Clinical Trial: A Phase II Study of EVEROLIMUS in Patients With Primary or Relapsed Chondrosarcomas

Study Status: Suspended
Recruit Status: Suspended
Study Type: Interventional

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 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The treatments will be taken for 4 weeks before surgery, apart from any premature withdrawn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 Summary:

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®
Sponsor: Centre Leon Berard

Current Primary Outcome: Success Rate obtained per arm [ Time Frame: 4 weeks after inclusion ]

A success is defined as a variation (decrease) of Ki67 expression > 10% during treatment


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Progression-Free Survival (PFS) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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


Original Secondary Outcome: Same as current

Information By: Centre Leon Berard

Dates:
Date Received: December 6, 2013
Date Started: March 2014
Date Completion: August 2019
Last Updated: November 21, 2016
Last Verified: November 2016