A Phase II Study of EVEROLIMUS in Patients With Primary or Relapsed Chondrosarcomas
- Conditions
- Chondrosarcoma
- Interventions
- Registration Number
- NCT02008019
- Lead Sponsor
- Centre Leon Berard
- Brief Summary
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The treatments will be taken for 4 weeks before surgery, apart from any premature withdrawn
- Detailed Description
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
Recruitment & Eligibility
- Status
- SUSPENDED
- Sex
- All
- Target Recruitment
- 57
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Everolimus 2,5 mg/day Everolimus 2.5 mg/day Everolimus treatment at 2,5 mg/day for 30 days Everolimus 10 mg/day Everolimus 10 mg/day Everolimus treatment at 10 mg/day for 30 days
- Primary Outcome Measures
Name Time Method Success Rate obtained per arm 4 weeks after inclusion A success is defined as a variation (decrease) of Ki67 expression \> 10% during treatment
- Secondary Outcome Measures
Name Time Method Progression-Free Survival (PFS) At time of progression in the course of the 3 years follow up after randomization PFS = Time from randomization until the date of event defined as the first documented progression or death due to any cause. Patients without any progression at the end of the 3 years follow up will be censured at this date.
Safety In the course of the 3 years after randomization Based on the frequency of Adverse Events according to common toxicity criteria (CTC V4.0), taking to account post operative complications and functional outcomes
Overall Survival At time of death if occuring during the 3 years of follow up after randomization Patients who are alive at the end of the 3 years follow up will be censured at this date.
Quality of Life From randomization to the end of the 3 years follow up Data collected from a questionnaire at inclusion, surgery, 3th month, 6th month, 12th month, 24th month and 36th month after surgery
Trial Locations
- Locations (12)
Institut Régional du Cancer de Montpellier
🇫🇷Montpellier, Hérault, France
Institut de Cancérologie de Lorraine
🇫🇷Vandoeuvre-les-Nancy, Meurthe et Moselle, France
Centre Hospitalier Universitaire de Limoges, Hôpital Dupuytren
🇫🇷Limoges, Haute Vienne, France
Centre Hospitalier Universitaire de Nantes, Hôtel Dieu
🇫🇷Nantes, Loire Atlantique, France
Institut de Cancérologie de l'Ouest - René Gauducheau
🇫🇷Saint-Herblain, Loire Atlantique, France
CHRU de Lille - Hôpital Roger Salengro
🇫🇷Lille, Nord, France
Institut Bergonié
🇫🇷Bordeaux, Gironde, France
Centre Hospitalier Régional Universitaire de Tours, Hôpital Trousseau
🇫🇷Tours, Indre et Loire, France
Centre Oscar Lambret
🇫🇷Lille, Nord, France
Centre Léon Bérard
🇫🇷Lyon, Rhône, France
Institut Gustave Roussy
🇫🇷Villejuif, Val de Marne, France
Institut Claudius Regaud
🇫🇷Toulouse, Haute Garonne, France