Back to resultsA Phase II Study of EVEROLIMUS in Patients With Primary or Relapsed Chondrosarcomas (CHONRAD)
Primary Purpose
Chondrosarcoma
Status
Suspended
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Everolimus 2.5 mg/day
Everolimus 10 mg/day
Sponsored by
About this trial
This is an interventional treatment trial for Chondrosarcoma focused on measuring Chondrosarcoma, Neoadjuvant therapy, Phase II, Everolimus, Success Rate, Progression Free Survival, Overall Survival, Safety, Quality of Life, Molecular study (ancillary study)
Eligibility Criteria
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).
Sites / Locations
- Institut Bergonié
- Institut Claudius Regaud
- Centre Hospitalier Universitaire de Limoges, Hôpital Dupuytren
- Institut Régional du Cancer de Montpellier
- Centre Hospitalier Régional Universitaire de Tours, Hôpital Trousseau
- Centre Hospitalier Universitaire de Nantes, Hôtel Dieu
- Institut de Cancérologie de l'Ouest - René Gauducheau
- Institut de Cancérologie de Lorraine
- Centre Oscar Lambret
- CHRU de Lille - Hôpital Roger Salengro
- Centre Léon Bérard
- Institut Gustave Roussy
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
No Intervention
Experimental
Experimental
Arm Label
No treatment
Everolimus 2,5 mg/day
Everolimus 10 mg/day
Arm Description
No Everolimus treatment before surgery
Everolimus treatment at 2,5 mg/day for 30 days
Everolimus treatment at 10 mg/day for 30 days
Outcomes
Primary Outcome Measures
Success Rate obtained per arm
A success is defined as a variation (decrease) of Ki67 expression > 10% during treatment
Secondary Outcome Measures
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.
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
Overall Survival
Patients who are alive at the end of the 3 years follow up will be censured at this date.
Quality of Life
Data collected from a questionnaire at inclusion, surgery, 3th month, 6th month, 12th month, 24th month and 36th month after surgery
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02008019
Brief Title
A Phase II Study of EVEROLIMUS in Patients With Primary or Relapsed Chondrosarcomas
Acronym
CHONRAD
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2017
Overall Recruitment Status
Suspended
Why Stopped
The study was suspended since july 27th 2016 because of unavailability of Everolimus
Study Start Date
August 14, 2014 (Actual)
Primary Completion Date
August 2018 (Anticipated)
Study Completion Date
August 2019 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Leon Berard
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chondrosarcoma
Keywords
Chondrosarcoma, Neoadjuvant therapy, Phase II, Everolimus, Success Rate, Progression Free Survival, Overall Survival, Safety, Quality of Life, Molecular study (ancillary study)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
57 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
No treatment
Arm Type
No Intervention
Arm Description
No Everolimus treatment before surgery
Arm Title
Everolimus 2,5 mg/day
Arm Type
Experimental
Arm Description
Everolimus treatment at 2,5 mg/day for 30 days
Arm Title
Everolimus 10 mg/day
Arm Type
Experimental
Arm Description
Everolimus treatment at 10 mg/day for 30 days
Intervention Type
Drug
Intervention Name(s)
Everolimus 2.5 mg/day
Other Intervention Name(s)
Afinitor; Votubia; RAD-001
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Everolimus 10 mg/day
Other Intervention Name(s)
Afinitor; Votubia; RAD-001
Intervention Description
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
Primary Outcome Measure Information:
Title
Success Rate obtained per arm
Description
A success is defined as a variation (decrease) of Ki67 expression > 10% during treatment
Time Frame
4 weeks after inclusion
Secondary Outcome Measure Information:
Title
Progression-Free Survival (PFS)
Description
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.
Time Frame
At time of progression in the course of the 3 years follow up after randomization
Title
Safety
Description
Based on the frequency of Adverse Events according to common toxicity criteria (CTC V4.0), taking to account post operative complications and functional outcomes
Time Frame
In the course of the 3 years after randomization
Title
Overall Survival
Description
Patients who are alive at the end of the 3 years follow up will be censured at this date.
Time Frame
At time of death if occuring during the 3 years of follow up after randomization
Title
Quality of Life
Description
Data collected from a questionnaire at inclusion, surgery, 3th month, 6th month, 12th month, 24th month and 36th month after surgery
Time Frame
From randomization to the end of the 3 years follow up
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jean-Yves Blay, Professor
Organizational Affiliation
Centre Léon Bérard, Lyon
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
François Gouin, Professor
Organizational Affiliation
Centre Hospitalier Universitaire de Nantes, Hôtel Dieu
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institut Bergonié
City
Bordeaux
State/Province
Gironde
ZIP/Postal Code
33076
Country
France
Facility Name
Institut Claudius Regaud
City
Toulouse
State/Province
Haute Garonne
ZIP/Postal Code
31052
Country
France
Facility Name
Centre Hospitalier Universitaire de Limoges, Hôpital Dupuytren
City
Limoges
State/Province
Haute Vienne
ZIP/Postal Code
87042
Country
France
Facility Name
Institut Régional du Cancer de Montpellier
City
Montpellier
State/Province
Hérault
ZIP/Postal Code
34298
Country
France
Facility Name
Centre Hospitalier Régional Universitaire de Tours, Hôpital Trousseau
City
Tours
State/Province
Indre et Loire
ZIP/Postal Code
37044
Country
France
Facility Name
Centre Hospitalier Universitaire de Nantes, Hôtel Dieu
City
Nantes
State/Province
Loire Atlantique
ZIP/Postal Code
44093
Country
France
Facility Name
Institut de Cancérologie de l'Ouest - René Gauducheau
City
Saint-Herblain
State/Province
Loire Atlantique
ZIP/Postal Code
44805
Country
France
Facility Name
Institut de Cancérologie de Lorraine
City
Vandoeuvre-les-Nancy
State/Province
Meurthe et Moselle
ZIP/Postal Code
54511
Country
France
Facility Name
Centre Oscar Lambret
City
Lille
State/Province
Nord
ZIP/Postal Code
59000
Country
France
Facility Name
CHRU de Lille - Hôpital Roger Salengro
City
Lille
State/Province
Nord
ZIP/Postal Code
59037
Country
France
Facility Name
Centre Léon Bérard
City
Lyon
State/Province
Rhône
ZIP/Postal Code
69373
Country
France
Facility Name
Institut Gustave Roussy
City
Villejuif
State/Province
Val de Marne
ZIP/Postal Code
94805
Country
France
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Learn more about this trial
A Phase II Study of EVEROLIMUS in Patients With Primary or Relapsed Chondrosarcomas
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