Chondrosarcoma Clinical Trial
Official title:
A Randomized Prospective, Multicentric, Open Label, Phase II Study Aiming to Evaluate the Efficacity and Safety of EVEROLIMUS as Neo-adjuvant Therapy in Patients With Primary or Relapsed Chondrosarcomas
The mainstay of chondrosarcoma treatment is a wide surgical resection. Unfortunately, this is
a rare occurrence, and patients with incomplete resection have very poor therapeutic options.
In this context, it becomes important to find new therapeutic strategies to slow down tumor
progression and to reduce tumor size before resection.
Pre-clinical and clinical data suggest that EVEROLIMUS should be efficient as adjuvant and
neo-adjuvant therapy in chondrosarcoma.
Then, investigators propose a phase II, randomized, open label study compounded by 3 arms
(1:1:1) to assess efficiency of EVEROLIMUS as neo-adjuvant therapy in patients with primary
or relapsed chondrosarcomas :
ARM 1 = No treatment; ARM 2 = 2,5 mg Everolimus/day; ARM 3 = 10 mg Everolimus/day.
The treatments will be taken for 4 weeks before surgery, apart from any premature withdrawn
Chondrosarcomas (CHS) represent 25% of bone sarcomas and are the second most frequent primary
malignant type of bone tumor. No effective systemic treatment has been identified in advanced
or adjuvant phases for CHS. As CHS are relatively resistant to chemo- and radiotherapy,
surgery remains the primary treatment of this tumor type. The aim of tumor resection is to
obtain complete removal of the malignant lesion with adequate margins taking into account
tumor control and functional reconstruction. However, considering the particular
localizations of CHS, a wide resection (i.e. R0 clear margins) is rarely achieved.
Unfortunately, therapeutic options are limited for patients with incomplete resection. In
this context, new therapeutic strategies are needed to slow down tumor progression and to
reduce tumor size before surgery.
Increasing knowledge of the signal transduction pathways involved in oncogenesis has led to
speculation that components of signalling pathways could be envisaged as novel targets for
cancer therapy. Mammalian Target of Rapamycin (mTOR), which lies downstream of the
Phosphatidylinositol 3-kinase/B kinase protein (PI3K/Akt) pathway, plays a central role in
the regulation of cancer cell growth, suggesting that mTOR could be an attractive target for
anti-cancer therapy. The PI3K-Akt-mTOR signaling pathway is intimately implicated in sarcoma
development and progression. Indeed, mutations and/ or overexpression of one or several
components of the PI3K-Akt-mTOR pathway are often observed in sarcoma. These alterations,
located both upstream and downstream of mTOR, lead to dysregulation of the mTOR pathway. mTOR
inhibitor evaluation as anticancer agents has began with rapamycin analogues (called
rapalogs). Currently, mTOR inhibitors under clinical development include temsirolimus
(CCI-779, Torisel®, Wyeth Pharmaceuticals), everolimus (RAD001, Afinitor®, Novartis
Pharmaceuticals), and ridaforolimus (AP23573, ARIAD Pharmaceuticals). mTOR inhibitors were
found to be efficient in various preclinical cancer models, for example in a preclinical
mouse model of follicular thyroid cancer, everolimus induced a significant decrease in
proliferation of cancer cells.
Two sets of recent data suggest that inhibition of mTOR pathway could be an effective
systemic treatment for chondrosarcoma. The first one is a case report describing an
impressive tumor response in a patient with myxoid chondrosarcoma treated by rapamycin in
combination with cyclophosphamide. The second one concerns nonclinical data generated by our
institution. Using an orthotopic rat chondrosarcoma model, we have shown that monotherapy
with everolimus inhibits chondrosarcoma proliferation as evaluated by Ki67 expression and
significantly reduced tumor volume. Importantly, when given in a "pseudo-adjuvant" setting
following R1 resection of the implanted tumor, everolimus significantly delayed tumor
recurrence. These preclinical data provide a strong rationale to evaluate the therapeutic
potential of everolimus in both the neo-adjuvant and adjuvant settings in patients with
chondrosarcoma.
In this context, the proposal of the investigators is to perform a multicenter, randomized,
Phase II study in patients with a primary or relapsed chondrosarcoma in neo-adjuvant setting
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