A Phase IIIb Multicentre Open-Label Study of Nilotinib in Adult Patients with Newly Diagnosed BCR-ABL Positive Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A European Clinical Initiative with EUTOS Collaboration for Standardisation of Molecular Remission

Nilotinib, a highly potent, selective inhibitor of BCR-ABL, is now approved for frontline treatment of Philadelphia chromosome positive (Ph+) CP CML. ENEST1st (Evaluating Nilotinib Efficacy and Safety trial as first line treatment) is a phase IIIb, open-label study of nilotinib in adult patients with newly diagnosed CP CML (ClinicalTrials.gov NCT01061177). The primary study aim is to establish the rate of molecular remission with a sensitivity of 4 log (MR⁴) rate through EUTOS (European Treatment and Outcomes Study) laboratories to improve the sensitivity and standardisation of RT-PCR for low level BCR-ABL detection and further refine the working definition of deep molecular response. The attainment of sustained MR⁴ will identify a patient population potentially eligible to join studies of tyrosine kinase inhibitor discontinuation in CP CML.

806 patients (pts) with newly diagnosed BCR-ABL+ CML-CP, diagnosed within 6 months, were to be treated with nilotinib 300 mg BID for a study period of 24 months. The primary study endpoint is MR⁴ rate at 18 months, initially defined as undetectable BCR-ABL transcripts by quantitative RT- PCR in a peripheral blood sample of at least 10 ml with a minimum sensitivity of 1:10,000. Molecular monitoring was performed by 13 EUTOS laboratories with conversion factors to the International Scale to facilitate standardised measurement. Key secondary endpoints include: rate of progressions to accelerated phase (AP) or blast crisis (BC) in year 1 and 2; rate of events in patients achieving MR⁴ at 1 year; rate of MMR (<0.1% IS) at and by 12/24 months; rate of CCyR at and by 12/24 months; rate of CHR at and by 12/24 months; the rate of early events, EFS, OS; and nilotinib safety/tolerability. Two interim analyses were planned: when the first 200 pts had reached 6 months, (1^st IA), and when a subsequent 400 pts had also reached 6 months of study treatment and the first 200 pts had 18 months follow up. Additionally, 11 translational and correlative science sub studies were performed.

The 1^st IA results are as follows: Baseline demographics: 208 pts were recruited in 102 sites in 15 countries. Median age was 53 years, median time from diagnosis 1.1 months (range 0.07–5.39). 39.0% pts were female, 91.8% had typical b2a2 or b3a2 BCR-ABL transcripts, 71.2% had been previously treated. 37.6% with standard dose imatinib (maximum of 12 weeks) and 55.1% with hydroxyurea. 34.0%, 37.2% and 17.8% pts were classified as Sokal low, intermediate and high risk. 80.4% and 9.3% pts were classified as EUTOS score low and high risk. The median dose intensity was 600 mg/day. 29.8% pts experienced a dose interruption of a median cumulative duration of 14 days. Rate of MMR by 3 and 6 months was 22.5% and 50.3%. MMR by 3 and 6 months was 43.9% and 61.1% for EUTOS low risk and 17.6% and 41.2% for EUTOS high risk pts. Quality control of molecular responses beyond MMR is ongoing. Adverse events (AE) were mostly grade 1 and 2, mainly rash (22.4%), pruritus (17.1%), alopecia (11.7%), fatigue (11.7%), headache and nausea (10.2%) which were usually manageable with appropriate dose interruptions/reduction. Grade 3–4 hematological AE rates were low, with thrombocytopenia and neutropenia reported in 5.3 and 3.5% pts respectively. The incidence of treatment –related Grade 3–4 non-hematological AEs was low, with lipase increase and hyperbilirubinaemia reported in 2.4% and 1.5% pts respectively. 8.8% patients reported study drug related SAEs. 7.8% and 0.5% of pts showed a prolongation of QTcF above 450ms and 500ms respectively. At 6 months, 88.8% pts remain on study, 14 pts (6.8%) have discontinued due to AE (3 discontinued due to hyperbilirubinemia), 1 due to abnormal laboratory value, 5 withdrew consent, 1 died due to a metastatic neoplasm, and 2 discontinued due to protocol violations. No pt has progressed during the first 6 months of study. Methodological improvements in RT-PCR have allowed refinement of the working definition of MR⁴ as either (i) detectable disease ≤0.01% BCR-ABL^IS or (ii) undetectable disease in cDNA with ≥10,000 ABL transcripts.

Results of the ENEST1st first IA with over 100 pt years of nilotinib treatment demonstrate nilotinib's efficacy and safety to be similar to that reported in other front line trials. Through methodological improvements of RT-PCR, a network of EUTOS laboratories are now able to define and measure MR⁴ in a standardised and validated manner.

Giles:Novartis: Consultancy, Honoraria, Research Funding. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Ossenkoppele:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria. Tulliez:Novartis: Investigator in Novartis Study. Stentoft:Novartis: Investigator in Novartis Study. Giagounidis:Novartis: Investigator in Novartis Study. Nobile:Novartis: Investigator in Novartis Study. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Gattermann:Novartis: Honoraria, Research Funding. Griskevicius:Novartis: Investigator in Novartis Study. Cross:Novartis: Research Funding. Hill:Novartis: Employment. Schuld:Novartis: Employment. Pellegrino:Novartis: Employment. Magazzù:Novartis: Employment. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding.