Background: Inhibition of phosphatidylinositol-3-kinase (PI3K)-mediated signaling may overcome resistance to different classes of chemotherapies as well as epidermal growth factor receptor (EGFR) inhibitors. PF-05212384 (PF384) is an intravenous (IV) inhibitor of PI3K/mammalian target of rapamycin (mTOR) in development for metastatic colorectal cancer and other solid tumors in combination with other agents. Methods: An ongoing phase I dose escalation study is enrolling cohorts of 3–6 patients (pts) to determine maximum tolerated dose (MTD) and safety of PF384 plus docetaxel (arm A), cisplatin (arm B), or the EGFR tyrosine kinase inhibitor dacomitinib (arm C). Eligible pts have castrate resistant prostate cancer, advanced breast cancer, or non-small cell lung cancer (NSCLC; arm A); urothelial transitional cell cancer, triple negative breast cancer, or NSCLC (arm B); or refractory Her2+ breast cancer, Her2+ esophagogastric cancer, head and neck squamous cell cancer, or EGFR-mutated NSCLC (arm C). Dose assignment is guided by a modified toxicity probability interval method (arms A,B) or zone-based design (arm C). Pts receive a lead-in PF384dose 7 (arms A,B) or 14 days (arm C) prior to cycle 1 day 1. Then, pts receive weekly PF384plus standard chemotherapy (docetaxel or cisplatin 75 mg IV every 3 wk) or dacomitinib (30–45 mg/d orally; started 7 days prior to cycle 1 day 1). Primary endpoint is cycle 1 dose-limiting toxicities (DLTs), including lead-in dose. Secondary endpoints include pharmacokinetics, tumor response, and PI3K pathway protein biomarkers. Results: 52 pts received escalating doses (90–150 mg) of PF384: 14, 12, and 26 pts in arms A, B, and C. Drug-related adverse events in > 30% pts were neutropenia, mucositis, and nausea in arm A; nausea, decreased appetite, fatigue, vomiting, anemia, and hypomagnesaemia in arm B; and mucositis, diarrhea, nausea, dermatitis acneiform, and decreased appetite in arm C. There were no DLTs in arms A or B; in arm C, DLTs were grade 3 mucositis, pneumonitis, and rash, and grade 2 fatigue ( < 75% of planned dose received). Conclusions: PF384can be combined with docetaxel, cisplatin, or dacomitinib with a manageable toxicity profile. Dose escalation to determine MTD is ongoing. Clinical trial information: NCT01920061