Phase I study of temozolomide in paediatric patients with advanced cancer

Estlin, Edward J.; Lashford, L. S.; Ablett, S; Price, L A; Gowing, R; Gholkar, A; Kohler, Janice A.; Lewis, I; Morland, Bruce; Pinkerton, CR; Stevens, M.F.G.; Mott, Michelle; Stevens, Ryan W; Newell,; Walker, David G.; Dicks‐Mireaux, C.; McDowell, Heather P.; Reidenberg, Pascale; Statkevich, Paul; Marco, Aliceanne; Batra, Vishal; Dugan, Margaret; Pearson, Adj

doi:10.1038/bjc.1998.555

Cited by 127 publications

(77 citation statements)

References 7 publications

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“…The DLT of cisplatin -temozolomide after the first treatment cycle in children and adolescents was haematologic. This was consistent with the phase I data of the cisplatin -temozolomide combination in adult malignancies (Britten et al, 1999), but also similar to paediatric data for temozolomide given as a single agent (Estlin et al, 1998;Nicholson et al, 1998;Lashford et al, 2002). Subsequently, the MTD of the cisplatin -temozolomide combination for both cohorts (A and B) were similar to those of the previous studies.…”

Section: Discussionsupporting

confidence: 90%

“…Both have marked activity in paediatric malignancies; cisplatin is part of many protocols for solid tumours and temozolomide has shown activity in malignant gliomas (Newlands et al, 1992;Estlin et al, 1998). Both agents target DNA, although they kill cells by different mechanisms: temozolomide via methylation at the O 6 position of guanine and the subsequent action of the mismatch repair system, whereas cisplatin produces DNA crosslinks preferentially via reaction at the N7 positions of guanine and adenine (O'Dwyer et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to our study, cisplatin was scheduled at day 1 beginning 4 h after the first of five daily doses of temozolomide. The paediatric phase I studies of the Children's Cancer Group and the UK group using temozolomide as single agent had stratified according to prior CSI and determined the MTD of temozolomide at 215 mg m À2 /day Â 5 administered every 21 days or 200 mg m À12 /day Â 5 every 28 days for children and adolescents in the non-CSI group and 180 mg m À2 day À1 Â 5 in the CSI-treated group (Estlin et al, 1998;Nicholson et al, 1998). Both of these paediatric dose-finding studies did not include patients after high-dose chemotherapy or with bone marrow involvement at study entry in the heavily pretreated cohort.…”

Section: Discussionmentioning

confidence: 99%

“…Temozolomide has shown activity in preclinical models and in clinical trials in patients with malignant gliomas and melanoma (Newlands et al, 1992;O'Reilly et al, 1993;Bleehen et al, 1995). Phase I and II clinical trials in children and adolescents demonstrated tumour responses in malignant gliomas (Estlin et al, 1998;Nicholson et al, 1998;Lashford et al, 2002).…”

mentioning

confidence: 99%

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Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies

et al. 2005

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Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age B13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m À2 / 150 mg m À2 day À1 , 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1 -7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin -temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m À2 cisplatin and 150 mg m À2 Â 5 temozolomide in heavily treated, and 200 mg m À2 Â 5 temozolomide in less-heavily pretreated children.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies

et al. 2005

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“…Sampling for temozolomide pharmacokinetics was repeated on day 5 of cycle 1. Determinations of concentrations of paclitaxel or temozolomide in plasma were performed by HPLC, as previously described (Siddiqui et al, 1997;Estlin et al, 1998). …”

Section: Clinical Studymentioning

confidence: 99%

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

et al. 2005

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The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1 -5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m À2 day À1 temozolomide and 225 mg m À2 day À1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

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