Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results.

1998 ◽  
Vol 16 (6) ◽  
pp. 2202-2212 ◽  
Author(s):  
D D Bigner ◽  
M T Brown ◽  
A H Friedman ◽  
R E Coleman ◽  
G Akabani ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Phase I ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
Metastatic Brain Tumors ◽  
Tumor Patients ◽  
Iodine 131 ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.

Phase I Trial Results of Iodine-131–Labeled Antitenascin Monoclonal Antibody 81C6 Treatment of Patients With Newly Diagnosed Malignant Gliomas

2000 ◽  
Vol 18 (22) ◽  
pp. 3862-3872 ◽  
Author(s):  
Ilkcan Cokgor ◽  
Gamal Akabani ◽  
Chien-Tsun Kuan ◽  
Henry S. Friedman ◽  
Allan H. Friedman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Phase I Trial ◽  
Radiation Necrosis ◽  
Malignant Gliomas ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Iodine 131 ◽  
Dose Limiting Toxicity

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine-131 (131I)–labeled 81C6 antitenascin monoclonal antibody (mAb) administered clinically into surgically created resection cavities (SCRCs) in malignant glioma patients and to identify any objective responses with this treatment. PATIENTS AND METHODS: In this phase I trial, newly diagnosed patients with malignant gliomas with no prior external-beam therapy or chemotherapy were treated with a single injection of 131I-labeled 81C6 through a Rickham reservoir into the resection cavity. The initial dose was 20 mCi and escalation was in 20-mCi increments. Patients were observed for toxicity and response until death or for a minimum of 1 year after treatment. RESULTS: We treated 42 patients with 131I-labeled 81C6 mAb in administered doses up to 180 mCi. Dose-limiting toxicity was observed at doses greater than 120 mCi and consisted of delayed neurotoxicity. None of the patients developed major hematologic toxicity. Median survival for patients with glioblastoma multiforme and for all patients was 69 and 79 weeks, respectively. CONCLUSION: The MTD for administration of 131I-labeled 81C6 into the SCRC of newly diagnosed patients with no prior radiation therapy or chemotherapy was 120 mCi. Dose-limiting toxicity was delayed neurologic toxicity. We are encouraged by the survival and toxicity and by the low 2.5% prevalence of debulking surgery for symptomatic radiation necrosis.

High-dose therapy with iodine-131-labeled monoclonal antibody CC49 in patients with gastrointestinal cancers: a phase I trial.

1997 ◽  
Vol 15 (4) ◽  
pp. 1518-1528 ◽  
Author(s):  
M Tempero ◽  
P Leichner ◽  
G Dalrymple ◽  
K Harrison ◽  
S Augustine ◽  
...  
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Radiation Dose ◽  
Phase I ◽  
Hematopoietic Stem Cells ◽  
Phase I Trial ◽  
Gastrointestinal Cancers ◽  
Hematopoietic Stem ◽  
Iodine 131 ◽  
Absorbed Radiation Dose

PURPOSE A phase I trial that evaluated for extrahematopoietic toxicity was conducted with iodine-131 (131I) labeled monoclonal antibody (MAb) CC49. Correlative studies included pharmacokinetic and biodistribution analyses, estimates of absorbed radiation dose, and measurement of human antimonoclonal antibodies (HAMA). PATIENTS AND METHODS After collection and cryopreservation of hematopoietic stem cells, 15 patients with gastrointestinal cancers were administered a tracer dose of 131I-MAb CC49. Within 5 to 6 days, 14 patients (two to three per activity level) underwent a single treatment with 131I-MAb CC49 (50, 100, 150, 200, 250, and 300 mCi/m2). Biodistribution was determined using planar and single photon emission computer tomographic (SPECT) imaging. Pharmacokinetic studies were performed by measuring radioactivity in serial blood samples. In some patients, biopsies of metastases and related normal tissues were obtained for radioactivity measurements. Radiation dosimetry estimates were calculated using available biodistribution, pharmacokinetic, and tissue biopsy data. Toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. RESULTS No dose-limiting extrahematopoietic toxicity was identified. Twelve patients experienced grade IV myelosuppression and met criteria for infusion of hematopoietic stem cells. Radioimmunolocalization was excellent. The T1/2 for 131I-MAb CC49 after diagnostic and therapeutic administration was 39.7 +/- 10.4 and 46.1 +/- 10.6 hours, respectively. The percent injected dose per killigram of tumor ranged from 0.2 to 2.1. Absorbed radiation dose in metastatic tumor sites ranged from 630 to 3300 cGy. CONCLUSION Although extrahematopoietic dose-limiting toxicity was neither observed or predicted, suboptimal absorbed dose estimates suggested that further escalation of 131I-MAb CC49 would not be useful. Future studies should focus on the use of radionuclides with high energy beta emissions, such as yttrium 90, and on strategies to optimize access of antibody to target antigens.

Immunohistochemical Study of Erythropoietin in Cerebellar Hemangioblastomas Associated with Secondary Polycythemia

Neurosurgery ◽  
1991 ◽  
Vol 28 (1) ◽  
pp. 24-26 ◽  
Author(s):  
Osamu Tachibana ◽  
Tetsumori Yamashima ◽  
Junkoh Yamashita
Keyword(s):  
Monoclonal Antibody ◽  
Brain Tumor ◽  
Mast Cells ◽  
Brain Tumors ◽  
Stromal Cells ◽  
Immunohistochemical Study ◽  
Metastatic Brain Tumors ◽  
Secondary Polycythemia

Abstract Although cerebellar hemangioblastomas are known to be associated with secondary polycythemia, the cellular derivation of erythropoietin (EPO) in hemangioblastomas still remains obscure. Specimens from 18 patients with cerebellar hemangioblastomas were immunohistochemically studied using anti-EPO monoclonal antibody. Eight cases of brain tumors, including 2 meningiomas, 2 medulloblastomas, 2 glioblastomas, and 2 metastatic brain tumors were studied as controls. In 9 of 18 cases, EPO-positive cells were scattered around the capillaries and were ultrastructurally shown to be mast cells. These cases were not, however, associated with secondary polycythemia. In contrast, the stromal cells were positive for EPO in 3 cases. Among them, one was associated with secondary polycythemia. Furthermore, one-half of the control cases of brain tumor contained EPO-positive mast cells. Accordingly, it was suggested that mast cells (or small granulocytes) have little relationship to the release of EPO; however, some stromal cells might release EPO with a resultant polycythemia.

Phase I trial of iodine 131-labeled COL-1 in patients with gastrointestinal malignancies: influence of serum carcinoembryonic antigen and tumor bulk on pharmacokinetics.

1996 ◽  
Vol 14 (6) ◽  
pp. 1798-1809 ◽  
Author(s):  
B Yu ◽  
J Carrasquillo ◽  
D Milenic ◽  
Y Chung ◽  
P Perentesis ◽  
...  
Keyword(s):  
Phase I ◽  
Carcinoembryonic Antigen ◽  
Phase I Trial ◽  
Nuclear Imaging ◽  
Hematologic Toxicity ◽  
Baseline Serum ◽  
Gastrointestinal Malignancies ◽  
Serum Carcinoembryonic Antigen ◽  
Serum Cea ◽  
Iodine 131

PURPOSE COL-1 is a high-affinity murine monoclonal antibody (MAb) specific for carcinoembryonic antigen (CEA). A phase I trial was conducted in which a uniform quantity of antibody labeled with escalating doses of iodine 131 (131I) was administered to patients with advanced gastrointestinal (GI) malignancies to evaluate tolerance and pharmacokinetics. PATIENTS AND METHODS Eighteen patients with advanced, assessable GI malignancies (16 colon, one pancreas, and one gastric) previously treated with conventional chemotherapy (but no pelvic radiation) received 20 mg of COL-1 labeled with 131I, with doses from 10 mCi/m2 to 75 mCi/m2. In this cohort, the baseline serum CEA level ranged from 6 to 2,739 ng/mL (mean +/- SD, 500 +/- 639). RESULTS Nuclear imaging detected at least one tumor site in all 18 patients; 82% of all tumor involved organs were positive and 58% of all lesions > or = 1.0 cm were detected. Immune complexes were detected in 89% of patients 5 minutes after completion of infusion, and levels correlated with CEA levels (r = .71). Elevated CEA (> 500 ng/mL) and tumor bulk (total tumor area > 150 cm2) correlated directly with clearance of serum radioactivity and inversely with serum half-life and cumulative serum radioactivity parameters. Nonhematologic toxicity was mild and non-dose-limiting. Hematologic toxicity, particularly thrombocytopenia, was both dose-related and dose-limiting. The maximal-tolerated dose is 65 mCi/m2. The correlation between dose (millicuries per square meter) and thrombocytopenia was made stronger, by accounting for either variation in pharmacokinetics, or variation in serum CEA and tumor bulk. CONCLUSION 131I-COL-1 is well tolerated, except for hematologic toxicity. These data suggest that patients with highly elevated circulating CEA levels and/or increased tumor bulk may clear 131I-labeled COL-1 more rapidly from the circulation and experience less myelosuppression.

scholarly journals Phase I Trial of Single-Dose Temozolomide and Continuous Administration of O6-Benzylguanine in Children with Brain Tumors: a Pediatric Brain Tumor Consortium Report

2007 ◽  
Vol 13 (22) ◽  
pp. 6712-6718 ◽  
Author(s):  
Alberto Broniscer ◽  
Sridharan Gururangan ◽  
Tobey J. MacDonald ◽  
Stewart Goldman ◽  
Roger J. Packer ◽  
...  
Keyword(s):  
Single Dose ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Phase I ◽  
Phase I Trial ◽  
Pediatric Brain Tumor ◽  
Continuous Administration ◽  
Pediatric Brain

scholarly journals Phase I Trial of VNP40101M (Cloretazine) in Children with Recurrent Brain Tumors: A Pediatric Brain Tumor Consortium Study

2008 ◽  
Vol 14 (4) ◽  
pp. 1124-1130 ◽  
Author(s):  
Sridharan Gururangan ◽  
Christopher D. Turner ◽  
Clinton F. Stewart ◽  
Melinda O'Shaughnessy ◽  
Mehmet Kocak ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Phase I ◽  
Phase I Trial ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain

scholarly journals Genetic variants and cognitive functions in patients with brain tumors

2019 ◽  
Vol 21 (10) ◽  
pp. 1297-1309 ◽  
Author(s):  
Denise D Correa ◽  
Jaya Satagopan ◽  
Axel Martin ◽  
Erica Braun ◽  
Maria Kryza-Lacombe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Dna Repair ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Cell Cycle Regulation ◽  
Cognitive Outcome ◽  
Cholesterol Transport ◽  
Tumor Patients ◽  
Cycle Regulation

AbstractBackgroundPatients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer’s disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this population.MethodsOne hundred and fifty brain tumor patients treated with RT ± CT or CT alone completed a neurocognitive assessment and provided a blood sample for genotyping. We genotyped genes/SNPs in these pathways: (i) LOAD risk/inflammation/cholesterol transport, (ii) dopamine regulation, (iii) myelin regulation, (iv) DNA repair, (v) blood–brain barrier disruption, (vi) cell cycle regulation, and (vii) response to oxidative stress. White matter (WM) abnormalities were rated on brain MRIs.ResultsMultivariable linear regression analysis with Bayesian shrinkage estimation of SNP effects, adjusting for relevant demographic, disease, and treatment variables, indicated strong associations (posterior association summary [PAS] ≥ 0.95) among tests of attention, executive functions, and memory and 33 SNPs in genes involved in: LOAD/inflammation/cholesterol transport (eg, PDE7A, IL-6), dopamine regulation (eg, DRD1, COMT), myelin repair (eg, TCF4), DNA repair (eg, RAD51), cell cycle regulation (eg, SESN1), and response to oxidative stress (eg, GSTP1). The SNPs were not significantly associated with WM abnormalities.ConclusionThis novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors.

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

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