Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma

Chastagner, Pascal; Devictor, B; Geoerger, Birgit; Aerts, Isabelle; Leblond, Pierre; Frappaz, Didier; Gentet, Jean‐Claude; Bracard, Serge; André, Nicolas

doi:10.1007/s00280-015-2781-0

Cited by 34 publications

(13 citation statements)

References 27 publications

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“…Just a few clinical trials of anthracyclines have been conducted in children with pHGG, DIPG, or other recurrent or progressive brain tumors. 11,32,51 Results have been variable thus far. In one study, 4 of 8 patients with recurrent or progressive pHGG responded with stable disease for a period of 9-48 weeks on a regimen of PLD and oral topotecan, but the toxicity of this systemic treatment was high.…”

Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma

Sewing

Lagerweij

Vuurden

et al. 2017

Journal of Neurosurgery: Pediatrics

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OBJECTIVEPediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models.METHODSThe sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model.RESULTSBoth pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors.CONCLUSIONSLocal delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic window for treating orthotopic brainstem tumors in mice. For tumors in the thalamus, therapeutic concentrations to slow down tumor growth could be reached. These data suggest that anatomical location determines the severity of toxicity after local delivery of therapeutic agents and that caution should be used when translating data from supratentorial CED studies to treat infratentorial tumors.

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Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma

Sewing

Lagerweij

Vuurden

et al. 2017

Journal of Neurosurgery: Pediatrics

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“…In conclusion, the results of some clinical trials reinforce the potential application of these new therapeutic strategies in GBM. In fact, Myocet ® , a non-PEG-DOX liposome, was used in pediatric patients with high-grade glioma (GBM, astrocytoma, oligodendroglioma or oligoastrocytoma) after TMZ-based chemotherapy (phase I clinical trial) [92]. With the same purpose, nanoliposomal IRI (nal-IRI) was used in adults (28–65 years) with high-grade glioma, making it possible to establish the maximum tolerated dose.…”

Section: Application Of Lipid-based Nanoparticles In Cancer Therapymentioning

confidence: 99%

Lipid-Based Nanoparticles: Application and Recent Advances in Cancer Treatment

et al. 2019

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Many therapeutically active molecules are non-soluble in aqueous systems, chemically and biologically fragile or present severe side effects. Lipid-based nanoparticle (LBNP) systems represent one of the most promising colloidal carriers for bioactive organic molecules. Their current application in oncology has revolutionized cancer treatment by improving the antitumor activity of several chemotherapeutic agents. LBNPs advantages include high temporal and thermal stability, high loading capacity, ease of preparation, low production costs, and large-scale industrial production since they can be prepared from natural sources. Moreover, the association of chemotherapeutic agents with lipid nanoparticles reduces active therapeutic dose and toxicity, decreases drug resistance and increases drug levels in tumor tissue by decreasing them in healthy tissue. LBNPs have been extensively assayed in in vitro cancer therapy but also in vivo, with promising results in some clinical trials. This review summarizes the types of LBNPs that have been developed in recent years and the main results when applied in cancer treatment, including essential assays in patients.

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“…The main purpose of Doxil in clinical is to avoid the severe cytotoxicity for cardio tissue, although the clearance of liver and kidney may reduce the dose in circulation, causing lower efficiency in lesions. Currently, more than 12 liposome-based drugs are approved for clinical use and more are in stages of clinical trials [ 52 , 53 , 54 ]. Generally, the liposomal formulation drugs are approved for intravenous treatment.…”

Section: Current Materials In Nanomedicinementioning

confidence: 99%

From Nanoparticles to Cancer Nanomedicine: Old Problems with New Solutions

2021

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Anticancer nanomedicines have been studied over 30 years, but fewer than 10 formulations have been approved for clinical therapy today. Despite abundant options of anticancer drugs, it remains challenging to have agents specifically target cancer cells while reducing collateral toxicity to healthy tissue. Nanocompartments that can be selective toward points deeply within malignant tissues are a promising concept, but the heterogeneity of tumor tissue, inefficiency of cargo loading and releasing, and low uniformity of manufacture required from preclinical to commercialization are major obstacles. Technological advances have been made in this field, creating engineered nanomaterials with improved uniformity, flexibility of cargo loading, diversity of surface modification, and less inducible immune responses. This review highlights the developmental process of approved nanomedicines and the opportunities for novel materials that combine insights of tumors and nanotechnology to develop a more effective nanomedicine for cancer patients.

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Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma

Abstract: The RD of Myocet® administered every 3 weeks to paediatric patients was 60 mg/m(2). The efficacy of Myocet® in paediatric patients with high-grade glioma remains to be determined and should be studied in Phase II trials.

Cited by 34 publications

References 27 publications

Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma

Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma

Lipid-Based Nanoparticles: Application and Recent Advances in Cancer Treatment

From Nanoparticles to Cancer Nanomedicine: Old Problems with New Solutions

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