A Phase I Study of Irinotecan As a 3-Week Schedule in Children With Refractory or Recurrent Solid Tumors

Vassal, Gilles; Doz, François; Frappaz, Didier; Imadalou, K.; Sicard, E.; Santos, Allan de Oliveira; O’Quigley, John; Germa, Caroline; Risse, Marie‐Laure; Mignard, D.; Pein, F

doi:10.1200/jco.2003.08.175

Cited by 97 publications

(59 citation statements)

References 18 publications

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“…Similar effects have been reported for topotecan, the topoisomerase I inhibitor, which induced tumor regression and a significant tumor growth delay in animals bearing NB xenografts (Vassal et al, 1997). Initial phase I trials of CPT-11 in children evaluated several doses and schedules and some partial responses or disease stabilization were reported in patients with NB (Furman et al, 1999;Blaney et al, 2001;Vassal et al, 2003). However, in a European phase II study in children with relapsed or refractory NB, CPT-11 showed no clinically useful activity (Vassal et al, 2002), suggesting the presence of drug resistance mechanisms.…”

Section: Introductionmentioning

confidence: 64%

Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan

et al. 2006

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In vivo neuroblastoma (NB) xenograft model, resistant to the DNA-topoisomerase I inhibitor irinotecan (CPT-11), has been established to study resistance mechanisms acquired in a therapeutic setting. Common mechanisms of resistance were not involved in this resistance. Thus, we compared the gene expression profiles of sensitive, resistant, and reverted tumors using cDNA expression arrays. Expression of selected transcripts was confirmed by quantitative real-time PCR. We found that pleiotrophin (PTN), a heparin-binding growth factor, was the only gene significantly affected: PTN gene expression was downregulated in all resistant tumors (8-14-fold) as compared to sensitive tumors, and was increased (2-4-fold) in all reverted tumors as compared to resistant tumors. PTN thus appeared to be a likely candidate gene associated with resistance to CPT-11 in this in vivo model. To investigate the direct implication of PTN in NB, we transfected two NB cell lines with RNA interferences in order to silence PTN. PTN failed to demonstrate implication in resistance to CPT-11 in vitro but could influence sensitivity to CPT-11 exclusively through an in vivo mechanism. Indeed, vasculature was significantly enhanced in resistant NB xenografts compared to sensitive and reverted xenografts, and we suggest that PTN is acting in our resistant in vivo NB model as an angiostatic factor.

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Section: Introductionmentioning

confidence: 64%

Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan

et al. 2006

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“…20 -22 A smaller number of children with gliomas have also received this agent. In 2 Phase I pediatric studies, which included a total of 8 children with recurrent high-grade glioma and 3 children with recurrent brainstem glioma, 23,24 irinotecan was administered intravenously every 3 weeks as a single dose or as multiple doses given over 5 consecutive days. One patient with highgrade glioma experienced a PR, and SD was documented in five patients with high-grade glioma and one patient with brainstem glioma.…”

Section: Discussionmentioning

confidence: 99%

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Broniscer

Iacono

Chintagumpala

et al. 2004

Cancer

100

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BACKGROUNDThe role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting.METHODSPatients ages 3–21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5‐day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5‐(3‐methyltriazen‐1‐yl)imidazole‐4‐carboxamide (MTIC), were analyzed during Cycles 1 and 3.RESULTSThirty‐three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n = 5) or toxicity (n = 1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty‐nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one‐third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1‐year survival rate was 48% (standard error, 8%).CONCLUSIONSThe administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children. Cancer 2005. © 2004 American Cancer Society.

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“…Due to small numbers of patients, phase I and II studies are slow to run, and ethical concerns may lead to reluctance to enroll young patients. It is clear, however, that in childhood, toxicities may be different from those in adults (Doz et al, 2001) and that the tolerance of children may be better (Vassal et al, 2003). When a DLT has been defined in adults, it should be also defined in a paediatric cohort.…”

Section: Discussionmentioning

confidence: 99%

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

et al. 2006

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Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m −2 for Group A and 100 mg m −2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

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A Phase I Study of Irinotecan As a 3-Week Schedule in Children With Refractory or Recurrent Solid Tumors

Abstract: The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m2 in less heavily, and heavily pretreated children with solid tumors.

Cited by 97 publications

References 18 publications

Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan

Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

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