A total of 53 patients were enrolled in the study from August 2005 to July 2006, at 5 participating centers (2 in the United States and 1 each in France, Germany and Italy). Data are presented as of November 2006. Fourteen patients were still on study at the data cut-off date.
Twenty one (40%) patients had a primary cancer site in the small intestine and the majority of tumors (n=48; 91%) were imatinib-resistant (). Most patients (n=42, 79%) had previously received imatinib for ≥24 months. Approximately 60% of patients experienced disease progression after 1 year of imatinib therapy and 20% during the first 6 months. The majority of patients had experienced disease progression on additional TKIs therapies, most commonly sunitinib (n=33; 62%).
Patient demographics and baseline disease characteristics
The median dose intensity of nilotinib and imatinib corresponded to 98-100% of the planned daily dose for the single-agent cohort and all combination cohorts, except for the nilotinib 800 mg plus imatinib 800 mg cohort where it was approximately 60%.
The median duration of treatment was 134 days across all cohorts (range 8-430 days). Thirty-nine patients (74%) discontinued the study. The most common primary reason for discontinuation was disease progression (n=32, 60%), followed by AEs (n=3, 6%) and death (n=2, 4%).
Tolerability and Dose-limiting Toxicities
Dose-limiting toxicities were rash and elevated bilirubin. Rash was the DLT in 5 patients receiving combination therapy, occurring in 2/5 (40%) patients receiving nilotinib 400 mg bid and imatinib 400 mg bid, and 3/16 (19%) patients receiving nilotinib 400 mg bid and imatinib 400 mg daily. The high frequency of severe skin rash in patients receiving nilotinib 400 mg bid and imatinib 400 mg bid resulted in dose reduction in all 5 patients, and no further dose escalation was undertaken. One of 18 (6%) patients in the single-agent nilotinib 400 mg bid cohort, with grade 2 elevated bilirubin at study entry, experienced grade 3 dose-limiting hyperbilirubinemia and was discontinued from the study.
The frequency of DLT in the nilotinib 400 mg bid plus imatinib 400 mg qd cohort (19%) was considered acceptable (i.e. the Bayesian model predicted only a 3% chance for this combination of being excessively toxic and a 47% chance of having an acceptable safety profile). Therefore, the combination dose of nilotinib 400 mg bid and imatinib 400 mg qd was deemed appropriate for future Phase II combination studies, as was the single-agent nilotinib 400 mg bid dose.
All patients experienced AEs during the study with the most frequently reported AEs being non-hematological AEs grade 1 or 2 (). The safety profiles of single-agent nilotinib or in combination with imatinib were generally similar. Overall, the most frequent AEs were rash (40%), fatigue (38%), abdominal pain (36%) and nausea (36%). Rash was more common in the combination cohorts and was generally manageable with temporary dose interruptions and/or topical corticosteroids. Fatigue and abdominal pain were more frequent in the single-agent nilotinib cohort. Peripheral edema was uncommon and reported only in the combination cohorts. Grade 3 or 4 toxicities occurred in 49% of patients overall () and resulted in discontinuation from the study in 2 patients: hyperbilirubinemia in 1 patient treated with nilotinib 400 mg bid single-agent and rash in the other receiving nilotinib 400 mg bid plus imatinib 400 mg bid.
Most frequent adverse events
Hematological toxicities were uncommon with only anemia reported as AE. There were no episodes of thrombocytopenia. Neutropenia was reported as a laboratory abnormality in 1 patient treated with nilotinib 200 mg plus imatinib 400 mg bid, without neutropenic fever.
The most frequent grade 3 or 4 laboratory abnormalities were hypophosphatemia (12%), which was more common in the combination cohorts, and hyperbilirubinemia (8%), which was more frequent in the single-agent nilotinib cohort. Grade 3 elevations of AST or ALT were uncommon (<2% overall), did not result in drug discontinuation and were reversible upon dose interruption.
One patient with a history of episodes of junctional rhythm and supraventricular arrhythmias developed atrial fibrillation that was considered related to nilotinib; nilotinib was continued without dose reduction or interruption. Four patients (13%) exhibited clinically insignificant post-baseline QTcF interval >480 msec, 1 patient in the nilotinib 400 mg bid plus imatinib 400 mg bid cohort, and 3 patients in the nilotinib 400 mg bid plus imatinib 400 mg daily combination. None of these four patients experienced cardiac events during the study and no QTcF >500 msec was reported.
Anti-Tumor Activity and Clinical Outcomes
Overall, 2 RECIST-defined partial responses were observed, 1 in a patient who had progressed during adjuvant imatinib and was intolerant to imatinib 800 mg, the other in a patient who had failed multiple regimens including imatinib and sunitinib (). The median duration of response was 197 days. The majority of patients (78%) had stable disease (SD). Thirteen patients (72%) in the single-agent group had SD lasting for >4 months in 9 (50%) patients and >6 months in 5 (28%) patients. Of the 16 patients treated with the combination cohort selected for further Phase II studies (nilotinib 400 mg bid and imatinib 400 mg qd), 9 had SD. The median PFS for the patients in the nilotinib single-agent group was 168 days (range 1-393) and among all patients was 134 days (range 1-393). The median PFS was not reached for the patients in both the nilotinib 400 mg bid plus imatinib 400 mg bid and the selected Phase II dose cohorts (). The Kaplan-Meier estimate of PFS at 6 months was 56% for the Phase II combination cohort compared with 47% for the single-agent group ().
KIT mutations were found in 19/23 (83%) patients; none of the analyzed tumors had PDGFR mutations (data not shown).
Nilotinib dose proportionality was observed during combination treatments. There was a linear relationship between Cmax or Cavg and total nilotinib daily dose for the combination cohorts (slope=0.881 and 0.946, respectively, based on power model). Oral clearance (CL/F) of nilotinib was similar across the 4 combination groups, but lower than that in the single-agent cohort. In comparison with the single-agent cohort, the AUC0-t values of niltotinib were 40% and 18% higher in the nilotinib 400 mg bid combination cohorts ().
Summary statistics* of Nilotinib pharmacokinetic parameter values at steady-state (Day 8 or 15)
As compared to monotherapy (Day -1), the AUC0-t values of imatinib were found to be increased by 18-39% during the combination therapy with nilotinib 200 mg QD, 400 mg QD, or 400 mg BID doses ().
Summary statistics* of Imatinib pharmacokinetic parameter values of imatinib administered as 400 mg bid alone (Day -1) and during combination therapy with nilotinib (Day 8 or 15)