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PURPOSE Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death worldwide. Platinum agents and fluoropyrimidines are the main compounds used in the first-line setting for advanced GC. Given the activity of fluorouracil (FU) bolus, the PFL protocol, a chemotherapy regimen combining cisplatin, FU bolus, and leucovorin, was incorporated at the Brazilian National Cancer Institute, because this schedule does not require hospitalization or infusion pumps. This study aims to evaluate the outcomes of PFL in the first-line setting for patients with advanced GC. MATERIALS AND METHODS This was a retrospective cohort study evaluating patients with advanced GC treated in the first-line setting with cisplatin 80 mg/m2 on day 1 and FU bolus 400 mg/m2 plus leucovorin 20 mg/m2 on days 1, 8, 15, and 22 every 4 weeks, from January 2008 to December 2014. RESULTS A total of 109 patients were enrolled. The median number of cycles received per patient was four (one to 11). Complete responses were achieved in 6.4% and partial responses in 14.7%. Median progression-free survival was 6.3 months (95% CI, 5.08 to 7.58 months) and median overall survival was 8.3 months (95% CI, 6.79 to 9.87 months). Thirty-four (31.2%) patients were alive in 1 year. Grade 3 and 4 adverse events were experienced by 26.6% and 3.7% of patients, respectively, with dose reduction necessary in 9.1%. CONCLUSION PFL is active in advanced GC and could be an alternative for FU continuous infusion protocols in institutions with limited resources and/or low budget, which is the reality in many nations all over the world.

Purpose: AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity. Patients and Methods: The trial followed a rolling six design during dose escalation. An intrapatient dose escalation arm to evaluate tolerability and a biopsy cohort to study pharmacodynamic effects were later added. AT13148 was administered orally three days a week (Mon–Wed–Fri) in 28-day cycles. Pharmacokinetic profiles were assessed using mass spectrometry and pharmacodynamic studies included quantifying p-GSK3β levels in platelet-rich plasma (PRP) and p-cofilin and p-MLC2 levels in tumor biopsies. Results: Fifty-one patients were treated on study. The safety of 5–300 mg of AT13148 was studied. Further, the doses of 120–180–240 mg were studied in an intrapatient dose escalation cohort. The dose-limiting toxicities included hypotension (300 mg), pneumonitis, and elevated liver enzymes (240 mg), and skin rash (180 mg). The most common side effects were fatigue, nausea, headaches, and hypotension. On the basis of tolerability, 180 mg was considered the maximally tolerated dose. At 180 mg, mean Cmax and AUC were 400 nmol/L and 13,000 nmol/L/hour, respectively. At 180 mg, ≥50% reduction of p-cofilin was observed in 3 of 8 posttreatment biopsies. Conclusions: AT13148 was the first dual potent ROCK-AKT inhibitor to be investigated for the treatment of solid tumors. The narrow therapeutic index and the pharmacokinetic profile led to recommend not developing this compound further. There are significant lessons learned in designing and testing agents that simultaneously inhibit multiple kinases including AGC kinases in cancer.

Background The incidence and clinical significance of electrolyte abnormalities (EAs) in phase I clinical trials are unknown. The objective of this study is to evaluate the incidence and severity of EAs, graded according to CTCAE, v4.03, to identify variables associated with EAs and their prognostic significance in a phase I population. Methods A retrospective chart review was performed of 1088 cases in 82 phase I clinical trials consecutively treated from 2011 to 2015 at the Drug Development Unit of the Royal Marsden Hospital. Cox regression analysis was performed to examine the relationship between overall survival (OS) and baseline characteristics, treating the occurrence of grade III/IV EAs as a time-varying covariate. Results The most common emergent EAs (all grades) were as follows: hyponatraemia 62%, hypokalaemia 40%, hypophosphataemia 32%, hypomagnesaemia 17% and hypocalcaemia 12%. Grade III/IV EAs occurred in 19% of cases. Grade III/IV EAs occurred during the dose-limiting toxicity window in 8.46% of cases. Diarrhoea was associated with hypomagnesaemia at all grades (p, Highlights • Patients who develop grade III/IV electrolyte abnormalities have poorer overall survival. • Hyponatraemia is linked to higher risk of developing other electrolyte abnormalities. • Hypoalbuminaemia is linked to higher risk of developing electrolyte abnormalities.

The treatment of advanced gynecologic cancers remains palliative in most of cases. Although systemic treatment has entered into the era of targeted drugs the antitumor efficacies of current therapies are still limited. In this context there is a great need for more active treatment and rationally designed targeted therapies. The PI3K/AKT/mTOR is a signaling pathway in mammal cells that coordinates important cell activities. It has a critical function in the survival, growth, and proliferation of malignant cells and was object of important research in the last two decades. The mTOR pathway emerges as an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli and, through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including endometrial, cervical, and ovarian cancers. The present study reviewed the available evidence regarding the potential impact of some mTOR pathway inhibitors in the treatment of gynecological cancer. Few advances in medical management have occurred in recent years in the treatment of advanced or recurrent gynecological malignancies, and a poor prognosis remains. Rationally designed molecularly targeted therapy is an emerging and important option in this setting; then more investigation in PI3K/AKT/mTOR pathway-targeted therapies is warranted.

Objective: Cervical cancer represents the third most commonly diagnosed cancer and is an important cause of death for women suffering with malignancies. Patients who are refractory or progressed after first-line palliative treatment have a dismal prognosis and no second-line chemotherapy is considered standard so far. Several agents have been investigated in this setting and topotecan is one of the most characterized. The objective of this study was to evaluate response rate (RR), progression-free survival (PFS), overall survival (OS) and toxicity of topotecan in second palliative line for cervical cancer. Methods: An analysis was performed of all patients with recurrent or metastatic cervical cancer treated with topotecan in second palliative line at Brazilian National Cancer Institute, between 2008 and 2010. Results: A total of 73 courses of topotecan were given in the current study (median: 3.5 cycles; range 1 - 6). Anemia was the most frequent adverse event (grade 2:35%; grade 3:30%). Of the 20 patients evaluable, there were 2 partial responders to the treatment. The overall response rate (ORR) was 10%; 3 patients (15%) had stable disease as maximum response. The median PFS for the entire group was 2.93 months (95% CI 2.41 - 3.45) and OS was 4.66 months (95% CI 1.21 - 8.11). Conclusion: The limited activity of topotecan schemas in second-line treatment of cervical cancer and the associated overall toxicity may not justify their use in this setting. Patients who progress after first-line treatment may be offered participation in clinical trials, other second-line agents or best supportive care measures.

Introduction Small cell lung cancer (SCLC) is aggressive and relapse is inevitable. Novel therapies in the context of phase I (Ph1) clinical trials should be considered in this setting. Next generation sequencing (NGS) identifying putative driver mutations may aid therapy allocation in such trial settings. Methods Retrospective analysis of characteristics and clinical outcomes of patients (pts) with advanced SCLC referred to the Phase I Clinical Trials Drug Development Unit at the Royal Marsden Hospital between 1992 and 2016, using electronic patient records Results 85 pts with advanced SCLC were included, of which 45 pts were allocated to ≥1 trial each (48 allocations). Of these, 21 (46.7%) pts started ≥1 trial, with a total of 24 trials commenced. Of the 64 pts who were unable to commence trials, 43 (67.2%) had rapid disease progression, 11 (17.2%) sought other therapies, 5 (7.8%) declined Ph1 trials, and 5 pts did not enrol for other reasons. Pts had a median of 2 previous lines of treatment (range:1-3). 13 pts had tumor molecular profiling with high coverage targeted NGS, yielding 22 distinct mutations; Aberrations in DNA damage repair (DDR) pathway were most common: TP53 (53.8%), FANC (30.8%), ATM (15.4%), ATR, BARD1 and CHEK2 (7.7% each). All pts found to have ≥1 DDR pathway mutation had platinum sensitive disease (disease progression ≥90 days from last platinum dose) in first line setting. Other mutations found include ALK, APC, AR, AXIN1, DDB2, ERBB2, mTOR, PI3K, NOTCH, NTRK17, PDGFR, RB1, RET, STK11, FKT3 and VGFR2. Pts were most commonly treated with novel inhibitors against PARP (n=9), PI3K/AKT (n=3), PD-1 (n=2) and BCL (n=2). Therapies were generally well tolerated with no dose limiting toxicities observed. Of 9 pts who received PARP inhibitors, 1 achieved a RECIST partial response (PR) and remained on trial for 16 weeks; 4 achieved RECIST stable disease (SD) for a median of 17 weeks (range:10.9-31.1 weeks). 1 exceptional responder whose tumor harbored multiple somatic aberrations (TP53, FANCF, AR, ERBB2, NOTCH2) was enrolled on 3 sequential phase I trials - she achieved durable RECIST SD on a PARP inhibitor (31.1 weeks), RECIST PR with a PD-1 inhibitor (38.7 weeks), and durable RECIST SD with carboplatin/ATR inhibitor (27.9 weeks). Platinum sensitivity in the first line setting predicted for improved disease control (RECIST PR/SD 73.3% vs 0%, p Discussion Novel therapeutic agents within the context of a dedicated Ph1 trials unit were well tolerated and led to preliminary signals of antitumor activity. Targeted NGS may aid in the identification of pts with putative gene aberrations, potentially predicting for response to novel therapies. Ph1 trials should be considered earlier in the pt's disease course to maximize their prospects of trial enrolment. Citation Format: Joline S. Lim, Samuel J. Harris, Malaka Ameratunga, Raghav Sundar, Joo Ern Ang, Dearbhaile Collins, Maxime Chénard-Poirier, Alvaro I. Garces, Stan B. Kaye, Juanita Lopez, Udai Banerji, Johann S. de Bono, Timothy A. Yap. Precision medicine for patients with advanced small cell lung cancer treated with novel therapeutic agents in a phase I clinical trials unit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3081. doi:10.1158/1538-7445.AM2017-3081