pazopanib and Brain-Neoplasms

Topics: Anilides; Brain Neoplasms; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Magnetic Resonance Imaging; Middle Aged; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

Hemangioblastoma is a rare benign neoplasm, accounting for less than 2% of all primitive brain tumors. It may arise sporadically in a solitary form, or associated with Von Hippel-Lindau (VHL) disease with multiple tumors. Surgery is the mainstay treatment, but management is challenging in case of recurrent and/or multiple tumors. VHL protein is defective in both forms of hemangioblastoma, leading to the accumulation of hypoxia-inducible factor, stimulating angiogenesis via VEGF and PDGF mainly. Here, we report a 37-year-old woman's case with recurrent and rapidly progressive VHL-associated hemangioblastomas, causing severe disability. She was treated 24 months with pazopanib, a multityrosine kinase inhibitor (TKI) targeting VEGF and PDGF-β pathways. Despite moderate radiological changes, progressive improvement in her clinical condition persisting over 3 years was observed. Inhibiting angiogenesis is a therapeutic option that may improve the quality of life and the autonomy of VHL patients disabled with multiple hemangioblastomas.

Topics: Adult; Angiogenesis Inhibitors; Brain Neoplasms; Cervical Vertebrae; Female; Follow-Up Studies; Hemangioblastoma; Humans; Indazoles; Magnetic Resonance Imaging; Neoplasm Recurrence, Local; Pyrimidines; Sulfonamides; von Hippel-Lindau Disease

Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib.. A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs.. The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib.. The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma.

Topics: Adult; Angiogenesis Inhibitors; Anticonvulsants; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Disease-Free Survival; Drug Delivery Systems; ErbB Receptors; Glioma; Humans; Indazoles; Lapatinib; Neoplasm Recurrence, Local; Neoplasm Staging; Pyrimidines; Quinazolines; Recurrence; Sulfonamides

The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-alpha and -beta, and c-Kit, in recurrent glioblastoma. Patients with < or =2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions. Brain magnetic resonance imaging and clinical reassessment were made every 8 weeks. The primary endpoint was efficacy as measured by 6-month progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose reduction. Two patients had a partial radiographic response by standard bidimensional measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% reduction in tumor. The median PFS was 12 weeks (95% confidence interval [CI]: 8-14 weeks) and only 1 patient had a PFS time > or =6 months (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 weeks (95% CI: 24-47 weeks). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses. ClinicalTrials.gov identifier: NCT00459381.

Topics: Administration, Oral; Adult; Aged; Angiogenesis Inhibitors; Brain Neoplasms; Disease Progression; Female; Glioblastoma; Humans; Indazoles; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Pyrimidines; Sulfonamides; Treatment Outcome

To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme.. Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.. A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged ≥75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received ≥2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7-6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus.. The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Immunological; Bone Neoplasms; Brain Neoplasms; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Progression-Free Survival; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Retreatment; Sulfonamides; Sunitinib; Survival Rate

Pulmonary carcinosarcoma (PCS) is a rare primary lung malignancy and has a poor prognosis among lung tumor histological subtypes. However, an appropriate treatment strategy has not been developed for unresectable PCS.. A 65-year-old man who was diagnosed with PCS was treated by surgical removal of the primary lung lesion, followed by six cycles of adjuvant chemotherapy with cisplatin plus irinotecan. Following the chemotherapy, he experienced a relapse with brain metastasis, which induced the rapid onset of left leg paralysis. Radical surgical resection and stereotactic radiosurgery to the resection cavity were performed. However, meningeal dissemination and new lung metastases occurred after a year and half. To control these multiple metastatic lesions, the patient was treated with the multiple kinase inhibitor pazopanib. No change was observed in the meningeal dissemination, while the metastatic lung lesions were prominently reduced in size following treatment with pazopanib. Consequently, the patient showed a partial response to pazopanib treatment, although the dose of pazopanib was reduced by half as a result of thrombocytopenia.. This is the first report of metastatic PCS showing an evident therapeutic response to tumor-targeted therapy. We suggest that pazopanib may be a therapeutic option for patients with metastatic PCS.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Brain Neoplasms; Carcinosarcoma; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Humans; Indazoles; Lung Neoplasms; Male; Meningeal Neoplasms; Neoplasm Staging; Pneumonectomy; Pyrimidines; Radiosurgery; Sulfonamides; Thrombocytopenia; Treatment Outcome

Previous research has identified disparities between urban and rural cancer care, including clinical trial access. Therefore, we addressed three different questions in patients with metastatic renal cell cancer managed according to national guidelines in a rural Norwegian standard practice setting. (1) How many patients would have been eligible for three recent landmark randomized clinical trials? (2) Is survival different between eligible and non-eligible patients receiving first-line systemic therapy? (3) Is survival different between eligible patients and published trial results? We performed a retrospective analysis of 101 consecutive patients (2006-2016). Only 52% of the patients were eligible for the first-line study of pazopanib versus sunitinib. The main reasons for violating inclusion or exclusion criteria were presence of brain metastases, absence of clear cell histology, and poor performance status. Even fewer patients were eligible for trials of nivolumab and cabozantinib in pre-treated patients. Eligible patients had significantly better survival than non-eligible patients, median 29.2 versus 8.5 months (p = 0.0001). These results confirm that many patients from rural practices do not fulfill all mandatory trial eligibility criteria. However, eligible patients managed according to national guidelines had survival outcomes in line with published first-line trial results.

Topics: Aged; Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Pyridines; Pyrimidines; Pyrroles; Retrospective Studies; Rural Population; Sulfonamides; Sunitinib

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Bevacizumab; Brain Edema; Brain Neoplasms; Carcinoma, Renal Cell; Female; Humans; Imidazoles; Indazoles; Lung Neoplasms; Middle Aged; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyrimidines; Radiation Injuries; Sulfonamides

Topics: Aged; Brain; Brain Neoplasms; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides

Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown.. mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3).. Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001).. The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Eligibility Determination; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Karnofsky Performance Status; Kidney Neoplasms; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome

Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β (at tyrosine 751; p751-PDGFRβ) was identified around perivascular brain micrometastases. p751-PDGFRβ(+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, we reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. Here, we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRβ(+) astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain micrometastases in breast cancer patients.

Topics: Animals; Antineoplastic Agents; Astrocytes; Brain Neoplasms; Breast Neoplasms; Drug Evaluation, Preclinical; Female; Humans; Indazoles; Mice; Neoplasm Micrometastasis; Neoplasm Proteins; Neoplasm Transplantation; Neuroglia; Phosphorylation; Pyrimidines; Receptor, Platelet-Derived Growth Factor beta; Sulfonamides; Tumor Cells, Cultured; Tumor Microenvironment

Topics: Aged; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Renal Cell; Disease Progression; Drug Administration Schedule; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Nephrectomy; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Treatment Outcome

Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested pazopanib, a recently approved antiangiogenic drug that targets VEGFR1, VEGFR2, VEGFR3, PDGFRβ, PDGFRα, and c-kit, for prevention of experimental brain metastases and mechanism of action.. In vitro assays included B-Raf enzymatic assays, Western blots, and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or pazopanib beginning on day 3 postinjection. Brain metastases were counted histologically, imaged, and immunostained.. Treatment with 100 mg/kg of pazopanib resulted in a 73% decline in large 231-BR-HER2 metastases (P < 0.0001) and a 39% decline in micrometastases (P = 0.004). In vitro, pazopanib was directly antiproliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that pazopanib directly inhibited the wild type and exon 11 oncogenic mutant, but not the V600E mutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in pazopanib-treated brain metastases whereas blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental brain metastasis model, pazopanib reduced overall brain metastasis volume upon magnetic resonance imaging (MRI) by 55% (P = 0.067), without affecting brain metastasis vascular density.. The data identify a new activity for pazopanib directly on tumor cells as a pan-Raf inhibitor and suggest its potential for prevention of brain metastatic colonization of HER2(+) breast cancer.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Indazoles; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Proto-Oncogene Proteins B-raf; Pyrimidines; Receptor, ErbB-2; Signal Transduction; Sulfonamides; Xenograft Model Antitumor Assays