Table 2.
DLTs observed during the first cycle in both treatment schedules
| Schedule A | |||
|---|---|---|---|
| BI 811283 dose (mg) | n | Patients with DLT | DLT (n) |
| 5 | 3 | 0 | – |
| 10 | 7 | 1 | Grade 3 AST increased and grade 3 ALT increased (1) |
| 13.5 | 3 | 0 | – |
| 18 | 3 | 0 | – |
| 24 | 4 | 0 | – |
| 32 | 3 | 0 | – |
| 43 | 5 | 0 | – |
| 58 | 3 | 0 | – |
| 78 | 7 | 1 | Grade 3 neutropenia and grade 3 thrombocytopenia (1) |
| 105 | 6 | 1 | Grade 3 hemoglobin decreased (1) |
| 125a | 16b | 1 | Grade 4 neutropenia (1) |
| 140 | 3 | 2 | Grade 3 neutropenia (1); grade 4 neutropenia (1) |
| Schedule B | |||||
|---|---|---|---|---|---|
| BI 811283 dose (mg) | n | Patients with DLT | DLT (n) | Patients with retrospectively identified potential DLT | DLT (n) |
| 13.5 | 3 | 0 | – | – | – |
| 18 | 3 | 0 | – | – | – |
| 24 | 3 | 0 | – | – | – |
| 32 | 4 | 0 | – | – | – |
| 43 | 3 | 0 | – | – | – |
| 58 | 3 | 0 | – | – | – |
| 78 | 3 | 0 | – | – | – |
| 105 | 6 | 1c | Grade 3 fatigue (1) | 2 | Grade 4 neutropenia ≥7 days (2); |
| 125 | 3 | 0c | – | 1 | Grade 4 neutropenia ≥7 days and grade 4 leukopenia (1) |
| 150 | 3 | 0 | – | – | – |
| 180 | 3 | 0c | – | 1 | Grade 4 neutropenia ≥7 days (1) |
| 230 | 3 | 0c | – | 1 | Grade 4 neutropenia ≥7 days (1) |
| 300 | 3 | 2 | Grade 4 febrile neutropenia (1); grade 3 febrile neutropenia (1) | – | – |
| 230 | 3 | 0 | – | – | – |
| 270 | 5 | 2 | Grade 4 neutropenia ≥7 days (2) | – | – |
| 230a
Expansion cohort |
7 | 5 | Grade 4 neutropenia ≥7 days (1); grade 4 febrile neutropenia (2); grade 3 febrile neutropenia (2) | – | – |
ALT alanine aminotransferase, AST aspartate aminotransferase, DLT dose-limiting toxicity, MTD maximum tolerated dose
aDefined as the maximum tolerated dose
bSeven patients initially plus nine patients in the expansion cohort
cUpon data review at the end of the study, two events in the schedule B 105 mg cohort (grade 4 neutropenia ≥7 days, n = 2) and one event (grade 4 neutropenia ≥7 days) in each of the following schedule B cohorts: 125, 180, and 230 mg were retrospectively determined to be DLTs, although they were not considered to be DLTs during MTD determination. These events were considered to have potentially met the study protocol definition for a DLT, but there was not sufficient information to conclusively determine their exact duration (i.e., no laboratory tests were performed on Day 7 or 8 after the start of the grade 4 neutropenia). The investigators and sponsor used a worst case/conservative approach and assumed that these were DLTs