Table 1.
Clinical trials combining PI3K/Akt/mTOR pathway inhibitors with other anti-cancer agents
| Pathway Inhibitor | Combination Agent | Trial phase/tumor type | Toxicity (CTC grade 3–5) ≥10% of patients | Response Rates | Comments | Reference |
|---|---|---|---|---|---|---|
| Perifosine | Radiation | Phase I Inoperable solid tumors | Nausea/ vomiting (10%), dysphagia (10%) | 6/21 (29%) CR
5/21 (24%) PR |
Perifosine as radiosensitizer is safe and tolerable | Vink et al, 2006 |
| Rapamycin | Radiation/cisplatin | Phase I Stage III NSCLC | Dysphagia (14%) MTD not defined | Not reported | Rapamycin as radiosensitizer is safe and tolerable | Sarkaria et al, 2007 |
| Gefitinib | Phase I Recurrent malignant glioma | Mucositis (68%), diarrhea (42%), fatigue (37%), anemia (32%), leukopenia (32%), infection (26%), hypercholesterolemia (21%), hypertriglyceridemia (21%), thrombocytopenia (21%), AST/ALT (16%), nausea/vomiting (16%). | 2/34 (6%) PR
13/34 (38%) SD |
Increased grade 3–4 toxicity due to high doses in attempt to cross blood-brain barrier
Combination of EGFR TKI and mTOR inhibitor in GBM currently in phase II |
Reardon et al, 2006 | |
| CCI-779 | 5-FU/leucovorin | Phase I Advanced solid tumors | Asthenia (19%), mucositis (19%), hyperglycemia (15%), diarrhea (15%), anemia (15%), nausea/vomiting (11%) | 3/26 (12%) PR
11/26 (42%) SD |
Discontinued due to two treatment- related deaths. Combination of agents at this dosing schedule not recommended | Punt et al, 2003 |
| IFN-alfa | Phase III Advanced RCC | Asthenia (28%), anemia (38%), dyspnea (10%), infection (11%), neutropenia (15%) | 8.1% CR/PR
28.1% SD |
No difference OS or PFS for combination vs. IFN-a alone
Single agent CCI-779 superior OS and PFS to IFN-a and combination Larger sample size (~210 patients per group) |
Hudes et al, 2007 | |
| RAD-001 | Gefitinib | Phase I Advanced NSCLC | Hypotension (11%), acidosis (11%), azotemia (11%), lymphopenia (11%), stomatitis (11%) | 2/8 (25%) PR | 2/2 responses seen in former smokers
Currently in phase II trials |
Riely et al, 2007 |
| Bevacizumab | Phase I Solid tumors | Pain (71%), mucositis (64%), anorexia (57%), bleeding (50%), rash(50%), hyperlipidemia (43%), fatigue (43%) | 2/16 (13%) PR
8/16 (50%) SD |
Presented only in abstract form
Currently in phase II trials |
Zafar et al, 2006 | |
| Imatinib | Phase I/II GI stromal tumors | Fatigue, diarrhea, vomiting, nausea, anemia, edema, headache, and rash | 2/31 (6%) PR
8/31 (26%) SD |
Presented only in abstract form | Van Oosterom et al, 2005 |
CR = complete response, PR = partial response, SD = stable disease, MTD = maximally tolerated dose, OS = overall survival, PFS = progression-free survival, TKI = tyrosine kinase inhibitor