The Experts below are selected from a list of 170304 Experts worldwide ranked by ideXlab platform
Erik Vandendries - One of the best experts on this subject based on the ideXlab platform.
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phase i study of anti CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed refractory b cell non hodgkin lymphoma
Cancer Science, 2012Co-Authors: Michinori Ogura, Kiyohiko Hatake, Kiyoshi Ando, Kensei Tobinai, Kota Tokushige, Taro Ishibashi, Erik VandendriesAbstract:Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 Antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m2 followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m2). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44–98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971. (Cancer Sci 2012; 103: 933–938)
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phase i study of anti CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed refractory b cell non hodgkin lymphoma
Cancer Science, 2012Co-Authors: Michinori Ogura, Kiyohiko Hatake, Kiyoshi Ando, Kensei Tobinai, Kota Tokushige, Taro Ishibashi, Chiho Ono, Erik VandendriesAbstract:Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 Antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m(2) followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m(2)). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44-98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971.
Ira Pastan - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic analysis of response in hairy cell leukemia treated by anti CD22 recombinant immunotoxin moxetumomab pasudotox
Blood, 2013Co-Authors: Robert J Kreitman, Evgeny Arons, Maryalice Stetlerstevenson, Wyndham H Wilson, David J Fitzgerald, Ira PastanAbstract:Background Moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, contains truncated Pseudomonas exotoxin and is currently undergoing pivotal phase III testing for relapsed and refractory hairy cell leukemia (HCL). The dose-escalation portion of the phase I trial was reported to achieve an overall response rate (ORR) of 86% including 46% complete remissions (CRs) in 28 HCL patients. A completely reversible form of grade 2 hemolytic uremic syndrome (HUS), based on laboratory changes but lacking clinical signs, was observed in 2 patients, and no dose-limiting toxicity (DLT) was observed. To determine the relationship between response and CD22 Antigen ‘sink’ from high CD22 density on HCL cells, plasma levels were studied. Those analyzed included the original 28 in the dose-escalation arm, an additional 20 at the highest dose level enrolled prior to 2012, and one additional patient enrolled prior to initiation of the pivotal trial. Methods Moxetumomab pasudotox was administered to 49 patients at 5, 10, 20, and 30 µg/kg every other day for 3 doses (QODx3, n=3 each dose level), and then 4 and 33 patients received 40 and 50 µg/kg QODx3, respectively. Patients received retreatment cycles at 4 week intervals, with retreatment halted after progressive disease, high levels of neutralizing antibodies, HUS, or 2 cycles after achievement of MRD-free CR. MRD was studied using bone marrow biopsy (BMBx) immunohistochemistry (IHC), and flow cytometry of blood or bone marrow aspirate (BMA). Pharmacokinetics was determined from cytotoxicity assays to quantify active moxetumomab pasudotox in the plasma. Results There were 28 (57%) CRs and 15 (31%) PRs for an ORR of 88% out of 49 patients. While CRs were insignificantly more frequent at 50 µg/kg QODx3 vs lower doses (64% of 33 vs 44% of 16, p=0.23), the difference in MRD-free CR rate was significant (39% vs 6%, p=0.02). Of the 21 CRs at 50 µg/kg QODx3, 13 (62%) remain in CR at a median relapse-free follow-up time of 32 months, and relapse occurred in 7 (88%) of 8 with MRD vs 1 (8%) of 13 without MRD (p Conclusions Moxetumomab pasudotox can achieve durable CR without MRD in relapsed and refractory HCL, with a safety profile supporting its current pivotal testing, including a dose level consistent with the activity of the 50 µg/kg QODx3 phase I dose. Our results also indicate that lower HCL tumor burden minimizes the CD22 ‘sink’ effect allowing higher plasma levels, and suggest that patients treated while tumor burden is relatively low may have improved chance of durable CR. Moreover, strategies for improving the efficacy of moxetumomab pasudotox might include combination or sequential use of other therapies to decrease HCL burden. This summary contains investigator reported data. This study was sponsored by MedImmune and supported by NCI’s Intramural Research Program and the Hairy Cell Leukemia Research Foundation. Disclosures: Kreitman:NIH: Co-inventor on the patent for moxetumomab pasudotox, Co-inventor on the patent for moxetumomab pasudotox Patents & Royalties, Employment, Research funding via CRADA with MedImmune Other. Arons:NIH: Employment. Stetler-Stevenson:NIH: Employment. Wilson:NIH: Employment. FitzGerald:National Cancer Institute, NIH: Employment, Moxetumomab Pasudotox, Moxetumomab Pasudotox Patents & Royalties. Pastan:NIH: Employment, Inventor on immunotoxin patents, which are all assigned to NIH, Inventor on immunotoxin patents, which are all assigned to NIH Patents & Royalties.
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antitumor activity of ss dsfv pe38 and ss1 dsfv pe38 recombinant antimesothelin immunotoxins against human gynecologic cancers grown in organotypic culture in vitro
Clinical Cancer Research, 2002Co-Authors: Raffit Hassan, Qingcheng Wang, Megan R. Lerner, Daniel J. Brackett, Doris M Benbrook, Stan Lightfoot, Ira PastanAbstract:Purpose: Mesothelin, a cell surface glycoprotein overexpressed in ovarian cancer, mesotheliomas, and some squamous cell carcinomas, is an attractive candidate for targeted therapy because it is not shed in significant amounts into the bloodstream and is not present in significant amounts on normal human tissues except for mesothelial cells. The objective of this study was to determine the antitumor activity of SS1(dsFv)PE38, a recombinant antimesothelin immunotoxin, against human gynecologic tumors grown in short-term culture in vitro . Experimental Design: Tumor cells obtained from primary cultures of five ovarian and one cervical tumor were mixed with an equal proportion of NIH-3T3 fibroblasts and plated inside collagen gels in tissue culture plates. After 4–7 days of growth, these organotypic cultures were treated with media alone, SS1(dsFv)PE38, and a control immunotoxin RFB4(dsFv)PE38, which targets the CD22 Antigen not present on gynecologic tumors, every other day × 3. The organotypic culture gels were then formalin fixed, paraffin embedded, and evaluated for immunotoxin sensitivity using light microscopic examination of H&E-stained slides and also evaluated for apoptosis using the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Results: Tumors expressing mesothelin showed a significant dose-dependent sensitivity to SS1(dsFv)PE38 even at concentrations as low as 1 ng/ml, whereas no antitumor activity was seen at 100 ng/ml in tumors that did not express mesothelin. This activity was specifically attributable to mesothelin targeting because RFB4 (dsFv)-PE38 had no activity against mesothelin-expressing tumors. Conclusions: These results demonstrate that ovarian and cervical tumor cells obtained from patients can be grown in short-term culture using an organotypic culture model. Our results also show low concentrations of an immunotoxin targeting mesothelin is cytotoxic to mesothelin-expressing human tumors by inducing apoptosis.
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recombinant rfb4 immunotoxins exhibit potent cytotoxic activity for CD22 bearing cells and tumors
Blood, 1997Co-Authors: Elizabeth Mansfield, Ira Pastan, Peter Lloyd AmlotAbstract:Many B-cell malignancies express the CD22 Antigen on their cell surface. To kill cells expressing this Antigen, the RFB4 monoclonal antibody (MoAb) has been linked chemically with either deglycosylated ricin A chain or truncated versions of Pseudomonas exotoxin. These immunotoxins exhibited selective cytotoxic activity for CD22+ cells and antitumor activity in nude mouse models bearing human B-cell lymphomas. To construct a recombinant immunotoxin targeted to CD22, we first cloned the variable portions of the heavy and light chains of RFB4. The cloned Fv fragments were joined by a newly created disulfide bond to form a disulfide stabilized (ds) construct. The RFB4 construct was combined by gene fusion with PE38, a truncated version of PE. The recombinant immunotoxin was then expressed in Escherichia coli, purified by column chromatography and tested for cytotoxicity activity. RFB4(dsFv)PE38 retained its binding activity for CD22, was very stable at 37 degrees C and exhibited selective cytotoxic activity for CD22+-cultured cell lines. Because of its favorable binding characteristics and potency for CD22-positive cell lines, RFB4(dsFv)PE38 was tested for antitumor activity in a nude mouse model of human lymphoma. CA46 cells were injected subcutaneously and then treated with the RFB4(dsFv)PE38 immunotoxin. Antitumor activity was dose responsive and was not evident when an irrelevant immunotoxin was administered on the same schedule.
Michinori Ogura - One of the best experts on this subject based on the ideXlab platform.
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phase i study of anti CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed refractory b cell non hodgkin lymphoma
Cancer Science, 2012Co-Authors: Michinori Ogura, Kiyohiko Hatake, Kiyoshi Ando, Kensei Tobinai, Kota Tokushige, Taro Ishibashi, Erik VandendriesAbstract:Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 Antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m2 followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m2). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44–98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971. (Cancer Sci 2012; 103: 933–938)
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phase i study of anti CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed refractory b cell non hodgkin lymphoma
Cancer Science, 2012Co-Authors: Michinori Ogura, Kiyohiko Hatake, Kiyoshi Ando, Kensei Tobinai, Kota Tokushige, Taro Ishibashi, Chiho Ono, Erik VandendriesAbstract:Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 Antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m(2) followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m(2)). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44-98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971.
Kiyohiko Hatake - One of the best experts on this subject based on the ideXlab platform.
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phase i study of anti CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed refractory b cell non hodgkin lymphoma
Cancer Science, 2012Co-Authors: Michinori Ogura, Kiyohiko Hatake, Kiyoshi Ando, Kensei Tobinai, Kota Tokushige, Taro Ishibashi, Erik VandendriesAbstract:Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 Antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m2 followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m2). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44–98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971. (Cancer Sci 2012; 103: 933–938)
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phase i study of anti CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed refractory b cell non hodgkin lymphoma
Cancer Science, 2012Co-Authors: Michinori Ogura, Kiyohiko Hatake, Kiyoshi Ando, Kensei Tobinai, Kota Tokushige, Taro Ishibashi, Chiho Ono, Erik VandendriesAbstract:Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 Antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m(2) followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m(2)). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44-98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971.
Taro Ishibashi - One of the best experts on this subject based on the ideXlab platform.
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phase i study of anti CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed refractory b cell non hodgkin lymphoma
Cancer Science, 2012Co-Authors: Michinori Ogura, Kiyohiko Hatake, Kiyoshi Ando, Kensei Tobinai, Kota Tokushige, Taro Ishibashi, Erik VandendriesAbstract:Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 Antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m2 followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m2). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44–98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971. (Cancer Sci 2012; 103: 933–938)
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phase i study of anti CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed refractory b cell non hodgkin lymphoma
Cancer Science, 2012Co-Authors: Michinori Ogura, Kiyohiko Hatake, Kiyoshi Ando, Kensei Tobinai, Kota Tokushige, Taro Ishibashi, Chiho Ono, Erik VandendriesAbstract:Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 Antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m(2) followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m(2)). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44-98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971.