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

May 16, 2019 updated by: Centre Leon Berard

Efficacy and Tolerance Adjuvant High-Dose Thiotepa With Peripheral Stem Cell Rescue Associated With Conventional Chemotherapy in Children and Adults With Relapsed Osteosarcoma

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

44

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Besancon, France, 25000
        • CHU BESANCON- Hôpital Jean Minjoz
      • Bordeaux, France, 33000
        • Chu - Hopital Des Enfants Bordeaux
      • Dijon, France, 21079
        • CHU Dijon Le Bocage, Hôpital d'Enfants
      • Grenoble, France, 38045
        • CHU Grenoble
      • LYON Cedex 08, France, 69373
        • Centre Léon Bérard - Institut d'Hémato-Oncologie Pediatrique
      • Lille, France, 59000
        • Centre Oscar Lambret
      • Marseille, France, 13273
        • Institut Paoli Calmettes
      • Marseille, France, 13385
        • Hôpital des Enfants de la Timone
      • Nantes, France, 44093
        • Chu Nantes - Hopital Meres Et Enfants
      • Nice, France, 06189
        • Centre Antoine Lacassagne
      • Nice, France, 06202
        • CHU Nice, Hôpital L'Archet 2
      • Paris, France, 75248
        • Institut Curie
      • Paris, France, 75571
        • Hôpital d'Enfants Armand Trousseau
      • Poitiers, France, 86021
        • CHU Poitiers, site de la Milétrie
      • Rennes, France, 35023
        • CHU Rennes - Hôpital sud
      • Saint Priest en Jarez, France, 42270
        • CHU de Saint-Etienne, Hopital Nord
      • Saint-Priest-en -Jarez, France, 42270
        • Institut Lucien Neurwith
      • Saint-denis, France, 97405
        • CHU La Réunion
      • Saint-herblain, France, 44805
        • Institut de cancérologie de l'Ouest - René Gauducheau
      • Strasbourg, France, 67098
        • Hopital de Hautepierre
      • Toulouse, France, 31059
        • Chu Toulouse - Hopital D'Enfants
      • Vandoeuvre Les Nancy, France, 54511
        • CHU Nancy - Hôpital d'Enfants
      • Villejuif, France, 95805
        • Institut Gustave Roussy

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 50 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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
Other: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Estimate the overall survival rate
Time Frame: 24 months
24 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Estimate overall survival after relapse diagnosis
Time Frame: 24 months
24 months
Estimate the survival free progression after randomization
Time Frame: 24 months
24 months
Evaluate the tolerance profile of experimental treatment (hematologic toxicity)
Time Frame: every 3 weeks
every 3 weeks
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
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
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)
If surgery is applicable, a few weeks after thiotepa cure (12 to 17 weeks after inclusion)
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
At inclusion,at surgery , and at the end of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Leon Berard

Investigators

  • Principal Investigator: Perrine MAREC-BÉRARD, Dr, Institut d'Hématologie et d'Oncologie Pédiatrique (IHOP) - CLB

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2009

Primary Completion (Actual)

October 29, 2018

Study Completion (Actual)

October 29, 2018

Study Registration Dates

First Submitted

September 16, 2009

First Submitted That Met QC Criteria

September 16, 2009

First Posted (Estimate)

September 17, 2009

Study Record Updates

Last Update Posted (Actual)

May 17, 2019

Last Update Submitted That Met QC Criteria

May 16, 2019

Last Verified

August 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OSII-TTP
  • 2009-009899-12 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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