LIVIVO - Search results -

Search results

Result 1 - 10 of total 130

Search options

Article ; Online: Antibody drug conjugates: The dos and don'ts in clinical development.

Tolcher, Anthony W

2022 Volume 240, Page(s) 108235

Abstract: Antibody Drug Conjugates (ADCs) entered clinical trials in the mid 1990s to selectively deliver cytotoxic chemotherapy to cancer cells with the goal to increase the antitumor activity and decrease normal tissue toxicity. Over nearly 30 years of ... ...

Abstract	Antibody Drug Conjugates (ADCs) entered clinical trials in the mid 1990s to selectively deliver cytotoxic chemotherapy to cancer cells with the goal to increase the antitumor activity and decrease normal tissue toxicity. Over nearly 30 years of development the ADC platform has become established with now 11 approved agents and many more in the pipeline. This review is designed to highlight some of the problems and solutions encountered in clinical development as well as provide practical instruction to both clinical investigators on the efficient protocol design for ADCs and the lessons learned.
MeSH term(s)	Humans ; Immunoconjugates ; Antineoplastic Agents/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Neoplasms/drug therapy
Chemical Substances	Immunoconjugates ; Antineoplastic Agents ; Antibodies, Monoclonal
Language	English
Publishing date	2022-06-20
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2022.108235
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1183: 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)

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: The Evolution of Antibody-Drug Conjugates: A Positive Inflexion Point.

Tolcher, Anthony W

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting

2020 Volume 40, Page(s) 1–8

Abstract: In 2019, an important inflection point occurred when the U.S. Food and Drug Administration approved three new antibody-drug conjugates (ADCs) for the treatment of malignancies, including urothelial cancer (enfortumab vedotin-ejfv), diffuse large B-cell ... ...

Abstract	In 2019, an important inflection point occurred when the U.S. Food and Drug Administration approved three new antibody-drug conjugates (ADCs) for the treatment of malignancies, including urothelial cancer (enfortumab vedotin-ejfv), diffuse large B-cell lymphoma (polatuzumab vedotin-piiq), and HER2 breast cancer (fam-trastuzumab deruxtecan-nxki), and expanded the indication for ado-trastuzumab emtansine to early breast cancer. This near doubling in the number of approved ADCs within 1 year validates the ADC platform and represents a successful evolution over the past 30 years. ADCs were born in an era when systemic therapy for cancer was largely cytotoxic chemotherapy. Many of the investigational cytotoxic agents were determined to be too toxic for oral and intravenous use. The agents were especially potent, with inhibitory concentrations that inhibited 50% of cells in the nanomolar and picomolar range but had poor therapeutic indexes when administered systemically. Now, over the last 30 years, we have seen an evolution of the many aspects of this complex platform with better antigen target selection, more sophisticated chemistry for the linkers, a growing diversity of payloads from cytotoxic chemotherapy to targeted therapies and immunostimulants, and, with the recent series of regulatory approvals, a buoyed sense of optimism for the technology. Nonetheless, we have not fully realized the full potential of this platform. In this review, the many components of ADCs will be discussed, the difficulties encountered will be highlighted, the innovative strategies that are being used to improve them will be assessed, and the direction that the field is going will be considered.
MeSH term(s)	Humans ; Immunoconjugates/therapeutic use
Chemical Substances	Immunoconjugates
Language	English
Publishing date	2020-04-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2431126-1
ISSN	1548-8756 ; 1548-8748
ISSN (online)	1548-8756
ISSN	1548-8748
DOI	10.1200/EDBK_281103
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Improving combination cancer therapy: the CombiPlex

Tolcher, Anthony W / Mayer, Lawrence D

Future oncology (London, England)

2018 Volume 14, Issue 13, Page(s) 1317–1332

Abstract: Current combination therapy approaches assume that better outcomes are achieved by combining drugs at their maximally tolerated doses. However, administration of individual agents cannot consistently deliver synergistic drug ratios to tumor cells due to ... ...

Abstract	Current combination therapy approaches assume that better outcomes are achieved by combining drugs at their maximally tolerated doses. However, administration of individual agents cannot consistently deliver synergistic drug ratios to tumor cells due to differences in pharmacokinetics of the individual drugs. Further, the toxicity of combination regimens often necessitates administration of suboptimal dosages. Delivery technologies, such as the CombiPlex
MeSH term(s)	Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biomedical Technology/methods ; Dose-Response Relationship, Drug ; Drug Compounding/methods ; Drug Delivery Systems/methods ; Drug Synergism ; Humans ; Liposomes ; Nanoparticles ; Neoplasms/drug therapy ; Treatment Outcome
Chemical Substances	Liposomes
Language	English
Publishing date	2018-01-24
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2184533-5
ISSN	1744-8301 ; 1479-6694
ISSN (online)	1744-8301
ISSN	1479-6694
DOI	10.2217/fon-2017-0607
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

Order via subito

Details ▾
- Full text online
- Order with fees

Article ; Online: Phase I Study of GS-3583, a FLT3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors.

Tolcher, Anthony W / Brody, Joshua D / Rajakumaraswamy, Nishanthan / Kuhne, Michelle / Trowe, Torsten / Dauki, Anees M / Kochikar Pai, Shantheri / Han, Ling / Lin, Kai-Wen / Petrarca, Michael / Kummar, Shivaani

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

2024

Abstract: Purpose: GS-3583, a FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDCs) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and ... ...

Abstract	Purpose: GS-3583, a FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDCs) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors. Patients and methods: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level. Results: Thirteen participants enrolled in 4 dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44-79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2-20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all 4 doses with a dose-dependent trend in the durability of the cDC expansion. Conclusions: GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism.
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-2808
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 4223: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: First-in-Human Study of the Ataxia Telangiectasia and Rad3-related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors.

Yap, Timothy A / Tolcher, Anthony W / Plummer, Ruth / Mukker, Jatinder Kaur / Enderlin, Marta / Hicking, Christine / Grombacher, Thomas / Locatelli, Giuseppe / Szucs, Zoltan / Gounaris, Ioannis / de Bono, Johann S

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

2024

Abstract: Purpose: Tuvusertib (M1774) is a potent, selective, orally administered ATR protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), ... ...

Abstract	Purpose: Tuvusertib (M1774) is a potent, selective, orally administered ATR protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of tuvusertib monotherapy. Patients and methods: Ascending tuvusertib doses were evaluated in 55 patients with metastatic or locally advanced unresectable solid tumors. A safety monitoring committee determined dose escalation based on PK, PD, and safety data guided by a Bayesian 2‑parameter logistic regression model. Molecular responses (MRs) were assessed in circulating tumor DNA samples. Results: Most common Grade ≥3 treatment-emergent adverse events were anemia (36%), neutropenia and lymphopenia (both 7%). Eleven patients experienced dose-limiting toxicities, most commonly Grade 2 (n=2) or Grade 3 (n=8) anemia. No persistent effects on blood immune cell populations were observed. The RDE was 180mg tuvusertib QD, 2 weeks on/1 week off, which was better tolerated than the MTD (180mg QD continuously). Tuvusertib median time to peak plasma concentration ranged from 0.5-3.5h and mean elimination half-life from 1.2-5.6h. Exposure-related PD analysis suggested maximum target engagement at ≥130mg tuvusertib QD. Tuvusertib induced frequent MRs in the predicted efficacious dose range, MRs were enriched in patients with radiological disease stabilization and complete MRs were detected for mutations in ARID1A, ATRX and DAXX. One patient with platinum- and PARP inhibitor‑resistant BRCA wild-type ovarian cancer achieved an unconfirmed RECIST v1.1 partial response. Conclusions: Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.
Language	English
Publishing date	2024-02-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-2409
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 4223: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article: The evolution of phase I trials in cancer medicine: a critical review of the last decade.

Tolcher, Anthony W

Chinese journal of cancer

2011 Volume 30, Issue 12, Page(s) 815–820

Abstract: The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual ... ...

Abstract	The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual success rate of late stage trials through evolving phase I trial methodologies, the addition of extensive pharmacodynamic studies, and early adoption of patient selection strategies. Unfortunately, some of these new approaches have met with mixed results. Furthermore, no clear metrics are available to determine whether these designs are more successful than previous strategies. This review examines the evolution of phase I trials and draws upon several examples of strategies that have been successful as well as those that have not, and outlines a pragmatic approach to phase I trials as our understanding of the molecular biology of individual malignancies emerges.
MeSH term(s)	Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Clinical Trials, Phase I as Topic ; Drug Delivery Systems/methods ; Gefitinib ; Humans ; Maximum Tolerated Dose ; Molecular Targeted Therapy/methods ; Neoplasms/diagnostic imaging ; Neoplasms/drug therapy ; Phthalazines/pharmacokinetics ; Positron-Emission Tomography ; Protein Kinase Inhibitors/pharmacokinetics ; Pyridines/pharmacokinetics ; Quinazolines/administration & dosage ; Quinazolines/pharmacokinetics ; Quinazolines/therapeutic use
Chemical Substances	Antineoplastic Agents ; Phthalazines ; Protein Kinase Inhibitors ; Pyridines ; Quinazolines ; vatalanib (5DX9U76296) ; Gefitinib (S65743JHBS)
Language	English
Publishing date	2011-11-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1045160-2
ISSN	1944-446X ; 1000-467X
ISSN (online)	1944-446X
ISSN	1000-467X
DOI	10.5732/cjc.011.10133
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 6213: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors.

Tolcher, Anthony W / Peng, Wei / Calvo, Emiliano

Molecular cancer therapeutics

2018 Volume 17, Issue 1, Page(s) 3–16

Abstract: Molecular characterization of oncogenic mutations within genes in the MAPK and PI3K/AKT/mTOR pathways has led to the rational development of targeted therapies. Combining BRAF and MEK inhibitors to target two steps in the MAPK pathway (vertical ... ...

Abstract	Molecular characterization of oncogenic mutations within genes in the MAPK and PI3K/AKT/mTOR pathways has led to the rational development of targeted therapies. Combining BRAF and MEK inhibitors to target two steps in the MAPK pathway (vertical inhibition) is now standard of care in advanced-stage melanoma harboring
MeSH term(s)	Humans ; MAP Kinase Kinase 1/antagonists & inhibitors ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Protein Kinase Inhibitors ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; MAP Kinase Kinase 1 (EC 2.7.12.2)
Language	English
Publishing date	2018-01-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-17-0349
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5750: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Stable disease is a valid end point in clinical trials.

Tolcher, Anthony W

Cancer journal (Sudbury, Mass.)

2009 Volume 15, Issue 5, Page(s) 374–378

Abstract: For most clinical oncologists trained before the 1990s, a 20% or greater response rate is the convention for a drug to be considered active in phase II studies. However, this no longer holds true with several targeted therapies repeatedly achieving the ... ...

Abstract	For most clinical oncologists trained before the 1990s, a 20% or greater response rate is the convention for a drug to be considered active in phase II studies. However, this no longer holds true with several targeted therapies repeatedly achieving the regulatory criteria of progression-free and overall survival benefit with considerably lower objective response rates but a sizeable proportion of patients having stable disease. Considerable skepticism persists as to the value of stable disease as a valid outcome in early clinical trials of new agents. With a high percentage of new oncologic agents failing in phase III studies, the confidence one has in predicting later success in randomized studies when stable disease alone is observed is understandably low. Continued uncertainty of the value of stable disease is based on the lack of precision in defining this as a meaningful outcome. With the term stable disease encompassing a broad range from <20% enlargement to <30% reduction using standard response criteria response evaluation criteria in solid tumors, what one refers to as stable disease is open to diverse interpretation. The evidence that stable disease is a valid end point in many recent clinical trials is therefore discussed in this review and along with contemporary methods that bring some accuracy to the interpretation of stable disease within the context of clinical trial results.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Clinical Trials, Phase II as Topic ; Disease Progression ; Disease-Free Survival ; Humans ; Neoplasms/drug therapy ; Neoplasms/pathology ; Treatment Outcome
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2009-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2018400-1
ISSN	1540-336X ; 1528-9117 ; 1081-4442
ISSN (online)	1540-336X
ISSN	1528-9117 ; 1081-4442
DOI	10.1097/PPO.0b013e3181bdbb05
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 4470: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 163: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Phase 1 first-in-human study of dalutrafusp alfa, an anti-CD73-TGF-β-trap bifunctional antibody, in patients with advanced solid tumors.

Tolcher, Anthony W / Gordon, Michael / Mahoney, Kathleen M / Seto, Anna / Zavodovskaya, Marianna / Hsueh, Chia-Hsiang / Zhai, Shuyan / Tarnowski, Thomas / Jürgensmeier, Juliane M / Stinson, Susanna / Othman, Ahmed A / Chen, Tianling / Strauss, James

Journal for immunotherapy of cancer

2023 Volume 11, Issue 2

Abstract: Background: Cluster of differentiation (CD)73-adenosine and transforming growth factor (TGF)-β pathways are involved in abrogated antitumor immune responses and can lead to protumor conditions. This Phase 1 study (NCT03954704) evaluated the safety, ... ...

Abstract	Background: Cluster of differentiation (CD)73-adenosine and transforming growth factor (TGF)-β pathways are involved in abrogated antitumor immune responses and can lead to protumor conditions. This Phase 1 study (NCT03954704) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of dalutrafusp alfa (also known as GS-1423 and AGEN1423), a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-β signaling in patients with advanced solid tumors. Methods: Dose escalation started with an accelerated titration followed by a 3+3 design. Patients received dalutrafusp alfa (0.3, 1, 3, 10, 20, 30, or 45 mg/kg) intravenously every 2 weeks (Q2W) up to 1 year or until progressive disease (PD) or unacceptable toxicity. Results: In total, 21/22 patients received at least one dose of dalutrafusp alfa. The median number of dalutrafusp alfa doses administered was 3 (range 1-14). All patients had at least one adverse event (AE), most commonly fatigue (47.6%), nausea (33.3%), diarrhea (28.6%), and vomiting (28.6%). Nine (42.9%) patients had a Grade 3 or 4 AE; two had Grade 5 AEs of pulmonary embolism and PD, both unrelated to dalutrafusp alfa. Target-mediated drug disposition appears to be saturated at dalutrafusp alfa doses above 20 mg/kg. Complete CD73 target occupancy on B cells and CD8+ T cells was observed, and TGF-β 1/2/3 levels were undetectable at dalutrafusp alfa doses of 20 mg/kg and higher. Free soluble (s)CD73 levels and sCD73 activity increased with dalutrafusp alfa treatment. Seventeen patients reached the first response assessment, with complete response, partial response, stable disease, and PD in 0, 1 (4.8%), 7 (33.3%), and 9 (42.9%) patients, respectively. Conclusions: Dalutrafusp alfa doses up to 45 mg/kg Q2W were well tolerated in patients with advanced solid tumors. Additional evaluation of dalutrafusp alfa could further elucidate the clinical utility of targeting CD73-adenosine and TGF-β pathways in oncology.
MeSH term(s)	Humans ; Antibodies, Monoclonal, Humanized/adverse effects ; Treatment Outcome ; Neoplasms/pathology ; Immunoglobulin G ; Transforming Growth Factor beta ; Antibodies, Bispecific/therapeutic use
Chemical Substances	Antibodies, Monoclonal, Humanized ; Immunoglobulin G ; Transforming Growth Factor beta ; Antibodies, Bispecific
Language	English
Publishing date	2023-02-06
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005267
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors.

Stathis, Anastasios / Tolcher, Anthony W / Wang, Judy S / Renouf, Daniel J / Chen, Lin-Chi / Suttner, Leah H / Freshwater, Tomoko / Webber, Andrea L / Nayak, Tapan / Siu, Lillian L

Investigational new drugs

2023 Volume 41, Issue 3, Page(s) 380–390

Abstract: Aim: We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors.: Methods: This phase 1b, ...

Abstract	Aim: We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors. Methods: This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologically documented, locally advanced/metastatic solid tumors. MK-8353/selumetinib dose combinations were intended to be investigated in sequence: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Each agent was administered orally BID 4 days on/3 days off in repeating cycles every 21 days. Primary objectives were safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy. Results: Thirty patients were enrolled. Median (range) age was 61.5 (26-78) years and 93% had received previous cancer therapy. Among 28 patients in the dose-limiting toxicities [DLT]-evaluable population, 8 experienced DLTs: 1/11 (9%) in the MK-8353/selumetinib 100/50-mg dose level experienced a grade 3 DLT (urticaria), and 7/14 (50%) in the 150/75-mg dose level experienced grade 2/3 DLTs (n = 2 each of blurred vision, retinal detachment, vomiting; n = 1 each of diarrhea, macular edema, nausea, retinopathy). The DLT rate in the latter dose level exceeded the prespecified target DLT rate (~30%). Twenty-six patients (87%) experienced treatment-related adverse events (grade 3, 30%; no grade 4/5), most commonly diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Three patients (10%) experienced treatment-related adverse events leading to treatment discontinuation. Best response was stable disease in 14 patients (n = 10 with MK-8353/selumetinib 150/75 mg). Conclusion: MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed.
MeSH term(s)	Adult ; Humans ; Middle Aged ; Aged ; Mitogen-Activated Protein Kinase 3 ; Neoplasms/drug therapy ; Protein Kinase Inhibitors/adverse effects ; Mitogen-Activated Protein Kinase Kinases ; Nausea/chemically induced ; Diarrhea/chemically induced ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Maximum Tolerated Dose
Chemical Substances	AZD 6244 ; MK-8353 ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; Protein Kinase Inhibitors ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2023-04-11
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	604895-x
ISSN	1573-0646 ; 0167-6997
ISSN (online)	1573-0646
ISSN	0167-6997
DOI	10.1007/s10637-022-01326-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 1823: 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)

Order via subito

Details ▾

To top

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito