Adjuvant High-Dose Thiotepa and Stem Cell Rescue Associated With Conventional Chemotherapy in Relapsed Osteosarcoma (OSII-TTP)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Centre Leon Berard
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard
ClinicalTrials.gov Identifier:
NCT00978471
First received: September 16, 2009
Last updated: August 4, 2014
Last verified: August 2014
  Purpose

Approximately 150 new cases of osteosarcoma are reported each year in France, of which 15 to 20% are metastatic.

Further to the initial standard care, about 45% of the patients relapse within a median duration of 20 months.

Result of the OS94 study results and of the investigation performed within the CRLCC, indicate that 25 to 30 patients (children and adults) experience an osteosarcoma relapse each year in FRANCE.

According to several studies, the 5-year overall survival rate of patients in first relapse is 23-28%,with a median post relapse survival of 10 to 17 months. Multiple relapse cases are also reported in the COSS study, with a median time to second relapse of 0.8 year.

At present, there is no reference treatment for the standard care of osteosarcoma relapse in FRANCE.

Thiotepa is known for its antitumor effect in numerous malignant tumors. In 2007, a study from our institution reported that about 35% of all osteosarcoma relapses are treated with a high-dose thiotepa while the efficacy and tolerance of this therapeutic strategy have never been assessed.

These results highlight the need to the evaluate the efficacy and tolerance of this high-dose of thiotepa within a clinical trial and its inclusion in the standard care of the osteosarcoma at relapse.


Condition Intervention Phase
Osteosarcoma
Drug: Thiotepa
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Efficacy and Tolerance Adjuvant High-Dose Thiotepa With Peripheral Stem Cell Rescue Associated With Conventional Chemotherapy in Children and Adults With Relapsed Osteosarcoma

Resource links provided by NLM:


Further study details as provided by Centre Leon Berard:

Primary Outcome Measures:
  • Estimate the overall survival rate [ Time Frame: 24 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Estimate overall survival after relapse diagnosis [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  • Estimate the survival free progression after randomization [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  • Evaluate the tolerance profile of experimental treatment (hematologic toxicity) [ Time Frame: every 3 weeks ] [ Designated as safety issue: No ]
  • Estimate the rate of tumor response to treatment as assessed by conventional CT-scan [ Time Frame: at inclusion, day 14-day 21 after the 2nd chemotherapy cycle, before randomization, day 14-day 21 after the 4th chemotherapy cycle, after thiotepa cure and 8 weeks after the end of treatment ] [ Designated as safety issue: No ]
  • Estimate histological response to treatment on surgical tumor samples [ Time Frame: If surgery is applicable, a few weeks after thiotepa cure (12 to 17 weeks after inclusion) ] [ Designated as safety issue: No ]
  • Study of biological and genomic properties and analysis of angiogenic markers correlated with relapse (optional) [ Time Frame: At inclusion,at surgery , and at the end of treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 66
Study Start Date: July 2009
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: experimental arm thiotepa
4 courses of conventional chemotherapy followed by high-dose Thiotepa with peripheral stem cell rescue. Surgical resection of all tumor masses will be performed as soon as possible.
Drug: Thiotepa
Thiotepa 8-12mg/m²/day/injection Total dose for one cure:15-50mg.
Other Names:
  • N N'N'triethylenethiophosphosphoramide
  • Tepadina
Reference arm
4 courses of conventional chemotherapy. Surgical resection of all tumor masses will be performed as soon as possible.
Drug: Thiotepa
Thiotepa 8-12mg/m²/day/injection Total dose for one cure:15-50mg.
Other Names:
  • N N'N'triethylenethiophosphosphoramide
  • Tepadina

Detailed Description:

Despite the absence of tumor registry, approximately 150 new cases of osteosarcoma are reported each year in France (100 cases per year in children and 50 cases in adults), of which 15 to 20% are metastatic. The standardized impact rate in the world population is estimated at 3 per million inhabitants per year.

Further to the initial standard care, about 45% of the patients relapse within a median interval of 20 months (range 3 months - 10 years).

Results of the OS94 study and of the investigation performed within the CRLCC indicate that 25 to 30 patients (children and adults) experience an osteosarcoma relapse each year in FRANCE.

Results of the five major published series indicate that the 5-year overall survival rate of patients in first relapse is between 23 and 28%, with a median post-relapse survival of 10 to 17 months. Multiple relapse cases are also reported in the COSS study, with a median time to second relapse of 0.8 year.

At present, there is no reference treatment for the standard care of osteosarcoma relapse in FRANCE.

Some recommendations have been given in the OS94 protocol, but they are generally not followed or they are implemented in a heterogeneous manner.

Thiotepa (N N' N'' triethylenethiophosphoramide), an alkylating agent of the chemical family of ethylene-imines, is known for its antitumor effect in a number of malignant tumors.

Its efficacy in osteosarcoma has been reported in the literature. A retrospective study of the SFCE (French Society for Childhood Cancer, results not yet published) in 45 patients presenting with refractory osteosarcoma or relapse has shown a radiological reaction rate of 30%.

Moreover, a preliminary investigation performed by the CLB in 2007 within the framework of the SFCE study explored all relapse cases diagnosed between the beginning of 2004 and the end of 2006. Results showed that about 35% of the patients with osteosarcoma relapses are treated with high-dose thiotepa while the efficacy and tolerance of this therapeutic strategy have never been assessed.

Altogether, these results led the SFCE osteosarcoma group to propose the evaluation of the efficacy and tolerance of this high-dose thiotepa chemotherapy within a clinical trial and to include the drug in the standard care of osteosarcoma in relapse.

  Eligibility

Ages Eligible for Study:   1 Year to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age > 1 year and < 50 years
  • First osteosarcoma relapse, either local or metastatic, or second relapse after exclusive surgery NB: Whenever possible, only patients with histological evidence of relapse will be included.
  • Indication for chemotherapy confirmed by a multidisciplinary committee.
  • Surgical resection of all tumor sites must be possible, either as first-line therapy or after chemotherapy.
  • Lansky score ≥ 60%, or ECOG Performance Status ≤ 2
  • ≥ 21-day interval after first-line chemotherapy
  • Blood tests, renal and liver functions within the normal range for age with, in particular, 7 days prior to study entry, blood or serum values as follows:
  • blood: neutrophil count > 1 G/L; platelets >100 G/L
  • renal: serum creatinine ≤ 1.5 x ULN depending on age; patients with serum creatinine values > 1.5 x ULN are eligible if creatinine clearance is > 70 mL/min/1.73 m²
  • liver: total bilirubin < 2 x ULN; ASAT and ALAT ≤ 5 x ULN
  • cardiac: isotopic or echographic Left Ventricular Ejection Fraction > 50 %.
  • Signed written informed consent; for children, signed consent from the patient (depending on age) and from the parents or legal representative is mandatory
  • Documented negative serum βHCG for female patients of childbearing age
  • Affiliation with health insurance.

Exclusion Criteria:

  • Patients with multiple relapses for whom surgical resection seems impossible, even after chemotherapy.
  • Patients already treated with high-dose chemotherapy regimens
  • Patients with a contra-indication to the treatment proposed
  • Patients not eligible for leukapheresis
  • Two-year follow-up impossible due to social, family, geographic or psychological reasons
  • Patient included in another protocol of clinical research
  • Pregnant or lactating women.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00978471

Contacts
Contact: Perrine MAREC-BERARD, MD 04 78 78 26 42 perrine.marec-berard@lyon.unicancer.fr
Contact: Séverine METZGER severine.metzger@lyon.unicancer.fr

Locations
France
CHU Besançon- Hôpital Jean Minjoz Recruiting
Besancon, France, 25000
Contact: LAITHIER Veronique, MD    03 81 66 81 66    vlaithier@chu-besancon.fr   
Principal Investigator: LAITHIER Veronique, MD         
Sub-Investigator: Loic CHAIGNEAU, MD         
Sub-Investigator: Emmanuel PLOUVIER, MD         
Chu - Hopital Des Enfants Bordeaux Not yet recruiting
Bordeaux, France, 33000
Contact: Cécile Vérité, MD    0556820438    cecile.verite@chu-bordeaux.fr   
Principal Investigator: VERITE Cecile, MD         
Sub-Investigator: De BOUYN-ICHER Céline, MD         
Chu Grenoble Not yet recruiting
Grenoble, France, 38045
Contact: Dominique Plantaz, MD    04 76 76 54 69    DPlantaz@chu-grenoble.fr   
Sub-Investigator: Corinne Armari-Alla, MD         
Sub-Investigator: Anne Pagnier, MD         
Principal Investigator: PLANTAZ Dominique, MD         
Sub-Investigator: Pauline GIRARD, MD         
Centre Oscar Lambret Recruiting
Lille, France, 59000
Principal Investigator: Cyril LERVAT, MD         
Sub-Investigator: Nicolas PENEL, MD         
Sub-Investigator: Pierre LEBLOND, MD         
Sub-Investigator: Hélène SUDOUR, MD         
Sub-Investigator: Anne-Sophie DEFACHELLES THOMASSIN, MD         
Centre Léon Bérard - Institut d'Hémato-Oncologie Pediatrique Recruiting
LYON Cedex 08, France, 69373
Contact: Perrine MAREC-BERARD, MD    04 78 78 26 42    perrine.marec-berard@lyon.unicancer.fr   
Sub-Investigator: Cécile Conter, MD         
Sub-Investigator: Pierre Biron, MD         
Sub-Investigator: Jean-yves Blay, MD         
Sub-Investigator: Isabelle Ray-Coquard, MD         
Principal Investigator: MAREC-BERARD Perrine, MD         
Sub-Investigator: FRAPPAZ Didier, MD         
Sub-Investigator: Florence DOMMANGE-ROMERO, MD         
Hôpital des Enfants de la Timone Recruiting
Marseille, France, 13385
Contact: GENTET Jean-Claude, Pr    0491386821    jcgentet@ap-hm.fr   
Principal Investigator: GENTET Jean-Claude, MD         
Sub-Investigator: Nicolas ANDRE, MD         
Sub-Investigator: Carole COZE, MD         
Sub-Investigator: Angélique ROME, MD         
Sub-Investigator: Arnauld VERSCHUUR, MD         
Institut Paoli Calmettes Not yet recruiting
Marseille, France, 13273
Contact: BERTUCCI François, MD    0491223537    bertuccif@marseille.fnclcc.fr   
Principal Investigator: BERTUCCI François, MD         
Sub-Investigator: Jean-Marc EXTRA, MD         
Sub-Investigator: Anthony GONCALVES, MD         
Sub-Investigator: Anne MADROSZYK-FLANDIN, MD         
Chu Nantes - Hopital Meres Et Enfants Recruiting
Nantes, France, 44093
Contact: Nadège Corradini, MD    02 40 08 78 25    ncorradini@chu-nantes.fr   
Principal Investigator: CORRADINI Nadège, MD         
Sub-Investigator: Caroline THOMAS, MD         
CHU Nice, Hôpital L'Archet 2 Recruiting
Nice, France, 06202
Principal Investigator: Marion LE MEIGNEN-DIOP, MD         
Sub-Investigator: Françoise BELLMANN-ROQUEPLAN, MD         
Sub-Investigator: Anne DEVILLE, MD         
Sub-Investigator: Marilyne POIREE, MD         
Sub-Investigator: Christine SOLER, MD         
Centre Antoine Lacassagne Not yet recruiting
Nice, France, 06189
Principal Investigator: Antoine THYSS, MD         
Sub-Investigator: Lauris GASTAUD, MD         
Sub-Investigator: Frédéric PEYRADE, MD         
Sub-Investigator: Esma SAADA-BOUZID, MD         
Hopital D'Enfants Armand Trousseau Not yet recruiting
Paris, France, 75571
Contact: Marie-Dominique Tabone, MD    01 44 73 69 06    marie-dominique.tabone@trs.ap-hop-paris.fr   
Sub-Investigator: Guy Leverger, MD         
Sub-Investigator: Anne Auvrignon, MD         
Sub-Investigator: Judith LandmanParker, MD         
Sub-Investigator: Arnaud Petit, MD         
Principal Investigator: TABONE Marie-Dominique, MD         
Institut Curie Recruiting
Paris, France, 75248
Contact: Hélène Pacquement, MD    0144324601    helenepacquement@curie.net   
Sub-Investigator: Daniel Orbach, MD         
Sub-Investigator: François Doz, MD         
Sub-Investigator: Gudrun Schleiemacher, MD         
Sub-Investigator: Jean Michon, MD         
Principal Investigator: PACQUEMENT Hélène, MD         
Sub-Investigator: Isabelle AERTS, MD         
Sub-Investigator: Dominique LEVY, MD         
CHU Poitiers, site de la Milétrie Not yet recruiting
Poitiers, France, 86021
Principal Investigator: Frédéric MILLOT, MD         
Sub-Investigator: Laurence BLANC, MD         
CHU RENNES - Hôpital Sud Not yet recruiting
Rennes, France, 35023
Contact: GANDEMER Virginie, MD    0299265835    virginie.gandemer@chu-rennes.fr   
Principal Investigator: GANDEMER Virginie, MD         
Sub-Investigator: TAQUE Sophie, MD         
Sub-Investigator: CHAPPE Céline, MD         
Sub-Investigator: TOUTAIN Fabienne, MD         
Sub-Investigator: BAYART Sophie, MD         
CHU de SAINT-ETIENNE, Hôpital Nord Recruiting
Saint Priest en Jarez, France, 42270
Contact: Claire Berger, MD    04 77 91 70 00    claire.berger@chu-st-etienne.fr   
Sub-Investigator: Jean Louis Stephan, MD         
Sub-Investigator: Sandrine Thouvenin, MD         
Principal Investigator: BERGER Claire, MD         
Institut de Cancérologie de l'Ouest - René Gauducheau Not yet recruiting
Saint-herblain, France, 44805
Contact: BOMPAS Emmanuelle, MD    0240679939    e-bompas@nantes.fnclcc.fr   
Principal Investigator: BOMPAS Emmanuelle, MD         
Sub-Investigator: Frédéric ROLLAND, MD         
Institut Lucien Neurwith Not yet recruiting
Saint-Priest-en -Jarez, France, 42270
Contact: COLLARD Olivier, MD    0477917034    olivier.collard@icloire.fr   
Principal Investigator: COLLARD Olivier, MD         
Hopital de Hautepierre Not yet recruiting
Strasbourg, France, 67098
Contact: Natacha Entz-Werlé, MD    0388128396    Natacha.Entz-Werle@chru-strasbourg.fr   
Sub-Investigator: Patrick Lutz, MD         
Principal Investigator: ENTZ-WERLE Natacha, MD         
Chu Toulouse - Hopital D'Enfants Recruiting
Toulouse, France, 31059
Contact: Hervé Rubie, MD    0534558633    rubie.h@chu-toulouse.fr   
Sub-Investigator: Anne-Isabelle Bertozzi-Salomon, MD         
Sub-Investigator: Marie-Pierre Castex, MD         
Sub-Investigator: Marlène PASQUET, MD         
Sub-Investigator: Geneviève PLAT, MD         
Principal Investigator: Hervé RUBIE, MD         
Chu Nancy - Hopital D'Enfants Recruiting
Vandoeuvre Les Nancy, France, 54511
Contact: Claudine Schmitt, MD    03831530    c.schmitt@chu-nancy.fr   
Principal Investigator: SCHMITT Claudine, MD         
Sub-Investigator: CHASTAGNER Pascal, MD         
Sub-Investigator: FOUYSSAC Fanny, MD         
Sub-Investigator: PHULPIN-WEIBEL Aurelie, MD         
Sub-Investigator: Ludovic MANSUY, MD         
Institut Gustave Roussy Recruiting
Villejuif, France, 95805
Contact: Laurence Brugières, MD    0142114180    brugières@igr.fr   
Sub-Investigator: Axel Le Cesne, MD         
Principal Investigator: BRUGIERES Laurence, MD         
Sponsors and Collaborators
Centre Leon Berard
Investigators
Principal Investigator: Perrine MAREC-BÉRARD, Dr Institut d'Hématologie et d'Oncologie Pédiatrique (IHOP) - CLB
  More Information

Publications:
Gelderblom H, Sydes MR, Morgan RC, Hogendoorn PC, Lewis IJ, Nooij MA, Taminiau AH, and whelan J. Survival after reccurent osteosarcoma: Data from three European Osteosarcoma Intergroup (EOI) randomized controlled trials.J Clin Oncol26.20-5-2008
Leary SE,Billups A, Watkins A, Wu J, Poe D, Neel MN, Rao BN and Daw NC.Survival of pediatric patients after relapsed osteosarcoma:The St.Jude Children's Research Hospital experience.JOclin Oncol 26.20-5-2008
Beron G, Euler A, winkley K.pulmonary metastase from osteogenic sarcoma: Complete resection and effective chemotherapy contributing to improved prognosis.Eur Paediatr Haematol Oncol 1985; 2:77-85

Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT00978471     History of Changes
Other Study ID Numbers: OSII-TTP, 2009-009899-12
Study First Received: September 16, 2009
Last Updated: August 4, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Centre Leon Berard:
Conventional chemotherapy
cytapheresis
Peripheral stem cell autograft
Surgical resection
Thiotepa

Additional relevant MeSH terms:
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Thiotepa
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 18, 2014