable tumor after nilotinib exposure
according to investigator evaluation
- The description of concomitant treatments use
- The correlation between trough levels of nilotinib and PFS
• To explore the relationship between the objective tumor response and the
following tumour characteristics (tissues collected in a prior surgery, or by
biopsy, upon specific acceptance by the patient):
- presence of COL6A3/CSF1 fusion gene
- presence of M-CSF, CSF1R, KIT, PDGFRA and B on immunohistochemistry
- presence of phosphorylated c-fms on tumor samples
- Activation of the PI3K/Akt/mTor pathway (Akt, P-Akt, Pp70S6K,..), presence of
activating mutations of ras, erk1/2 expression and P-erk1/2
• To assess the safety of nilotinib for PVNS/TGCT patients

The efficacy of nilotinib will be assessed for most of the criteria using
RECIST. Tumor will be evaluated at each visit of the study by Magnetic
resonance imaging (MRI) or CT scan. All images will be read locally at the site
and this interpretation will be used for all clinical decision making.
Assessments will be then validated by a central review committee. Centrally
reviewed tumor assessments data will be used in all efficacy analysis.
Upon patient specific acceptance, tumor specimen obtained from a prior surgery
or from a biopsy, as well as tumor samples collected after the initiation of
the treatment, will be analysed by a central laboratory (one laboratory per
continent: Europe, North America and Australia) for col6A3-M-CSF fusion gene
expression, MCSFR, KIT, PDGFRs expression, phospho M-CSFR expression, Akt,
P-Akt, P-p70S6K, ras mutation, erk

Treatment with nilotinib 400 mg BID up to one year or untill disease
progression

Limited side effects of venapuncture (5 times) limited risk of MRI contrast
allergy