Phase II study of gemcitabine in children with relapsed leukemia

Wagner-Bohn, Alexandra; Henze, Günter; Stackelberg, A von; Boos, Joachim

doi:10.1002/pbc.20632

Cited by 12 publications

(8 citation statements)

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“…Furthermore, these preclinical models do not mimic the real clinical situations. In addition, gemcitabine was recently shown to be insufficiently active against leukemia in phase II clinical trials (Angiolillo et al, 2006, Wagner-Bohn et al, 2006. We have recently developed a new prodrug of gemcitabine by conjugation with squalene (squalenoylation) (Couvreur et al, 2006a).…”

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confidence: 99%

Preclinical Toxicology (Subacute and Acute) and Efficacy of a New Squalenoyl Gemcitabine Anticancer Nanomedicine

Reddy¹,

Marque²,

Dubernet³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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This study investigates 1) the anticancer efficacy of a new squalenoyl prodrug of gemcitabine (SQgem) in nanoassembly form compared with gemcitabine at equitoxic doses and 2) the subacute and acute preclinical toxicity of these compounds. The toxicity studies revealed that SQgem nanoassemblies, like gemcitabine, were toxic, and they led to dose-dependent mortality after daily i.v. injections for 1 week, irrespective of the route of administration. However, a 4-to 5-day spaced dosing schedule (injections on day 0, 4, 8, and 13) was proved to be safer in terms of weight loss and hematological and other toxicity. Using this spaced dosing schedule, SQgem nanoassemblies exhibited impressive anticancer activity in mice bearing L1210 leukemia because this treatment led to 75% long-term survivors. In contrast, at equitoxic doses, neither free gemcitabine nor cytarabine led to longterm survivors and all the mice of these groups died of the disease. Further toxicity studies performed at lethal doses by blood and serum analysis and organ weight determinations revealed that the hematological toxicity was the dose-limiting toxicity in both SQgem nanoassemblies and gemcitabine, whereas probable gastrointestinal toxicity was also associated with free gemcitabine. The SQgem nanoassemblies did not display hepatotoxicity, which is one of the clinically encountered toxicities of gemcitabine. To summarize, these preclinical studies demonstrated that the toxicological profile of new squalenoyl gemcitabine nanomedicine was not distinct from that of the parent gemcitabine, whereas it was much more potent than gemcitabine at equitoxic doses and cytarabine at clinically relevant doses. These data support the candidature of SQgem for clinical trials.Gemcitabine is an anticancer nucleoside analog indicated in the clinic for the treatment of various solid tumors. Although the anticancer activity of gemcitabine against leukemia has been demonstrated in preclinical models in which the leukemia cells were introduced intraperitoneally (Hertel et al., 1990), it is not indicated in the clinic for this purpose. Furthermore, these preclinical models do not mimic the real clinical situations. In addition, gemcitabine was recently shown to be insufficiently active against leukemia in phase II clinical trials (Angiolillo et al., 2006, Wagner-Bohn et al., 2006. We have recently developed a new prodrug of gemcitabine by conjugation with squalene (squalenoylation) (Couvreur et al., 2006a). The linkage of squalene was performed at the level of the 4-amino group of gemcitabine, rendering the molecule more amphiphilic, and resulting in their spontaneous aggregation as nanoassemblies of approximately 130 nm in diameter. These squalenoyl gemcitabine (SQgem) nanoassemblies were demonstrated to prevent the deamination of gemcitabine in vitro, thus overcoming one of the main drawbacks to its use, its short biological half-life (Couvreur et al., 2006b). In addition, in vitro, the SQgem nanoassemblies were demonstrated to be more cytotoxic than gemcitabin...

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confidence: 99%

Preclinical Toxicology (Subacute and Acute) and Efficacy of a New Squalenoyl Gemcitabine Anticancer Nanomedicine

Reddy¹,

Marque²,

Dubernet³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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“…Unfortunately, both trials had to be stopped earlier than expected [5,6]. Still, aiming to contribute to a potential expansion of labelling meant to observe GCP.…”

Section: Discussionmentioning

confidence: 99%

“…However, the challenge is to cooperate with the authorities to explore the scope of the EU Regulations to apply them effectively and in a useful manner, so that there will be better quality and increased evidence rather than less progress [4]. The Coordination Center for Clinical Trials (KKS) of the University Hospital of Münster conducted two prospective open-label multicenter phase II studies of gemcitabine in children with relapsed malignancies [5,6]. Gemcitabine is a well-known drug in adults, and its therapeutic benefit and excellent side effect profile have been evidenced in relapse situations.…”

Section: Introductionmentioning

confidence: 99%

Implementing Good Clinical Practice in Two Noncommercial Phase II Studies in Children with Cancer

et al. 2007

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In noncommercial clinical drug research the implementation of the principles of Good Clinical Practice (GCP) has been criticized for introducing unnecessary bureaucracy at the expense of scientific activity, especially when small populations such as children or patients with orphan diseases are concerned. Patients and Methods: From May 2003 to September 2005, we conducted two prospective open-label multicenter phase II studies in pediatric oncology. Aside from medical questions, these studies set out to explore the requirements according to the essential standards of the ICH-GCP Guideline in anticipation of the implementation of the EU Regulation in German Drug Law in August 2004; the latter, prospective investigation was initiated by the Coordinating Center for Clinical Trials (KKS). Results: The main GCP requirements were systematically reviewed and critically discussed by focusing mainly on the situation of noncommercial pediatric drug research. Conclusion: While putting GCP into practice in academic research increases costs, the challenge will be to apply these guidelines to good effect, for better quality and increased evidence. Implementing Good Clinical Practice in Two Noncommercial Phase II Studies in Children with Cancer Alexandra Wagner-Bohna Anita Ripkens-Reinharda Gerlinde Benninger-Döringa Joachim Boosb a Coordinating Centre for Clinical Trials, University Hospital of Münster, bDepartment of Pediatric Hematology and Oncology, University Children’s Hospital of Münster, Germany

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“…Auf die se Op ti on kann der Sponsor nicht ver zich ten, da die Ge samt ver antwor tung letzt lich bei ihm bleibt. In Müns-ter wur de die se De le ga ti ons kas ka de mit dem KKS als "durch füh ren de Stel le" modell haft für 3 nicht kom mer zi el le, wis senschaft si ni ti ier te kli ni sche Prü fun gen mit dem Uni ver si täts kli ni kum Müns ter als Spon sor im Sin ne der EU-Di rek ti ve um gesetzt [9,10,11]. Be dingt durch un ter schiedli che Rechts for men und lo ka le Be son derhei ten kann die Über nah me der Spon sorver ant wor tung durch In sti tu tio nen nicht über all iden tisch ge re gelt wer den.…”

Section: Zu Wei Sung Von Ver Ant Wort Lich Kei Tenunclassified

Nichtkommerzielle klinische Prüfung – wer wird Sponsor?

Benninger-Döring

Boos

2006

Bundesgesundheitsbl.

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Non-commercial clinical trials may be of great benefit to the patients concerned. The 12th amendment to the German Drug Law (AMG) changed legal liability of the initiators of investigator-initiated clinical trials with extensive consequences for traditional project leaders. The central point under discussion is the sponsor's responsibility according to the AMG. Presently leading management divisions of university hospitals and universities are developing proceedings to assume sponsor responsibility by institutions (institutional sponsorship), which should enable investigator-initiated clinical trials to be conducted according to legal requirements in the future. Detailed problems and special questions can only be resolved in a single-minded fashion, and if necessary political processes should be catalyzed.

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Phase II study of gemcitabine in children with relapsed leukemia

Cited by 12 publications

References 1 publication

Preclinical Toxicology (Subacute and Acute) and Efficacy of a New Squalenoyl Gemcitabine Anticancer Nanomedicine

Preclinical Toxicology (Subacute and Acute) and Efficacy of a New Squalenoyl Gemcitabine Anticancer Nanomedicine

Implementing Good Clinical Practice in Two Noncommercial Phase II Studies in Children with Cancer

Nichtkommerzielle klinische Prüfung – wer wird Sponsor?

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