Clinical trial NCT01355445: Vincristine and Irinotecan With or Without Temozolomide in Children and Adults With Refractory/Relapsed Rhabdomyosarcoma
Official title: International Randomized Phase II Trial of the Combination of Vincristine and Irinotecan With or Without Temozolomide (VI or VIT) in Children and Adults With Refractory or Relapsed Rhabdomyosarcoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: RHABDOMYOSARCOMA
Lead sponsor: Centre Oscar Lambret
Sponsor class: OTHER
Collaborators: name: SFCE
First posted: 2011-05-18
Enrollment: 120
Sex: ALL
Minimum age (years): 6
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an international open-label, randomized, multicenter phase II study of VIT and VI for the treatment of patients with recurrent or refractory rhabdomyosarcoma. The study will evaluate the safety and efficacy of these combinations in patients with recurrent or refractory rhabdomyosarcoma.

Detailed description: The dose of vincristine will be 1.5 mg/m² or 0.05 mg/kg for patient ≤ 10 kg (maximum 2 mg) and will be administered by direct intravenous infusion on day 1 and 8 of each course, before irinotecan.

The dose of irinotecan will be 50 mg/m²/d. Irinotecan will be given intravenously over 1 hour on days 1-5 of each course, one hour following the administration of temozolomide.

In the absence of any contraindication (ie known allergies), treatment with oral cefixime 8 mg/kg once daily (maximum daily dose 400 mg) is recommended and will be started 2 days before chemotherapy until day 7.

Temozolomide will be given according to the randomization. The starting dose of temozolomide will be 125 mg/m²/d. The dose of temozolomide will be escalated to 150 mg/m²/day at cycle 2 for patients who do not experience \> grade 3 toxicity of any kind. Temozolomide will be given orally, on an empty stomach, on days 1 through 5 of each course.

Dose reductions and/or administration delays will be performed using specific predefined rules to accommodate individual patient tolerance of treatment and to maintain optimal dose intensity.

Eligibility criteria: Inclusion Criteria:

* TUMOR CHARACTERISTICS :

  * Histologically or cytologically confirmed diagnosis of rhabdomyosarcoma (RMS) (new biopsy recommended)
  * Relapsed or refractory disease which has failed standard treatment approaches
  * Patients must have measurable disease defined as lesions that can be measured in 3 dimensions by medical imaging techniques such as CT or MRI. Ascites, pleural fluid, bone marrow disease and lesions seen on Tc scintigraphy or PET scan only are not considered measurable for these patients
* PATIENT CHARACTERISTICS :

  * Age \> 6 months and ≤ 50 years
  * Karnofsky performance status (PS) 70-100% (for patients \> 12 years of age) OR Lansky Play Score 70-100% (for patients ≤ 12 years of age)
  * Life expectancy ≥ 12 weeks
  * Adequate bone marrow function :

    * Absolute neutrophil count ≥ 1000/mm3; and ≥ 500/mm3 in case of bone marrow disease
    * Platelet count ≥ 100000/mm3 ; and ≥ 75000/mm3 in case of bone marrow disease (transfusion independent)
    * Hemoglobin ≥ 8.5 g/dl (transfusion allowed)
  * Adequate renal function

    * Serum creatinine ≤ 1.5 X ULN for age
    * If serum creatinine \> 1.5 ULN, creatinine clearance (or radioisotope GFR) must be \>70 ml/min/1.73 m²
  * Adequate hepatic function :

    * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, except if the patient is known to have Gilbert's syndrome
    * ALT and AST ≤ 2.5 times ULN for age
  * Negative pregnancy test in females with childbearing potential
  * Fertile patients must use effective contraception
  * No active \> grade 2 diarrhea or uncontrolled infection
  * No other malignancy, including secondary malignancy
  * Patient affiliated with a health insurance system. Applicable for French patients only Written informed consent of patient and/or parents/guardians
* PRIOR or CONCURRENT THERAPY :

  * More than 3 weeks since prior radiation therapy to the site of any progressive lesion that will be identified as a target lesion to measure tumor response
  * At least 3 weeks since prior myelosuppressive therapy (6 weeks for nitrosourea. 2 weeks for vincristine, vinblastine, vinorelbine or low dose cyclophosphamide)
  * No concurrent enzyme-inducing anticonvulsants (EIAC), including phenytoin, phenobarbital or carbamazepine
  * No concurrent administration of any of the following: rifampicin, voriconazole,itraconazole, ketoconazole, aprepitant, St John's Wort
  * No prior irinotecan or temozolomide administration
  * Prior vincristine administration allowed
  * Concurrent palliative radiation therapy to sites allowed other than the main measurable target
  * Prior allo- or autologous SCT allowed

Exclusion Criteria:

* Inclusion criteria failure
* Concomitant anti-cancer treatment
* Know hypersensitivity to any component of study drugs or ingredients
* Pregnancy or breast feeding
* Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
* Neuromuscular disorders (e.g. Charcot-Marie Tooth disease)
* Uncontrolled intercurrent illness or active infection
* Unavailable for medical follow-up (geographic, social or psychological reasons)

Primary outcomes:
measure: Objective tumour response and progression in each treatment arm.
timeFrame: at least 6 weeks (two cycles of treatment)
Secondary outcomes:
measure: To assess the duration of tumor response in each treatment arm
timeFrame: During all the study
measure: To determine the time to tumor progression in each treatment arm
timeFrame: During all the study
measure: To assess the time to treatment failure in each treatment arm
timeFrame: Before 1 year
measure: To assess the overall survival in each treament arm
timeFrame: During all the study
measure: To assess the safety profile and tolerability in each treatment arm
timeFrame: During all the study
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU d'Amiens Picardie Site Sud
city: Bordeaux
country: France
facility: Hôpital des Enfants, Groupe Hospitalier Pellegrin
city: Lille cedex
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: CHU, Hôpital d'Enfants de la Timone
city: Montpellier
country: France
facility: Hôpital Arnaud de Villeneuve - CHU
city: Nantes
country: France
facility: CHU, Hôpital Mère enfants
city: Paris
country: France
facility: Hôpital Armand Trousseau
city: Paris
country: France
facility: Institut Curie
city: Poitiers
country: France
facility: Hôpital Jean Bernard
city: Rennes
country: France
facility: CHU Rennes - Hôpital Sud
city: Saint-Etienne
country: France
facility: CHU St Etienne - Hôpital Nord
city: Toulouse
country: France
facility: Hôpital des enfants
city: Tours
country: France
facility: CHRU
city: Vandoeuvre les Nancy
country: France
facility: CHRU Hôpital d'Enfants
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Ocsar Lambret, Lille, France
name: Anne-Sophie DEFACHELLES, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Marsden NHS Foundation Trust, Surrey, Uinted Kingdom
name: Julia CHISHOLM, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emma Children's Hospital, Amsterdam, The Netherlands
name: J.H.M. MD MERKS
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
name: Michela CASANOVA, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Materno - Infantil Vall D' Hebron, Barcelona, Spain
name: Soledad GALLEGO, MDn
role: PRINCIPAL_INVESTIGATOR
References:
citation: Defachelles AS, Bogart E, Casanova M, Merks JHM, Bisogno G, Calareso G, Gallego Melcon S, Gatz SA, Le Deley MC, McHugh K, Probst A, Rocourt N, van Rijn RR, Wheatley K, Minard-Colin V, Chisholm JC. Randomized Phase II Trial of Vincristine-Irinotecan With or Without Temozolomide, in Children and Adults With Relapsed or Refractory Rhabdomyosarcoma: A European Paediatric Soft Tissue Sarcoma Study Group and Innovative Therapies for Children With Cancer Trial. J Clin Oncol. 2021 Sep 20;39(27):2979-2990. doi: 10.1200/JCO.21.00124. Epub 2021 Aug 3.