Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors

Punt, Cornelis J.A.; Boni, Joseph; Bruntsch, U; Peters, Matthew F.; Thielert, C.

doi:10.1093/annonc/mdg248

Cited by 114 publications

(76 citation statements)

References 7 publications

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“…No pharmacokinetic interactions were apparent, and neutropenia was the only toxicity considered dose limiting. It is noteworthy that previous attempts to combine mTOR inhibitors with cytotoxic agents were associated with an increased incidence of toxicity that included dose-limiting diarrhoea and stomatitis with 5-fluorouracil (Punt et al, 2003) and thrombocytopenia with gemcitabine (Pacey et al, 2004). In this regard, the feasibility of combining everolimus with paclitaxel at clinically effective doses of each agent and the delayed tumour progression observed in this heavily pretreated population warrant further investigation in paclitaxelsensitive tumours.…”

Section: Discussionmentioning

confidence: 99%

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

et al. 2009

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Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m À2 on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33 -69) were entered; 11 had prior taxane therapy for breast (n ¼ 5), ovarian (n ¼ 3), and vaginal cancer (n ¼ 1) or angiosarcoma (n ¼ 2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m À2 , warranting further clinical investigation.

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Section: Discussionmentioning

confidence: 99%

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

et al. 2009

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“…The bioanalytic method for sirolimus was validated through the quantitation range of 0.1 -100 ng ml À1 and exhibited interday and intraday variabilities of o12.7% and biases of o11.3% (Punt et al, 2003). No interferences were observed in blank blood or in blood spiked with internal standard.…”

Section: Bioanalytic Assaysmentioning

confidence: 98%

“…The concentrations of temsirolimus and sirolimus in blood were measured simultaneously using validated liquid chromatography/ tandem mass spectrometry combination procedures with deuterated internal standard (Punt et al, 2003). Analytes and internal standard were extracted from a 1-ml sample of EDTA-treated whole blood by liquid -liquid extraction with 1-chlorobutane and separated with a YMC PDS AQ HPLC column (Waters, Milford, MA, USA).…”

Section: Bioanalytic Assaysmentioning

confidence: 99%

“…The bioanalytic method for temsirolimus was validated through the quantitation range of 0.25 -100 ng ml À1 and exhibited interday and intraday variabilities, expressed as CV of o5% and biases of o9.4% (Punt et al, 2003). The bioanalytic method for sirolimus was validated through the quantitation range of 0.1 -100 ng ml À1 and exhibited interday and intraday variabilities of o12.7% and biases of o11.3% (Punt et al, 2003).…”

Section: Bioanalytic Assaysmentioning

confidence: 99%

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Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Leister¹,

Burns²,

Hug³

2008

Br J Cancer

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Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (C max ) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUC sum (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.

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“…Results from phase 1 studies evaluating temsirolimus with interferon-alpha, 94 and 5-fluorouracil 95 showed enhanced toxicities at relatively low doses. Similar to the experience with temsirolimus, phase I studies of everolimus combined with gemcitabine 96 and with gefitinib 97 demonstrated limiting toxicities at doses considerably less than the recommended phase II single agent doses.…”

Section: Combination Studies With Sirolimus Derivativesmentioning

confidence: 99%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

184

134

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The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

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Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors

Cited by 114 publications

References 7 publications

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Therapeutic targets: MTOR and related pathways

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