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Article ; Online: Phase Ib Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer.

Aggarwal, Rahul / Starodub, Alexander N / Koh, Brian D / Xing, Guan / Armstrong, Andrew J / Carducci, Michael A

Clinical cancer research : an official journal of the American Association for Cancer Research

2022 Volume 28, Issue 18, Page(s) 3979–3989

Abstract: Purpose: A phase Ib study (1604) was conducted to evaluate the safety and efficacy of GS-5829, an oral bromodomain and extraterminal inhibitor, alone and in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). A ... ...

Abstract	Purpose: A phase Ib study (1604) was conducted to evaluate the safety and efficacy of GS-5829, an oral bromodomain and extraterminal inhibitor, alone and in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). A phase I study (1599) in solid tumors/lymphoma was also conducted. Patients and methods: Men with confirmed mCRPC and disease progression despite abiraterone and/or enzalutamide treatment were enrolled in a 3 + 3 dose escalation paradigm starting at 2 mg daily with GS-5829 alone and in combination with 160 mg daily enzalutamide. The primary efficacy endpoint was nonprogression rate at week 24; secondary endpoints included prostate-specific antigen reduction from baseline, progression-free survival, and GS-5829 pharmacokinetics (PK). PK and safety were also evaluated in Study 1599. Results: Thirty-one men, with a median of five prior regimens, received at least 1 dose of study drug in Study 1604. Treatment-emergent adverse events (TEAE) were reported in 94% of patients; 16% discontinued for TEAEs. There were no dose-dependent increases in the AUCtau or Cmax after once-daily administration of GS-5829 2 to 9 mg, and biomarkers CCR2 inhibition and HEXIM1 induction were increased only at higher doses of monotherapy. A high degree of interpatient variability existed across all doses in PK and pharmacodynamic parameters. The proportion with nonprogression at week 24, estimated by Kaplan-Meier model, was 25% (95% confidence interval, 10-42) for all treated patients. Conclusions: GS-5829 was generally tolerated but demonstrated limited efficacy and lack of dose proportional increases in plasma concentrations in patients with mCRPC.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Benzamides ; Humans ; Male ; Nitriles/therapeutic use ; Phenylthiohydantoin ; Prostate-Specific Antigen ; Prostatic Neoplasms, Castration-Resistant/pathology ; RNA-Binding Proteins ; Transcription Factors ; Treatment Outcome
Chemical Substances	Benzamides ; HEXIM1 protein, human ; Nitriles ; RNA-Binding Proteins ; Transcription Factors ; Phenylthiohydantoin (2010-15-3) ; enzalutamide (93T0T9GKNU) ; Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2022-07-11
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-0175
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Article: Stabilization of Pancake Bonding in (TCNQ)

Starodub, Tetiana N / Čižmár, Erik / Kliuikov, Andrii / Starodub, Vladimir A / Feher, Alexander / Kozlowska, Mariana

ChemistryOpen

2019 Volume 8, Issue 7, Page(s) 984–988

Abstract: ... tetracyanquinonedimethane (TCNQ) anion and 2-amino-5-chloro-pyridine cation with the composition of (N-CH ...

Abstract	We report a new antiferromagnetic radical-anion salt (RAS) formed from 7,7,8,8-tetracyanquinonedimethane (TCNQ) anion and 2-amino-5-chloro-pyridine cation with the composition of (N-CH
Language	English
Publishing date	2019-07-18
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2655605-4
ISSN	2191-1363
ISSN	2191-1363
DOI	10.1002/open.201900179
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Article ; Online: Stabilization of Pancake Bonding in (TCNQ)2.− Dimers in the Radical‐Anionic Salt (N−CH3−2‐NH2−5Cl−Py)(TCNQ)(CH3CN) Solvate and Antiferromagnetism Induction

Dr. Tetiana N. Starodub / Dr. Erik Čižmár / Andrii Kliuikov / Prof. Vladimir A. Starodub / Prof. Alexander Feher / Dr. Mariana Kozlowska

ChemistryOpen, Vol 8, Iss 7, Pp 984-

2019 Volume 988

Abstract: Abstract We report a new antiferromagnetic radical‐anion salt (RAS) formed from 7,7,8,8‐tetracyanquinonedimethane (TCNQ) anion and 2‐amino‐5‐chloro‐pyridine cation with the composition of (N−CH3−2‐NH2−5Cl−Py)(TCNQ)(CH3CN). The crystallographic data ... ...

Abstract	Abstract We report a new antiferromagnetic radical‐anion salt (RAS) formed from 7,7,8,8‐tetracyanquinonedimethane (TCNQ) anion and 2‐amino‐5‐chloro‐pyridine cation with the composition of (N−CH3−2‐NH2−5Cl−Py)(TCNQ)(CH3CN). The crystallographic data indicates the formation of (TCNQ)2.− radical‐anion π‐dimers in the synthesized RAS. Unrestricted density functional theory calculations show that the formed π‐dimers characterize with strong π‐stacking “pancake” interactions, resulting in high electronic coupling, enabling efficient charge transfer properties, but π‐dimers cannot be stable in the isolated conditions as a result of strong Coulomb repulsions. In a crystal, where (TCNQ)2.− π‐dimers bound in the endless chainlets via supramolecular bonds with (N−CH3−2‐NH2−5‐Cl−Py)+ cations, the repulsion forces are screened, allowing for specific parallel π‐stacking interactions and stable radical‐anion dimers formation. Measurements of magnetic susceptibility and magnetization confirm antiferromagnetic properties of RAS, what is in line with the higher stability of ground singlet state of the radical‐anion pair, calculated by means of the DFT. Therefore, the reported radical‐anion (N−CH3−2‐NH2−5Cl−Py)(TCNQ)(CH3CN) solvate has promising applications in novel magnetics with supramolecular structures.
Keywords	charge transfer processes ; crystal engineering ; density functional calculations ; magnetic properties ; radical ions ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Wiley-VCH
Document type	Article ; Online
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Article ; Online: Phase 1 dose-escalation study of momelotinib, a Janus kinase 1/2 inhibitor, combined with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic ductal adenocarcinoma.

Ng, Kimmie / Hendifar, Andrew / Starodub, Alexander / Chaves, Jorge / Yang, Yingsi / Koh, Brian / Barbie, David / Hahn, William C / Fuchs, Charles S

Investigational new drugs

2018 Volume 37, Issue 1, Page(s) 159–165

Abstract: Purpose Preclinical evidence suggests the importance of Janus activating kinase (JAK) and TANK-binding kinase 1 (TBK1) in pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and efficacy of momelotinib (MMB), a JAK1/2 inhibitor with ... ...

Abstract	Purpose Preclinical evidence suggests the importance of Janus activating kinase (JAK) and TANK-binding kinase 1 (TBK1) in pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and efficacy of momelotinib (MMB), a JAK1/2 inhibitor with additional activity against TBK1, plus albumin-bound paclitaxel + gemcitabine (nab-P + G), in patients with previously untreated metastatic PDAC. Experimental Design Patients were enrolled into five cohorts of increasing doses of MMB between 100 and 200 mg administered once or twice daily in combination with nab-P + G in 28-day cycles to determine maximum tolerated dose (MTD). Safety, efficacy, pharmacokinetics, and pharmacodynamics were assessed for all patients. Results Twenty-five patients were enrolled. Dose-limiting toxicities of Grade 3 diarrhea occurred in 1 patient each in the 100 and 200 mg MMB once-daily dose groups. MTD was not reached. The 200 mg MMB twice-daily was the maximum administered dose. Objective response rate was 28% (all partial responses), and 13 (52%) patients had a best response of stable disease. The most common adverse events (AEs) were fatigue (80%), nausea (76%), and anemia (68%). Grade 3 or 4 AEs, most commonly neutropenia (32%), were reported by 88% of patients, of which 44% were considered related to MMB. Pharmacokinetic analyses showed MMB concentrations were too low for TBK1 inhibition. Conclusions MMB was safe and well tolerated in combination with nab-P + G. As no OS or PFS benefit vs nab-P + G was apparent in context of suboptimal engagement of the target TBK1, this study does not support further development of MMB as a first-line therapy in pancreatic cancer.
MeSH term(s)	Albumins/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Benzamides/administration & dosage ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/enzymology ; Carcinoma, Pancreatic Ductal/secondary ; Deoxycytidine/administration & dosage ; Deoxycytidine/analogs & derivatives ; Female ; Follow-Up Studies ; Humans ; Janus Kinase 1/antagonists & inhibitors ; Janus Kinase 2/antagonists & inhibitors ; Male ; Maximum Tolerated Dose ; Middle Aged ; Paclitaxel/administration & dosage ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/enzymology ; Pancreatic Neoplasms/pathology ; Prognosis ; Pyrimidines/administration & dosage ; Tissue Distribution
Chemical Substances	130-nm albumin-bound paclitaxel ; Albumins ; Benzamides ; Pyrimidines ; Deoxycytidine (0W860991D6) ; N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide (6O01GMS00P) ; gemcitabine (B76N6SBZ8R) ; JAK1 protein, human (EC 2.7.10.2) ; JAK2 protein, human (EC 2.7.10.2) ; Janus Kinase 1 (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2) ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2018-07-30
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604895-x
ISSN	1573-0646 ; 0167-6997
ISSN (online)	1573-0646
ISSN	0167-6997
DOI	10.1007/s10637-018-0650-5
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Article ; Online: Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics.

Ocean, Allyson J / Starodub, Alexander N / Bardia, Aditya / Vahdat, Linda T / Isakoff, Steven J / Guarino, Michael / Messersmith, Wells A / Picozzi, Vincent J / Mayer, Ingrid A / Wegener, William A / Maliakal, Pius / Govindan, Serengulam V / Sharkey, Robert M / Goldenberg, David M

Cancer

2017 Volume 123, Issue 19, Page(s) 3843–3854

Abstract: ... IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93 ...

Abstract	Background: Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers. Methods: Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU-132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93% of the available specimens. IMMU-132 cleared with a half-life of approximately 11 to 14 hours, reflecting the release of SN-38 from the conjugate; IgG cleared more slowly (half-life, approximately 103-114 hours). Most SN-38 in the serum (>95%) was bound to IgG. SN-38G concentrations were lower than SN-38 concentrations. Dose-limiting neutropenia after the first cycle was not correlated with SN-38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple-negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response. Conclusions: Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843-3854. © 2017 American Cancer Society.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Antigens, Neoplasm/metabolism ; Antineoplastic Agents, Phytogenic/administration & dosage ; Antineoplastic Agents, Phytogenic/adverse effects ; Antineoplastic Agents, Phytogenic/pharmacokinetics ; Camptothecin/administration & dosage ; Camptothecin/adverse effects ; Camptothecin/analogs & derivatives ; Camptothecin/blood ; Camptothecin/pharmacokinetics ; Cell Adhesion Molecules/metabolism ; Female ; Glucuronosyltransferase/genetics ; Half-Life ; Humans ; Immunoconjugates/administration & dosage ; Immunoconjugates/adverse effects ; Immunoconjugates/pharmacokinetics ; Immunoglobulin G/metabolism ; Irinotecan ; Male ; Middle Aged ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neutropenia/chemically induced ; Response Evaluation Criteria in Solid Tumors ; Time Factors
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antigens, Neoplasm ; Antineoplastic Agents, Phytogenic ; Cell Adhesion Molecules ; Immunoconjugates ; Immunoglobulin G ; TACSTD2 protein, human ; Irinotecan (7673326042) ; Glucuronosyltransferase (EC 2.4.1.17) ; sacituzumab govitecan (M9BYU8XDQ6) ; Camptothecin (XT3Z54Z28A)
Language	English
Publishing date	2017-05-30
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study
ZDB-ID	1429-1
ISSN	1097-0142 ; 0008-543X ; 1934-662X
ISSN (online)	1097-0142
ISSN	0008-543X ; 1934-662X
DOI	10.1002/cncr.30789
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Article ; Online: Phase I/II Trial of Labetuzumab Govitecan (Anti-CEACAM5/SN-38 Antibody-Drug Conjugate) in Patients With Refractory or Relapsing Metastatic Colorectal Cancer.

Dotan, Efrat / Cohen, Steven J / Starodub, Alexander N / Lieu, Christopher H / Messersmith, Wells A / Simpson, Pamela S / Guarino, Michael J / Marshall, John L / Goldberg, Richard M / Hecht, J Randolph / Wegener, William A / Sharkey, Robert M / Govindan, Serengulam V / Goldenberg, David M / Berlin, Jordan D

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2017 Volume 35, Issue 29, Page(s) 3338–3346

Abstract: Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10-hydroxycamptothecin (SN-38), in ... ...

Abstract	Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10-hydroxycamptothecin (SN-38), in an expanded phase II trial of patients with relapsed or refractory metastatic colorectal cancer. Patients and Methods Eligible patients with at least one prior irinotecan-containing therapy received labetuzumab govitecan once weekly at 8 and 10 mg/kg, or two times per week at 4 and 6 mg/km on weeks 1 and 2 of 3-week repeated cycles. End points were safety, response, pharmacokinetics, and immunogenicity. Results Eighty-six patients who had undergone a median of five prior therapies (range, one to 13) were each enrolled into one of the four cohorts. On the basis of Response Evaluation Criteria in Solid Tumors 1.1, 38% of these patients had a tumor as well as plasma carcinoembryonic antigen reduction from baseline after labetuzumab govitecan treatment; one patient achieved a partial response with a sustained response spanning > 2 years, whereas 42 patients had stable disease as the best overall response. Median progression-free survival and overall survival were 3.6 and 6.9 months, respectively. The major toxicities (grade ≥ 3) among all cohorts were neutropenia (16%), leukopenia (11%), anemia (9%), and diarrhea (7%). The antibody-drug conjugate's mean half-life was 16.5 hours for the four cohorts. Anti-drug/anti-antibody antibodies were not detected. The two once-weekly dose schedules, showing comparable toxicity and efficacy, were chosen for further study. Conclusion Monotherapy with labetuzumab govitecan demonstrated a manageable safety profile and therapeutic activity in heavily pretreated patients with metastatic colorectal cancer, all with prior irinotecan therapy. Further studies of labetuzumab govitecan treatment alone or in combination with other therapies in earlier settings are indicated.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/pharmacokinetics ; Camptothecin/administration & dosage ; Camptothecin/adverse effects ; Camptothecin/analogs & derivatives ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/pathology ; Disease Progression ; Disease-Free Survival ; Drug Administration Schedule ; Drug Resistance, Neoplasm ; Female ; Half-Life ; Humans ; Infusions, Intravenous ; Irinotecan ; Male ; Middle Aged ; Neoplasm Metastasis ; Survival Analysis ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Irinotecan (7673326042) ; labetuzumab govitecan (8E3HI6QQ9J) ; Camptothecin (XT3Z54Z28A)
Language	English
Publishing date	2017-08-17
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.2017.73.9011
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Zs.A 1847: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Safety and Efficacy of Andecaliximab (GS-5745) Plus Gemcitabine and Nab-Paclitaxel in Patients with Advanced Pancreatic Adenocarcinoma: Results from a Phase I Study.

Bendell, Johanna / Sharma, Sunil / Patel, Manish R / Windsor, Kevin S / Wainberg, Zev A / Gordon, Michael / Chaves, Jorge / Berlin, Jordan / Brachmann, Carrie Baker / Zavodovskaya, Marianna / Liu, JieJane / Thai, Dung / Bhargava, Pankaj / Shah, Manish A / Khan, Saad A / Starodub, Alexander

The oncologist

2020 Volume 25, Issue 11, Page(s) 954–962

Abstract: ... patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg ...

Abstract	Background: Matrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma. Patients and methods: This phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed. Results: Andecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9-11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed. Conclusion: Andecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma. Implications for practice: The combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.
MeSH term(s)	Adenocarcinoma/drug therapy ; Albumins ; Antibodies, Monoclonal, Humanized ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Deoxycytidine/analogs & derivatives ; Humans ; Paclitaxel/therapeutic use ; Pancreatic Neoplasms/drug therapy ; Treatment Outcome ; Tumor Microenvironment
Chemical Substances	130-nm albumin-bound paclitaxel ; Albumins ; Antibodies, Monoclonal, Humanized ; Deoxycytidine (0W860991D6) ; andecaliximab (571045EIM4) ; gemcitabine (B76N6SBZ8R) ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2020-09-17
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1634/theoncologist.2020-0474
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Article: Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan.

Gray, Jhanelle E / Heist, Rebecca S / Starodub, Alexander N / Camidge, D Ross / Kio, Ebenezer A / Masters, Gregory A / Purcell, W Thomas / Guarino, Michael J / Misleh, Jamal / Schneider, Charles J / Schneider, Bryan J / Ocean, Allyson / Johnson, Tirrell / Gandhi, Leena / Kalinsky, Kevin / Scheff, Ronald / Messersmith, Wells A / Govindan, Serengulam V / Maliakal, Pius P /

Mudenda, Boyd / Wegener, William A / Sharkey, Robert M / Goldenberg, David M

Clinical cancer research : an official journal of the American Association for Cancer Research

2017 Volume 23, Issue 19, Page(s) 5711–5719

Abstract: Purpose: ...

Abstract	Purpose:
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antigens, Neoplasm/immunology ; Camptothecin/administration & dosage ; Camptothecin/adverse effects ; Camptothecin/analogs & derivatives ; Camptothecin/immunology ; Cell Adhesion Molecules/antagonists & inhibitors ; Cell Adhesion Molecules/immunology ; DNA Topoisomerases, Type I/genetics ; DNA Topoisomerases, Type I/immunology ; Disease-Free Survival ; Drug-Related Side Effects and Adverse Reactions/classification ; Drug-Related Side Effects and Adverse Reactions/pathology ; Female ; Humans ; Immunoconjugates/administration & dosage ; Immunoconjugates/adverse effects ; Immunoconjugates/chemistry ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Molecular Targeted Therapy ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/immunology ; Small Cell Lung Carcinoma/pathology ; Topoisomerase I Inhibitors/administration & dosage ; Topoisomerase I Inhibitors/adverse effects
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antigens, Neoplasm ; Cell Adhesion Molecules ; Immunoconjugates ; TACSTD2 protein, human ; Topoisomerase I Inhibitors ; DNA Topoisomerases, Type I (EC 5.99.1.2) ; sacituzumab govitecan (M9BYU8XDQ6) ; Camptothecin (XT3Z54Z28A)
Language	English
Publishing date	2017-07-05
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-17-0933
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Article: First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors.

Starodub, Alexander N / Ocean, Allyson J / Shah, Manish A / Guarino, Michael J / Picozzi, Vincent J / Vahdat, Linda T / Thomas, Sajeve S / Govindan, Serengulam V / Maliakal, Pius P / Wegener, William A / Hamburger, Steven A / Sharkey, Robert M / Goldenberg, David M

Clinical cancer research : an official journal of the American Association for Cancer Research

2015 Volume 21, Issue 17, Page(s) 3870–3878

Abstract: ... of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg ... to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1 ...

Abstract	Purpose: Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers. Experimental design: Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed. Results: Twenty-five patients (52-60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done. Conclusions: Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/pharmacology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antigens, Neoplasm/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Camptothecin/analogs & derivatives ; Camptothecin/pharmacology ; Camptothecin/therapeutic use ; Cell Adhesion Molecules/metabolism ; Combined Modality Therapy ; Drug Monitoring ; Female ; Humans ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasms/diagnosis ; Neoplasms/drug therapy ; Neoplasms/therapy ; Tomography, X-Ray Computed ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antigens, Neoplasm ; Antineoplastic Agents ; Cell Adhesion Molecules ; Immunoconjugates ; TACSTD2 protein, human ; sacituzumab govitecan (M9BYU8XDQ6) ; Camptothecin (XT3Z54Z28A)
Language	English
Publishing date	2015-05-05
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-14-3321
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2017 Volume 35, Issue 19, Page(s) 2141–2148

Abstract: ... since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2 ...

Abstract	Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antigens, Neoplasm/biosynthesis ; Antigens, Neoplasm/immunology ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Breast Neoplasms, Male/drug therapy ; Breast Neoplasms, Male/immunology ; Breast Neoplasms, Male/metabolism ; Camptothecin/administration & dosage ; Camptothecin/adverse effects ; Camptothecin/analogs & derivatives ; Cell Adhesion Molecules/biosynthesis ; Cell Adhesion Molecules/immunology ; Female ; Humans ; Immunoconjugates/administration & dosage ; Immunoconjugates/adverse effects ; Male ; Middle Aged ; Neoplasm Metastasis ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/immunology ; Triple Negative Breast Neoplasms/metabolism
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antigens, Neoplasm ; Antineoplastic Agents ; Cell Adhesion Molecules ; Immunoconjugates ; TACSTD2 protein, human ; sacituzumab govitecan (M9BYU8XDQ6) ; Camptothecin (XT3Z54Z28A)
Language	English
Publishing date	2017-03-14
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.2016.70.8297
Database	MEDical Literature Analysis and Retrieval System OnLINE

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