Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: A European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study

Giannatale, Angela Di; Dias-Gastellier, Nathalie; Devos, Annick S.; Hugh, Kieran Mc; Boubaker, Ariane; Courbon, F.; Verschuur, Arnaud; Ducassoul, Stéphane; Malekzadeh, Katty; Casanova, Michela; Amoroso, Loredana; Chastagner, Pascal; Zwaan, C. Michel; Munzer, Caroline; Aerts, Isabelle; Landman‐Parker, Judith; Riccardi, Riccardo; Deley, Marie-Cécile Le; Geoerger, Birgit; Rubie, H

doi:10.1016/j.ejca.2013.08.012

Cited by 45 publications

(52 citation statements)

References 32 publications

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“…Outcome data including time on trial, number of cycles received, responses per protocol criteria, timing of the responses, and events are summarized in Table . Patients were on trial for a median of 3.5 months . Twenty‐one of them (30%) experienced CR or PR as per protocol‐defined criteria.…”

Section: Resultsmentioning

confidence: 99%

“…Fourth, response is a complex and difficult endpoint to measure and requires a central review for single‐arm studies. A central review of computerized tomography (CT) and MIBG scans was organized for two of the three studies . Trial endpoints such as PFS can also be used in the relapsed setting and a common definition of progression versus no progression is less complex to achieve in comparison to response rate based on the integration of RECIST‐type measurements, MIBG scoring, and bone marrow histology.…”

Section: Discussionmentioning

confidence: 99%

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Outcome of children with relapsed or refractory neuroblastoma: A meta‐analysis of ITCC/SIOPEN European phase II clinical trials

Moreno

Rubie

Varo

et al. 2016

Pediatric Blood & Cancer

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Background: Few randomized trials have been conducted in children with relapsed/refractory neuroblastoma and data about outcomes including progression-free survival (PFS) in these patients are scarce. Procedure:A meta-analysis of three phase II studies of children with relapsed/refractory neuroblastoma conducted in Europe (temozolomide, topotecan-vincristine-doxorubicin and topotecantemozolomide) was performed. Individual patient data with extended follow-up were collected from the trial databases after publication to describe trial outcomes (response rate, clinical benefit ratio, duration of treatment, PFS, and overall survival [OS]). Characteristics of subjects with relapsed/refractory neuroblastoma were compared.Results: Data from 71 children and adolescents with relapsed/refractory neuroblastoma were collected. Response definitions were not homogeneous in the three trials. Patients were on study for a median of 3.5 months (interquartile range [IQR] 1.9-6.2). Of those, 35.2% achieved a complete or partial response, 26.3% experienced a response after more than two cycles, and 23.9% received more than six cycles. Median PFS from study entry for all, refractory, and relapsed patients was 6.4 ± 1.0, 12.5 ± 6.8, and 5.7 ± 1.0 months, respectively (P = 0.006). Median OS from study entry for all, refractory, and relapsed patients was 16.1 ± 4.3, 27.9 ± 20.2, and 11.0 ± 1.6 months, respectively (P = 0.03). Conclusions:Baseline data for response rate, clinical benefit ratio, duration of treatment, PFS, and OS were provided. Two subpopulations (relapsed/refractory) were clearly distinct and should be included in the interpretation of all trials. These results should help informing the design of forthcoming studies in relapsed/refractory neuroblastoma.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Outcome of children with relapsed or refractory neuroblastoma: A meta‐analysis of ITCC/SIOPEN European phase II clinical trials

Moreno

Rubie

Varo

et al. 2016

Pediatric Blood & Cancer

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“…Thus, it is not surprising to find high levels of MYCN in a subset of poorly differentiated aggressive neuroblastomas (7). This has translated to clinical approaches targeting MYCN and other downstream pathways such as MDM2 (RG3788, Roche Pharmaceuticals) (41, 42), ODC1 (difluoromethylornithine -DFMO) (43) and mTOR (Temazolamide) (44, 45). However, many high-risk cases have minimal MYCN expression, suggesting additional mechanisms for tumorigenesis independent of MYCN deregulation (46).…”

Section: Molecular Pathogenesis Of Neuroblastoma – a Tumor Of The Neumentioning

confidence: 99%

Neuroblastoma: Molecular Pathogenesis and Therapy

2015

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Neuroblastoma is a developmental tumor of young children arising from the embryonic sympathoadrenal lineage of the neural crest. Currently neuroblastoma is the primary cause of death from pediatric cancer for children between the age of 1 and 5 years and accounts for approximately 13% of all pediatric cancer mortality. Its clinical impact and its unique biology have made this aggressive malignancy the focus of a large concerted translational research effort. New insights into tumor biology are driving the development of new classification schemas; novel targeted therapeutic approaches include small molecule inhibitors, epigenetic, non-coding RNA, and cell-based immunologic therapies. Recent insights regarding the pathogenesis and biology of neuroblastoma will be placed in context with the current understanding of tumor biology and tumor/host interactions. Systematic classification of patients coupled with therapeutic advances point to a future of improved clinical outcomes for this biologically distinct and highly aggressive pediatric malignancy.

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“…This international multicenter, nonrandomized, phase 2 study (NCT00918320) explored the efficacy of TOTEM in three disease strata, namely, neuroblastoma (reported separately in Di Giannatale et al), and two basket cohorts with extracranial solid tumors and central nervous system (CNS) tumors. The trial was designed to be extended with a confirmatory phase II part in diseases where signals of activity were observed, which was the case in medulloblastoma and primitive neuroectodermal tumors (PNET).…”

Section: Introductionmentioning

confidence: 99%

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study

Teuff

Castaneda-Heredia

Dufour

et al. 2019

Pediatric Blood & Cancer

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Aim To assess objective response after two cycles of temozolomide and topotecan (TOTEM) in children with refractory or relapsed miscellaneous extracranial solid and central nervous system (CNS) tumors, including medulloblastoma and primitive neuroectodermal tumors (PNET). Procedure Multicenter, nonrandomized, phase 2 basket trial including children with solid tumors, completed by a one‐stage design confirmatory cohort for medulloblastoma, and an exploratory cohort for PNET. Main eligibility criteria were refractory/relapsed measurable disease and no more than two prior treatment lines. Temozolomide was administered orally at 150 mg/m2/day followed by topotecan at 0.75 mg/m2/day intravenously for five consecutive days every 28 days. Tumor response was assessed every two cycles according to WHO criteria and reviewed independently. Results Thirty‐two patients were enrolled and treated in the miscellaneous solid tumor and 33 in the CNS strata; 20 patients with medulloblastoma and six with PNET were included in the expansion cohorts. The median age at inclusion was 10.0 years (range, 0.9‐20.9). In the basket cohorts, confirmed complete and partial responses were observed in one glioma, four medulloblastoma, and one PNET, leading to the extension. The overall objective response rate (ORR) in medulloblastoma was 28% (95% CI, 12.7‐47.2) with 1/29 complete and 7/29 partial responses, those for PNET 10% (95% CI, 0.3‐44.5). Post hoc Bayesian analysis estimates that the true ORR in medulloblastoma is probably between 20% and 30% and below 20% in PNET. The most common treatment‐related toxicities of the combination therapy were hematologic. Conclusions Temozolomide‐topotecan results in significant ORR in children with recurrent and refractory medulloblastoma with a favorable toxicity profile.

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Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: A European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study

Cited by 45 publications

References 32 publications

Outcome of children with relapsed or refractory neuroblastoma: A meta‐analysis of ITCC/SIOPEN European phase II clinical trials

Outcome of children with relapsed or refractory neuroblastoma: A meta‐analysis of ITCC/SIOPEN European phase II clinical trials

Neuroblastoma: Molecular Pathogenesis and Therapy

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study

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