SPIRIT3 support includes

Biobanking: broadly as for SPIRIT2, but plus genomic DNA (mouth wash via kit)

Correlative Science: BiomarkersLSC biologyNGS: mutation analysis

: hypothesis generation

Example: Imatinib Metabolism

NQO1 &2TXN

CYP3A4/5

St John’s Wortcarbamazepine

phenytoin

ketoconazoleerythromycin

grapefruit juice

minormetabolites

CYPs:1A1, 1B1, 1A2,2D6, 2C9, 2C19

HN

N

N

N

HN

O

N

N

imatinib(t½ = 18hrs)

HN

N

N

N

HN

O

N

HN

CGP-74588(t½ = 40hrs)

EXCRETIONEXCRETIONROS

GSTsNATs, UGTs

DNAdamage

celldamage

T1 v M1 v T1+M1 v none

Time to CCR 0.255

Overall Survival 0.273

Treatment Failure 0.041

Treatment Failure and Intolerance < 0.000

Progression Free Survival (PFS) 0.029

Event Free Survival (EFS) 0.047

Mantel-Cox Log Rank Test (p values)

p < 0.000

n = 11

n = 17

n = 88

n = 77

GSTT1{del} and GSTM1{del} Results

Davies et al 2012, EHA Amsterdam (abstract)

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)RANDOMISED*

Nilotinib 400 mg BID (n = 281)

• N = 846• 217 centres• 35 countries

* 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).

ENESTnd: Study Design

Kantarjian HM, et al. Blood. 2012;120(21):[abstract 1676].

Arterial Events by 3 Years (All Grades)

Patients, n (%)

Nilotinib300 mg BID

n = 279

Nilotinib400 mg BID

n = 277

Imatinib400 mg QD

n = 280

IHD 9 (3.2) 11 (4.0) 3 (1.1)PAOD 4 (1.4) 3 (1.1) 0

• 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%

IHD, ischaemic heart disease; PAOD, peripheral arterial occlusive disease.

5LVEF, left ventricular ejection fraction. Data cutoff: 27Jul2011.

ENESTnd: arterial Events by 4 Years

Patients, n (%)

Nilotinib300 mg BID

n = 279

Nilotinib400 mg BID

n = 277

Imatinib400 mg QD

n = 280

IHD (3 yrs in brackets) 11 (9) 14 (11) 3 (3)PAOD (3 yrs in brackets) 4 (4) 5 (3) 0

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

Including cerebrovascular events: 18 24 4

6 Data cutoff: 27Jul 2012.