Targeted Therapy
Efficacy: Phase I
A phase I dose-escalation clinical trial with Tasigna enrolled 119 patients with imatinibresistant Ph+ CML or Ph+ acute lymphoblastic leukemia (ALL) from May 2004 to May 2005 (Table 4).1 Patients were assigned to receive doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily, and 400 mg and 600 mg twice daily. As the current indications for Tasigna are for CML-CP and CML-AP, efficacy results from clinical trials with Tasigna will be restricted to these phases.
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The median duration of therapy was 4.9 months, and 17 patients in the phase I trial were in CML-CP1 (Table 5). Of 12 patients with active disease, 11 achieved a CHR. Among 17 evaluable patients, 9 achieved cytogenetic responses; of those, 6 were CCyRs. Of 46 patients with CML-AP (excluding those with clonal evolution only), 33 achieved a hematologic response and 22 had a cytogenetic response, of which 9 were MCyRs (Table 6).1 Ten patients had clonal evolution as the only feature of CML-AP, 5 had active disease, and 5 were in CHR. All 5 patients with CML-AP and clonal evolution achieved a CHR; 6 of 10 had a MCyR.
| Tasigna Phase I Study | |||||
|---|---|---|---|---|---|
| Diagnosis | N Evaluable | OR n (%) | CHR n | MR n | RTC n |
| CP | 12 | 11 (92) | 11 | - | - |
| AP | 46 | 33 (72) | 21 | 3 | 9 |
| AP clonal evolution only | 10/5a | 5 (100) | 5 | - | - |
| aTotal/active. MR, marrow response; OR, overall response; RTC, return to chronic phase. |
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| Diagnosis | N | OR n (%) | Complete n | Partial n | Minor/Minimal n |
|---|---|---|---|---|---|
| CP | 17 | 9 (53) | 6 | 0 | 0/3 |
| AP | 46 | 22 (48) | 6 | 3 | 4/9 |
| AP clonal evolution only | 10/5a | 9 (90) | 2 | 4 | 1/2 |
| aTotal/active. OR, overall response. |
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In the entire population of this trial, Tasigna® was active in patients with and without mutations at baseline. No significant difference in response rates was detected between these 2 groups.1
The phase I study indicated that Tasigna has activity in imatinib-resistant CML, including patients expressing BCR-ABL mutations that lead to imatinib resistance. The phase I study also provided evidence that twice-daily dosing yielded optimal nilotinib exposure, therefore Tasigna 400 mg twice daily was the dose used in subsequent phase II trials.
References:
1. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosomepositive ALL. N Engl J Med. 2006;354:2542-2551.