Temsirolimus and Valproic Acid in Treating Young Patients With Relapsed Neuroblastoma, Bone Sarcoma, or Soft Tissue Sarcoma
A Multi-center Phase I Trial of Temsirolimus in Combination With Valproic Acid in Children and Adolescents With Multiply Relapsed Pediatric Solid Tumors
RATIONALE: Drugs such as temsirolimus and valproic acid may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Valproic acid may also stop the growth of solid tumors by blocking blood flow to the tumor.
PURPOSE: This phase I trial is studying the side effects and the best dose of temsirolimus when given together with valproic acid in treating young patients with relapsed neuroblastoma, bone sarcoma, or soft tissue sarcoma.
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
OBJECTIVES:
Primary
- To identify the maximum-tolerated dose of temsirolimus in combination with valproic acid in highly pretreated pediatric patients with refractory solid tumors.
Secondary
- To estimate the objective response rate in patients treated with this regimen.
- To estimate the progression-free survival of patients treated with this regimen.
- To explore the association between tumor IGF-IR, mTOR expression, HDAC, autophagy biomarkers, and sera levels of temsirolimus, valproate, and VEGF-A with toxicity and disease response.
- To evaluate the ability of selected member divisions of a newly developed North Carolina-based pediatric oncology consortium to cooperate in clinical trials.
OUTLINE: This a multicenter, dose-escalation study of temsirolimus.
Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and oral valproic acid* 3 times daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Blood samples are collected at baseline and periodically during study for pharmacokinetic and VEGF-A studies. Tumor tissue samples from archived biopsy are also analyzed for IGF-IR, mTOR expression, HDAC, and autophagy biomarkers.
After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 2 years, and then every 6 months for 2 years.
NOTE: * Doses of valproic acid are titrated beginning 3-7 days prior to starting temsirolimus to achieve plasma levels of 75-100 µg/mL.
Type d'étude
Inscription (Réel)
Phase
- La phase 1
Contacts et emplacements
Lieux d'étude
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North Carolina
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Chapel Hill, North Carolina, États-Unis, 27599-7295
- Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
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Charlotte, North Carolina, États-Unis
- Carolina Healthcare System
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
DISEASE CHARACTERISTICS:
Histologically confirmed malignant solid tumor at original diagnosis, including the following:
- Neuroblastoma
- Bone sarcomas (primary neuroectodermal tumors/ Ewing sarcoma (PNET/ES), osteosarcoma)
- Soft tissue sarcomas (rhabdosarcoma and related tumors)
- Histologically confirmed of relapsed disease is highly recommended but not mandatory
- Measurable disease according to RECIST
Refractory or progressive disease after ≥ 1 and ≤ 4 prior chemotherapy regimens
- Patients with neuroblastoma, PNET/ES, or rhabdosarcoma must have failed a cyclophosphamide/topotecan-containing regimen
- Stem cell transplantation, including preparative regimen and post-transplant immunotherapy, is considered to be 1 regimen
PATIENT CHARACTERISTICS:
- Karnofsky performance status (PS) 50-100% (or Lansky PS 50-100%)
- Life expectancy ≥ 8 weeks
- ANC ≥ 750/mm^3
- Platelet count ≥ 75,000/mm^3 (transfusion independent)
Hemoglobin 8.0 g/dL (may receive RBC transfusions)
- Patients with tumor metastatic to bone marrow are allowed to receive transfusions to maintain hemoglobin and platelet counts
- Serum creatinine normal
- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin < 1.0 mg/dL (if total bilirubin > 2.0 mg/dL)
- ALT < 5 times ULN
- Negative pregnancy test
- Not pregnant or nursing
- Fertile patients must use effective contraception
- Families must be able to give consent in English or Spanish
- No allergy to H1 antihistamines
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- More than 2 weeks since prior chemotherapy, immunotherapy, or radiotherapy and recovered
- No concurrent anticonvulsants, including valproic acid
- No concurrent strong inducers or inhibitors of CYP3A4, including grapefruit juice
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: N / A
- Modèle interventionnel: Affectation à un seul groupe
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
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Autre: Single Arm Temsirolimus + Valproic Acid
Drug: temsirolimus 60-230mg/m2 weekly during each 28 day course, for up to 12 courses Drug: valproic acid (VPA) All patients will be given oral VPA (5 mg/kg, 3 times a day for each 28 day course, up to 12 courses |
60-230mg/m2 weekly during each 28 day course, for up to 12 courses
Autres noms:
All patients will be given oral VPA (5 mg/kg, 3 times a day for each 28 day course, up to 12 courses
Autres noms:
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid
Délai: 4 weeks
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The planned starting dose of Temsirolimus is 60mg/M2.
The traditional 3+3 design will be used, where the MTD is defined as the dose with the probability of a DLT of 0.20
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4 weeks
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Objective response rate
Délai: every 12 weeks
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Each patient will be classified according to their "best response".
Best response is determined from the sequence of the objective statuses as described in RECIST 1.1
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every 12 weeks
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Progression-free survival
Délai: 3 years
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If the patient's disease has not progressed at the time protocol-directed therapy is complete, any tumor assessments available during the follow-up period (up to 3 years) will be evaluated using RECSIT 1.1
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3 years
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Temsirolimus pharmakokinetic parameters (Maximum plasma concentration)
Délai: doses 1 and 5
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Blood will be drawn prior to, 30 minutes, 1hr, 2hr, 5hr, 24hr after completion of doses 1 and 5. Levels of Temsirolimus will be measured using validated liquid chromatography and tandem mass spectroscopic methods
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doses 1 and 5
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Collaborateurs et enquêteurs
Collaborateurs
Les enquêteurs
- Chercheur principal: Julie Blatt, MD, UNC Lineberger Comprehensive Cancer Center
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude
Achèvement primaire (Réel)
Achèvement de l'étude (Réel)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Estimation)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Estimation)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
- tumeur solide de l'enfant, sans précision, protocole spécifique
- rhabdomyosarcome infantile récurrent
- neuroblastome récurrent
- sarcome d'Ewing récurrent/tumeur neuroectodermique primitive périphérique
- ostéosarcome récurrent
- tumeur neuroectodermique primitive sus-tentorielle récidivante de l'enfant
- tumeur cérébrale infantile récurrente
- sarcome récurrent des tissus mous de l'enfant
Termes MeSH pertinents supplémentaires
- Maladies du système nerveux
- Tumeurs, tissus conjonctifs et mous
- Tumeurs par type histologique
- Tumeurs par site
- Tumeurs, glandulaires et épithéliales
- Tumeurs, neuroépithéliales
- Tumeurs neuroectodermiques
- Tumeurs, cellules germinales et embryonnaires
- Tumeurs, tissu nerveux
- Tumeurs neuroectodermiques primitives
- Tumeurs neuroectodermiques, primitives, périphériques
- Tumeurs
- Sarcome
- Tumeurs du système nerveux
- Tumeurs du système nerveux central
- Neuroblastome
- Effets physiologiques des médicaments
- Agents neurotransmetteurs
- Mécanismes moléculaires de l'action pharmacologique
- Agents anti-infectieux
- Dépresseurs du système nerveux central
- Inhibiteurs d'enzymes
- Agents antinéoplasiques
- Agents immunosuppresseurs
- Facteurs immunologiques
- Agents antibactériens
- Agents tranquillisants
- Médicaments psychotropes
- Agents GABA
- Anticonvulsivants
- Agents antimaniaques
- Antibiotiques, Antinéoplasiques
- Agents antifongiques
- Acide valproïque
- Sirolimus
Autres numéros d'identification d'étude
- LCCC 0901
- P30CA016086 (Subvention/contrat des NIH des États-Unis)
- CDR0000665319 (Autre identifiant: PDQ)
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