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Introduction Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 and inhibit insulin like growth factor-1. Blocking of IGF-1 receptor (IGF-1R) in combination with cytotoxic chemotherapy has demonstrated additive or synergistic activity in pre-clinical models. This study aimed to evaluate the maximum tolerated dose (MTD) of pasireotide in combination with standard FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimen in patients with gastrointestinal malignancies. Methods This was a phase 1, 3 + 3 design, open-label dose escalation study conducted in sequential cohorts to determine the MTD of pasireotide in combination with FOLFIRI. All patients had gastrointestinal malignancies and were previously treated. Sixteen patients enrolled in five dose cohorts at pasireotide doses of 40, 60, 80, 100 and 120 mg were evaluated for safety and tolerability of the combination. Results The tumor types of the enrolled subjects included esophageal (n = 5), biliary tract (n = 3), colon (n = 3), gastric (n = 2), pancreatic (n = 1), anal (n = 1) and small bowel (n = 1). No dose limiting toxicities were observed. The most common adverse events related to the study treatment included hyperglycemia (81 %), neutropenia (62 %), thrombocytopenia (44 %), anorexia (44 %), dehydration (25 %) and elevated alkaline phosphatase (25 %). Two patients had partial response and 7 patients had stable disease. Plasma levels of IGF-1 and IGFBP-3 were significantly reduced after treatment with pasireotide. Discussion Combination of pasireotide and FOLFIRI has manageable safety profile and is feasible in patients with gastrointestinal malignancies. Preliminary signals of activity were observed. Larger phase II trials are warranted.

Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers. Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5–6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated. Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1–5 and 8–12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1–12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles. Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle. ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).

e17031Background: Ridaforolimus (Rida) is a mammalian target of rapamycin (mTOR) inhibitor that has activity in solid tumors. Paclitaxel and carboplatin (PC) have broad antineoplastic activity in m...

TPS467 Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway which is aberrantly stimulated in many tumors has emerged as a potential target for anticancer therapy. Although several class I PI3K inhibitors are under development, there is considerable evidence suggesting that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. The PI3K pathway is frequently activated and plays an important role in pancreatic cancer. Further, PI3KCA mutations, the gene encoding isoform p110α, are observed in this disease. BYL719 is an oral class I α-specific PI3K inhibitor that showed anti-tumor activity in different preclinical models. Recently, the first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400 mg once daily. Methods: This is a single institution, open label, single group, phase I study with cohort expansion that utilizes the standard 3+3 design for dose. The primary objective is to determine the MTD of BYL719 in combination with gemcitabine and nab-paclitaxel as frontline therapy in patients with locally advanced, recurrent or metastatic pancreatic adenocarcinoma. Up to 24 patients will be enrolled in 4 dose escalation levels. The MTD is defined as the highest dose level at which 1 or less of 6 patients experience a dose limiting toxicity (DLT). Once the MTD is reached and/or the recommended dose for expansion is determined, an additional dose expansion cohort of 15 patients will be included. Secondary endpoints include characterizing the safety profile at the MTD and DLTs associated with it as well as obtaining pharmacokinetic data. Peripheral blood and pre-treatment tumor samples will be collected for evaluation of biomarkers that could predict treatment response, including levels of pAKT, p4EBP1 and pS6. BYL719 will be administered daily. Standard doses of gemcitabine and nab-paclitaxel will be given on days 1, 8 and 15 of the 28 days cycle. Patients will get restaging scans every 2 cycles. As per September 2015, twelve patients have been included in this study which is currently enrolling patients on cohort 3. Clinical trial information: NCT02155088 Clinical trial information: NCT02155088.

e15201 Background: Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors. It is hypothesized to induce apoptosis by decreasing insulin like growth fact...

e15010 Background: ALT-801 is a human IL-2/single-chain T-cell receptor fusion protein previously tested in a phase 1 in patients with advanced malignancy (Fishman 2011 CCR 17:7765) (CA097550). In various murine models, ALT-801 demonstrated potent activity against syngeneic and xenograft UC, suggesting sensitivity of this disease to IL-2 based immunotherapy (Wong, unpubl. data.). Although UC are sensitive to platinum-based chemotherapy, combinations such as gemcitabine (G) + cisplatin (C) are associated with CR rates of around 15%, and limited durability of responses with limited effects of retreatment. Methods: We report here initial efficacy results of co-administration of G (1000 mg/m2/dose, d 1 & 8), C (70 mg/m2/dose, d 1) and ALT-801 (escalating doses, d 3, 5, 8, 10) on a 21 day schedule, for 3 cycles, in patients with UC that was locally advanced, or metastatic, for whom GC chemotherapy would be considered. ALT-801 planned doses are 0.04 to 0.12 mg/kg/dose in 5 dose cohorts with a 3+3 escalation design. Subjects with at least stable disease after 3 courses may receive 4 additional weekly doses of ALT-801 alone. Results: To date, three Stage IV UC patients (1F, 2M; 59-63 yrs; 2 patients had predominantly nodal metastases and one patient liver metastases) completed treatment with 0.04 mg/kg ALT-801+GC. Two had previously undergone radical cystectomy and had then later failed following GC treatment. Grade 3/4 toxicities observed include neutropenia (2), thrombocytopenia (2), leukopenia (1), lymphopenia (1) and anemia (1), consistent with GC and ALT-801 known pharmacodynamic effects. All 3 had radiological CRs by week 13. One patient underwent radical cystectomy had a pCR. The next (0.06 mg/kg/dose) cohort has started treatment. A phase II expansion cohort is planned at the MTD. Conclusions: The early response pattern is encouraging in that ALT-801 may be a novel, active immunotherapy for UC. NCT01326871