pazopanib and Adenocarcinoma

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Doxorubicin; Humans; Indazoles; Japan; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Quinolines; Slovenia; Sorafenib; Sulfonamides; Thyroid Neoplasms; Treatment Outcome

VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR-1, -2 and -3, c-kit and PDGF-R resulting in inhibition of angiogenesis. This open-label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5-fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first-line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty-seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval [CI] 2.87-6.46) vs 4.47 months (95% CI 1.79-7.14) (95% CI, hazard ratio [HR] 0.96 (0.60-1.55), P = .882 [exploratory]); median OS was 10.19 months (95% CI 5.46-14.92) vs 7.33 months (95% CI 4.93-9.73), (95% CI HR 1.01 [0.62-1.65], P = .953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Esophagogastric Junction; Female; Fluorouracil; Humans; Indazoles; Male; Middle Aged; Oxaliplatin; Pyrimidines; Stomach Neoplasms; Sulfonamides

We designed a single-arm, open label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx (capecitabine and oxaliplatin) in metastatic /recurrent advanced gastric cancer (AGC) patients. Previously untreated AGC patients received capecitabine (850 mg/m2 bid, day 1-14) plus oxaliplatin (130 mg/m2, day 1) in combination with pazopanib (800 mg, day 1-21) every three weeks. Treatment was continued until progression of the disease or intolerable toxicity was observed. In all, 66 patients were treated with pazopanib plus CapeOx. The median age of the patients was 51.5 years (range, 23.0-77), and the median ECOG performance status was 1 (0-1). Among all 66 patients, one complete response and 37 partial responses were observed (overall response rate, 62.4%; 95% confidence interval (CI), 45.7-73.5% accounting for the 2-stage design of this trial). Stable disease was observed in 23 patients (34.8%), revealing a 92.4% disease control rate. The median progression free survival and overall survival were 6.5 months (95% CI, 5.6-7.4) and 10.5 months (95% CI, 8.1-12.9), respectively. Thirty-four patients (51.5%) experienced a treatment-related toxicity of grade 3 or more. The most common toxicities of grade 3 or more were neutropenia (15.1%), anemia (10.6%), thrombocytopenia (10.6%), anorexia (7.6%), nausea (3.0%), and vomiting (3.0%). There were no treatment-related deaths. The combination of pazopanib and CapeOx showed moderate activity and an acceptable toxicity profile as a first-line treatment in metastatic / recurrent AGC patients (ClinicalTrials.gov NCT01130805).

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Female; Follow-Up Studies; Humans; Indazoles; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Pyrimidines; Stomach Neoplasms; Sulfonamides; Young Adult

This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non-small-cell lung cancer.. Patients were randomized (2:1 ratio) to receive pemetrexed 500 mg/m(2) intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m(2) intravenously once every 3 weeks up to six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. The primary endpoint was progression-free survival (PFS).. The study was terminated after 106 of 150 patients were randomized due to a higher incidence of adverse events leading to withdrawal from the study and severe and fatal adverse events in the pazopanib/pemetrexed arm than in the cisplatin/pemetrexed arm. At the time enrolment was discontinued, there were three fatal adverse events in the pazopanib/pemetrexed arm, including ileus, tumor embolism, and bronchopneumonia/sepsis. Treatment with pazopanib/pemetrexed was discontinued resulting in more PFS data censored for patients in the pazopanib/pemetrexed arm than those in the cisplatin/pemetrexed arm. There was no statistically significant difference between the pazopanib/pemetrexed and cisplatin/pemetrexed arms for PFS (median PFS, 25.0 versus 22.9 weeks, respectively; hazard ratio = 0.75; 95% confidence interval, 0.43%-1.28%; p = 0.26) or objective response rate (23% versus 34%, respectively; 95% confidence interval, -30.6% to 7.2%; p = 0.21).. The combination of pazopanib/pemetrexed in first-line treatment of non-small-cell lung cancer showed some antitumor activity but had unacceptable levels of toxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Follow-Up Studies; Glutamates; Guanine; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pemetrexed; Prognosis; Pyrimidines; Sulfonamides; Survival Rate

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged, 80 and over; Drug Resistance, Neoplasm; Esophageal Neoplasms; Esophagus; Fatal Outcome; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Recurrence, Local; Pyrimidines; Stomach; Stomach Neoplasms; Sulfonamides; Treatment Outcome

Significant progress has been made in the identification of molecular targets and targeted therapy is becoming a realistic option for patients with tumors for which potential driver mutations are identified. We present a case that highlights that the identification of a potential driver mutation does not confirm it as a key mutational event in every case and emphasizes the need for ongoing research to enable therapy to be more accurately directed for the benefit of patients.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fatal Outcome; Female; Humans; Indazoles; Liver Neoplasms; Microtubule-Associated Proteins; Middle Aged; Molecular Targeted Therapy; Mutation; Oncogenes; Pancreatic Neoplasms; Paraneoplastic Syndromes; Pyrimidines; Radiography; Receptor, Fibroblast Growth Factor, Type 3; Sulfonamides