Purpose To evaluate safety (primary endpoint) tolerability pharmacokinetics pharmacodynamic profile and preliminary activity of the intravenous pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. of the 78 enrolled patients received treatment. The MTD for PF-05212384 administered intravenously once weekly was estimated to be 154 mg. The most common treatment-related adverse events (AEs) were mucosal inflammation/stomatitis (58.4%) nausea (42.9%) hyperglycemia (26%) decreased appetite (24.7%) fatigue (24.7%) and vomiting (24.7%). The majority of Lomustine (CeeNU) patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient populace with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life 30 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. Conclusions These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384 supporting further clinical development for Trp53 patients with advanced Lomustine (CeeNU) solid malignancies. mutation or amplification mutation and loss of function mutation and receptor tyrosine kinase overexpression or mutation. Activation of the PI3K pathway may represent a mechanism of resistance to treatment with tyrosine kinase inhibitors (TKIs) or chemotherapeutic brokers (1-3). PF-05212384 is an intravenous (IV) ATP-competitive highly selective and potent pan-class I isoform PI3K and mTOR inhibitor (5) with an IC50 of 0.4nM for p110α 6 nM for p110β 6 nM for p110γ 8 nM for p110δ and 1 nM for mTOR. Preclinical studies have exhibited activity of PF-05212384 in cell assays and xenograft models (5). Preclinical safety and pharmacologic evaluation Lomustine (CeeNU) of PF-05212384 did not show any significant effect on cardiac central nervous system or respiratory function. Here we report the safety tolerability pharmacokinetics (PK) pharmacodynamic (PD) profile and preliminary activity of PF-05212384 in patients with advanced solid tumors. Methods and Patients Study design and treatment This open-label phase I study of PF-05212384 was conducted at eight centers (one in Spain one in the United Kingdom Lomustine (CeeNU) six in the United States) and divided into two parts. Part 1 estimated the maximum tolerated dose (MTD) in patients with unselected solid tumors (MTD estimation phase). The starting dose of PF-05212384 was 10 mg administered once weekly as an IV infusion over 30 minutes in 28-day cycles. No premedication was required. Additional doses initially ranged from 21 mg to 154 mg once weekly with further escalation in 20% increments over 154 mg if the lower doses appeared tolerable. A altered continual reassessment method (CRM) was used to guide dose escalation for each cohort with the final choice of dose being determined based on Lomustine (CeeNU) the CRM guidance as well as other safety considerations. Treatment was continued until disease progression if tolerated by the patient and deemed of clinical benefit by the investigator. Patients were assessed for dose-limiting toxicity (DLT) during the first 28 days of treatment. DLTs defined by investigator assessment as potentially related to study treatment included a ≥ grade 3 non-hematologic adverse event (AE) despite optimal treatment including fasting glucose >250 mg/dL or ≥ grade 3 asthenia >2 days; ≥ grade 4 thrombocytopenia grade 3 thrombocytopenia with bleeding grade 4 neutropenia for >7 days febrile neutropenia or a delay of treatment for more than 2 consecutive weeks due to treatment-related toxicity. In Part 2 (MTD confirmation phase) the MTD was confirmed in two distinct patient cohorts. The Molecular Selection cohort (MTD1) enrolled patients to further define tolerability of PF-05212384 at the MTD and to assess preliminary activity in patients with selected tumor types and documented evidence of dysregulation of the PI3K pathway (mutation amplification or PTEN deficiency). The Tumor Biopsy cohort (MTD2) included at least five evaluable patients with baseline and on-treatment tumor biopsies to evaluate the Lomustine (CeeNU) effect of PF-05212384 at the MTD around the PI3K pathway. All patients in the dose escalation should have had disease evaluable for response. All the patients in the MTD cohorts were required to have at least one measurable lesion at baseline. CT scans and MRI were the.