Pierre Leblond

Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors

This multicenter phase I study aimed to establish the recommended dose (RD) of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, given as monotherapy or with radiotherapy to children with malignant brain tumors. Group 1 included patients with refractory or relapsing brain tumors receiving erlotinib alone, and group 2 included newly diagnosed patients with brainstem gliomas receiving radiotherapy and erlotinib. A conventional 3 + 3 dose escalation and a continual reassessment method, respectively, were utilized in 4 dose levels: 75, 100, 125, and 150 mg/m² per day. Fifty-one children were enrolled (30 and 21, respectively); 50 received treatment. The RD of erlotinib was 125 mg/m² per day as monotherapy or in combination with radiotherapy. Overall, 230 adverse events in 44 patients were possibly treatment related (216, grades 1 and 2; 9, grade 3; 1, grade 4; 4, grade 5). Dermatologic and neurologic symptoms were common; intratumoral hemorrhage was confirmed in 3 patients. In group 1, 8 of 29 patients (28%) had stable disease with tumor regression approaching 50% in a malignant glioma and an anaplastic oligoastrocytoma. In group 2, overall survival was 12.0 months. EGFR overexpression by immunohistochemistry was found in 17 of 38 (45%) tumor samples analyzed, with a partial gain of 7p11.2 in 1 glioblastoma; phosphate and tensin homolog loss was frequent in brainstem glioma (15 of 19). Mean (95% CI) apparent clearance and volume of distribution for erlotinib were 4.0 L/h (3.4-4.5 L/h) and 98.6 L (69.8-127.0 L), respectively, and were independent of the dose level; mean half-life was 16.6 hours. Thus, erlotinib 125 mg/m² per day has an acceptable tolerability profile in pediatric patients with brain tumors and can be combined with radiotherapy.

Clinicopathologic prognostic factors in childhood atypical teratoid and rhabdoid tumor of the central nervous system: a multicenter study.

The objective of this study was to describe the clinical and pathologic features and to identify prognostic factors in patients with atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS).

Predicting the risk of severe bacterial infection in children with chemotherapy‐induced febrile neutropenia

The prognosis of febrile neutropenia (FN) in childhood cancer has been considerably improved by the intensification of treatment, including systematic hospitalization and broad‐spectrum antibiotics. As only few children present with a severe bacterial infection (SBI), clinical decision rules have been developed to distinguish those at risk for SBI. The aim of this study was to evaluate the reproducibility of six clinical decision rules proposed in the literature and to compare their performance.

Phase II study of gemcitabine combined with oxaliplatin in relapsed or refractory paediatric solid malignancies: An innovative therapy for children with Cancer European Consortium Study

AIM To assess objective response rates after 4 cycles of gemcitabine in combination with oxaliplatin in children and adolescents with relapsed or refractory solid tumours. METHODS This multicentre, non-randomised Phase II study included five strata: neuroblastoma, osteosarcoma, medulloblastoma and other CNS tumours strata with two-stage Simon designs and a miscellaneous, extra-cranial solid tumour stratum with descriptive design. Eligibility criteria included: age 6 months to 21 years; measurable, relapsed or refractory solid malignancy; no more than one previous salvage therapy. Gemcitabine was administered intravenously at 1000 mg/m(2) over 100 min followed by oxaliplatin at 100mg/m(2) over 120 min on Day 1 of a 14-d cycle. Tumour response was assessed every 4 cycles according to WHO criteria. RESULTS Ninety-three out of 95 patients enrolled in 25 centres received treatment: 12 neuroblastoma; 12 osteosarcoma; 14 medulloblastoma; 13 other CNS tumours and 42 miscellaneous non-CNS solid tumours. Median age was 11.7 years (range, 1.3-20.8 years). Tumour control (CR+PR+SD) at 4 cycles was obtained in 30/93 evaluable patients (32.3%; 95% confidence interval (CI), 22.9-42.7%), including four PR: 1/12 patients with osteosarcoma, 1/12 with medulloblastoma, 1/12 with rhabdomyosarcoma and 1/4 with other sarcoma. Five out of 12 eligible patients with neuroblastoma experienced stable disease. During a total of 481 treatment cycles (median 4, range 1-24 per patient), the most common treatment-related toxicities were haematologic (leukopenia, neutropenia, thrombocytopenia) and neurological (dysesthesia, paresthesia). CONCLUDING STATEMENT The gemcitabine-oxaliplatin combination administered in a bi-weekly schedule has acceptable safety profile with limited activity in children with relapsed or refractory solid tumours.

Bevacizumab and irinotecan in children with recurrent or refractory brain tumors: Toxicity and efficacy trends

Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor, has proven efficacy in some adult tumors; it is now proposed as a new therapeutic strategy for refractory or recurrent brain tumors in some children, either alone or combinated.

Long survival in a child with a mutated K27M‐H3.3 pilocytic astrocytoma

We report the first case of a child with a H3F3A K27M mutated pilocytic astrocytoma, who presented with a 10 years survival, and underwent spontaneous malignant transformation. The complex tumoral chromosomal rearrangements were consistent for genomic instability and for the histopathological features of malignant transformation into glioblastoma. H3F3A K27M mutations are rarely observed in benign neoplasms and may be associated with an adverse outcome. This mutation might not be the major driver that led to the onset of tumorigenesis, and we could consider that the associated TP53 mutation, would be required for malignant transformation.

Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study.

BACKGROUND This multicenter phase II study investigated temozolomide + irinotecan (TEMIRI) treatment in children with relapsed or refractory medulloblastoma. METHODS Patients received temozolomide 100-125 mg/m(2)/day (days 1-5) and irinotecan 10 mg/m(2)/day (days 1-5 and 8-12) every 3 weeks. The primary endpoint was tumor response within the first 4 cycles confirmed ≥4 weeks and assessed by an external response review committee (ERRC). In a 2-stage Optimum Simon design, ≥6 responses in the first 15 evaluable patients were required within the first 4 cycles for continued enrollment; a total of 19 responses from the first 46 evaluable patients was considered successful. RESULTS Sixty-six patients were treated. Seven responses were recorded during stage 1 and 15 in the first 46 ERRC evaluated patients (2 complete responses and 13 partial responses). The objective response rate during the first 4 cycles was 32.6% (95% confidence interval [CI], 19.5%-48.0%). Median duration of response was 27.0 weeks (7.7-44.1 wk). In 63 patients evaluated by local investigators, the objective response rate was 33.3% (95% CI, 22.0%-46.3%), and 68.3% (95% CI, 55.3%-79.4%) experienced clinical benefit. Median survival was 16.7 months (95% CI, 13.3-19.8). The most common grade 3 treatment-related nonhematologic adverse event was diarrhea (7.6%). Grade 3/4 treatment-related hematologic adverse events included neutropenia (16.7%), thrombocytopenia (12.1%), anemia (9.1%), and lymphopenia (9%). CONCLUSIONS The planned study primary endpoint was not met. However, its tolerability makes TEMIRI a suitable candidate chemotherapy backbone for molecularly targeted agents in future trials in this setting.

Outcome and prognostic factors in high‐risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT)

The aim of this retrospective international analysis was to evaluate the role of risk factors in pediatric patients with adrenocortical carcinoma (ACC) observed in European countries (2000–2013) in an attempt to identify factors associated with poor prognosis.

Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.

SummaryThe poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology.

Cutaneous metastases during an aggressive course of Xp11.2 translocation renal cell carcinoma in a teenager

We reported a rare case of cutaneous metastases of renal cell carcinoma (RCC) with an Xp11.2 translocation in a 15‐year‐old female. Clinicians should be aware of the possibility of this uncommon site of metastasis, which can indicate multivisceral dissemination of the disease. We discuss the feasibility and opportunity of treating such a patient with multiple line of tyrosine kinase inhibitor (TKI) targeting vascular endothelial and platelet‐derived growth factor receptors. Pediatr Blood Cancer 2014;61:1698–1700.