A phase II trial of the Src kinase inhibitor saracatinib (AZD0530) in patients with metastatic or locally advanced gastric or gastro esophageal junction (GEJ) adenocarcinoma: a trial of the PMH phase II consortium.

PURPOSE: The Src family of kinases may play a role in the development and progression of gastric cancer. We evaluated the activity and safety of saracatinib an oral, anilinoquinazolone, non-receptor tyrosine kinase inhibitor targeting Src kinases, in patients with metastatic or locally advanced gastric carcinoma. METHODS: Eligible patients who had received ≤1 prior line of chemotherapy for metastatic disease received saracatinib 175 mg/day of a 28 day cycle until progression. The primary endpoint was the objective response and/or prolonged stable disease rate (pSD ≥ 16 weeks). RESULTS: Ten patients with gastric carcinoma and 11 with adenocarcinoma of the gastroesophageal junction received a median of 2 cycles (range 1-10 cycles) of treatment per patient. 17 patients were evaluable for response. No objective response was seen. One patient experienced prolonged Stable disease (pSD). Three patients had SD and 13 progressive disease. Median overall survival was 7.8 months (95% CI, 3.9-12.2 months) and median time to progression was 1.8 months (95% CI: 1.5-1.9 months). Grade 3 events possibly related to saracatinib included: fatigue (2 patients), hypoxia (2) anemia (3) and lymphopenia (2). CONCLUSION: Saracatinib has insufficient activity as a single agent in patients with advanced gastric adenocarcinoma to warrant further investigation. Further development in gastric cancer would require rational drug combinations or identification of a tumor phenotype sensitive to Src inhibition.

Evaluation of pandemic H1N1 (2009) influenza vaccine in adults with solid tumor and hematological malignancies on active systemic treatment.

BACKGROUND: Over 85% of healthy individuals vaccinated with the pandemic H1N1 (pH1N1) vaccine achieve seroprotection. OBJECTIVES: We evaluated the safety and immunogenicity of pH1N1 vaccine in patients undergoing chemotherapy for hematological and solid tumor malignancies. STUDY DESIGN: Adult patients, receiving chemotherapy undergoing pH1N1 vaccination at our institution had blood samples drawn for CBC (baseline only) and serology prior to and ≥ 21 days post vaccination. HAI antibody testing was performed for pH1N1 (A/California/7/2009 strain) and seasonal H1 (A/Brisbane/59/07 strain). Seroprotection was defined as a pH1N1 antibody titre ≥ 1:40 and seroconversion as an antibody titre >4 × baseline. Patients completed a symptom diary card. RESULTS: Paired samples were available for 46 patients (20 solid tumor, 26 hematological), median age 56 (range 23-76) years. The seroprotective rate post-vaccination for solid tumors was 50% compared to 27% for hematological malignancy (p=0.11), respective seroconversion rates were 45% and 19% (p=0.06). In patients with solid tumors vaccination mid cycle resulted in the highest pH1N1 titres, although timing and blood count were not associated with seroconversion or seroprotection. For hematological patients, a normal leukocyte count and vaccination at the beginning of a cycle were associated with higher rates of seroconversion (p ≤ 0.05). Addition of rituximab to chemotherapy resulted in a failure to seroconvert (p=0.05). Vaccination was well tolerated by all patients. CONCLUSIONS: Although well tolerated, the seroprotection rate following pH1N1 vaccination is lower than that would be expected. Further investigation into immunization strategies in patients receiving chemotherapy is required.

Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer: a study of the Princess Margaret Hospital Phase II Consortium.

OBJECTIVES: Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). Sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. Gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC. METHODS: Patients with recurrent EOC after platinum-based chemotherapy and who had subsequently received up to 3 prior chemotherapy regimens were eligible. Gemcitabine (1000 mg/m intravenous [IV]) was administered weekly for 7 of 8 weeks in the first cycle, then weekly for 3 weeks of each subsequent 4-week cycle. Sorafenib (400 mg p.o. bid) was given continuously. The primary end point for this trial was objective response rate by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included Gynecologic Cancer Intergroup (GCIG) CA-125 response, time to progression, overall survival, and toxicity. RESULTS: Forty-three patients were enrolled, and 33 completed at least 1 cycle. Two patients had a partial response (Response Evaluation Criteria in Solid Tumors objective response rate = 4.7%). Ten patients (23.3%) maintained response or stable disease for at least 6 months. GCIG CA-125 response was 27.9%. The median time to progression was 5.4 months, and the median overall survival was 13.0 months. Hematologic toxicity was common but manageable. The most common nonhematologic adverse events were hand-foot syndrome, fatigue, hypokalemia, and diarrhea. CONCLUSION: This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response.

Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours.

AIM: Micropapillary/borderline (LMP) ovarian tumours are rarely included in clinical trials and are intrinsically resistant to radiation and chemotherapy. Platinum resistant epithelial ovarian cancer (EOC) has a poor prognosis. The histone deacetylase inhibitor belinostat demonstrated antitumour activity in pre-clinical ovarian cancer models. METHODS: A phase II study was performed to evaluate the activity of belinostat in two patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) EOC and LMP ovarian tumours, both groups had received no more than 3 prior lines of chemotherapy. Belinostat 1000 mg/m(2)/d was administered iv days 1-5 of a 21 d cycle. Peripheral blood mononuclear cells (PBMCs) and tumour biopsies, where possible, for correlative studies were obtained prior to and following treatment. RESULTS: Eighteen patients with EOC and 14 patients with LMP tumours were enrolled on study. Belinostat was well tolerated with no grade four toxicity (179 cycles). Grade 3 toxicity consisted of thrombosis (3 patients), hypersensitivity (1) and elevated ALP (1). One patient with LMP tumour had a partial response (unconfirmed) and 10 had stable disease (SD), 3 were non-evaluable. Median progression-free survival (PFS) was 13.4 months (95% confidence interval (CI), 5.6--not reached). Best response in patients with EOC was SD (nine patients) and median PFS was 2.3 months (95% CI, 1.2-5.7 months). An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumour tissue. CONCLUSIONS: Belinostat is well tolerated in both patient groups and shows some activity in patients with micropapillary (LMP) disease.