Trabectedin in Malignant Pleural Mesothelioma: Results From the Multicentre, Single Arm, Phase II ATREUS Study.

INTRODUCTION: New therapeutic approaches in unresectable malignant pleural mesothelioma (MPM) are eagerly awaited. Trabectedin is an antitumor agent with an effect on cancer cell proliferation and a modulating action on tumor microenvironment. The ATREUS study explored the activity and safety of trabectedin in patients with unresectable MPM. METHODS: Epithelioid patients with MPM received trabectedin as second-line while biphasic/sarcomatoid patients with MPM as first- or second-line therapy. Treatment was given intravenously at an initially planned dose of 1.3 mg/m2 every 3 weeks, until progression or unacceptable toxicity. The primary endpoint was progression-free survival rate at 12 weeks (PFS12wks). RESULTS: Overall, 78 patients (54%) had epithelioid and 67 (46%) nonepithelioid MPM. PFS12wks in 62 evaluable patients with epithelioid MPM was 43.5% (80% confidence interval 34.9%-52.5%); median progression-free and overall survival were 2.4 and 9.0 months, respectively. PFS12wks in 52 evaluable patients with nonepithelioid MPM was 30.8% (90% confidence interval 20.3%-42.9%); median progression-free and overall survival were 1.7 and 5.4 months. Trabectedin starting dose was amended due to excess of liver toxicity. Eighty-four (64%) and 48 (36%) patients received 1.3 mg/m2 and 1.1. mg/m2, respectively. The most common grade 3-4 toxicities were hepatotoxicity, leukopenia/neutropenia, and fatigue. Grade 3-4 hepatotoxicity was reported in 59 (70%) patients treated at 1.3 mg/m2, and in 19 (40%) treated at 1.1 mg/m2. CONCLUSIONS: Trabectedin showed modest clinical activity, at the expense of relevant liver toxicity. Further development of this drug in MPM at full doses is not warranted.

Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma: The FAME Trial.

Advanced lung adenocarcinoma with inactive liver kinase B1 (LKB1) tumor suppressor protein is associated with poor response to immune checkpoint inhibitors and molecularly targeted agents, and with dismal patient prognosis. LKB1 is a central orchestrator of cancer cell metabolism, and halts tumor growth/proliferation during metabolic stress. Recent preclinical evidence suggests that LKB1-inactive lung adenocarcinoma is highly sensitive to metformin, a safe and low-cost antidiabetic compound that inhibits mitochondrial oxidative phosphorylation. The effects of metformin can be enhanced by nutrient deprivation (ie, glucose, amino acids), which reduces intracellular levels of ATP and anabolic precursors and can be achieved by the fasting mimicking diet (FMD). Noticeably, metformin also prevents resistance to cisplatin in preclinical in vitro and in vivo models of LKB1-inactive lung adenocarcinoma. Based on such preclinical evidence, the phase II FAME trial was designed to test the hypothesis that the addition of metformin, with or without cyclic FMD, to standard platinum-based chemotherapy improves the progression-free survival of patients with advanced, LKB-1 inactive lung adenocarcinoma. Enrolled patients will be randomized in a 1:1 ratio to receive cisplatin/carboplatin and pemetrexed with the addition of metformin alone (Arm A) or metformin plus FMD (Arm B). The FAME study will use a "pick-the-winner" design with the aim of establishing which of the 2 experimental treatments is superior in terms of antitumor efficacy and safety. The primary assumption of the study is that the combination of the 2 experimental treatments shall improve median progression-free survival from 7.6 months (historical data with chemotherapy alone) to 12 months. Secondary study endpoints are: objective response rate, overall survival, treatment tolerability, and compliance to the experimental treatment.

RELEVENT Trial: Phase II Trial of Ramucirumab, Carboplatin, and Paclitaxel in Previously Untreated Thymic Carcinoma/B3 Thymoma With Area of Carcinoma.

Thymic epithelial tumors are rare malignancies. Thymic carcinoma represents about 20% of all thymic epithelial tumors and has aggressive behavior, with a greater tendency to metastatic spread. Thymic carcinoma is often diagnosed in advanced stages for which systemic treatment is the main therapeutic option. The association of chemotherapy and antiangiogenic agents in the first-line setting has never been investigated in this very rare cancer. However, preclinical and clinical evidence has suggested that inhibition of angiogenesis could be beneficial. The RELEVENT trial is a multicenter, open-label, single-arm, phase II study aimed at investigating the activity and safety of ramucirumab combined with paclitaxel and carboplatin in chemotherapy-naive patients affected by thymic carcinoma or B3 thymoma with area of carcinoma. The primary endpoint of the trial is the overall response rate. Progression-free survival, overall survival, and safety are secondary endpoints. Patient-reported outcomes will be collected at each visit. The mutational status of a subset of genes, polymorphisms, and selected micro-RNA expression will be evaluated.

Latanoprost and Dorzolamide for the Treatment of Pediatric Glaucoma: The Glaucoma Italian Pediatric Study (Gipsy), Design and Baseline Characteristics.

INTRODUCTION: To investigate the efficacy of a treatment strategy with latanoprost and dorzolamide in primary pediatric glaucoma patients partially responsive to surgery. METHODS: Single arm, prospective, interventional multicenter study. Primary pediatric glaucoma patients younger than 13 years after a single surgical procedure with IOP between 22 and 26 mmHg were considered eligible. At baseline, patients were allocated to latanoprost monotherapy once daily. Depending on intraocular pressure (IOP) reduction at first visit, the patients were allocated to one of three groups: continuation of latanoprost monotherapy, addition of dorzolamide twice daily, or switch to dorzolamide three times daily. The same approach for allocation in medication groups was used in all subsequent visits. Patients in the dorzolamide monotherapy group with IOP reduction <20% from baseline were considered non-responders and withdrawn. Study treatment and patient follow-up will continue for 3 years or until treatment failure. The primary endpoint is the percentage of responders. Secondary endpoints are time to treatment failure and frequency of adverse events. RESULTS: A total of 37 patients (69 eyes) were enrolled. The mean age was 4.0 ± 3.8 years, the female/male ratio was 1/1.7, and the majority of patients were Caucasian. Eighty percent of patients had bilateral glaucoma. Goniotomy was the most frequently performed surgery (38.6%), followed by trabeculotomy (22.8%), trabeculectomy (21.1%), and trabeculectomy plus trabeculotomy (17.5%). The baseline IOP was 23.6 ± 1.5 mmHg. CONCLUSION: The study population is representative of patients frequently encountered after the first surgery for primary pediatric glaucoma. The study will produce evidence on the medium-term efficacy of a defined pharmacological approach.

Needle Revision With 5-fluorouracil for the Treatment of Ahmed Glaucoma Valve Filtering Blebs: 5-Fluoruracil Needling Revision can be a Useful and Safe Tool in the Management of Failing Ahmed Glaucoma Valve Filtering Blebs.

PURPOSE: To determine the outcome of needling with adjunctive 5-fluorouracil (5-FU) in patients with a failing Ahmed glaucoma valve (AGV) implant, and to identify predictors of long-term intraocular pressure (IOP) control. METHODS: A prospective observational study was performed on consecutive patients with medically uncontrolled primary open-angle glaucoma (POAG) with AGV encapsulation or fibrosis and inadequate IOP control. Bleb needling with 5-FU injection (0.1 mL of 50 mg/mL) was performed at the slit-lamp. Patients were examined 1 week following the needling, and then at months 1, 3, and 6. Subsequent follow-up visits were scheduled at 6-month intervals for at least 2 years. Needling with 5-FU was repeated no more than twice during the first 3 months of the follow-up. Procedure outcome was determined on the basis of the recorded IOP levels. RESULTS: Thirty-six patients with an encapsulated or fibrotic AGV underwent 67procedures (mean 1.86 ± 0.83). Complete success, defined as IOP ≤ 18 mm Hg without medications, was obtained in 25% at 24 months of observation. The cumulative proportion of cases achieving either qualified (ie, IOP ≤ 18 mm Hg with medications) or complete success at 24 months of observation was 72.2%. In a univariate Cox proportional hazards model, age was the only variable that independently influenced the risk of failing 5-FU needling revision. Fourteen eyes (38.8%) had a documented complication. CONCLUSIONS: Needling over the plate of an AGV supplemented with 5-FU is an effective and safe choice in a significant proportion of POAG patients with elevated IOP due to encapsulation or fibrosis.

The ORCHIDEE study: gathering new evidence on the use of everolimus in clinical practice.

Randomized clinical trials are the gold standard to test the efficacy of an intervention within a specified patient population. However, the results of the trials may not be generalizable to routine clinical practice. Observational cohort studies may provide information that complements trial results. Targeted therapies are characterized by tolerability profiles that may differ from those of 'traditional' chemotherapy. Therefore, the post-approval evaluation of these drugs by large, well-designed observational cohort studies in real life populations is warranted. Everolimus is an orally-administered inhibitor of the mammalian target of rapamycin. A number of observational cohort studies have been conducted to characterize the effectiveness and safety of everolimus in clinical practice. In particular, the ORCHIDEE study was designed to identify factors predictive of favorable outcome in patients treated with everolimus such as second-line treatment for metastatic renal cell carcinoma after failure of a first-line treatment with a VEGF TKI. ORCHIDEE is a multicenter, single-arm, phase IV study. The study will enroll approximately 200 metastatic renal cell carcinoma metastatic renal cell carcinoma patients from 20 Italian centers over a 24-month period.