A Phase III Multi-center, Open-label, Randomized Study of the Efficacy of Nilotinib Versus Imatinib in Adult Patients With Ph+ CML in Early CP Who Have a Suboptimal Molecular Response to Imatinib
Imatinib mesylate (imatinib) binds to the inactive conformation of Bcr-Abl tyrosine kinase
suppressing the Ph+ clone in CML (Giles et al, 2005). It is effective in CML and is a major
advance in therapy. With standard dose imatinib, the MMR and complete molecular response
(CMR) rates are 35% to 40% and 6% to 10% respectively at 12 months. These surrogate
endpoints have been associated with high long term survival rates (Kantarjian et al, 2004).
For patients who had a CCyR and MMR (defined as a reduction in Bcr-Abl transcript levels of
at least 3 log at 12 months following imatinib therapy), the probability of remaining
progression-free was 100 percent at 24 months, compared with 95% for patients achieved a
CCyR but no MMR and 85% for patients who did not achieve a CCyR (P<0.001) (Hughes et al,
2003/Druker et al, 2006).
With continued doses of imatinib 400 mg/day, MMR at 24 months is 54% (IRIS SmPC data),
however with high dose imatinib 800 mg/day, MMR may be 70%. Higher doses of imatinib
improved the CCyR rates to 90% both in patients who failed prior IFN-alfa therapy and in
those previously untreated (Cortes et al, 2005). Higher doses are expected to yield higher
MMR rates at 24 months (Cortes et al, ASH 2004 poster). There is also a continued increase
in the cumulative major/complete cytogenetic and molecular response rates with therapy, even
after 2 years (Kantarjian 2004).
Nilotinib is a novel, oral tyrosine kinase inhibitor with improved potency compared with
imatinib. In pre-clinical models of imatinib-sensitive CML cell lines, nilotinib was 20-50
times more potent than imatinib, and 3-7 times more potent in imatinib-resistant cell lines.
In a Phase I dose-escalation trial [Study CAMN107A2101], 119 imatinib-resistant Ph+ CML and
ALL patients were treated with single oral doses of nilotinib ranging from 50-1200 mg daily
or 400 mg and 600 mg given twice daily. Nilotinib produced high hematologic and cytogenetic
response rates of 92% and 53%, respectively (CCyR in 35%), in patients with chronic phase
CML, who were resistant to imatinib. Nilotinib was found to have an acceptable tolerability
profile (Kantarjian et al, 2005). Preliminary results from an ongoing Phase II study appear
to confirm the efficacy and safety profile of nilotinib (Kantarjian et al, 2006).
Achievement of a major molecular response is an important short-term goal in CML therapy as
it appears to predict for long-term event-free survival. This study is designed to compare
the efficacy of nilotinib 400 mg twice daily with patients' maximum tolerated doses of
imatinib (optimally 800 mg/day) in producing a major molecular response after 12 months of
treatment in individuals previously not in major molecular remission. It will also examine
the rates of major molecular and complete molecular response in each of the treatment arms,
as achievement of these endpoints may also be of prognostic significance.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
the cumulative rate of MMR
To evaluate the cumulative rate of MMR at 12 months of nilotinib compared to imatinib in adult patients with Ph+ CML in early CP who have suboptimal molecular response to imatinib
Dong-Wook Kim, MD, PhD
Seoul St. Mary's Hospital
Korea: Food and Drug Administration