pazopanib and Genital-Neoplasms--Female

As precision medicine has become a focus in oncology in recent years, many targeted and biologic agents are being used along with or in place of traditional cytotoxic chemotherapy. As these drugs have been developed and some have received FDA approval, we have gained substantial data about the adverse event profiles. However, the management and approach to the toxicities incurred and subsequent complications are often not well understood, especially for physicians who have a varied clinical practice. The purpose of this review is to provide an overview of the frequency and types of adverse events and appropriate management steps when prescribing modern targeted therapies for gynecologic cancers in the classes of anti-angiogenic agents, poly-ADP-ribose polymerase (PARP) inhibitors, and immunotherapy drugs.

Topics: Anemia; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Autoimmune Diseases; Bevacizumab; Diarrhea; Epistaxis; Fatigue; Female; Genital Neoplasms, Female; Headache; Hemorrhage; Humans; Hypertension; Indazoles; Intestinal Perforation; Molecular Targeted Therapy; Nausea; Neutropenia; Poly(ADP-ribose) Polymerase Inhibitors; Precision Medicine; Proteinuria; Pyrimidines; Risk Assessment; Sulfonamides; Vomiting; Water-Electrolyte Imbalance

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.

Topics: Animals; Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colorectal Neoplasms; Digestive System; Enzyme Inhibitors; Female; Genital Neoplasms, Female; Humans; Imidazoles; Indazoles; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

Although most patients with advanced gynaecologic malignancies respond to first-line treatment with platinum-taxane doublets, a significant proportion of patients relapse. Combining targeted agents that have non-overlapping mechanisms of action with chemotherapy may potentially increase the disease-free interval. Accordingly, this study evaluated the feasibility of combining pazopanib, an oral angiogenesis inhibitor, with paclitaxel and carboplatin.. This open-label, phase I/II study planned to evaluate the safety and efficacy of paclitaxel 175 mg m(-2) plus carboplatin (AUC5 (Arm A) or AUC6 (Arm B)) once in every 3 weeks for up to six cycles with either 800 or 400 mg per day pazopanib.. Dose-limiting toxicities (DLTs) were observed in two of the first six patients enrolled at pazopanib 800 mg plus paclitaxel 175 mg m(-2) plus carboplatin AUC5. Of the six patients enrolled in the next and lowest dosing level planned in the study, pazopanib 400 mg plus paclitaxel 175 mg m(-2) plus carboplatin AUC5, two patients also experienced DLTs and the study was terminated. Two of the 4 DLTs observed overall were gastrointestinal perforations. Severe myelotoxicity was reported in 6 of 12 patients.. Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Early Termination of Clinical Trials; Feasibility Studies; Female; Genital Neoplasms, Female; Humans; Indazoles; Middle Aged; Paclitaxel; Pyrimidines; Sulfonamides

Combination metronomic topotecan plus pazopanib is active against preclinical models of gynecological cancer. Both agents are substrates for ATP-binding cassette family transporters so there is an increased likelihood for pharmacokinetic (PK) drug-drug interactions.. PK analyses of topotecan were performed during three cycles of a phase I dose-escalation study of metronomic topotecan and pazopanib in consenting adult patients with gynecological cancer. Concentration time data were analyzed using a population PK approach.. Twenty-one patients were evaluable for serial PK studies. Considerable inter- and intra-patient variability was observed in the PK parameters, attributable primarily to highly variable oral bioavailability. No difference in topotecan disposition was detected between administration cycles, nor between the off- versus on-pazopanib studies.. The lack of a statistically significant drug-drug interaction agrees with preclinical findings suggesting that pazopanib does not influence the PK of metronomic topotecan. No adjustment of low dose metronomic topotecan dosing is merited when used in conjunction with pazopanib.

Topics: Administration, Oral; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Chromatography, High Pressure Liquid; Female; Genital Neoplasms, Female; Humans; Indazoles; Middle Aged; Pyrimidines; Sulfonamides; Topotecan