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1.
J Immunother Cancer ; 9(8)2021 08.
Article in English | MEDLINE | ID: mdl-34452928

ABSTRACT

Resistance to immune checkpoint inhibitors (ICI) and other anticancer therapies is often associated with the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Therefore, targeting MDSC recruitment or function is of significant interest as a strategy to treat patients with ICI-resistant cancer. The migration and recruitment of MDSCs to the TME is mediated in part by the CD11b/CD18 integrin heterodimer (Mac-1; αMß2), expressed on both MDSCs and TAMs. However, inhibition or blockade of CD11b/CD18 has had limited success in clinical trials to date, likely since saturation of CD11b requires doses that are not clinically tolerable with the agents tested so far. Interestingly, activation of CD11b with leukadherin-1 was found to reduce macrophage and neutrophil migration in animal models of inflammatory conditions. Preclinical studies with GB1275, a salt form of leukadherin-1, demonstrated that activation of CD11b improves the antitumor immune response and enhances the response to immunotherapy in mouse models of pancreatic adenocarcinoma, breast cancer and lung cancer. Based on the promising results from preclinical studies, a phase 1/2 clinical study (NCT04060342) of GB1275 in patients with advanced solid tumor types known to be resistant or less likely responsive to immuno-oncology therapies, including pancreatic, breast, prostate, and microsatellite-stable colorectal cancer, is ongoing. In this review, we examine targeting MDSCs as a therapeutic approach in cancer therapy, with a special focus on GB1275 preclinical studies laying the rationale for the phase 1/2 clinical study.


Subject(s)
Benzoates/pharmacology , CD11b Antigen/agonists , Immunotherapy/methods , Neoplasms/drug therapy , Thiohydantoins/pharmacology , Animals , Benzoates/chemistry , Benzoates/immunology , CD11b Antigen/immunology , Cell Line, Tumor , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Humans , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/pathology , Neoplasms/immunology , Neoplasms/pathology , Thiohydantoins/chemistry , Thiohydantoins/immunology , Tumor Microenvironment
2.
Cancer Med ; 8(11): 5148-5157, 2019 09.
Article in English | MEDLINE | ID: mdl-31347292

ABSTRACT

PURPOSE: Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. PATIENTS AND METHODS: Aphase 2, randomized, placebo-controlled, multicenter trial evaluated the activity of tarextumab in combination with nab-paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19-9 level and randomized 1:1 to nab-paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti-tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression-free survival (PFS), 12-month OS, overall response rate (ORR), and safety and biomarker investigation. RESULTS: Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. CONCLUSIONS: The addition of tarextumab to nab-paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first-line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab-treated patients. CLINICAL TRIAL REGISTRY NO: NCT01647828.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Albumins/administration & dosage , Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease Management , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Molecular Targeted Therapy , Paclitaxel/administration & dosage , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Prognosis , Receptor, Notch2/antagonists & inhibitors , Receptor, Notch3/antagonists & inhibitors , Treatment Outcome , Gemcitabine
3.
Invest New Drugs ; 37(4): 722-730, 2019 08.
Article in English | MEDLINE | ID: mdl-30591982

ABSTRACT

Purpose This Phase I trial evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of tarextumab (OMP-5948), a novel cross-reactive antibody which binds and selectively inhibits signaling via both Notch2 and Notch3, in adult patients with advanced malignancies. Methods Standard 3 + 3 design with tarextumab 0.5, 1, 2.5, or 5 mg/kg weekly, or 5, 7.5, or 10 mg/kg every other week, or 7.5 mg every 3 weeks. Dose-limiting toxicities (DLT) were assessed during the first 28 days. Results Forty-two patients received tarextumab (21 weekly, 15 every other week, 6 every three weeks). 2/6 subjects at the 5 mg/kg weekly dose, 2/3 at 10 mg/kg every other week, and 0/6 at 7.5 mg/kg every three weeks had a DLT. The maximum tolerated dose (MTD) was 2.5 mg/kg weekly, and 7.5 mg/kg on the every other and every three week schedules. Gastrointestinal (GI) toxicity was the most common adverse event with diarrhea (81%), fatigue (48%), nausea (45%), anorexia (38%), and vomiting (38%) and abdominal pain and constipation (24% each). Biomarker analysis showed regulation of stem cell and Notch gene signaling. Conclusion Tarextumab was generally well-tolerated at doses <2.5 mg weekly and 7.5 mg/kg every other and every third week. Diarrhea was dose-limiting above these levels, but relatively easily managed at lower doses. Inhibition of Notch pathway signaling was demonstrated at these doses. ClinicalTrials.gov Identifier: NCT01277146.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Neoplasms/drug therapy , Receptor, Notch2/antagonists & inhibitors , Receptor, Notch3/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Anorexia/chemically induced , Antibodies/blood , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/immunology , Antineoplastic Agents/pharmacokinetics , Diarrhea/chemically induced , Fatigue/chemically induced , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Neoplasms/genetics , Neoplasms/metabolism , Receptor, Notch2/genetics , Receptor, Notch3/genetics , Transcriptome , Vomiting/chemically induced
4.
Clin Cancer Res ; 23(24): 7490-7497, 2017 Dec 15.
Article in English | MEDLINE | ID: mdl-28954784

ABSTRACT

Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors.Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy.Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had ß-C-terminal telopeptide (ß-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months.Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490-7. ©2017 AACR.


Subject(s)
Immunoglobulin Fc Fragments/administration & dosage , Neoplasms/drug therapy , Neoplastic Stem Cells/drug effects , Receptors, G-Protein-Coupled/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Wnt Signaling Pathway/drug effects , Adult , Aged , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/classification , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Immunoglobulin Fc Fragments/adverse effects , Ligands , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/genetics , Neoplasms/pathology , Neoplastic Stem Cells/pathology , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/pharmacokinetics
5.
J Clin Oncol ; 35(3): 352-360, 2017 Jan 20.
Article in English | MEDLINE | ID: mdl-27870570

ABSTRACT

Purpose Adenoid cystic carcinomas (ACCs) represent a heterogeneous group of chemotherapy refractory tumors, with a subset demonstrating an aggressive phenotype. We investigated the molecular underpinnings of this phenotype and assessed the Notch1 pathway as a potential therapeutic target. Methods We genotyped 102 ACCs that had available pathologic and clinical data. Notch1 activation was assessed by immunohistochemistry for Notch1 intracellular domain. Luciferase reporter assays were used to confirm Notch1 target gene expression in vitro. The Notch1 inhibitor brontictuzumab was tested in patient-derived xenografts from patients with ACC and in a patient with ACC who was enrolled in a phase I study. Results NOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative regulatory region and Pro-Glu-Ser-Thr-rich domains, the same two hotspots seen in T-cell acute lymphoblastic leukemias, and led to pathway activation in vitro. NOTCH1-mutant tumors demonstrated significantly higher levels of Notch1 pathway activation than wild-type tumors on the basis of Notch1 intracellular domain staining ( P = .004). NOTCH1 mutations define a distinct aggressive ACC subgroup with a significantly higher likelihood of solid subtype ( P < .001), advanced-stage disease at diagnosis ( P = .02), higher rate of liver and bone metastasis ( P ≤ .02), shorter relapse-free survival (median, 13 v 34 months; P = .01), and shorter overall survival (median 30 v 122 months; P = .001) when compared with NOTCH1 wild-type tumors. Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation. Furthermore, an index patient with NOTCH1-mutant ACC had a partial response to brontictuzumab. Conclusion NOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors. Clinical studies targeting Notch1 in a genotype-defined ACC subgroup are warranted.


Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Bone Neoplasms/genetics , Carcinoma, Adenoid Cystic/genetics , Liver Neoplasms/genetics , Mutation , Receptor, Notch1/genetics , Salivary Gland Neoplasms/genetics , Adult , Aged , Animals , Bone Neoplasms/drug therapy , Bone Neoplasms/mortality , Bone Neoplasms/secondary , Carcinoma, Adenoid Cystic/drug therapy , Carcinoma, Adenoid Cystic/mortality , Carcinoma, Adenoid Cystic/secondary , DNA Mutational Analysis , Disease-Free Survival , Female , Genetic Predisposition to Disease , HEK293 Cells , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Male , Mice, Nude , Middle Aged , Molecular Targeted Therapy , Phenotype , Predictive Value of Tests , Proportional Hazards Models , Receptor, Notch1/antagonists & inhibitors , Receptor, Notch1/metabolism , Retrospective Studies , Risk Factors , Salivary Gland Neoplasms/drug therapy , Salivary Gland Neoplasms/mortality , Salivary Gland Neoplasms/pathology , Time Factors , Transfection , Treatment Outcome , Xenograft Model Antitumor Assays
6.
Clin Cancer Res ; 20(24): 6295-303, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25324140

ABSTRACT

PURPOSE: This phase I trial evaluated the safety, pharmacokinetics, and pharmacodynamics of demcizumab (OMP-21M18), a humanized IgG2 mAb targeting the Notch ligand DLL4 in adult patients with advanced malignancies. EXPERIMENTAL DESIGN: Standard 3+3 design, with demcizumab 0.5, 1, 2.5, or 5 mg/kg weekly or 2.5, 5, or 10 mg/kg every other week, with an expansion cohort at 10 mg/kg every other week. Dose-limiting toxicities (DLT) were assessed during the first 28 days. RESULTS: Fifty-five patients received demcizumab (15 weekly, 18 every other week, 21 expansion cohort, 1 loading dose). No more than one DLT was seen at any dose level. The MTD was not reached for either schedule. Treatment-related adverse events occurring in >10% of patients were hypertension or blood pressure increased (47%), fatigue (31%), anemia (22%), headache (20%), nausea (13%), hypoalbuminemia (11%), dizziness (11%), and dyspnea (11%). One patient dosed at 2.5 mg/kg developed reversible right-sided heart failure after 63 days on treatment and 4 dosed at 10 mg/kg developed congestive heart failure after ≥98 days on treatment. Five patients were hospitalized with bleeding episodes (2 episodes of tumor-associated bleeding). Sixteen of 25 (64%) evaluable patients at 10 mg/kg had evidence of stabilization of disease or response. CONCLUSION: Demcizumab was generally well tolerated at doses ≤5 mg weekly with disease stabilization and decreases in tumor size demonstrating antitumor activity. Hypertension was the most common adverse event that was clearly related to treatment. Prolonged administration was associated with an increased risk of congestive heart failure.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplastic Stem Cells/drug effects , Adult , Aged , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents/pharmacology , Biomarkers/blood , Drug Monitoring , Female , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Male , Membrane Proteins/antagonists & inhibitors , Middle Aged , Neoplasm Staging , Neoplasms/blood , Neoplasms/diagnosis , Neoplastic Stem Cells/metabolism , Retreatment , Treatment Outcome , Tumor Burden/drug effects
7.
Invest New Drugs ; 30(5): 1958-61, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22002018

ABSTRACT

Targeting angiogenesis is a valid anti-cancer strategy. Aflibercept is designed to sequester circulating vascular endothelial growth factor (VEGF) by preventing VEGF from binding to its receptors. This phase I study was to evaluate a new formulation of subcutaneously administered aflibercept in patients with advanced solid tumors. Here we report our experience with the toxicity, pharmacokinetic profile and efficacy of the new 100 mg/mL subcutaneous (SC) formulation of aflibercept administered at a dose of at 4 mg/kg every 2 weeks.


Subject(s)
Neoplasms/drug therapy , Receptors, Vascular Endothelial Growth Factor/administration & dosage , Receptors, Vascular Endothelial Growth Factor/adverse effects , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Chemistry, Pharmaceutical , Cohort Studies , Female , Humans , Male , Middle Aged , Neoplasms/metabolism , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Receptors, Vascular Endothelial Growth Factor/pharmacokinetics , Recombinant Fusion Proteins/pharmacokinetics , Vascular Endothelial Growth Factor A/metabolism
8.
Invest New Drugs ; 30(6): 2294-302, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22072399

ABSTRACT

PURPOSE: To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. PATIENTS AND METHODS: Patients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16-120 mg/m(2)). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m(2). RESULTS: Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m(2). PK data were linear from 16 to 100 mg/m(2), with proportional increases in mean C(max) and AUC(tot) as a function of dose. Full PK analysis (mean ± SD) at 100 mg/m(2) revealed the following: half-life (t (½)) = 9.1 ± 2.2 h; volume of distribution (V(z)) = 119 ± 41 L/m(2); clearance (CL) = 9.3 ± 3.2 L/h/m(2). MTBF (n = 9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m(2). Tumor shrinkage (n = 2, lymphoma), stable disease >3 months (n = 5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (n = 1, colorectal cancer/CEA) were observed. CONCLUSION: KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m(2) weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.


Subject(s)
Epothilones/administration & dosage , Tubulin Modulators/administration & dosage , Adult , Aged , Epothilones/blood , Epothilones/pharmacokinetics , Female , Humans , Leukocytes, Mononuclear/metabolism , Lymphoma/metabolism , Male , Microtubules/metabolism , Middle Aged , Neoplasms/metabolism , Tubulin Modulators/blood , Tubulin Modulators/pharmacokinetics
9.
Mod Pathol ; 23(8): 1104-12, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20495537

ABSTRACT

B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and immunotherapeutic implications in ovarian carcinomas.


Subject(s)
Adenocarcinoma/blood supply , Antigens, CD/metabolism , Endothelium, Vascular/metabolism , Ovarian Neoplasms/blood supply , Receptors, Immunologic/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , B7 Antigens , B7-1 Antigen/metabolism , Biomarkers, Tumor/metabolism , Endothelium, Vascular/pathology , Female , Fluorescent Antibody Technique, Indirect , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Ovary/metabolism , Ovary/pathology , Prognosis , Survival Rate , Tissue Array Analysis
10.
J Clin Oncol ; 28(2): 207-14, 2010 Jan 10.
Article in English | MEDLINE | ID: mdl-19949018

ABSTRACT

PURPOSE: Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks. PATIENTS AND METHODS: Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability. RESULTS: The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) -defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses > or = 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker. CONCLUSION: IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.


Subject(s)
Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/therapeutic use , Neoplasms/drug therapy , Recombinant Fusion Proteins/therapeutic use , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Receptors, Vascular Endothelial Growth Factor , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/pharmacokinetics , Vascular Endothelial Growth Factor A/metabolism
11.
Clin Cancer Res ; 16(1): 358-66, 2010 Jan 01.
Article in English | MEDLINE | ID: mdl-20028764

ABSTRACT

PURPOSE: To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent. EXPERIMENTAL DESIGN: In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease. RESULTS: Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 microg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t(1/2) of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for >1 year. CONCLUSION: Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Recombinant Fusion Proteins/therapeutic use , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/immunology , Antineoplastic Agents/pharmacokinetics , Female , Humans , Hypodermoclysis , Male , Maximum Tolerated Dose , Middle Aged , Receptors, Vascular Endothelial Growth Factor , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/pharmacokinetics , Vascular Endothelial Growth Factor A/metabolism
12.
Clin Cancer Res ; 14(9): 2740-8, 2008 May 01.
Article in English | MEDLINE | ID: mdl-18451240

ABSTRACT

PURPOSE: The cancer-testis antigen NY-ESO-1 is expressed by >40% of advanced epithelial ovarian cancers and is a promising immunotherapeutic target. In this study, we describe the effects of vaccination with the HLA-A*0201-restricted NY-ESO-1b peptide on patients with epithelial ovarian cancer in high-risk first remission. EXPERIMENTAL DESIGN: After primary surgery and chemotherapy, high-risk epithelial ovarian cancer patients in first clinical remission received NY-ESO-1b peptide and Montanide every 3 weeks for five vaccinations. Tumor expression was evaluated by immunohistochemistry. Toxicity was monitored using National Cancer Institute Common Toxicity Criteria Scale Version 2. NY-ESO-1 specific humoral immunity (ELISA), T-cell immunity (tetramer and ELISPOT), and delayed-type hypersensitivity were assessed on weeks 0, 1, 4, 7, 10, 13, and 16. RESULTS: Treatment-related adverse events included grade 1 fatigue, anemia, pruritus, myalgias, and hyperthyroidism and grade 2 hypothyroidism. There were no grade 3/grade 4 adverse events. Three of four patients (75%) with NY-ESO-1-positive tumor showed T-cell immunity by tetramer (0.6-9.5%) and ELISPOT (range, 35-260 spots). Four of five patients (80%) with NY-ESO-1-negative tumor showed T-cell immunity by tetramer (1.0-12.1%) and/or ELISPOT (range, 35-400 spots). With a median follow-up of 11.3 months, six of nine patients (67%) have recurred, with a median progression-free survival of 13 months (95% confidence interval, 11.2 months-not reached). Three of nine patients remain in complete clinical remission at 25, 38, and 52 months. CONCLUSION: Vaccination of high-risk HLA-A*0201-positive epithelial ovarian cancer patients with NY-ESO-1b and Montanide has minimal toxicity and induces specific T-cell immunity in patients with both NY-ESO-1-positive and NY-ESO-1-negative tumors. Additional study is warranted.


Subject(s)
Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/therapeutic use , Mannitol/analogs & derivatives , Membrane Proteins/immunology , Oleic Acids/immunology , Ovarian Neoplasms/therapy , Peptide Fragments/immunology , Adult , Aged , Antigens, Neoplasm/administration & dosage , Antigens, Neoplasm/metabolism , Cancer Vaccines/adverse effects , Cancer Vaccines/immunology , Female , HLA-A Antigens/immunology , Humans , Mannitol/administration & dosage , Mannitol/immunology , Membrane Proteins/administration & dosage , Membrane Proteins/metabolism , Middle Aged , Oleic Acids/administration & dosage , Ovarian Neoplasms/immunology
13.
J Clin Oncol ; 25(33): 5180-6, 2007 Nov 20.
Article in English | MEDLINE | ID: mdl-18024865

ABSTRACT

PURPOSE: We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin. PATIENTS AND METHODS: No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment. CONCLUSION: Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Intestinal Perforation/drug therapy , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Bevacizumab , Drug Resistance, Neoplasm , Female , Humans , Intestinal Perforation/etiology , Intestinal Perforation/mortality , Middle Aged , Neoplasms, Glandular and Epithelial/mortality , Organoplatinum Compounds/therapeutic use , Ovarian Neoplasms/mortality , Peritoneal Neoplasms/mortality
14.
Clin Cancer Res ; 13(16): 4840-8, 2007 Aug 15.
Article in English | MEDLINE | ID: mdl-17699863

ABSTRACT

PURPOSE: Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis. EXPERIMENTAL DESIGN: Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment. RESULTS: VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC. CONCLUSIONS: Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.


Subject(s)
Dendritic Cells/immunology , Immunoglobulin Fc Fragments/therapeutic use , Neoplasms/drug therapy , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Adult , Aged , Cell Differentiation , Dendritic Cells/cytology , Female , Humans , Male , Middle Aged , Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Vascular Endothelial Growth Factor A/physiology
15.
Invest New Drugs ; 25(4): 335-41, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17364235

ABSTRACT

The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received or=7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m2 plus BMS-247550 30 mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m2 plus BMS-247550 30 mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicities included neutropenia, thrombocytopenia, neutropenic fever, hypophosphatemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m2 over 90 min days 1 and 8 plus BMS-247550 20 mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Small Cell/drug therapy , Cohort Studies , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Dose-Response Relationship, Drug , Epothilones/administration & dosage , Female , Humans , Kidney Neoplasms/drug therapy , Leukopenia/chemically induced , Lung Neoplasms/drug therapy , Male , Melanoma/drug therapy , Middle Aged , Ovarian Neoplasms/drug therapy , Sarcoma/drug therapy , Urinary Bladder Neoplasms/drug therapy , Uterine Neoplasms/drug therapy , Water-Electrolyte Imbalance/chemically induced , Gemcitabine
16.
J Clin Oncol ; 25(9): 1082-8, 2007 Mar 20.
Article in English | MEDLINE | ID: mdl-17261851

ABSTRACT

PURPOSE: To establish the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or relapsed/refractory non-Hodgkin's lymphoma. Dosing schedules of 40 mg/m2 and 50 mg/m2 over 3 hours were also evaluated. PATIENTS AND METHODS: Sixty-one patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase, with doses of ixabepilone ranging from 7.4 to 65 mg/m2. The pharmacokinetics of ixabepilone and two of its chemical degradation products were evaluated. Plasma pharmacodynamics were evaluated for both 1- and 3-hour infusions using an assay that measures the amount of endogenous tubulin in peripheral-blood mononuclear cells that exists in the polymerized versus the unpolymerized state. Response evaluation was performed every 6 weeks. RESULTS: The most common DLTs were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase less than proportionally to dose. Durable objective responses were seen in eight patients, including two complete responses. Five of the responders had experienced treatment failure with a taxane. CONCLUSION: The recommended dose of ixabepilone for the initiation of phase II studies on the basis of these results is 50 mg/m2 over 1 hour every 3 weeks. The promising efficacy and tolerability results demonstrated by ixabepilone in this study warrant its continued development.


Subject(s)
Antineoplastic Agents/administration & dosage , Epothilones/administration & dosage , Lymphoma, Non-Hodgkin/drug therapy , Tubulin Modulators/administration & dosage , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Cohort Studies , Drug Administration Schedule , Drug Hypersensitivity/etiology , Epothilones/adverse effects , Epothilones/pharmacokinetics , Female , Humans , Infusions, Intravenous , Lymphoma, Non-Hodgkin/mortality , Lymphoma, Non-Hodgkin/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Neoplasms/drug therapy , Neutropenia/chemically induced , Peripheral Nervous System Diseases/chemically induced , Practice Guidelines as Topic , Survival Analysis , Thrombocytopenia/chemically induced , Time Factors , Treatment Failure , Treatment Outcome , Tubulin Modulators/adverse effects , Tubulin Modulators/pharmacokinetics , United States
17.
Gynecol Oncol ; 104(2): 435-42, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17023034

ABSTRACT

OBJECTIVE: YKL-40 is a secreted glycoprotein of the chitinase family that has been previously described as a diagnostic and prognostic marker for a number of cancers, including epithelial ovarian cancer. In this study, we examined the frequency of serum elevation as well as the diagnostic and prognostic significance of this serum marker in endometrial cancer. MATERIALS AND METHODS: Preoperative serum levels of YKL-40 and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) for all endometrial cancer patient samples (34) available in the Memorial Sloan-Kettering Cancer Center Gynecology Service Tissue Bank between the years 1987 and 2002, and compared to a cohort of normal individuals. A YKL-40 value of 61 ng/mL has previously been determined to represent the upper limit of normal. YKL-40 values were correlated with clinical characteristics, including patient age, tumor grade, histology, clinical stage, and clinical outcome (progression-free survival [PFS] and overall survival [OS]). RESULTS: YKL-40 was elevated (>61 ng/mL) in 26 (76%) of 34 endometrial cancer patients compared with elevations of CA125 in 21 (62%) of 34 patients (P=0.09). Twenty-eight (82%) of all 34 patients had elevations of either CA125 or YKL-40 or both; 16 (89%) of 18 advanced-stage endometrial cancer patients had elevation of at least one of these two markers. Median preoperative YKL-40 value was 137 ng/mL (range, 22-1738 ng/mL) for endometrial cancer patients compared with 28 ng/mL (range, 15-72 ng/mL) for normal healthy subjects (P<0.0001). There was no statistically significant association of YKL-40 with patient age, tumor grade, histology, or stage. Elevation of YKL-40 (>80 ng/mL) was correlated with poor clinical outcome in univariate analysis, but was not demonstrated in multivariate analysis. At 5 years' follow-up, the PFS rate was 80% for patients with YKL-40<80 ng/mL compared with 43% for patients with YKL-40>80 ng/mL (P=0.004). The 5-year OS rate for patients with YKL-40<80 ng/mL was 79% compared with 48% for patients with YKL-40>80 ng/mL (P=0.047). CONCLUSION: Preoperative serum YKL-40 is frequently elevated and may represent a novel marker for the detection of endometrial cancer and the identification of high-risk subsets of patients with worse clinical outcome. Further investigation of this promising endometrial cancer marker in larger studies is warranted.


Subject(s)
Biomarkers, Tumor/blood , Endometrial Neoplasms/blood , Glycoproteins/blood , Adipokines , Adult , Aged , CA-125 Antigen/blood , Chitinase-3-Like Protein 1 , Endometrial Neoplasms/pathology , Endometrial Neoplasms/surgery , Female , Humans , Lectins , Middle Aged , Neoplasm Staging , Preoperative Care , ROC Curve , Treatment Outcome
18.
Gynecol Oncol ; 104(1): 176-80, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16996584

ABSTRACT

OBJECTIVES: Recent data suggest that differences in CA125 levels within the normal range may predict progression-free survival (PFS), but limited information is available regarding the value of these differences in predicting overall survival (OS) in patients with epithelial ovarian cancer. The objective of this study was to determine whether CA125 is an independent predictor of OS in patients with surgically defined disease status at the end of primary therapy prior to intraperitoneal (IP) consolidation chemotherapy. A secondary objective was to assess the relationship of CA125 level to PFS. METHODS: Using data from a retrospective cohort of 433 patients who received intraperitoneal (IP) therapy following primary treatment for ovarian cancer between 1984 and 1998, we identified 241 patients with a complete clinical response and CA125 data at the time of second-look surgery prior to IP chemotherapy. Patient demographics and updated follow-up status were abstracted from medical records. Kaplan-Meier survival curves were compared using the log-rank test, and Cox regression models were used for multivariate analysis. RESULTS: The majority of patients had advanced stage III or IV disease (n=201, 83%) and high-grade histology (n=163, 68%). Taxane was used as part of primary platinum-based therapy in 56% (n=134) of patients, and subsequent IP chemotherapy was platinum-based in 85% (n=206). When considered as a continuous variable, CA125 was a predictor of OS (P=0.029). Using the median CA125 level in our study group as a cut-off, OS was increased in patients with CA125 < or =12 U/ml (median 5.8 years) compared with >12 (3.7 years) (P=0.0027). CA125 level was an independent predictor of OS (HR: 1.410; 95% CI, 1.044, 1.904, P=0.0248) in a multivariate model that included stage (P=0.0166), grade (P=0.0001), and findings at second-look surgery (P=0.0003). CA125 level was also a predictor of clinical PFS (radiographic or CA125 elevation criteria alone) in a subset of 161 patients as a continuous variable (P=0.0036), and when divided at the median (< or = or >12; median 2.8 years vs. 1.7 years; P=0.0017). CONCLUSIONS: In our study population, CA125 level at the end of primary therapy was a predictor of OS and PFS when considered as a continuous variable, or when divided at the median (< or = or >12 U/ml). Further prospective study is required to optimize clinically significant cut-off values within the normal range of CA125 levels for both OS and PFS endpoints.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , CA-125 Antigen/blood , Ovarian Neoplasms/blood , Ovarian Neoplasms/therapy , Adult , Aged , Cohort Studies , Disease-Free Survival , Female , Humans , Infusions, Parenteral , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Paclitaxel/administration & dosage , Predictive Value of Tests , Retrospective Studies , Second-Look Surgery , Survival Rate
20.
Cancer ; 107(7): 1511-9, 2006 Oct 01.
Article in English | MEDLINE | ID: mdl-16944535

ABSTRACT

BACKGROUND: Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) tumor expression is an emerging prognostic, diagnostic, and therapeutic target in early epithelial ovarian cancer (EOC). The significance of tumor overexpression of LPAAT-beta was investigated in a large number of advanced- and early-stage EOC patients. METHODS: LPAAT-beta expression was analyzed by immunohistochemistry (IHC) in 158 ovarian tumors, including 68 advanced and 90 low-stage tumors, representing all grades and histologies (including 33 borderline tumors). In advanced-stage patients, tissue from multiple sites was evaluated to assess differential expression of LPAAT-beta in local tumor and distant metastases. RESULTS: LPAAT-beta was overexpressed in 90 (57%) of all 158 ovarian tumors. Forty-nine (72%) of 68 advanced tumors overexpressed LPAAT-beta. LPAAT-beta was associated with the presence of carcinoma versus borderline histology (67% vs. 18%, P < .0001), high histologic grade [according to the Silverberg Grading Scheme] (Grade 1, 25%; Grade 2, 21%; and Grade 3, 54%; P < .0001), and with papillary-serous histology. In an analysis of the 125 carcinoma patients, LPAAT-beta increased with but was not significantly associated with advanced clinical stage (P = .1431). LPAAT-beta expression was associated with shortened progression-free survival (PFS) (5-year PFS, 32% for LPAAT-beta-positive vs. 60% for LPAAT-beta-negative; P = .0318) and decreased overall survival (OS) (5-year OS, 54% for LPAAT-beta-positive vs. 74% for LPAAT-beta-negative; P = .0173). CONCLUSIONS: LPAAT-beta is highly expressed in advanced ovarian tumors and is associated with aggressive histology and decreased PFS and OS. LPAAT-beta is an intriguing prognostic tool for the identification of high-risk EOC and a potential target for directed therapy that warrants further study.


Subject(s)
Acyltransferases/analysis , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Ovary/enzymology , Ovary/pathology , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Neoplasm Metastasis , Neoplasm Staging , Ovarian Neoplasms/diagnosis , Survival Analysis
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