Table 1.
Current pediatric clinical trials targeting the PI3K pathway.
| Drug | Mechanism | Study type | Study phase | Study aims/findings |
|---|---|---|---|---|
| Perifosine | Akt inhibition | Single agent dose escalation study (NCT00776867) | I | Determine molecular predictors of response (PI3K/AKT/mTOR and RAS/MAPK signaling, cell cycle markers) |
| Perifosine + Temsirolimus | Akt + mTOR inhibition | Single arm study (NCT01049841) | I | Establish preliminary data on efficacy of combination therapy; determine molecular predictors of response |
| MK-2206 | Akt (allosteric) inhibition | Dose escalation study followed by treatment at MTD (NCT01231919) | I/II | Evaluate biological activity in tumor and PBMC in recurrent or refractory leukemia, lymphoma or solid tumors |
| Everolimus | mTOR inhibition | Single agent dose escalation study (Fouladi et al., 2007) | I | MTD dose level correlated with degree of mTOR inhibition in PBMC |
| Deforolimus | mTOR inhibition | Single agent dose escalation study (Hartford et al., 2009) | I | Toxicity profile similar to other mTOR inhibitors; no objective disease responses seen |
| Ridaforolimus | mTOR inhibition | Single agent safety study (NCT01431534), and in combination with Dalotuzumab (NCT01431547) | I | Establish MTD, and recommended Phase 2 dose and potential efficacy of the combination therapy |
| Temsirolimus | mTOR inhibition | Single agent dose escalation study (Spunt et al., 2011) | I | Well tolerated; MTD not identified |
| Temsirolimus | mTOR inhibition | Single agent study (Geoerger et al., 2012) | II | Did not meet criteria to continue study as single agent; significant number with disease stabilization |
| Temsirolimus | mTOR inhibition | Combination therapy with Cixutumumab (Naing et al., 2011) | I | Well tolerated |
| Temsirolimus | mTOR inhibition | Combination therapy with liposomal Doxorubicin (Thornton et al., 2013) | I | MTD defined, toxicity profile acceptable; combination therapy increased exposure to the active metabolite of Temsirolimus |
| Temsirolimus | mTOR inhibition | Combination therapy with Cixutumumab (NCT01614795) | II | Evaluate IGF-1R, insulin receptor, ERK, RON, mTOR activation in refractory or recurrent sarcomas |
| Temsirolimus | mTOR inhibition | Combination with Irinotecan, Temozolomide (NCT01141244/COG-ADVL0918) | I | In younger patients with recurrent or refractory solid tumors; establish MTD and efficacy of combination therapy |
| Rapamycin (Sirolimus) | mTOR inhibition | Combination with Topotecan, Cyclophosphamide (NCT01670175) | I | Determine dose-limiting toxicity, antitumor activity, biologic and anti-angiogenic effects of drug combination |
| Rapamycin (Sirolimus) | mTOR inhibition | Single arm efficacy study (NCT01265030) | I | Determine tolerability of preoperative administration in children and young adults with desmoid-type fibromatosis; evaluate disease recurrence, pain improvement, mTOR pathway activation |
| Rapamycin (Sirolimus) | mTOR inhibition | Combination with Vinblastine (NCT01135563) | I | In relapsed solid tumors including selected brain tumors and lymphoma; establish MTD and response to combination therapy |
| Enzastaurin | PKC-β inhibition | Fine et al. (2005) | II | In recurrent glioblastoma multiforme; good preliminary radiographic response |
| Enzastaurin | PKC-β inhibition | Randomized trial comparing Lomustine (Wick et al., 2010) | III | No significant differences on interim analysis; early study termination |
MTD, maximum-tolerated dose; PBMC, peripheral blood mononuclear cells.