TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: A randomized phase 1b/2 trial.

BACKGROUND: In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5). METHODS: Twelve patients were enrolled in a phase 1b open-label dose-escalation trial of conatumumab with mFOLFOX6/bev; thereafter, 190 patients were randomized 1:1:1 to receive mFOLFOX6/bev in combination with 2 mg/kg conatumumab, 10 mg/kg conatumumab, or placebo. Therapy cycles were repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity. RESULTS: In phase 1b, conatumumab with mFOLFOX6/bev was tolerated without apparent added toxicity over mFOLFOX6/bev alone. In phase 2, conatumumab with mFOLFOX6/bev did not confer a benefit in progression-free survival when compared with placebo with mFOLFOX6/bev. Toxicity was similar in all treatment arms. Following treatment, similar increases in circulating caspase-3 levels were observed in all arms. CONCLUSIONS: Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first-line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC.

A phase III, open-label, single-arm study of tenecteplase for restoration of function in dysfunctional central venous catheters.

PURPOSE: To evaluate, in a phase III, single-arm study, the safety and efficacy of the thrombolytic agent tenecteplase in restoring function to dysfunctional central venous catheters (CVCs). MATERIALS AND METHODS: Pediatric and adult patients with dysfunctional CVCs were eligible to receive as much as 2 mL (2 mg) of intraluminal tenecteplase, which was left to dwell in the CVC lumen for a maximum of 120 minutes. If CVC function was not restored at 120 minutes, a second dose was instilled for an additional 120 minutes. RESULTS: Tenecteplase was administered to 246 patients. Mean patient age was 44 years (range, 0-92 y); 72 patients (29%) were younger than 17 years of age. Chemotherapy was the most common reason for catheter insertion. Restoration of CVC function was achieved in 177 patients (72%) within 120 minutes after the first dose. After instillation of a maximum of two doses of tenecteplase, CVC function was restored in 200 patients (81%), with similar frequencies in pediatric (83%) and adult (80%) patients. Adverse events (AEs) were reported in 31 patients (13%); fever (2%), neutropenia (1%), and nausea (0.8%) were most common. One serious AE, an allergic hypersensitivity reaction, was judged to be related to tenecteplase and/or a chemotherapeutic agent that the patient was receiving concurrently. CONCLUSIONS: Consecutive administration of one or two doses of tenecteplase into CVCs showed efficacy in the restoration of catheter function in patients with dysfunctional CVCs.

Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial.

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.

Fatal Bacillus cereus endocarditis masquerading as an anthrax-like infection in a patient with acute lymphoblastic leukemia: case report.

A 38-year-old male farm worker with relapsing acute lymphoblastic leukemia spontaneously developed an ulcerating ulcer on his anterior thigh which was surrounded by a non-tender area of erythema. Bacillus cereus was isolated from the ulcer and blood, and the patient received intravenous penicillin and vancomycin for one week. When sensitivity studies were returned he was treated with gatifloxacin orally. After two weeks of combined antimicrobial therapy and negative blood cultures, the patient received combination chemotherapy with vincristine, prednisone, doxorubicin and cyclophosphamide. He was hospitalized a day after completing chemotherapy with neutropenic sepsis due to B. cereus. He received similar antimicrobial therapy as previously, but died three days later. At autopsy, the patient was found to have acute mitral valve endocarditis and bilateral brain abscesses. This was the first case of B. cereus endocarditis reported in a patient with acute lymphoblastic leukemia.

Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.

Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099.

PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This multicenter, open-label, phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigator's discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for < or = six cycles; cetuximab (400 mg/m(2) on day 1, 250 mg/m(2) weekly) was administered until progression or unacceptable toxicity. The primary end point was progression-free survival assessed by independent radiologic review committee (PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life (QoL), and safety were key secondary end points. PFS and ORR assessed by investigators were also evaluated. Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC (hazard ratio [HR] = 0.902; 95% CI, 0.761 to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7% with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this combination was manageable and consistent with its individual components. CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC. The difference in OS favored cetuximab but did not reach statistical significance.

Phase I study of fixed dose gemcitabine plus epirubicin in patients with advanced solid malignancies.

OBJECTIVES: A Phase I study was initiated to investigate fixed dose rate gemcitabine (GEM) combined with epirubicin (EPI) given weekly or every other week, since, GEM given as a standard 30 minute infusion has modest activity. The study was designed based on the hypothesis that prolonged exposure (over 90 minutes) may improve response rates and combination with epirubicin (EPI) is synergistic. METHODS: Eligible patients had measurable refractory solid malignancies with adequate bone marrow, renal, and liver functions. Patients received GEM 800, 1000, 1250 mg/m(2) over 90 minutes followed by EPI 10 or 15 mg/m(2) as a 30 minutes infusion on days 1, 8, and 15 or days 1 and 15 of a 28 day cycle. RESULTS: Twenty-eight patients were enrolled and 24 are evaluable for overall toxicities and response rate. Toxicities include neutropenia (Gr 3 of Gr 4, 9 pts), thrombocytopenia (Gr 3 of Gr 4, 3 pts), fatigue (Gr 3 of Gr 4, 4 pts), and myalgia (Gr 3 of Gr 4, 1 pt). Dose limiting toxicity was grade 4 neutropenia. Seven patients experienced stable disease for >16 weeks and 3 patients with pancreatic cancer had partial responses. CONCLUSIONS: The maximum tolerated dose is GEM 800 mg/m(2)/EPI 10 mg/m(2) days 1, 8, 15 or GEM 1000 mg/m(2)/EPI 15 mg/m(2) days 1, 15 given every 4 weeks. Further studies are warranted with targeted therapies to define the efficacy of this doublet.

Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q.

Lenalidomide is approved for red blood cell (RBC) transfusion-dependent anemia due to low or intermediate-1 (int-1) risk myelodysplastic syndromes (MDSs) associated with a chromosome 5q deletion with or without additional cytogenetic abnormalities. We report results of a multicenter, phase 2 trial evaluating lenalidomide therapy for transfusion-dependent patients with low- or int-1-risk MDS without deletion 5q. Eligible patients had 50,000/mm(3) or more platelets and required 2 U or more RBCs within the previous 8 weeks; 214 patients received 10 mg oral lenalidomide daily or 10 mg on days 1 to 21 of a 28-day cycle. The most common grade 3/4 adverse events were neutropenia (30%) and thrombocytopenia (25%). Using an intention-to-treat analysis, 56 (26%) patients achieved transfusion independence (TI) after a median of 4.8 weeks of treatment with a median duration of TI of 41.0 weeks. In patients who achieved TI, the median rise in hemoglobin was 32 g/L (3.2 g/dL; range, 10-98 g/L [1.0-9.8 g/dL]) from baseline. A 50% or greater reduction in transfusion requirement occurred in 37 additional patients, yielding a 43% overall rate of hematologic improvement (TI response + ||>or= 50% reduction in transfusion requirement). Lenalidomide has clinically meaningful activity in transfusion-dependent patients with low- or int-1-risk MDS who lack the deletion 5q karyotypic abnormality.

Cellulitis and septic arthritis caused by Campylobacter fetus and Campylobacter jejuni: report of 2 cases and review of the literature.

Bacteremia caused by gram-negative bacteria occasionally causes soft tissue infections, including cellulitis and septic arthritis. We describe 1 patient each with Campylobacter fetus cellulitis and septic arthritis and review the world literature with regard to C. fetus and C. jejuni infections at these sites. Altogether, 14 patients with cellulitis (12 due to C. fetus and 2 due to C. jejuni) and 20 patients with septic arthritis (15 due to C. fetus and 4 caused by C. jejuni) have been described. Most infections, particularly those causing cellulitis, are found in elderly men with underlying systemic disease. Most patients are febrile but less than half manifest a leukocytosis. There were only 3 deaths in this series of 33 patients. The newer macrolides, including azithromycin and clarithromycin, are considered the drugs of choice, particularly with C. jejuni, while soft tissue infections caused by C. fetus respond nicely to many beta-lactams, particularly to cephalosporins and carbapenems, as well as to macrolides and quinolones.