pazopanib and Nausea

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

Temsirolimus has long been the only approved first-line standard of care (SOC) with overall survival (OS) benefit in poor-risk patients with advanced or metastatic renal cell cancer (mRCC). However, tyrosine kinase inhibitors are also commonly used in clinical practice. Pazopanib is an SOC for first-line mRCC treatment, but for poor-risk patients data are scarce. The FLIPPER (First-Line Pazopanib in Poor-Risk Patients with Metastatic Renal Cell Carcinoma) study aimed to assess efficacy and safety of first-line pazopanib in poor-risk mRCC patients. FLIPPER was a single-arm, multicenter, Phase IV trial. Key inclusion criteria were treatment-naive clear cell, inoperable advanced or mRCC, poor-risk according to MSKCC with slight modification, Karnofsky performance status (KPS) ≥60% and adequate organ function. Oral pazopanib 800 mg was given daily. Primary endpoint was the 6-month progression-free survival rate (PFS6). Secondary endpoints included PFS, OS, overall response rate (ORR), duration of response (DOR) and safety. For analysis, descriptive statistics were used. Between 2012 and 2016, 60 patients had been included. Forty-three patients qualified for safety analyses, 34 for efficacy. Median age was 66 years, 64.7% of patients were poor-risk, 82.4% had a KPS ≤70%. PFS6 was 35.3% (95% CI, 19.7-53.5). Median PFS and OS were 4.5 months (95% CI, 3.6-7.8) and 9.3 months (95% CI, 6.6-22.2), respectively. ORR was 32.4% (95% CI, 17.4-50.5), median DOR 9.7 months (95% CI, 1.8-12.4). The most common treatment-related grade 3/4 adverse event reported in 4.7% of patients was hypertension. No treatment-related death occurred. Since pazopanib is active and well tolerated in poor-risk patients with clear cell mRCC, our results support its use as first-line treatment in this setting.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Diarrhea; Fatigue; Female; Humans; Hypothyroidism; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Nausea; Neoplasm Metastasis; Pyrimidines; Sulfonamides; Treatment Outcome

Evaluation of the safety and efficacy of pazopanib, a multikinase angiogenesis inhibitor, in a single-arm, open-label, extension study (VEG107769/NCT00387764) for placebo-treated patients with advanced renal cell carcinoma (RCC) from a randomized, double-blind, placebo-controlled phase III study (VEG105192/NCT00334282).. Patients received pazopanib 800 mg/day. The primary endpoint was the safety and tolerability of pazopanib treatment. Secondary endpoints included response rate per Response Evaluation Criteria in Solid Tumors, progression-free survival (PFS), and overall survival (OS).. Seventy-nine placebo-treated patients from VEG105192/NCT00334282 who experienced disease progression and one pazopanib-treated patient (an exemption) were enrolled. Forty-one patients (51%) were treatment-naive; 39 (49%) were cytokine-pretreated. Median exposure to pazopanib was 9.7 months. All patients had discontinued pazopanib at the time of analysis. The most common reason for discontinuation was disease progression (61%). The most common adverse events were hypertension (45%), diarrhea (45%), hair color changes (44%), anorexia (30%), and nausea (25%). The response rate was 37.5% [95% confidence interval (CI): 26.9-48.1]; median PFS was 9.2 months (95% CI: 7.3-12.0); median OS was 23.5 months (95% CI: 16.3-28.0).. Efficacy and safety profiles for pazopanib in this extension study of patients with RCC previously treated with placebo were very similar to those observed for pazopanib-treated patients in the pivotal phase III study.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Anorexia; Carcinoma, Renal Cell; Diarrhea; Disease-Free Survival; Female; Hair Color; Humans; Hypertension; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Nausea; Neoplasm Staging; Pyrimidines; Randomized Controlled Trials as Topic; Severity of Illness Index; Sulfonamides; Treatment Outcome

The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors.. Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks.. Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of >or=800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C(24)) >or=15 microg/mL (34 micromol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of >or=6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of >or=800 mg once daily or 300 mg twice daily.. Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.

Topics: Administration, Oral; Adult; Aged; Angiogenesis Inhibitors; Anorexia; Cohort Studies; Diarrhea; Drug Administration Schedule; Fatigue; Female; Humans; Hypertension; Indazoles; Male; Middle Aged; Nausea; Neoplasms; Pyrimidines; Sulfonamides; Vomiting

Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United States. Painkillers and fever antipyretics are the most common cause of DILI. Hepatic injury can be provoked by DILI as hepatocellular or cholestatic type.. A 48-year-old woman presented jaundice accompanied by nausea and vomiting. The patient was an inactive hepatitis B carrier with low viral titer and was diagnosed renal cell carcinoma (RCC) with hepatic metastasis requiring pazopanib treatment. Prior to administration of pazopanib, tenofovir administration was started to prevent exacerbation of hepatitis B. The patient was referred to clinic of gastroenterology department due to sudden elevation of bilirubin after 5 weeks of pazopanib treatment.. Abdominal ultrasound and computed tomography showed non-specific finding other than metastatic nodule in the liver and liver cirrhosis. After then, the patient was performed liver biopsy, and the biopsy result was acute cholestatic hepatitis with centrilobular area necrosis and portal inflammation. Therefore, considering the clinical history and biopsy results, the patient was diagnosed as DILI due to pazopanib.. After the biopsy, empirical steroid therapy was initiated and after 7 weeks of pazopanib discontinuation.. The total bilirubin level returned to normal from peak level of 24.61 to 1.52 mg/dL.. In patients with renal cell carcinoma, pazopanib treatment requires clinical caution as it causes rare complications such as severe jaundice and acute cholestatic hepatitis.

Topics: Bilirubin; Biopsy; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Female; Hepatitis B; Humans; Indazoles; Jaundice; Kidney Neoplasms; Middle Aged; Nausea; Pyrimidines; Steroids; Sulfonamides; Tomography, X-Ray Computed; Ultrasonography; United States; Vomiting