A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial.

BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer.

BACKGROUND: Efficacy and safety of first-line axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin in advanced non-squamous non-small-cell lung cancer (NSCLC) was evaluated. PATIENTS AND METHODS: Patients with stage IIIB/IV disease stratified by adjuvant therapy and gender were randomised 1 : 1 to axitinib (5 mg twice daily) or bevacizumab [15 mg/kg every 3 weeks (Q3W)], both with paclitaxel (200 mg/m(2) Q3W)/carboplatin (AUC 6 mg min/ml Q3W). RESULTS: The trial was discontinued after preliminary analysis. Median progression-free survival (primary end point) for axitinib (N = 58) and bevacizumab (N = 60), respectively, was 5.7 and 6.1 months [hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.68-1.76; one-sided stratified P = 0.64]; median overall survival was 10.6 and 13.3 months (HR 1.12, 95% CI 0.74-1.69; one-sided stratified P = 0.70). Objective response rates (95% CI) were 29.3% (18.1-42.7) and 43.3% (30.6-56.8), respectively; risk ratio 0.676 (95% CI 0.41-1.11; one-sided stratified P = 0.94). The most common grade 3/4 adverse events included neutropenia (28% versus 20%), fatigue (14% versus 7%), and hypertension (14% versus 5%). Patient-reported outcomes based on the EORTC QLQ-C30 were similar between arms. CONCLUSIONS: In patients with advanced non-squamous NSCLC, axitinib/paclitaxel/carboplatin did not improve efficacy versus bevacizumab/paclitaxel/carboplatin, and was less well tolerated.

Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer.

BACKGROUND: We evaluated AMG 386, an investigational peptibody that neutralizes the interaction between angiopoietins-1 and -2 and the Tie2 receptor, combined with cisplatin/capecitabine (CX) as first-line treatment for metastatic gastro-oesophageal cancer. PATIENTS AND METHODS: Patients with metastatic gastric, gastro-oesophageal junction, or distal oesophageal adenocarcinoma were randomized 1:1:1 to CX (cisplatin 80 mg/m(2) IV Q3W; capecitabine 1000 mg/m(2) P.O. BID for 14 days Q3W) plus intravenous AMG 386 10 mg/kg QW (Arm A) or 3 mg/kg QW (Arm B), or placebo QW (Arm C). The primary end point was estimated progression-free survival (PFS). RESULTS: A total of 171 patients were enrolled. Median estimated PFS in Arms A, B, and C was 4.2, 4.9, and 5.2 months, respectively (hazard ratio for Arms A+B combined versus Arm C, 0.98; 95% CI 0.67-1.43; P = 0.92). Objective response rates were 27% (Arm A), 43% (Arm B), and 35% (Arm C). Incidence of grade ≥3 adverse events was 80% in Arm A, 84% in Arm B, and 75% in Arm C. There was no evidence of pharmacokinetic interactions. CONCLUSIONS: In this study, PFS and ORR were estimated to be similar with AMG 386 plus CX and placebo plus CX treatment. Compared with placebo, toxicity of AMG 386 plus CX was greater but manageable. PREVIOUS PRESENTATION: The results of this study have not been previously published or submitted for publication elsewhere. The results were presented in part at the Gastrointestinal Cancers Symposium, San Francisco, CA, January 20-22, 2011. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT00583674.

Use of darbepoetin alfa in European clinical practice for the management of chemotherapy-induced anaemia in four tumour types: final data from the CHOICE study.

OBJECTIVES: The CHOICE study was a prospective, multicentre, observational study designed to assess levels of adherence in current clinical practice to the European product label and EORTC guidelines for the treatment of chemotherapy-induced anaemia (CIA) with darbepoetin alfa (DA). Here we present data split by tumour types: breast, colorectal, ovarian and lung. METHODS: Haemoglobin (Hb) levels and red blood cell transfusion requirements were evaluated among patients with solid tumours in 11 European countries. The primary outcome measure was the proportion of patients with a target Hb level of ≥10-≤12 g/dL. RESULTS: The full analysis set included 1887 patients (mean ± SD 62.4 ± 11.4 years); 1585 (84%) had a current disease stage of ≥3. Common chemotherapy regimens were non-platinum + non-taxane based (n = 696 [37%]) or platinum + non-taxane based (n = 660 [35%]). Breast cancer (n = 575): The mean ± SD Hb level at baseline was 9.9 ± 0.8 g/dL (n = 568). Target Hb level was reached by 187 (55%) patients. Colorectal cancer (n = 310): At baseline the mean ± SD Hb level was 9.8 ± 0.8 g/dL (n = 306). Target Hb level was reached by 107 patients (56%). Ovarian cancer (n = 301): The mean ± SD Hb level at baseline was 9.7 ± 0.8 g/dL (n = 294). Target Hb level was reached by 81 patients (44%). Lung cancer (n = 701): At baseline the mean ± SD Hb level was 9.8 ± 0.9 g/dL (n = 692). Target Hb level was reached by 142 patients (39%). SAFETY: Five severe or life-threatening adverse drug reactions were seen (three patients with breast cancer, one patient with colorectal cancer and one patient with ovarian cancer). LIMITATIONS: Potential bias could not be excluded due to the study's observational nature. CONCLUSIONS: This study demonstrates that the recommendations are adhered to in clinical practice, with the mean starting Hb level <10 g/dL irrespective of tumour type. Furthermore, DA is likely to be effective and well tolerated for the treatment of CIA in patients with breast, colorectal, ovarian or lung cancer.

A final analysis from the CHOICE study examining darbepoetin alfa use for chemotherapy-induced anaemia in current European clinical practice.

OBJECTIVES: The CHOICE study was a prospective, multicentre, observational study designed to assess the level of adherence in current clinical practice to the European product label and the EORTC guidelines for the treatment of chemotherapy-induced anaemia with darbepoetin alfa (DA). METHODS: Hb levels and red blood cell (RBC) transfusion requirements were evaluated among 1900 patients with solid tumours in 11 European countries. The primary outcome measure was the proportion of patients with a target Hb level of ≥10-≤12 g/dL after 9 weeks' DA treatment. RESULTS: The full analysis set (FAS) comprised 1887 patients (mean ± SD age 62.4 ± 11.4 years) divided into categories by baseline Hb < 9 g/dL (n = 281); 9-<10 g/dL (n = 770); 10-<11 g/dL (n = 695); ≥11 g/dL (n = 114). The proportion of patients who remained on the study at week 9 achieving the target Hb level was 37% (n = 60), 48% (n = 217), 54% (n = 210) and 38% (n = 23) in the subgroups with a baseline Hb level of <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL, respectively. In the <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL subgroups of the FAS, the number of patients maintaining Hb levels ≥10 g/dL after their first achievement of an Hb value of 10 g/dL was 95 (34%), 372 (48%), 476 (68%) and 87 (76%), respectively. The Kaplan-Meier percentages of patients who required an RBC transfusion from week 5 until end of treatment period were: 29%, 20%, 12% and 17% in the <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL subgroups, respectively. Kaplan-Meier percentages of patients reaching an Hb level of >13 g/dL were 10%, 9%, 21% and 29%, respectively. Potential bias could not be excluded due to the study's observational nature. CONCLUSIONS: DA initiation and target Hb ranges adhered to current guidelines in the majority of patients. Furthermore, this study demonstrates faster achievement of the target range and reduced transfusion requirements are associated with initiation of DA at Hb levels of 9-<10 g/dL and 10-<11 g/dL rather than <9 g/dL.

[Serum thrombopoietin and interleukin-6 concentration in diagnosis of thrombocytopenia]. / Stezenie trombopoetyny i interleukiny 6 w surowicy w diagnostyce nadplytkowosci.

Serum concentration of thrombopoietin (Tpo) and interleukin 6 (IL-6) were measured in 37 patients with thrombocythaemia and in the healthy volunteers. 27 patient were classified as persons with chronic myeloproliferative disorder (MPD) and 10 as with reactive thrombocythaemia (RT). The mean plasma Tpo concentration did not differ statistically between the groups. IL-6 levels were significantly higher in patients with RT than in patients with MPD and controls. The mean plasma IL-6 levels was lowest in patients with essential thrombocythaemia. In conclusion, serum IL-6 concentration may be useful in the differential diagnosis of thrombocytosis.