Background: Inhibition of phosphatidylinositol-3-kinase (PI3K)-mediated signaling may overcome resistance to chemotherapy or human epidermal growth factor receptor (EGFR) inhibitors. Gedatolisib (G) is a dual inhibitor of PI3K/mammalian target of rapamycin (mTOR) in development for solid tumors. Methods: This is an ongoing study to determine the maximum tolerated dose (MTD) and safety of G in combination with: 1) docetaxel: Arm A, in castrate resistant prostate cancer, advanced breast cancer (BC), or non-small cell lung cancer (NSCLC) patients (pts); 2) cisplatin: Arm B, in urothelial transitional cell cancer (TCC), triple negative BC (TNBC), NSCLC or ovarian cancer pts; 3) the pan-EGFR TKI dacomitinib: Arm C, in refractory HER2+BC, HER2+esophagogastric cancer, head and neck cancer, or EGFR-mutated NSCLC pts. Pts received a G lead-in dose 7 days (A, B) or 14 days (C) prior to day 1, followed by weekly intravenous (IV) G plus: docetaxel or cisplatin (75 mg IV every 3 weeks); or oral dacomitinib (30–45 mg/d). Secondary objectives included pharmacokinetics (PK), clinical efficacy (partial or complete response [PR or CR]), and associated biomarkers. Results: 74 pts (median prior therapies: 2; range: 0–6) received 90–260 mg/week of G in: A, 21; B, 21; and C, 32. The top drug related adverse events: A: neutropenia, mucositis, alopecia; B: nausea, fatigue, vomiting; and C: mucositis, diarrhea, nausea, fatigue. Cycle 1 dose limiting toxicities (DLTs) were: A: grade 3 mucositis (n = 1); B: no DLT; C: grade 3 mucositis (n = 1), pneumonitis (n = 1), rash (n = 1), and grade 2 fatigue (n = 1). PK parameters for G were similar regardless of combination agent. Best overall response was A: 4/21 PRs; B: 8/21 PRs (5 TNBC, 2 NSCLC, 1 TCC), and C: 6/32, (1 CR, 5 PRs). In Arm B, 3 of the 8 PRs (2 NSCLC, 1 TCC) had prior platinum exposure. Next generation sequencing involving PI3K data from a subset of patients is under evaluation. Conclusions: G can be combined with docetaxel, cisplatin, or dacomitinib, with manageable toxicity profiles and preliminary antitumor activity, even when heavily pre-treated. Due to portfolio prioritization, dose escalation and expansion continues in Arm B, with closure of Arms A and C (MTD not reached). Clinical trial information: NCT01920061