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

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The treatments will be taken for 4 weeks before surgery, apart from any premature withdrawn

Study Overview

• Status: Suspended
• Conditions: Chondrosarcoma
• Intervention / Treatment: Drug: Everolimus 2.5 mg/day; Drug: Everolimus 10 mg/day

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

• Study Type: Interventional
• Enrollment (Anticipated): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Gironde
    • Bordeaux, Gironde, France, 33076
      • Institut Bergonie
  • Haute Garonne
    • Toulouse, Haute Garonne, France, 31052
      • Institut Claudius Regaud
  • Haute Vienne
    • Limoges, Haute Vienne, France, 87042
      • Centre Hospitalier Universitaire de Limoges, Hôpital Dupuytren
  • Hérault
    • Montpellier, Hérault, France, 34298
      • Institut régional du Cancer de Montpellier
  • Indre et Loire
    • Tours, Indre et Loire, France, 37044
      • Centre Hospitalier Régional Universitaire de Tours, Hôpital Trousseau
  • Loire Atlantique
    • Nantes, Loire Atlantique, France, 44093
      • Centre Hospitalier Universitaire de Nantes, Hôtel Dieu
    • Saint-Herblain, Loire Atlantique, France, 44805
      • Institut de cancérologie de l'Ouest - René Gauducheau
  • Meurthe et Moselle
    • Vandoeuvre-les-Nancy, Meurthe et Moselle, France, 54511
      • Institut de Cancérologie de Lorraine
  • Nord
    • Lille, Nord, France, 59000
      • Centre Oscar Lambret
    • Lille, Nord, France, 59037
      • CHRU de Lille - Hôpital Roger Salengro
  • Rhône
    • Lyon, Rhône, France, 69373
      • Centre Leon Berard
  • Val de Marne
    • Villejuif, Val de Marne, France, 94805
      • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No treatment; No Everolimus treatment before surgery
Experimental: Everolimus 2,5 mg/day; Everolimus treatment at 2,5 mg/day for 30 days	Drug: Everolimus 2.5 mg/day; 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; Other Names: Afinitor; Votubia; RAD-001
Experimental: Everolimus 10 mg/day; Everolimus treatment at 10 mg/day for 30 days	Drug: Everolimus 10 mg/day; 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; Other Names: Afinitor; Votubia; RAD-001

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Centre Leon Berard
• Investigators: Principal Investigator: Jean-Yves Blay, Professor, Centre Leon Berard, Lyon; Principal Investigator: François Gouin, Professor, Centre Hospitalier Universitaire de Nantes, Hôtel Dieu

Publications and helpful links

General Publications

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• Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol. 2004 Jun 15;22(12):2336-47. doi: 10.1200/JCO.2004.08.116. Epub 2004 May 10.
• Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs. 2002 Feb;3(2):295-304.
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• Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006 Aug;5(8):671-88. doi: 10.1038/nrd2062.
• Lichtenstein L, Jaffe HL. Chondrosarcoma of Bone. Am J Pathol. 1943 Jul;19(4):553-89. No abstract available.
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• Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer. 1977 Aug;40(2):818-31. doi: 10.1002/1097-0142(197708)40:23.0.co;2-b. No abstract available.
• Pring ME, Weber KL, Unni KK, Sim FH. Chondrosarcoma of the pelvis. A review of sixty-four cases. J Bone Joint Surg Am. 2001 Nov;83(11):1630-42.
• Miser JS, Pappo AS, Triche TJ et al. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. Other soft tissue sarcomas of childhood. Philadelphia, PA: Lippincott Williams & Wilkins, 2002:1017-1050.
• Marina N, Gebhardt M, Teot L, Gorlick R. Biology and therapeutic advances for pediatric osteosarcoma. Oncologist. 2004;9(4):422-41. doi: 10.1634/theoncologist.9-4-422.
• Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 2004 Apr 19;23(18):3151-71. doi: 10.1038/sj.onc.1207542.
• Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004 Aug 15;18(16):1926-45. doi: 10.1101/gad.1212704.
• Wan X, Mendoza A, Khanna C, Helman LJ. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res. 2005 Mar 15;65(6):2406-11. doi: 10.1158/0008-5472.CAN-04-3135.
• O'Donnell A, Faivre S, Judson I et al. A phase I study of the oral mTOR inhibitors RAD001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in patients with solid tumors. Proc Am Soc Clin Oncol 2003;22:803a
• Amornphimoltham P, Patel V, Sodhi A, Nikitakis NG, Sauk JJ, Sausville EA, Molinolo AA, Gutkind JS. Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res. 2005 Nov 1;65(21):9953-61. doi: 10.1158/0008-5472.CAN-05-0921.
• Guigon CJ, Fozzatti L, Lu C, Willingham MC, Cheng SY. Inhibition of mTORC1 signaling reduces tumor growth but does not prevent cancer progression in a mouse model of thyroid cancer. Carcinogenesis. 2010 Jul;31(7):1284-91. doi: 10.1093/carcin/bgq059. Epub 2010 Mar 18.
• Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009 May 1;27(13):2278-87. doi: 10.1200/JCO.2008.20.0766. Epub 2009 Mar 30.
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• Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opin Investig Drugs. 2008 Dec;17(12):1947-54. doi: 10.1517/13543780802556485.
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Study record dates

Study Major Dates

• Study Start (Actual): August 14, 2014
• Primary Completion (Anticipated): August 1, 2018
• Study Completion (Anticipated): August 1, 2019

Study Registration Dates

• First Submitted: December 6, 2013
• First Submitted That Met QC Criteria: December 6, 2013
• First Posted (Estimate): December 11, 2013

Study Record Updates

• Last Update Posted (Actual): August 7, 2017
• Last Update Submitted That Met QC Criteria: August 4, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Safety; Quality of Life; Everolimus; Progression Free Survival; Phase II; Neoadjuvant therapy; Overall Survival; Chondrosarcoma; Success Rate; Molecular study (ancillary study)
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Sarcoma; Chondrosarcoma; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CHONRAD