Table 2. Dose-limiting toxicities, grade 3 toxicities beyond cycle 1 and other reasons for treatment discontinuation.
| Dose level | Dose of HSP990 (mg) | Total no. of DLT evaluable patients | Total no. of patients with DLTs | Description of DLT | Grade ⩾3 drug-related AEs beyond cycle 1 | Description of grade ⩾3 drug-related AEs beyond cycle 1 | Total no. of patients who discontinue HSP990 (cause) beyond cycle 1 |
|---|---|---|---|---|---|---|---|
|
Once weekly | |||||||
| 1 | 2.5 | 3 | 0 | NA | 0 | NA | 0 |
| 2 | 5 | 5 | 0 | NA | 0 | NA | 0 |
| 3 | 10 | 7 | 0 | NA | 0 | NA | 0 |
| 4 | 20 | 6 | 0 | NA | 7 | Abdominal pain, cramping, bloating, digestive disorder, nausea, vomiting, diarrhoea, fatigue | 1 (digestive disorder) |
| 5 | 30 | 4 | 0 | NA | 0 | NA | 0 |
| 6 | 50 | 22 | 4 | G3 bilateral myoclonic hand movement G3 diarrhoea, and prolonged QTc G3 prolonged QTc G4 ALT and AST | 6 | Fatigue, QT prolongation, presyncope, syncope, ALT elevation | 5 (fatigue, QT prolongation, presyncope, syncope) |
| 7 |
60 |
5 |
2 |
G1 decreased appetite, dysdiadochokinesia, fatigue, hyperreflexia and tremor leading to inability to administer 75% of the planned dose of HSP990
G3 tremor |
3 |
Diarrhoea |
2 (diarrhoea) |
|
Twice weekly | |||||||
| 1 | 25 | 11 | 1 | G1 extremities tremors, superior limb extrapyramidal hypertrophia, G2 ataxia, confusion and visual hallucination | 2 | Diarrhoea | 0 |
Abbreviations: ALT=alanine transaminase; AST=aspartate aminotransferase; DLT=dose-limiting toxicity; G=grade; HSP=heat-shock protein; NA=not applicable.