Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer.

PURPOSE: Epidermal growth factor receptor is overexpressed in metastatic triple-negative breast cancers (mTNBCs), an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting. PATIENTS AND METHODS: Patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive no more than six cycles of cisplatin plus cetuximab or cisplatin alone. Patients receiving cisplatin alone could switch to cisplatin plus cetuximab or cetuximab alone on disease progression. The primary end point was overall response rate (ORR). Secondary end points studied included progression-free survival (PFS), overall survival (OS), and safety profiles. Analyses included a significance level of α = .10 with no adjustments for multiplicity. RESULTS: The full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy. The ORR was 20% (95% CI, 13 to 29) with cisplatin plus cetuximab and 10% (95% CI, 4 to 21) with cisplatin alone (odds ratio, 2.13; 95% CI, 0.81 to 5.59; P = .11). Cisplatin plus cetuximab resulted in longer PFS compared with cisplatin alone (median, 3.7 v 1.5 months; hazard ratio [HR], 0.67; 95% CI, 0.47 to 0.97; P = .032). Corresponding median OS was 12.9 versus 9.4 months (HR, 0.82; 95% CI, 0.56 to 1.20; P = .31). Common grade 3/4 adverse events included acne-like rash, neutropenia, and fatigue. CONCLUSION: While the primary study end point was not met, adding cetuximab to cisplatin doubled the ORR and appeared to prolong PFS and OS, warranting further investigation in mTNBC.

Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.

BACKGROUND: Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer. METHODS: In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m(2) (on days 1-14) and intravenous cisplatin 80 mg/m(2) (on day 1), with or without weekly cetuximab (400 mg/m(2) initial infusion on day 1 followed by 250 mg/m(2) per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75. FINDINGS: Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4.4 months (95% CI 4.2-5.5) compared with 5.6 months (5.1-5.7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1.09, 95% CI 0.92-1.29; p=0.32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3-4 adverse events, including grade 3-4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3-4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3-4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event. INTERPRETATION: Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial. FUNDING: Merck KGaA.

Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT).

OBJECTIVE: To evaluate the efficacy, tolerability, and pharmacokinetics of bicalutamide plus anastrozole in young males with testotoxicosis. METHODS: This was a multicenter, open-label, single-arm, 12-month, Phase II pilot trial in 14 males (2-9 years) with testotoxicosis treated with bicalutamide (12.5, 25, 50, or 100 mg) and anastrozole (0.5 or 1 mg) daily. The primary outcome was change in growth rate. RESULTS: At 1 year, the mean (standard deviation) change from baseline in growth rate was -1.6 (+/- 5.1) cm/year and -0.1 (+/- 1.8) SD units, and in bone maturation was -2.3 (+/- 0.5) years. The bone age/chronological age ratio was reduced from 2.1 (+/- 0.6) at baseline to 1.0 (+/- 0.4) (p = 0.00013). Steady-state trough R-bicalutamide and anastrozole concentrations were attained by Day 21 and 8, respectively. Gynecomastia (42.9%) and breast tenderness (12.5%) were the most common treatment-related adverse events. CONCLUSIONS: Treatment of testotoxicosis with bicalutamide plus anastrozole resulted in slower growth rate.

Long-term efficacy and safety of rosuvastatin 40 mg in patients with severe hypercholesterolemia.

Patients with elevated low-density lipoprotein (LDL) cholesteral levels are at high risk of cardiovascular events but are often undertreated and fail to achieve lipid goals. This open-label, noncomparative, multicenter study assessed efficacy and safety of rosuvastatin 40 mg for < or =96 weeks in 1,380 patients with severe hypercholesterolemia, including heterozygous familial hypercholesterolemia. Patients > or =18 years old with fasting LDL cholesterol > or =190 and < or =260 mg/dl and triglycerides <400 mg/dl entered a 6-week dietary lead-in, before receiving rosuvastatin 40 mg for 48 weeks. An optional additional 48-week treatment period followed. The initial period had 2 primary end points: percentage of patients achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL cholesterol goals at 12 weeks, and long-term safety, assessed during 48 weeks by incidence and severity of adverse events (AEs) and abnormal laboratory values. Safety was the primary end point in the extension period. At 12 weeks, 83% of patients achieved NCEP ATP III LDL cholesterol goals, which were maintained during 48 and 96 weeks (81% and 84%, respectively). At 48 weeks, rosuvastatin 40 mg reduced LDL cholesterol from baseline by 52% and increased high-density lipoprotein (HDL) cholesterol by 11% (both p <0.0001). At 96 weeks, LDL cholesterol was reduced by 54% and HDL cholesterol increased by 13%. Rosuvastatin 40 mg was well tolerated during 96 weeks. The overall pattern and incidence of AEs and abnormal laboratory values were consistent with the published safety profile of rosuvastatin and higher doses of other statins. In conclusion, long-term treatment with rosuvastatin 40 mg is safe and effective in patients with severe hypercholesterolemia.

Comparison of short-term renal effects and efficacy of rosuvastatin 40 mg and simvastatin 80 mg, followed by assessment of long-term renal effects of rosuvastatin 40 mg, in patients with dyslipidemia.

BACKGROUND: An open-label, randomized, multinational, parallel-group trial compared the short-term (6-week) renal effects of rosuvastatin 40 mg and simvastatin 80 mg in patients with hypercholesterolemia. Most patients (93%) then entered an optional open-label extension (OLE) to assess long-term (up to 72 weeks) renal effects of rosuvastatin. METHODS: After dietary lead-in, 626 patients were randomized to rosuvastatin or simvastatin for 6 weeks, followed by an optional, single-arm OLE to assess longer-term effects of rosuvastatin on renal function, safety, and efficacy. RESULTS: The primary endpoint, a shift in urine dipstick protein from "none" or "trace" at baseline to "+" or greater in the first 4 weeks, was observed in 6.4% of patients receiving rosuvastatin and 1.0% of those receiving simvastatin. The incidence of shifts in urine dipstick protein at any time from none or trace to "++" or greater (proteinuria), was low (1.3%, rosuvastatin; 0.3%, simvastatin), transient and urine protein was predominantly of tubular or mixed origin. More patients achieved Third Adult Treatment Panel of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) low-density lipoprotein cholesterol (LDL-C) goals with rosuvastatin vs simvastatin after 6 weeks (77.9% vs 60.4%). Results from the OLE (median rosuvastatin treatment = 47 weeks) were consistent with the randomized period. Mean serum creatinine levels remained stable, indicating no decline in renal function. CONCLUSION: A small proportion of patients treated with rosuvastatin 40 mg may experience a transient proteinuria, predominantly of tubular origin and not associated with declining renal function. Rosuvastatin modified lipid levels effectively, enabled more patients to attain LDL-C goals, and demonstrated a favorable benefit/risk profile.