Background SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. Patients and methods SF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Results Forty four patients were treated at 9 dose levels (90–1110 mg/m2/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m2 (diarrhoea). Exposure measured by peak concentration (Cmax) and area under the time-concentration curve (AUC0-t) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m2. The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m2. A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. Conclusion SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Purpose A randomized phase II trial (E1200) was designed to assess toxicities and surgical resection rates in two neoadjuvant gemcitabine-based chemoradiation regimens in patients with borderline resectable pancreatic cancer. The trial was terminated early due to poor accrual. Patients and Methods Patients with borderline resectable adenocarcinomas of the pancreas were enrolled. Arm A patients (n=10) received gemcitabine 500mg/m2 q6 weeks, with radiation to 50.4Gy followed by surgical resection. Arm B patients (n=11) received preoperative gemcitabine 175mg/m2 on days 1, 5, 29, and 33, cisplatin 20mg/m2 on days 1-5 and 29-32, 5-FU 600mg/m2 on days 1-5 and 29-32, followed by radiation with continuous infusion 5-FU 225mg/m2 for 6 weeks. All patients received adjuvant gemcitabine 1000 mg/m2 weekly × 3 for five cycles. Results 3 patients in arm A, and 2 patients in arm B were resected. Hematologic toxicity was comparable between the two arms except more patients in arm B developed grade 3 or 4 thrombocytopenia than those in arm A. Arm B had fewer grade 1-2 GI toxicities although more patients (45%) experienced grade 3-4 GI toxicity. Conclusions This phase II trial showed that both regimens were tolerable, and resectability and survival were comparable to previous studies.

Participants experienced severe difficulty with "state maintenance", or the ability to maintain both the sleep and waking states. Research designed to identify the etiology of these problems is needed to develop effective interventions.

Pretreatment NLR < 5.5 is associated with superior PFS and OS. NLR is a biomarker that can inform prognosis for patients with mRCC and should be further validated in larger cohorts and in prospective studies.