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Artikel ; Online: Enzalutamide: Understanding and Managing Drug Interactions to Improve Patient Safety and Drug Efficacy.

Lennep, Brandon W / Mack, Jesse / Poondru, Srinivasu / Hood, Elizabeth / Looney, Brooke D / Williams, Monique / Bianco, Judeth J / Morgans, Alicia K

Drug safety

2024

Abstract: Enzalutamide is an oral androgen receptor signaling inhibitor utilized in the treatment of men with prostate cancer. It is a moderate inducer of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and a strong inducer of CYP3A4. It was also shown to be ...

Abstract	Enzalutamide is an oral androgen receptor signaling inhibitor utilized in the treatment of men with prostate cancer. It is a moderate inducer of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and a strong inducer of CYP3A4. It was also shown to be a mild inhibitor of the efflux transporter P-glycoprotein in patients with prostate cancer. Enzalutamide is primarily metabolized by CYP3A4 and CYP2C8. The risk of enzalutamide drug interactions arises primarily when it is coadministered with other drugs that interact with these CYPs, including CYP3A4. In this review, we begin by providing an overview of enzalutamide including its dosing, use in special populations, pharmacokinetics, changes to its prescribing information, and potential for interaction with coadministered drugs. Enzalutamide interactions with drugs from a wide range of medication classes commonly prescribed to patients with prostate cancer are described, including oral androgen deprivation therapy, agents used to treat a range of cardiovascular diseases, antidiabetic drugs, antidepressants, anti-seizure medications, common urology medications, analgesics, proton pump inhibitors, immunosuppressants, and antigout drugs. Enzalutamide interactions with common vitamins and supplements are also briefly discussed. This review provides a resource for healthcare practitioners and patients that will help provide a basis for the understanding and management of enzalutamide drug-drug interactions to inform decision making, improve patient safety, and optimize drug efficacy.
Sprache	Englisch
Erscheinungsdatum	2024-04-12
Erscheinungsland	New Zealand
Dokumenttyp	Journal Article ; Review
ZDB-ID	1018059-x
ISSN	1179-1942 ; 0114-5916
ISSN (online)	1179-1942
ISSN	0114-5916
DOI	10.1007/s40264-024-01415-7
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates.

Otsuka, Yukio / Poondru, Srinivasu / Bonate, Peter L / Rose, Rachel H / Jamei, Masoud / Ushigome, Fumihiko / Minematsu, Tsuyoshi

Journal of pharmacokinetics and pharmacodynamics

2023 Band 50, Heft 5, Seite(n) 365–376

Abstract: Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, ... ...

Abstract	Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide's net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in C
Mesh-Begriff(e)	Male ; Humans ; Cytochrome P-450 CYP3A/metabolism ; Rivaroxaban ; Drug Interactions ; Pharmaceutical Preparations/metabolism ; Models, Biological
Chemische Substanzen	Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Rivaroxaban (9NDF7JZ4M3) ; enzalutamide (93T0T9GKNU) ; Pharmaceutical Preparations
Sprache	Englisch
Erscheinungsdatum	2023-06-21
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-023-09867-7
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Effect of enzalutamide on PK of P-gp and BCRP substrates in cancer patients: CYP450 induction may not always predict overall effect on transporters.

Poondru, Srinivasu / Ghicavii, Vitalii / Khosravan, Reza / Manchandani, Pooja / Heo, Nakyo / Moy, Selina / Wojtkowski, Tomasz / Patton, Melanie / Haas, Gabriel P

Clinical and translational science

2022 Band 15, Heft 5, Seite(n) 1131–1142

Abstract: Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) ...

Abstract	Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P-glycoprotein [P-gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I, open-label, fixed-sequence, crossover study (NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo-to-match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (C
Mesh-Begriff(e)	ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Benzamides ; Cross-Over Studies ; Digoxin/pharmacokinetics ; Drug Interactions ; Humans ; Male ; Membrane Transport Proteins/metabolism ; Neoplasm Proteins/metabolism ; Nitriles ; Pharmaceutical Preparations ; Phenylthiohydantoin ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Rosuvastatin Calcium/pharmacokinetics
Chemische Substanzen	ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Benzamides ; Membrane Transport Proteins ; Neoplasm Proteins ; Nitriles ; Pharmaceutical Preparations ; Phenylthiohydantoin (2010-15-3) ; Digoxin (73K4184T59) ; Rosuvastatin Calcium (83MVU38M7Q) ; enzalutamide (93T0T9GKNU)
Sprache	Englisch
Erscheinungsdatum	2022-02-04
Erscheinungsland	United States
Dokumenttyp	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.13229
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Clinical Pharmacology of the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial Carcinoma and Other Malignant Solid Tumors.

Tang, Mei / Garg, Amit / Bonate, Peter L / Rosenberg, Jonathan E / Matsangou, Maria / Kadokura, Takeshi / Yamada, Akihiro / Choules, Mary / Pavese, Janet / Nagata, Masanori / Tenmizu, Daisuke / Koibuchi, Akira / Heo, Nakyo / Wang, Lu / Wojtkowski, Tomasz / Hanley, William D / Poondru, Srinivasu

Clinical pharmacokinetics

2024 Band 63, Heft 4, Seite(n) 423–438

Abstract: Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of ...

Abstract	Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.
Mesh-Begriff(e)	Humans ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Immunoconjugates/pharmacokinetics ; Immunoconjugates/administration & dosage ; Immunoconjugates/pharmacology ; Immunoconjugates/adverse effects ; Immunoconjugates/therapeutic use ; Oligopeptides/pharmacokinetics ; Oligopeptides/administration & dosage ; Oligopeptides/therapeutic use ; Oligopeptides/pharmacology ; Oligopeptides/adverse effects ; Urologic Neoplasms/drug therapy ; Urologic Neoplasms/pathology ; Dose-Response Relationship, Drug ; Carcinoma, Transitional Cell/drug therapy ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents/pharmacology ; Nectins
Chemische Substanzen	enfortumab vedotin (DLE8519RWM) ; Antibodies, Monoclonal ; Immunoconjugates ; monomethyl auristatin E (V7I58RC5EJ) ; Oligopeptides ; Antineoplastic Agents ; NECTIN4 protein, human ; Nectins
Sprache	Englisch
Erscheinungsdatum	2024-04-12
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-024-01369-0
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A Randomized Phase II Study of AGS-16C3F Versus Axitinib in Previously Treated Patients with Metastatic Renal Cell Carcinoma.

Kollmannsberger, Christian / Choueiri, Toni K / Heng, Daniel Y C / George, Saby / Jie, Fei / Croitoru, Ruslan / Poondru, Srinivasu / Thompson, John A

The oncologist

2021 Band 26, Heft 3, Seite(n) 182–e361

Abstract: Lessons learned: The primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS-16C3F, versus axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC) was not met. ... ...

Abstract	Lessons learned: The primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS-16C3F, versus axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC) was not met. Median progression-free survival, the primary endpoint, was 2.9 months with AGS-16C3F and 5.7 months with axitinib (HR, 1.676; 95% CI, 1.107-2.537; p = .015), per investigator assessment The safety profile for each study drug was as expected, with the most commonly reported adverse events being fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. These results provide a benchmark for axitinib use in heavily pretreated patients with mRCC. Background: AGS-16C3F is a novel antibody-drug conjugate that targets cell-surface ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) and is conjugated to a microtubule disruptive agent. Here we present findings from a phase II study of AGS-16C3F versus axitinib in metastatic renal cell carcinoma (mRCC). Methods: Patients with mRCC of any histology and disease progression during or after their last treatment regimen were randomized 1:1 to intravenous AGS-16C3F 1.8 mg/kg every 3 weeks or oral axitinib 5 mg twice daily (starting dose). The primary objective was investigator-assessed progression-free survival (PFS) of AGS-16C3F versus axitinib (RECIST version 1.1). Results: In the total population (N = 133), 63% (n = 84) of patients had completed the study at data cutoff (August 21, 2019). Median PFS was 2.9 months with AGS-16C3F and 5.7 months with axitinib (hazard ratio [HR], 1.676; 95% confidence interval [CI], 1.107-2.537; p = .015). There were no significant differences between arms in secondary efficacy endpoints, including overall survival (13.1 months, AGS-16C3F and 15.4 months, axitinib; HR, 1.079; 95% CI, 0.681-1.707; p = .747). In the safety population (n = 131), the most commonly reported adverse events were fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. The incidence of diarrhea was lower in the AGS-16C3F arm than in the axitinib arm (17% vs. 48%), and ocular toxicities were more frequent in the AGS-16C3F arm than in the axitinib arm (44% vs. 26%). Conclusion: The investigational compound, AGS-16C3F, did not meet the primary endpoint of this trial. These study results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.
Mesh-Begriff(e)	Antibodies, Monoclonal, Humanized ; Axitinib ; Carcinoma, Renal Cell/drug therapy ; Humans ; Kidney Neoplasms/drug therapy ; Treatment Outcome
Chemische Substanzen	AGS-16C3F ; Antibodies, Monoclonal, Humanized ; Axitinib (C9LVQ0YUXG)
Sprache	Englisch
Erscheinungsdatum	2021-01-19
Erscheinungsland	United States
Dokumenttyp	Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1002/onco.13628
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper.

Clinical pharmacology and therapeutics

2024

Abstract: The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug ... ...

Abstract	The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.
Sprache	Englisch
Erscheinungsdatum	2024-05-16
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Review
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.3298
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Mass balance, pharmacokinetics, and metabolism of linsitinib in cancer patients.

Poondru, Srinivasu / Chaves, Jorge / Yuen, Geoffrey / Parker, Barbara / Conklin, Elizabeth / Singh, Margaret / Nagata, Masanori / Gill, Stanley

Cancer chemotherapy and pharmacology

2016 Band 77, Heft 4, Seite(n) 829–837

Abstract: Purpose: This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability ... ...

Abstract	Purpose: This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in those patients who wished to continue treatment beyond the single (14)C-linsitinib dose. Methods: Five patients received a single oral dose of 150 mg (14)C-linsitinib, followed by collection of blood, plasma, urine, and feces for 10 days. The collected material was analyzed for total radioactivity, linsitinib, and metabolites. The safety of 150 mg of unlabeled linsitinib administered twice daily until disease progression was also assessed. Results: The median time to reach the maximum plasma concentration of linsitinib was 3.0 h, median maximum plasma concentration was 1789 ng/mL, median terminal half-life was 2.4 h, and median apparent oral clearance was 12.45 L/h. After a single dose of (14)C-linsitinib, 5.44 and 76.4 % of mean total radioactivity administered were recovered in urine and feces, respectively. Eighteen linsitinib metabolites (M1-M18) were detected in plasma, urine, and feces samples, and their structures were elucidated. The main metabolic reactions of linsitinib in humans were oxidation and sulfate conjugation. Linsitinib was well tolerated after a single dose of (14)C-linsitinib, and fatigue was the most frequent adverse event following multiple doses of unlabeled linsitinib. Conclusions: (14)C-linsitinib is rapidly absorbed and extensively metabolized. Linsitinib excretion via bile into feces is the predominant elimination route from plasma with minor renal elimination.
Mesh-Begriff(e)	Aged ; Female ; Humans ; Imidazoles/adverse effects ; Imidazoles/pharmacokinetics ; Male ; Metabolic Networks and Pathways ; Middle Aged ; Neoplasms/drug therapy ; Protein Kinase Inhibitors/pharmacokinetics ; Pyrazines/adverse effects ; Pyrazines/pharmacokinetics
Chemische Substanzen	3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol ; Imidazoles ; Protein Kinase Inhibitors ; Pyrazines
Sprache	Englisch
Erscheinungsdatum	2016-04
Erscheinungsland	Germany
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-016-2999-5
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Phase 2 study evaluating intermittent and continuous linsitinib and weekly paclitaxel in patients with recurrent platinum resistant ovarian epithelial cancer.

Oza, Amit / Kaye, Stanley / Van Tornout, Jan / Sessa, Cristiana / Gore, Martin / Naumann, R Wendel / Hirte, Hal / Colombo, Nicoletta / Chen, Jihong / Gorla, Seema / Poondru, Srinivasu / Singh, Margaret / Steinberg, Joyce / Yuen, Geoff / Banerjee, Susana

Gynecologic oncology

2018 Band 149, Heft 2, Seite(n) 275–282

Abstract: Background: Linsitinib, an oral, dual inhibitor of insulin-like growth factor-1 receptor and insulin receptor, in combination with weekly paclitaxel, may improve clinical outcomes compared with paclitaxel alone in patients with refractory or platinum- ... ...

Abstract	Background: Linsitinib, an oral, dual inhibitor of insulin-like growth factor-1 receptor and insulin receptor, in combination with weekly paclitaxel, may improve clinical outcomes compared with paclitaxel alone in patients with refractory or platinum-resistant ovarian cancer. Patients and methods: This open-label phase 1/2 clinical trial (NCT00889382) randomized patients with refractory or platinum-resistant ovarian cancer (1:1:1) to receive either oral intermittent linsitinib (600mg once daily on Days 1-3 per week) combined with paclitaxel (80mg/m Results: A total of 152 women were randomized to treatment (n=51 Arm A; n=51 Arm B, n=50 Arm C). In combination with paclitaxel, neither intermittent linsitinib (median PFS 2.8months; 95% confidence interval [CI]:2.5-4.4) nor continuous linsitinib (median PFS 4.2months; 95% CI:2.8-5.1) improved PFS over weekly paclitaxel alone (median PFS 5.6months; 95% CI:3.2-6.9). No improvement in ORR, DCR, or OS in either linsitinib dosing schedule was observed compared with paclitaxel alone. Adverse event (AE) rates, including all-grade and grade 3/4 treatment-related AEs, and treatment-related AEs leading to discontinuation, were higher among patients receiving intermittent linsitinib compared with the other treatment arms. Conclusion: Addition of intermittent or continuous linsitinib with paclitaxel did not improve outcomes in patients with platinum-resistant/refractory ovarian cancer compared with paclitaxel alone.
Mesh-Begriff(e)	Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Carcinoma, Ovarian Epithelial ; Drug Administration Schedule ; Drug Resistance, Neoplasm ; Female ; Humans ; Imidazoles/administration & dosage ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/pathology ; Neoplasms, Glandular and Epithelial/drug therapy ; Neoplasms, Glandular and Epithelial/pathology ; Organoplatinum Compounds/pharmacology ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/pathology ; Paclitaxel/administration & dosage ; Pyrazines/administration & dosage ; Treatment Outcome ; Young Adult
Chemische Substanzen	3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol ; Imidazoles ; Organoplatinum Compounds ; Pyrazines ; Paclitaxel (P88XT4IS4D)
Sprache	Englisch
Erscheinungsdatum	2018-02-14
Erscheinungsland	United States
Dokumenttyp	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2018.01.019
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer.

Ciuleanu, Tudor-Eliade / Ahmed, Samreen / Kim, Joo-Hang / Mezger, Jörg / Park, Keunchil / Thomas, Michael / Chen, Jihong / Poondru, Srinivasu / VanTornout, Jan M / Whitcomb, Debbie / Blackhall, Fiona

British journal of cancer

2017 Band 117, Heft 6, Seite(n) 757–766

Abstract: Background: Maintenance therapy is important in advanced/metastatic non-small cell lung cancer (NSCLC). Erlotinib as switch maintenance following platinum-based chemotherapy increases survival. Cross-talk between the epidermal growth factor receptor and ...

Abstract	Background: Maintenance therapy is important in advanced/metastatic non-small cell lung cancer (NSCLC). Erlotinib as switch maintenance following platinum-based chemotherapy increases survival. Cross-talk between the epidermal growth factor receptor and insulin-like growth factor receptor (IGFR) pathways mediate resistance to individual receptor blockade. This study compared maintenance linsitinib plus erlotinib vs erlotinib plus placebo in patients with NSCLC. Methods: In this Phase II randomised trial, patients without progression following four cycles of first-line platinum-based chemotherapy (N=205) received continuous schedule maintenance oral linsitinib 150 mg or placebo BID combined with erlotinib 150 mg QD for 21-day cycles. The primary endpoint was progression-free survival (PFS). Results: The study was unblinded early due to linsitinib non-superiority. No difference was found between the two treatment groups in median PFS of 125 days linsitinib vs 129 days placebo (P=0.601); no difference in overall survival (OS) was observed. Tolerability was similar, although in the linsitinib group, treatment-related adverse events and discontinuations were more frequent. No drug-drug interaction was implicated. Conclusions: Linsitinib maintenance therapy added to erlotinib did not improve PFS or OS in non-progressing NSCLC patients. This highlights the need for robust biomarkers of response for combinations that incorporate IGFR-targeted therapies in maintenance or other therapeutic settings.
Mesh-Begriff(e)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/pathology ; Erlotinib Hydrochloride/adverse effects ; Erlotinib Hydrochloride/therapeutic use ; Female ; Humans ; Imidazoles/adverse effects ; Imidazoles/therapeutic use ; Kaplan-Meier Estimate ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Maintenance Chemotherapy ; Male ; Middle Aged ; Placebos/therapeutic use ; Platinum Compounds/therapeutic use ; Pyrazines/adverse effects ; Pyrazines/therapeutic use ; Receptors, Somatomedin/antagonists & inhibitors ; Receptors, Somatomedin/genetics
Chemische Substanzen	3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol ; Imidazoles ; Placebos ; Platinum Compounds ; Pyrazines ; Receptors, Somatomedin ; Erlotinib Hydrochloride (DA87705X9K)
Sprache	Englisch
Erscheinungsdatum	2017-08-03
Erscheinungsland	England
Dokumenttyp	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/bjc.2017.226
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors.

Macaulay, Valentine M / Middleton, Mark R / Eckhardt, S Gail / Rudin, Charles M / Juergens, Rosalyn A / Gedrich, Richard / Gogov, Sven / McCarthy, Sean / Poondru, Srinivasu / Stephens, Andrew W / Gadgeel, Shirish M

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

2016 Band 22, Heft 12, Seite(n) 2897–2907

Abstract: Purpose: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, ... ...

Abstract	Purpose: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib. Experimental design: This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1-3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100-150 mg once daily; and a non-small cell lung cancer (NSCLC) expansion cohort. Results: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug-drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study >12 weeks. Conclusions: The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897-907. ©2016 AACR.
Mesh-Begriff(e)	Adult ; Aged ; Aged, 80 and over ; Antigens, CD ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Dose-Response Relationship, Drug ; Erlotinib Hydrochloride/adverse effects ; Erlotinib Hydrochloride/pharmacokinetics ; Erlotinib Hydrochloride/therapeutic use ; Female ; Humans ; Imidazoles/adverse effects ; Imidazoles/pharmacokinetics ; Imidazoles/therapeutic use ; Lung Neoplasms/drug therapy ; Male ; Maximum Tolerated Dose ; Middle Aged ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/therapeutic use ; Pyrazines/adverse effects ; Pyrazines/pharmacokinetics ; Pyrazines/therapeutic use ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Insulin/antagonists & inhibitors ; Receptors, Somatomedin/antagonists & inhibitors ; Young Adult
Chemische Substanzen	3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol ; Antigens, CD ; Antineoplastic Agents ; IGF1R protein, human ; Imidazoles ; Protein Kinase Inhibitors ; Pyrazines ; Receptors, Somatomedin ; Erlotinib Hydrochloride (DA87705X9K) ; EGFR protein, human (EC 2.7.10.1) ; INSR protein, human (EC 2.7.10.1) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Receptor, Insulin (EC 2.7.10.1)
Sprache	Englisch
Erscheinungsdatum	2016-02-01
Erscheinungsland	United States
Dokumenttyp	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; 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-15-2218
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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