sirolimus and Central-Nervous-System-Neoplasms

In this phase II study (NCT00942747), temsirolimus was tested in patients with relapsed or refractory primary CNS lymphoma (PCNSL).. Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once per week. All consecutive patients received 75 mg intravenously once per week.. Thirty-seven eligible patients (median age, 70 years) were included whose median time since their last treatment was 3.9 months (range, 0.1 to 14.6 months). Complete response was seen in five patients (13.5%), complete response unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent Common Toxicity Criteria ≥ 3° adverse event was hyperglycemia in 11 (29.7%) patients, thrombocytopenia in eight (21.6%), infection in seven (19%), anemia in four (10.8%), and rash in three (8.1%). Fourteen blood/CSF pairs were collected in nine patients (10 pairs in five patients in the 25-mg cohort and four pairs in four patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient in the 75-mg cohort; in all others, no drug was found in their CSF.. Single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short lived.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Sirolimus

Pre-clinical findings suggest that combination treatment with bevacizumab and temsirolimus could be effective against malignant pediatric central nervous system (CNS) tumors.. Six pediatric patients were treated as part of a phase I trial with intravenous temsirolimus 25 mg on days 1, 8, 15, and bevacizumab at 5, 10, or 15 mg/kg on day 1 of each 21-day cycle until disease progression or patient withdrawal.. The median patient age was six years (range=3-14 years). The primary diagnoses were glioblastoma multiforme (n=2), medullobalstoma (n=2), pontine glioma (n=1) and ependymoma (n=1). All patients had disease refractory to standard-of-care (2-3 prior systemic therapies). Grade 3 toxicities possibly related to drugs used occurred in two patients: anorexia, nausea, and weight loss in one, and thrombocytopenia and alanine aminotransferase elevation in another. One patient with glioblastoma multiforme achieved a partial response (51% regression) and two patients (with medulloblastoma and pontine glioma) had stable disease for four months or more (20 and 47 weeks, respectively). One other patient (with glioblastoma multiforme) showed 18% tumor regression (duration=12 weeks).. The combination of bevacizumab with temsirolimus was well-tolerated and resulted in stable disease of at least four months/partial response in three out of six pediatric patients with chemorefractory CNS tumors.

Topics: Adolescent; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Central Nervous System Neoplasms; Child; Child, Preschool; Humans; Magnetic Resonance Imaging; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Central Nervous System Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Erlotinib Hydrochloride; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Quinazolines; Sirolimus; Treatment Outcome

Tuberous sclerosis complex (TSC) is associated with hamartomatous growths including subependymal giant cell astrocytomas (SEGAs). Since chemo-radiation therapies offer scant benefit, oncologists had traditionally been little involved in managing SEGAs. Recent evidence demonstrating rapamycin efficacy in adults and children with TSC-associated tumors foresee a practice change. We summarize our institutional experience and literature review that highlight potential benefits and hazards of rapamycin therapy, for TSC patients with SEGA, and other syndromal brain tumors.

Topics: Adolescent; Antibiotics, Antineoplastic; Central Nervous System Neoplasms; Child; Female; Humans; Male; Sirolimus; Tuberous Sclerosis

A number of important studies were presented at the CNS tumors section of the 2010 American Society of Oncology (ASCO) Annual Meeting. There was particular interest in a Phase II study showing that the mTOR inhibitor everolimus had significant activity in tuberous patients with subependymal giant cell astrocytomas. Two Phase III studies reported on the relative benefits of radiotherapy and chemotherapy in elderly patients with glioblastomas. Other studies focused on promising new agents such as XL184 and ANG1005.

Topics: Aged; Astrocytoma; Central Nervous System Neoplasms; Clinical Trials as Topic; Everolimus; Glioblastoma; Humans; Immunosuppressive Agents; Sirolimus; Tuberous Sclerosis

Topics: Antineoplastic Agents; Central Nervous System Neoplasms; Combined Modality Therapy; Drug Therapy, Combination; ErbB Receptors; Gefitinib; Glioma; Humans; Indoles; Protein Kinase C; Protein Kinase Inhibitors; Protein Kinases; Quinazolines; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases