Phase I and Pharmacokinetic Study of PKC412, an Inhibitor of Protein Kinase C

Propper, David; McDonald, A. C.; Man, A.; Thavasu, Parames; Balkwill, Frances R.; Braybrooke, Jeremy; Caponigro, Francesco; Gräf, Peter; Dutreix, Catherine; Blackie, R.; Kaye, Stanley B.; Ganesan, Trivadi S.; Talbot, Dennis; Harris, Adrian L.; Twelves, Christopher

doi:10.1200/jco.2001.19.5.1485

Cited by 218 publications

(168 citation statements)

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“…A remarkable phenomenon is that even in patients who have resistant disease or relapse, mediator-related symptoms improve or disappear during therapy (30). treatment, followed by a significant decrease, before reaching a stable plateau after 3-4 weeks (33)(34)(35)(36)(37). The drug has two active metabolites (Supplementary Figure S1), which result from cytochrome CYP3A4-mediated oxidation of the parent-drug (36,37).…”

Section: Introductionmentioning

confidence: 99%

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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Proteomic-based drug testing is an emerging approach to establish the clinical value and antineoplastic potential of multi-kinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction-profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC 50 values. Midostaurin and CGP62221 also produced growth-inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, that accumulates in vivo, showed no substantial effects.Chemical proteomic profiling and drug-competition experiments revealed that midostaurin interacts with KIT and several additional kinase-targets. The key downstream-regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgEreceptor-downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP52421 inhibits IgE-dependent histamine release, but is a weak inhibitor of MC proliferation which may have clinical implications and may explain why mediator-related symptoms improve in SM patients even when disease progression occurs.

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Section: Introductionmentioning

confidence: 99%

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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“…Grade 3 toxicity was infrequent, but a constellation of less severe symptoms including nausea, vomiting, diarrhoea and fatigue, contributed to the decision to discontinue midostaurin in seven out of 17 (41%) patients. After the start of this trial, the final report of a Phase I study (Propper et al, 2001) suggested 75 mg bid (150 mg day À1 ) as more tolerable midostaurin dosing for longterm administration. However, a recent Phase II trial of midostaurin to inhibit activated Flt3 kinase in acute myeloid leukaemia (AML) found 225 mg day À1 well-tolerated and had promising activity (Stone et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Drug concentrations in plasma and tumour tissue Plasma concentrations of midostaurin and its two main metabolites CGP 62221 and CGP52421 e2 were determined using an HPLC method with fluorescence detection as reported previously (Van Gijn et al, 1995;Propper et al, 2001). Homogenisation of the tumour tissue by freeze-fractionating proved impossible.…”

Section: Assays For Biologic Activitymentioning

confidence: 99%

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The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

et al. 2006

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Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCa), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had 450% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.

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“…91,92 Staurosporine derivatives (UCN-O1, CGP41251, and protein kinase C 412 [PKC412]) inhibit PKC signaling and have been examined in cell lines and clinical studies. [93][94][95] Aberrant MEK and ERK activities have been demonstrated in AML and CML. 96,97 MEK inhibitors (PD098059, PD184352, and UO126) modulate cellular proliferation, differentiation, and apoptosis.…”

Section: Other Targetsmentioning

confidence: 99%

New agents in acute myeloid leukemia and other myeloid disorders

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Kantarjian

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et al. 2004

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Phase I and Pharmacokinetic Study of PKC412, an Inhibitor of Protein Kinase C

Abstract: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.

Cited by 218 publications

References 21 publications

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

New agents in acute myeloid leukemia and other myeloid disorders

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