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Example: Imatinib Metabolism

SPIRIT3 support includes Biobanking : broadly as for SPIRIT2, but plus genomic DNA (mouth wash via kit) Correlative Science: B iomarkers LSC biology NGS: mutation analysis : hypothesis generation. Example: Imatinib Metabolism. St John’s Wort carbamazepine phenytoin. CYP3A4/5.

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Example: Imatinib Metabolism

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  1. SPIRIT3 support includesBiobanking: broadly as for SPIRIT2, but plus genomic DNA (mouth wash via kit)Correlative Science: BiomarkersLSC biologyNGS: mutation analysis: hypothesis generation

  2. Example: Imatinib Metabolism St John’s Wort carbamazepine phenytoin CYP3A4/5 ketoconazole erythromycin grapefruit juice CGP-74588 (t½ = 40hrs) imatinib (t½ = 18hrs) CYPs: 1A1, 1B1, 1A2, 2D6, 2C9, 2C19 NQO1 &2 TXN minor metabolites GSTs NATs, UGTs cell damage EXCRETION EXCRETION ROS DNA damage

  3. GSTT1{del} and GSTM1{del} Results n = 77 Mantel-Cox Log Rank Test (p values) n = 88 n = 17 n = 11 p < 0.000 Davies et al 2012, EHA Amsterdam (abstract)

  4. ENESTnd: Study Design R A N DO M I S ED * Nilotinib 300 mg BID (n = 282) • N = 846 • 217 centres • 35 countries Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) * Stratification by Sokal risk score. 10 years of follow-up are planned Primary endpoint = MMR at 12 months. This is superior in nilotinib recipients (either dose) compared with imatinib (P < .0001; Saglio et al NEJM 2010). Kantarjian HM, et al. Blood. 2012;120(21):[abstract 1676].

  5. Arterial Events by 3 Years (All Grades) • IHD, ischaemic heart disease; PAOD, peripheral arterial occlusive disease. • 11/23 IHD events occurred between years 2 and 3 (4 on nilotinib 300 mg BID, 5 on nilotinib 400 mg BID, 2 on imatinib) • 3 patients on nilotinib 400 mg BID discontinued study drug due to IHD • 2/7 PAOD events occurred between years 2 and 3; both occurred on nilotinib 400 mg BID • 6/7 patients (85%) with PAOD had pre-existing risk factors at baseline • No patient discontinued because of PAOD • No patient at any time on study in either nilotinib arm had a QTcF > 500 ms or LVEF < 45% LVEF, left ventricular ejection fraction. Data cutoff: 27Jul2011.

  6. ENESTnd: arterial Events by 4 Years Including cerebrovascular events: 18 24 4 • Between years 3 and 4, five new patients had an IHD event (2 in the nilotinib 300 mg BID arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event (both in the nilotinib 400 mg BID arm) • 1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly reported drug-related SAE (arterial stenosis limb) leading to treatment discontinuation Data cutoff: 27Jul 2012.

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