piperidines and Central-Nervous-System-Neoplasms

The standard regimen for the treatment of newly diagnosed primary CNS lymphoma (PCNSL) remains regimens that contain high-dose methotrexate (MTX). While these regimens can provide control for some patients, there is a dearth of options for the treatment of patients with PCNSL who cannot tolerate MTX-containing regimens, or whose cancers are refractory to MTX. In this article, we review a promising new option; ibrutinib, a Bruton tyrosine kinase inhibitor, for patients with relapsed and refractory PCNSL.

Topics: Adenine; Central Nervous System Neoplasms; Humans; Lymphoma, Large B-Cell, Diffuse; Piperidines; Prognosis

Novel insights into the pathophysiology of primary central nervous system lymphoma (PCNSL) have identified the B-cell receptor and Toll-like receptor pathway as well as immune evasion and suppressed tumor immune microenvironment as a key mechanism in the pathogenesis of PCNSL. Small molecules and novel agents targeting these aberrant pathways have been introduced into clinical trials targeting the recurrent or refractory PCNSL patient population. Agents like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs (IMiDs) like pomalidomide and lenalidomide have shown promising high response rates in the salvage setting. Here, we give an overview about the recent, exciting developments in PCNSL and summarize the results of clinical trials using novel agents in the recurrent and refractory salvage setting, which include immune checkpoint inhibitors, IMiDs, as well as BTK, phosphatidylinositol-3 kinase, and mammalian target of rapamycin inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aminopyridines; Antineoplastic Agents, Immunological; Burkitt Lymphoma; Central Nervous System Neoplasms; Humans; Immunologic Factors; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rituximab; Salvage Therapy; Thalidomide; Toll-Like Receptors; TOR Serine-Threonine Kinases; Tumor Escape

Primary central nervous system lymphoma (PCNSL) is a rare aggressive extranodal non- Hodgkin lymphoma. Although high remission rates can be achieved with high-dose methotrexate-based immunochemotherapy, risk of relapse and associated death is still substantial in at least a third of patients. Novel agents for treating lymphoid malignancies have substantially enriched treatment options for PCNSL. We herein systematically review the existing clinical evidence of novel agents in treatment of PCNSL, summarize ongoing studies, and discuss perspectives. The body of evidence for novel agents is still limited to noncomparative studies, but the most promising approaches include Bruton kinase inhibition with ibrutinib and immunomodulatory treatment (eg, with lenalidomide). Targeting the mammalian target of rapamycin pathway does not seem to have a meaningful clinical benefit, and evidence of checkpoint inhibition with nivolumab is limited to anecdotal evidence. Future studies should embrace the concept of induction and maintenance therapy as well as the combination of drugs with different mechanisms of action. Selection of patients based on molecular profiling and relapse patterns should be another aspect informing future comparative trials, which are urgently needed to improve prognosis for patients with PCNSL.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Humans; Lenalidomide; Lymphoma, Non-Hodgkin; Nivolumab; Piperidines; Pyrazoles; Pyrimidines; Recurrence

Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases.. TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAF. Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAF. Adding atezolizumab to vemurafenib plus cobimetinib provided promising intracranial activity in patients with BRAF. F Hoffmann-La Roche.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Central Nervous System Neoplasms; Humans; Melanoma; Mutation; Neoplasms, Second Primary; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Central Nervous System Neoplasms; Disease-Free Survival; Female; Follow-Up Studies; Humans; Lymphoma; Male; Middle Aged; Piperidines; Survival Rate

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Circulating Tumor DNA; Female; Humans; Lymphoma; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rituximab; Treatment Outcome; Young Adult

Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal centre B-cell subtype, with unmet medical needs. This study aimed to evaluate the efficacy and toxicity of ibrutinib in DLBCL-PCNSL PATIENTS AND METHODS: This prospective, multicentre, phase II study involved patients with relapse or refractory(R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma. The treatment consisted of ibrutinib (560 mg/day) until disease progression or unacceptable toxicity occurred. The primary outcome was the disease control (DC) rate after two months of treatment (P0 < 10%; P1 > 30%).. Fifty-two patients were recruited. Forty-four patients were evaluable for response. After 2 months of treatment, the DC was 70% in evaluable patients and 62% in the intent-to-treat analysis, including 10 complete responses (19%), 17 partial responses (33%) and 5 stable diseases (10%). With a median follow-up of 25.7 months (range, 0.7-30.5), the median progression-free and overall survivals were 4.8 months (95% confidence interval [CI]; 2.8-12.7) and 19.2 months (95% CI; 7.2-NR), respectively. Thirteen patients received ibrutinib for more than 12 months. Two patients experienced pulmonary aspergillosis with a favourable (n = 1) or fatal outcome (n = 1). Ibrutinib was detectable in the cerebrospinal fluid (CSF). The clinical response to ibrutinib seemed independent of the gene mutations in the BCR pathway.. Ibrutinib showed clinical activity in the brain, the CSF and the intraocular compartment and was tolerated in R/R PCNSL. The addition of ibrutinib to standard methotrexate-base induction chemotherapy will be further evaluated in the first-line treatment.. NCT02542514.

Topics: Adenine; Aged; Aged, 80 and over; Central Nervous System Neoplasms; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Lymphoma; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Prognosis; Prospective Studies; Pyrazoles; Pyrimidines; Retinal Neoplasms; Salvage Therapy; Survival Rate

We evaluated the cumulative incidence rate (CIR) of central nervous system (CNS) and non-CNS progression in alectinib-treated patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) to determine the extent to which alectinib may treat or control CNS disease.. Patients with crizotinib-pretreated locally advanced or metastatic disease received alectinib 600 mg orally twice daily in two phase II trials. All patients underwent baseline imaging and regular centrally reviewed scans.. At 24 months, the CIR for CNS progression was lower in patients without vs with baseline CNS metastases (8.0 vs 43.9%). Patients with baseline CNS disease and prior radiotherapy had a higher CIR of CNS progression than radiotherapy-naive patients (50.5 vs 27.4%) and a lower CIR of non-CNS progression (25.8 vs 42.5%). Adverse events leading to withdrawal occurred in 5.9% and 6.7% of patients with and without baseline CNS metastases, respectively.. This analysis indicates a potential role for alectinib in controlling and preventing CNS metastases.

Topics: Administration, Oral; Adult; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Disease Progression; Female; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Treatment Outcome; Young Adult

This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib.. ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS).. Altogether, 107 patients were randomized (alectinib, n = 72; chemotherapy, n = 35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months [95% confidence interval (CI): 6.9-12.2] with alectinib and 1.4 months (95% CI: 1.3-1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08-0.29); P < 0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17-0.59); median PFS was 7.1 months (95% CI: 6.3-10.8) with alectinib and 1.6 months (95% CI: 1.3-4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n = 24; chemotherapy, n = 16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P < 0.001). Grade ≥3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 weeks versus 6.0 weeks).. Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile.. ClinicalTrials.gov NCT02604342; Roche study MO29750.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Pemetrexed; Piperidines; Prognosis; Salvage Therapy; Survival Rate

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease.. In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival.. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib).. As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).

Topics: Adult; Aged, 80 and over; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Disease-Free Survival; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Young Adult

Findings from the global phase III ALEX trial unequivocally show that alectinib is superior to crizotinib as first-line therapy for ALK+ non-small cell lung cancer. Alectinib more than doubled progression-free survival, significantly reduced the incidence of brain and CNS metastases, and should be considered the new standard of care.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Central nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria.. Both studies enrolled patients aged ≥18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee.. Baseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2-77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7-68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate).. Alectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used.

Topics: Adult; Aged; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Young Adult

Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC.. Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC).. Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2.. Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.

Topics: Administration, Oral; Adult; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC.

Topics: Adult; Aged; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Endpoint Determination; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Treatment Outcome

A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured.. Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment.. Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer.. Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.

Topics: Administration, Oral; Adolescent; Adult; Central Nervous System Neoplasms; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Farnesyltranstransferase; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Maximum Tolerated Dose; Neoplasm Invasiveness; Neoplasm Staging; Piperidines; Pyridines; Risk Assessment; Survival Analysis; Treatment Outcome

Topics: Adenine; Central Nervous System; Central Nervous System Neoplasms; Humans; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Mediastinal Neoplasms; Piperidines; Salvage Therapy

Topics: Adenine; Adult; Central Nervous System Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Transplantation, Homologous; Treatment Outcome; Young Adult

Topics: Adenine; Aged; Blood Cell Count; Central Nervous System Neoplasms; Cerebrospinal Fluid; Diagnosis, Differential; Eye Diseases; Eye Pain; Humans; Magnetic Resonance Imaging; Male; Optic Disk; Optic Nerve; Pain; Piperidines; Tomography, X-Ray Computed; Vision Disorders; Waldenstrom Macroglobulinemia

Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking.. Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy.. Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib.. Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Topics: Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Taiwan

Most patients treated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors for ALK-positive non-small cell lung cancer (NSCLC) develop resistance, leading to metastasis, with progression to the central nervous system (CNS) being a primary concern. Although alectinib has better CNS penetration than crizotinib, patients treated with alectinib also develop CNS progression. CNS metastases more likely occurs during crizotinib treatment due to less blood-brain barrier (BBB) penetration capability than alectinib. CNS progression pattern may be different during crizotinib and alecitinib treatment. Understanding the characteristics of CNS progression is important for developing treatment strategies.. We compared the clinical-radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK-positive NSCLCs.. We retrospectively analyzed the radiographic and clinical characteristics of CNS progression in ALK-positive NSCLC patients treated with crizotinib or alectinib at our hospital between July 2011 and May 2020. CNS and systemic tumor progression were evaluated using computed tomography or magnetic resonance imaging. Fifty-three and 65 patients were treated with crizotinib and alectinib, respectively. Baseline CNS metastasis was observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the patients in the crizotinib and alectinib groups who developed disease progression, 15/49 (30.6%) and 9/44 (20.5%) had CNS progression, respectively (P = .344). Intra-CNS progression-free survival was significantly longer in the alectinib group than in the crizotinib group (median: 14.0 vs 5.6 months, P = .042). The number of CNS metastases sized ≥3 cm, rate of peritumoral brain edema, and the second progression pattern after treatment continuation was not significantly different between the groups.. We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Prognosis; Retrospective Studies; Survival Rate; Young Adult

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Piperidines; Prognosis; Retrospective Studies; Survival Analysis; Temozolomide

Topics: Adenine; Administration, Oral; Central Nervous System Neoplasms; Female; Humans; Hypersensitivity, Immediate; Middle Aged; Piperidines

Topics: Adenine; Aged; Brain Diseases; Central Nervous System Neoplasms; Female; Humans; Immunotherapy; Piperidines; Syndrome

Topics: Adenine; Central Nervous System Neoplasms; Humans; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Aged, 80 and over; Central Nervous System Neoplasms; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Retrospective Studies

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Temozolomide

Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL.. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry.. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages.. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Central Nervous System Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Exportin 1 Protein; Female; Humans; Hydrazines; Karyopherins; Lymphoma, Non-Hodgkin; Macrophages; Mice; Mice, Nude; Piperidines; Receptors, Cytoplasmic and Nuclear; Survival Rate; Triazoles; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Disease Progression; Female; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Off-Label Use; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Retrospective Studies; Time Factors

Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon. Here we present the case of a 70-year-old male patient who was diagnosed with classic MCL in 2015. The patient achieved complete remission (CR) in 2017 but relapsed with CNS involvement in 2019. He entered a deep coma and was treated with ibrutinib (560 mg daily) via nasogastric tube. He regained full consciousness after 15 days, and the presence of lymphoma cells in his cerebrospinal fluid disappeared 3 months later. We believe that ibrutinib administration via nasogastric tube is effective for MCL patients with CNS relapse.

Topics: Adenine; Aged; Central Nervous System; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Recurrence, Local; Piperidines

Topics: Adenine; Antineoplastic Agents; Central Nervous System Neoplasms; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

Chronic lymphocytic leukemia (CLL) is a disorder of B cells that affects humoral as well as cell-mediated immunity. Protection against cryptococcal infections is mounted by an intricate and synchronized interplay of both integral arms of immunity. Whether CLL or small molecule tyrosine kinase inhibitors are independently predisposing hosts to cryptococcal infections remain to be explored. Herein, we present a report of a patient who developed disseminated cryptococcosis while receiving ibrutinib therapy for CLL in the salvage setting. We further present relevant literature available thus far on the topic and discuss immunologic mechanisms that may be involved in the fungal pathogenesis in such patients.

Topics: Adenine; Aged, 80 and over; Central Nervous System Neoplasms; Cryptococcosis; Humans; Male; Piperidines; Pyrazoles; Pyrimidines

Primary CNS lymphomas (PCNSL) are rare and poor prognosis diffuse large B-cell lymphomas. Because of the brain tumor environment and the restricted distribution of drugs in the CNS, specific PCNSL patient-derived orthotopic xenograft (PDOX) models are needed for preclinical research to improve the prognosis of PCNSL patients. PCNSL patient specimens (n = 6) were grafted in the caudate nucleus of immunodeficient nude mice with a 83% rate of success, while subcutaneous implantation in nude mice of human PCNSL sample did not generate lymphoma, supporting the role of the brain microenvironment in the PCNSL physiopathology. PDOXs showed diffuse infiltration of B-cell lymphoma cells in the brain parenchyma. Each model had a unique mutational signature for genes in the BCR and NF-κB pathways and retained the mutational profile of the primary tumor. The models can be stored as cryopreserved biobank. Human IL-10 levels measured in the plasma of PCNSL-PDOX mice showed to be a reliable tool to monitor the tumor burden. Treatment response could be measured after a short treatment with the targeted therapy ibrutinib. In summary, we established a panel of human PCNSL-PDOX models that capture the histological and molecular characteristics of the disease and that proved suitable for preclinical experiments. Our methods of generation and characterization will enable the generation of additional PDOX-PCNSL models, essential tools for cognitive and preclinical drug discovery.

Topics: Adenine; Animals; Caudate Nucleus; Central Nervous System Neoplasms; Disease Models, Animal; Heterografts; Humans; Interleukin-10; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Nude; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Tumor Burden

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Central Nervous System Neoplasms; Gene Rearrangement; Humans; Lymphoma, Large-Cell, Anaplastic; Male; Neoplasm Proteins; Piperidines; Recurrence

Monotherapy clinical trials with mutation-targeted kinase inhibitors, despite some success in other cancers, have yet to impact glioblastoma (GBM). Besides insufficient blood-brain barrier penetration, combinations are key to overcoming obstacles such as intratumoral heterogeneity, adaptive resistance, and the epistatic nature of tumor genomics that cause mutation-targeted therapies to fail. With now hundreds of potential drugs, exploring the combination space clinically and preclinically is daunting. We are building a simulation-based approach that integrates patient-specific data with a mechanistic computational model of pan-cancer driver pathways (receptor tyrosine kinases, RAS/RAF/ERK, PI3K/AKT/mTOR, cell cycle, apoptosis, and DNA damage) to prioritize drug combinations by their simulated effects on tumor cell proliferation and death. Here we illustrate a first step, tailoring the model to 14 GBM patients from The Cancer Genome Atlas defined by an mRNA-seq transcriptome, and then simulating responses to three promiscuous FDA-approved kinase inhibitors (bosutinib, ibrutinib, and cabozantinib) with evidence for blood-brain barrier penetration. The model captures binding of the drug to primary targets and off-targets based on published affinity data and simulates responses of 100 heterogeneous tumor cells within a patient. Single drugs are marginally effective or even counterproductive. Common copy number alterations (PTEN loss, EGFR amplification, and NF1 loss) have a negligible correlation with single-drug or combination efficacy, reinforcing the importance of postgenetic approaches that account for kinase inhibitor promiscuity to match drugs to patients. Drug combinations tend to be either cytostatic or cytotoxic, but seldom both, highlighting the need for considering targeted and nontargeted therapy. Although we focus on GBM, the approach is generally applicable.

Topics: Adenine; Anilides; Aniline Compounds; Antineoplastic Agents; Apoptosis; Blood-Brain Barrier; Cell Cycle; Cell Proliferation; Central Nervous System Neoplasms; Clinical Trials as Topic; Computer Simulation; Drug Discovery; Drug Therapy, Combination; Genomics; Glioblastoma; Humans; Models, Theoretical; Nitriles; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Quinolines; RNA, Messenger; Stochastic Processes; Transcriptome

Topics: Adenine; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retreatment; Salvage Therapy; Treatment Outcome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Central Nervous System; Central Nervous System Neoplasms; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

We determined the central nervous system (CNS) efficacy of alectinib by calculating time to CNS progression and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and death in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) enrolled in the J-ALEX phase III study.. Japanese patients aged ≥20 years with ALK-positive NSCLC who were ALK inhibitor-naïve and chemotherapy-naïve, or who had received one previous chemotherapy regimen, were enrolled. Patients with treated or untreated asymptomatic CNS metastases were eligible. Treatment comprised oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death or withdrawal. Imaging scans (computed tomography/magnetic resonance imaging) were taken at baseline and at regular intervals throughout the study. The CIRs for CNS progression, non-CNS progression and death were calculated for patients with and without baseline CNS metastases using a competing risks method.. The hazard ratio for time to CNS progression in patients with and without baseline CNS metastases was 0.51 (95% confidence interval [CI]: 0.16-1.64; P = 0.2502) and 0.19 (95% CI: 0.07-0.53; P = 0.0004), respectively. The CIRs of CNS progression and non-CNS progression were lower in the alectinib group than in the crizotinib group at all time points. The 1-year CIRs of CNS progression were 16.8% and 5.9% with crizotinib and alectinib, respectively, and the 1-year CIRs of non-CNS progression were 38.4% and 17.5%, respectively. Comparable findings were obtained in patients with or without baseline CNS metastases.. Alectinib appears to avert the progression of CNS metastases in patients with ALK-positive NSCLC and baseline CNS metastases, and to prevent the development of new CNS lesions in patients without baseline CNS disease.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Central Nervous System Neoplasms; Crizotinib; Disease Progression; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Piperidines; Treatment Outcome

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Male; Middle Aged; Multicenter Studies as Topic; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Treatment Outcome; United Kingdom

Topics: Adenine; Antineoplastic Agents; Biomarkers; Blood-Brain Barrier; Central Nervous System Neoplasms; Humans; Immunophenotyping; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Follow-Up Studies; Humans; International Cooperation; Lymphoma; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies

In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Brain; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Retrospective Studies

The risk of central nervous system (CNS) dissemination in mantle cell lymphoma (MCL) is low and occurs late in the course of the disease. However, prognosis in such cases remains extremely poor despite high-dose antimetabolite chemotherapy. Among novel drugs used to treat relapsing MCL patients, ibrutinib, an oral inhibitor of Bruton tyrosine kinase, shows great promise. Here we report the clinical observation of 3 MCL patients with symptomatic CNS relapse treated with single-agent ibrutinib. All 3 patients had dramatic and rapid responses with almost immediate recovery from symptoms. We also confirmed that ibrutinib crosses the blood-brain barrier with parallel pharmacokinetic analyses in plasma and cerebrospinal fluid using a validated LC-MS/MS method. All responses were ongoing after 2 months to 1 year of follow-up.

Topics: Adenine; Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Recurrence

The importance of aberrant EGFR signaling in glioblastoma progression and the promise of EGFR-specific therapies, prompted us to determine the efficacy of novel EGFR inhibitor BIBU-1361 [(3-chloro-4-fluoro-phenyl)-[6-(4-diethylaminomethyl-piperidin-1-yl)-pyrimido [5,4-d]pyrimidin-4-yl]-amine] in affecting glioma survival. BIBU induced apoptosis in a caspase-dependent manner and induced cell cycle arrest in glioma cells. Apoptosis was accompanied by decreased EGFR levels and its increased distribution towards caveolin rich lipid raft microdomains. BIBU inhibited pro-survival pathways Akt/mTOR and gp130/JAK/STAT3; and decreased levels of pro-inflammatory cytokine IL-6. BIBU caused increased LC3-I to LC3-II conversion and triggered the internalization of EGFR within vacuoles along with its increased co-localization with LC3-II. BIBU caused accumulation of p62 and increased levels of cleaved forms of Beclin-1 in all the cell lines tested. Importantly, BIBU failed to initiate execution of autophagy as pharmacological inhibition of autophagy with 3-Methyladenine or Bafilomycin failed to rescue BIBU mediated death. The ability of BIBU to abrogate Akt and STAT3 activation, induce apoptosis and prevent execution of autophagy warrants its investigation as a potent anti-glioma target.

Topics: Adenine; Apoptosis; Autophagy; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Central Nervous System Neoplasms; ErbB Receptors; Glioma; Humans; Interleukin-6; Membrane Microdomains; Microtubule-Associated Proteins; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; STAT3 Transcription Factor; TOR Serine-Threonine Kinases

Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies.. ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types.. In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control.. In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Central Nervous System Neoplasms; Dose-Response Relationship, Drug; Ependymoma; ErbB Receptors; Glioma; Humans; Immunohistochemistry; Ki-67 Antigen; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neovascularization, Pathologic; Phosphorylation; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Xenograft Model Antitumor Assays