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

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 The treatments will be taken for 4 weeks before surgery, apart from any premature withdrawn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

Official Title
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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

Conditions
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Chondrosarcoma

Intervention / Treatment
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* Drug: Everolimus 2.5 mg/day
* Drug: Everolimus 10 mg/day


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA : Male or Female ≥ 18 years Histopathologically confirmed diagnosis of primary or relapsed conventional CHS of the bone (with or without metastases), CHS of any size on MRI if relapse OR size ≥ 10 cm on MRI at diagnosis OR CHS < 10 cm if R0 resection with adequate margins is not feasible at 1st examination (localization, tumor infiltration within surrounding tissues). Patient with life expectancy > 6 months Planned surgery between D32- D40 after inclusion Performance status of Eastern Cooperative Oncology Group (ECOG) ≤ 2 No contra-indication to Everolimus as per Summary of Product Characteristics (SPC) Adequate bone marrow, liver and renal functions including the following: Hemoglobin > 9 g/dL Neutrophil count ≥ 1500 x 109/L Platelets ≥ 100 x 109/L Total bilirubin ≤ 1,5x upper limit of normal (ULN) Serum Glutamate Oxaloacetate Transaminase (SGOT) and Serum Glutamate Pyruvate Transaminase (SGPT) ≤ 3 x ULN Alkaline Phosphatase ≤ 2,5 x ULN Serum creatinine < 110 µmol/L or creatinine clearance > 55 ml/min (estimated by Cockcroft Formula) Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication. Ability to understand and willingness to sign a written informed consent In accordance with French Regulatory Authorities: Patients with French Social Security in compliance with the French law relating to biomedical research (Huriet Law 88-1128 and related decrees) Women of child-bearing potential and men must agree to use adequate double contraception prior to study entry, for the duration of study participation and 30 days after the last study drug intake. EXCLUSION CRITERIA : Mesenchymal, dedifferentiated, clear cell subtype chondrosarcoma, and soft tissues chondrosarcoma Tumor tissue sample not available for pathological review/or correlative studies Patients may not be receiving any other investigational agents Prior treatment with mTOR inhibitors Symptomatic congestive heart failure of New York heart Association Class III or IV Uncontrolled diabetes as defined by fasting serum glucose >160 mg/dl or 8.9 mmol/l Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease Chemotherapy within the last 4 weeks before inclusion; radiotherapy, or any other investigational agent within 14 days or 5 half-lives, whichever is longer prior to the first dose of study drug Any concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study Impaired cardiac function or clinically significant cardiac diseases, or liver, respiratory or hepatic disease Known diagnosis of HIV infection Patient with ongoing toxicity Grade ≥ 2 according to the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0 Pregnant or breast feeding women (a pregnancy test will be performed within 7 days before inclusion).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No treatment<br>No Everolimus treatment before surgery | |
| Experimental: Everolimus 2,5 mg/day<br>Everolimus treatment at 2,5 mg/day for 30 days | Drug: Everolimus 2.5 mg/day<br>* Comparison between 2,5 mg/day of Everolimus per os to 10 mg/day, or to no treatment, taken during 30 days before chondrosarcoma surgery<br>* Other names: Afinitor; Votubia; RAD-001;|
| Experimental: Everolimus 10 mg/day<br>Everolimus treatment at 10 mg/day for 30 days | Drug: Everolimus 10 mg/day<br>* Comparison between 10 mg/day of Everolimus per os to 2.5 mg/day, or to no treatment taken during 30 days before chondrosarcoma surgery<br>* Other names: Afinitor; Votubia; RAD-001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success Rate obtained per arm | A success is defined as a variation (decrease) of Ki67 expression > 10% during treatment | 4 weeks after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | 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. | At time of progression in the course of the 3 years follow up after randomization | 
| Safety | Based on the frequency of Adverse Events according to common toxicity criteria (CTC V4.0), taking to account post operative complications and functional outcomes | In the course of the 3 years after randomization | 
| Overall Survival | Patients who are alive at the end of the 3 years follow up will be censured at this date. | At time of death if occuring during the 3 years of follow up after randomization | 
| Quality of Life | Data collected from a questionnaire at inclusion, surgery, 3th month, 6th month, 12th month, 24th month and 36th month after surgery | From randomization to the end of the 3 years follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chondrosarcoma, Neoadjuvant therapy, Phase II, Everolimus, Success Rate, Progression Free Survival, Overall Survival, Safety, Quality of Life, Molecular study (ancillary study)