A Phase 2 Randomized, Double-Blind, Multicenter Trial of Imexon Plus Gemcitabine Versus Gemcitabine Plus Placebo in Patients With Metastatic Chemotherapy-naïve Pancreatic Adenocarcinoma.

BACKGROUND: Imexon is a cyanoaziridine-derived iminopyrrolidone which has synergistic cytotoxicity with gemcitabine. A phase 1 study of the combination demonstrated good tolerance with encouraging clinical activity and thus we conducted this randomized phase II study. MATERIALS AND METHODS: Patients with measurable, metastatic, treatment-naive pancreatic adenocarcinoma were randomized 1:1 to receive gemcitabine at 1000 mg/m days 1, 8, and 15 with either imexon, 875 mg/m or placebo days 1, 8, and 15 every 28 days. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and response rate. RESULTS: A total of 142 patients were randomized, 72 to the imexon containing arm and 70 to the placebo arm. Patients in the imexon arm received an average of 3.6 cycles (range, 1 to 23) compared with 4.4 (range, 1 to 21) in the placebo arm. There was no increased rate of ≥grade 3 toxicity in the imexon arm. Seven patients had objective responses in the imexon arm (13.7%), whereas 9 did in the placebo arm (17%). In the imexon arm, 23 patients had ≥50% reduction in CA 19-9 from baseline (33%), whereas 22 did in the placebo arm (31.4%). The median progression-free survival was 2.8 months in the imexon arm (95% confidence interval [CI], 2.0-4.1 m) and 3.8 months in the placebo arm (95% CI, 2.2-4.7 m), P=0.504. The median overall survival time in the imexon arm was 5.2 months (95% CI, 4.2-6.7 m) as compared with 6.8 m (95% CI, 4.9-8.5 m) in the placebo arm, P=0.6822. CONCLUSIONS: The combination of imexon and gemcitabine does not result in improved outcome as initial therapy of metastatic pancreatic adenocarcinoma.

Early-Onset 5-Fluorouracil Toxicity in a Patient Negative for Dihydropyrimidine Dehydrogenase Mutations: The Clinical Course of Reversal with Uridine Triacetate.

An antimetabolite pyridine analog, 5-fluorouracil (5-FU), is used to treat solid tumors. Early toxicities may occur at standard doses of 5-FU due to dihydropyrimidine dehydrogenase (DPD) deficiency. Uridine triacetate, approved by the Food and Drug Administration in 2015, is an oral prodrug of uridine, a pharmacologic antidote for 5-FU toxicity. To our knowledge, this is the first case report that documents the clinical course of a patient treated with uridine triacetate to reverse early-onset 5-FU toxicity negative for DPD mutations. We describe the case of a 73-year-old man with anal cancer treated with standard-of-care chemotherapy and radiation. Two days after completion of his initial 5-FU infusion, the patient developed severe mucositis and extreme fatigue, followed by a rapid decline in his blood cell counts and fevers. The patient was initiated on uridine triacetate 86 hours after completion of his 5-FU infusion. Over a 10-day hospital length of stay, the patient's absolute neutrophil count recovered to within normal limits, and his mucositis significantly improved. At follow-up visits, the patient denied any residual symptoms of 5-FU toxicity. We describe the patient's clinical course from hospital presentation to 31 days after initiation of uridine triacetate.

A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer.

PURPOSE: To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers. EXPERIMENTAL DESIGN: Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients. RESULTS: Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6-5.7], ORR was 9.5% (95% CI, 2.7-22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95% CI, 6.1-19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5-9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1-23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥ 3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2. CONCLUSION: Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents.

Phase I/II trial of custirsen (OGX-011), an inhibitor of clusterin, in combination with a gemcitabine and platinum regimen in patients with previously untreated advanced non-small cell lung cancer.

PURPOSE: Clusterin (CLU), an antiapoptotic, stress-associated protein, confers resistance to therapy when overexpressed. This trial tested custirsen (OGX-011), an inhibitor of CLU protein production, combined with gemcitabine/platinum in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a single-arm, multicenter, phase I/II study in chemotherapy-naive stage IIIB/IV NSCLC. Custirsen was infused during a loading dose period and weekly in combination with gemcitabine (1250 mg/m) on days 1 and 8 and with cisplatin (75 mg/m) or carboplatin (area under the curve 5) on day 1 of each 21-day cycle. Ten patients were treated in a phase I lead-in and 71 in the phase II component. The primary efficacy endpoint was response rate, with exploratory analyses of other efficacy outcomes and biomarker relationships. RESULTS: Eighty-one patients received custirsen and were included in the primary analysis. The median age was 61 years; 82% had stage IV disease. Overall response was 25 of 81 (31%; 95% confidence interval 21-42). The 1- and 2-year survivals were 54 and 30%, respectively. Toxicity of the combination was not appreciably different from what is reported for gemcitabine/platinum combinations. Custirsen treatment decreased serum CLU levels in 95% of patients evaluated. Patients who achieved a minimum median CLU level for the population of ≤38 µg/ml during treatment had a median survival of 27.1 compared with 16.1 months for patients who did not (p = 0.02). CONCLUSION: Based on the above results, a randomized phase 3 trial to evaluate the survival benefit of custirsen in patients with NSCLC is warranted.

Role of fluorine-18 fluoro-deoxyglucose positron emission tomography scan in the evaluation and follow-up of patients with low-grade lymphomas.

BACKGROUND: Fluorine-18 fluoro-deoxyglucose positron emission tomography (FDG-PET) scanning has excellent sensitivity and specificity for staging non-Hodgkin lymphomas, but to the authors' knowledge few studies to date have evaluated FDG-PET in low-grade lymphomas only. METHODS: A retrospective study was performed on patients with biopsy-proven nontransformed and transformed follicular lymphoma (FL), B-cell small-cell lymphocytic lymphoma (SLL/CLL), or marginal zone lymphoma (MZL) who underwent PET and computed tomography (CT) scans within 3 weeks. Standard uptake values (SUV) of all abnormal foci were measured. RESULTS: In FL, PET demonstrated 94% sensitivity and 100% specificity for staging. PET was more specific than CT for detecting recurrence or assessing therapeutic responses (91% vs. 50%). FDG avidity among patients with WHO Grades 1, 2, and 3 disease was not significantly different (analysis of variance [ANOVA]). For MZL staging, PET had moderate sensitivity (71%) and outperformed CT alone in the depiction of extranodal sites (85% vs. 57% sensitivity). In SLL/CLL, PET sensitivity was 53% and underestimated disease extent in 5 of 19 patients (26%) compared with CT. PET did not affect initial management but confirmed suspected recurrences in 75% of patients. Nontransformed FL had a higher SUV (ANOVA, P < .05) compared with MZL and SLL/CLL. SUV was higher in transformed than in nontransformed tumors (P < .001, Student t test). CONCLUSIONS: PET usefulness in staging low-grade lymphomas varies depending on histology. PET sensitivity is excellent in FL and moderate in MZL. PET is more specific than CT for follow-up in all types. PET has limited usefulness for SLL/CLL staging. However, a suggestive pattern of hazy and mild uptake was often noted in positive scans. In all low-grade lymphomas, the emergence of foci of intense uptake should raise suspicion of conversion to high-grade disease.

Docetaxel and cyclooxygenase-2 inhibition with celecoxib for advanced non-small cell lung cancer progressing after platinum-based chemotherapy: a multicenter phase II trial.

PURPOSE: To assess the overall and progression-free survival, response rate, and toxicity of combined docetaxel and celecoxib in the treatment of patients with non-small cell lung cancer progressing after initial chemotherapy for advanced disease. PATIENTS AND METHODS: Patients with non-small cell lung cancer and either measurable or evaluable disease experiencing progression after one or more platinum-based chemotherapy regimens given for advanced or metastatic disease, ECOG performance status 0-2, and adequate hematologic and biochemistry parameters were eligible for study inclusion; exclusion criteria included symptomatic brain metastases and full dose anti-coagulation. Therapy consisted of docetaxel 75 mg/m(2) every 21 days for a maximum of six cycles and celecoxib 400 mg orally twice daily commencing 7 days prior to docetaxel and continuing until disease progression. RESULTS: A total of 41 patients were enrolled of whom 39 were deemed eligible and received at least one course of docetaxel. The mean age of enrolled patients was 60.5 years (range, 44-77); 67% were men and 79% white. All but one patient had an Eastern Clinical Oncology Group (ECOG) performance status of 0 or 1. Most (72%) had been treated with a prior taxane. Overall survival was 11.3 months (95% confidence interval [CI]: 7.9, 15.7) and progression-free survival 19.6 weeks (95% CI: 13.5, 25.0). A response rate of 10.2% (95% CI: 3%, 24%) for all eligible and treated patients was found. Grade 3 or 4 neutropenia occurred in 10/39 patients (25.6%); one death due to neutropenic sepsis occurred. No grade 3 or 4 renal or hepatic toxicities were documented. CONCLUSION: Treatment with combination celecoxib and docetaxel is a safe regimen with a toxicity profile similar to that of docetaxel alone. Survival data are encouraging compared to historical controls and may prolong time to disease progression compared with single-agent docetaxel.