imetelstat and Nausea

This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors.. Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6).. Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease.. Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone.. ClinicalTrials.gov NCT01235416.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Cohort Studies; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Erlotinib Hydrochloride; Female; Gemcitabine; Humans; Hypertension; Indoles; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasms; Niacinamide; Oligonucleotides; Quinazolines; Treatment Outcome; Venous Thrombosis; Vomiting; Young Adult

This phase Ib study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 102, a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in combination with bevacizumab or motesanib in patients with advanced solid tumors.. Patients with treatment-refractory advanced solid tumors were sequentially enrolled into four cohorts (3, 10, or 20 mg/kg AMG 102 plus 10 mg/kg bevacizumab i.v. every 2 weeks, or 3 mg/kg AMG 102 i.v. every 2 weeks plus 75 mg motesanib orally once daily).. Fourteen patients were enrolled and received AMG 102. The combination of AMG 102 with bevacizumab (n = 12) seemed to have acceptable toxicity. The number of patients (n = 2) who received AMG 102 plus motesanib was insufficient to adequately assess safety. No dose-limiting toxicities were reported. Enrollment in the motesanib cohort was suspended because of reports of cholecystitis in other motesanib studies. Treatment-emergent adverse events among patients receiving AMG 102 plus bevacizumab were generally mild and included fatigue (75%), nausea (58%), constipation (42%), and peripheral edema (42%). No anti-AMG 102 antibodies were detected. Bevacizumab did not seem to affect AMG 102 pharmacokinetics. Circulating total HGF/SF increased from baseline throughout the study. Eight of 10 evaluable patients had reductions in tumor dimensions, and stable disease at > or =8, > or =16, and > or =24 weeks occurred in 9, 7, and 4 patients, respectively. Progression-free survival ranged from 7.9 to 121.9 weeks.. AMG 102 in combination with bevacizumab was well tolerated. Further evaluation of AMG 102 in combination with antiangiogenic agents is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bevacizumab; Cohort Studies; Constipation; Dose-Response Relationship, Drug; Fatigue; Female; Hepatocyte Growth Factor; Humans; Indoles; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasm Staging; Neoplasms; Niacinamide; Oligonucleotides; Treatment Outcome