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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

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


Example imatinib metabolism

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


Gstt1 del and gstm1 del results
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)


Enestnd study design
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].


Arterial events by 3 years all grades
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.


Enestnd arterial events by 4 years
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.