A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients

<p>Abstract</p> <p>Background</p> <p>The phosphate ester PR-104 is rapidly converted in vivo to the alcohol PR-104A, a nitrogen mustard prodrug that is metabolised to hydroxylamine (PR-104H) and amine (PR-104M) DNA crosslinking agents by one-electron reductases in hypoxic cells and by aldo-keto reductase 1C3 independently of oxygen. In a previous phase I study using a q 3 week schedule of PR-104, the maximum tolerated dose (MTD) was 1100 mg/m²and fatigue, neutropenic fever and infection were dose-limiting. The primary objective of the current study was to determine the dose-limiting toxicity (DLT) and MTD of weekly PR-104.</p> <p>Methods</p> <p>Patients with advanced solid tumours received PR-104 as a 1-hour intravenous infusion on days 1, 8 and 15 every 28 days with assessment of pharmacokinetics on cycle 1 day 1. Twenty-six patients (pts) were enrolled (16 male/10 female; median age 58 yrs, range 30 to 70 yrs) who had received a median of two prior chemotherapy regimens (range, 0 to 3) for melanoma (8 pts), colorectal or anal cancer (3 pts), NSCLC (3 pts), sarcoma (3 pts), glioblastoma (2 pts), salivary gland tumours (2 pts) or other solid tumours (5 pts). PR-104 was administered at 135 mg/m²(3 pts), 270 mg/m²(6 pts), 540 mg/m²(6 pts), 675 mg/m²(7 pts) and 900 mg/m²(4 pts) for a median of two treatment cycles (range, 1 to 7 cycles) and five infusions (range, 1 to 18) per patient.</p> <p>Results</p> <p>Dose-limiting toxicities (DLTs) during cycle one included grade four thrombocytopenia at 540 mg/m²(1 of 6 pts) and grade four thrombocytopenia and neutropenia at 900 mg/m²(2 of 4 pts). At an intermediate dose of 675 mg/m², there were no DLTs among a total of seven patients given 12 treatment cycles but all experienced moderate to severe (grade 2 to 4) haematological toxicity. Thrombocytopenia was delayed in its onset and nadir, and its recovery was protracted and incomplete in many patients. There were no complete or partial tumour responses. PR-104-induced thrombocytopenia and neutropenia correlated with plasma AUC of PR-104, PR-104A and an oxidative semi-mustard metabolite (PR-104S1), but no more strongly than with PR-104 dose-level. There was no significant correlation between plasma AUC for the reduced metabolites and myelotoxicity.</p> <p>Conclusions</p> <p>Thrombocytopenia, and to a lesser extent neutropenia, was the DLT of weekly PR-104. The MTD was 675 mg/m²/week. PR-104 given weekly may be a suitable protocol for further clinical evaluation as a short course of treatment with fractionated radiotherapy or haematopoietic stem cell support, as its duration of dosing is restricted by delayed-onset and protracted thrombocytopenia.</p

Amarogentin Inhibits Liver Cancer Cell Angiogenesis after Insufficient Radiofrequency Ablation via Affecting Stemness and the p53-Dependent VEGFA/Dll4/Notch1 Pathway

Background. Whether and how amarogentin suppresses the angiogenesis effect in liver cancer cells after insufficient radiofrequency ablation (iRFA) are still poorly studied. Methods. The number of liver cancer stem cells (LCSCs) and the level of vascular endothelial growth factor A (VEGFA) were assessed in liver cancer tissue after iRFA. Then, CD133-positive cells were detected in iRFA models of HepG2 and Huh7 cell lines treated with amarogentin. Tube formation assays were applied to observe the antiangiogenesis effects of amarogentin. In addition, the angiogenesis-related molecules p53, delta-like ligand 4 (Dll4), and Notch1 were detected in the iRFA cells and mouse models treated with amarogentin. Results. The mRNA and protein expression levels of CD133 and VEGFA were significantly higher in the residual liver cancer tissue than in the liver cancer tissues treated by hepatectomy. Amarogentin then markedly decreased the percentage of CD133-positive cells in the iRFA model in both HepG2 and Huh7 cell lines. The number of tubules formed by human umbilical vein endothelial cells (HUVECs) was significantly decreased by amarogentin. Inversely, the antiangiogenesis effect of amarogentin was counteracted after p53 silencing in the iRFA cell models. Conclusion. Amarogentin prevents the malignant transformation of liver cancer after iRFA via affecting stemness and the p53-dependent VEGFA/Dll4/Notch1 pathway to inhibit cancer cell angiogenesis

PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours

<p>Abstract</p> <p>Background</p> <p>The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours.</p> <p>Methods</p> <p>PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m² on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m² on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m² and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and ¹⁸F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles.</p> <p>Results</p> <p>Forty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m² when combined with gemcitabine, 200 mg/m² when combined with docetaxel 60 mg/m², 770 mg/m² when combined with docetaxel 60 mg/m² plus G-CSF and ≥770 mg/m² when combined with docetaxel 75 mg/m² plus G-CSF. Dose-limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents.</p> <p>Conclusions</p> <p>Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR-104 dose escalation with docetaxel. Dose-limiting thrombocytopenia prohibited further evaluation of the PR104-gemcitabine combination. A recommended dose was identified for phase II trials of PR-104 of 770 mg/m² combined with docetaxel 60 to 75 mg/m² both given on day one of a 21-day treatment cycle supported by prophylactic G-CSF (NCT00459836).</p