Table 1. Summary of presented results from PI3K inhibitors in phase I clinical trials.
BW – twice weekly; QD – once daily; BD – twice daily; 21/7 – 21 days on, 7 days off; CDD – continuous daily dosing; MTD – maximum tolerated dose; MAD – maximum administered dose; AST – aspartate transaminase; ALT – alanine transaminase; AE – adverse event; NHL – non-Hodgkin's lymphoma; MCL – mantle cell lymphoma; CLL – chronic lymphocytic leukemia.
| Dual PI3K/mTOR inhibitors | Pure PI3K inhibitors | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Compound (Company) | SF1126 (Semafore) | NVP-BEZ235 (Novartis) | XL765 (Exelixis-Sanofi) | GDC-0980 (Roche-Genentech) | NVP-BKM120 (Novartis) | XL147 (Exelixis-Sanofi) | PX-866 (Oncothyreon) - Irreversible inhibitor | GDC-0941 (Roche-Genentech) | CAL-101 (Calistoga) - p110δ isoform specific inhibitor |
| No. of patients | 39 | 59 | 83 | 17 | 35 | 78 | 60 | 59 | 106 |
| Administration schedule | Intravenous BW | Oral QD |
Oral BD or QD |
Oral QD 21/7 |
Oral QD |
Oral, QD: 21/7 or CDD | Oral, QD: Intermittent or CDD | Oral QD or BD (21/7) |
Oral BD or QD |
| MTD (or MAD) | 1110mg/m2 (MAD) | 1100mg (MAD) | 50mg (BD) 90mg (QD) |
16mg (MAD) | 100mg | 600mg (both schedules) | 12mg (intermittent) 8mg (CDD) |
245mg (QD) 180mg TDD (BD) |
350mg (MAD BD), 300mg (MAD QD) |
| DLTs | Diarrhea | None | Rash, nausea, vomiting, ↓ PO4 / anorexia, transa-minitis (BD) Abnormal ECG, rash / fatigue, dyskinesia (QD) |
None | Mood alteration, epigastralgia, rash, hyper-glycemia | Rash (21/7) Hyper-sensitivity (CDD) |
Diarrhea, ↑ AST (intermittent) Diarrhea (CDD) |
Headache, pleural effusion, ↓ DLCO | ↑ AST / ALT |
| AEs (most common) | Nausea, vomiting, diarrhea, fever, fatigue | Fatigue, diarrhea, nausea, vomiting, anorexia | Nausea, diarrhea, anorexia, vomiting, transa-minitis | Nausea, fatigue, diarrhea, flatulence | Rash, hyper-glycemia, diarrhea, anorexia, nausea | Nausea, fatigue, diarrhea, rash, cough | Diarrhea, nausea, vomiting, ↑ AST/ALT, fatigue | Nausea, fatigue, diarrhea, dysguesia | ↑AST/ALT, pneumonia, neutropenia, anemia, thrombocytopenia |
| Best response (in evaluable patients) | Stable disease | Partial response (2 pts) | Stable disease | Stable disease | Partial response (2 pts) | Partial response (1 pt) | Stable disease | Partial response (1 pt) | Partial response (31 pts) NHL 57% MCL 67% CLL 30% |
| Reference | [49] | [53] | [54] | [55] | [60] | [61] | [63] | [66] | [68] |