29 results on '"Joe J. Stephenson"'
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2. Supplementary Table 3 from A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer
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Neil J. Clendeninn, Heiko Krissel, Prabhu Rajagopalan, Kimberly J. Manhard, David M. Wilson, Sonny Gunawan, Li-Tain Yeh, Zancong Shen, Jeffrey N. Miner, Cory Iverson, Diane P. Leffingwell, Lawrence Garbo, Morris Sherman, Aram F. Hezel, Joe J. Stephenson, Carlos H.R. Becerra, Fadi Braiteh, Anthony El-Khoueiry, Donald A. Richards, and Alex A. Adjei
- Abstract
Overview of dose-limiting toxicities and adverse events leading to discontinuation and relationship to study treatment
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- 2023
3. Supplementary Table 5 from A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer
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Neil J. Clendeninn, Heiko Krissel, Prabhu Rajagopalan, Kimberly J. Manhard, David M. Wilson, Sonny Gunawan, Li-Tain Yeh, Zancong Shen, Jeffrey N. Miner, Cory Iverson, Diane P. Leffingwell, Lawrence Garbo, Morris Sherman, Aram F. Hezel, Joe J. Stephenson, Carlos H.R. Becerra, Fadi Braiteh, Anthony El-Khoueiry, Donald A. Richards, and Alex A. Adjei
- Abstract
Refametinib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2
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- 2023
4. Supplementary Table 1 from A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer
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Neil J. Clendeninn, Heiko Krissel, Prabhu Rajagopalan, Kimberly J. Manhard, David M. Wilson, Sonny Gunawan, Li-Tain Yeh, Zancong Shen, Jeffrey N. Miner, Cory Iverson, Diane P. Leffingwell, Lawrence Garbo, Morris Sherman, Aram F. Hezel, Joe J. Stephenson, Carlos H.R. Becerra, Fadi Braiteh, Anthony El-Khoueiry, Donald A. Richards, and Alex A. Adjei
- Abstract
Incidence of treatment-emergent adverse events, all grades, occurring in {greater than or equal to}20% of patients in either cohort
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- 2023
5. Supplementary Figure 2 from A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer
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Neil J. Clendeninn, Heiko Krissel, Prabhu Rajagopalan, Kimberly J. Manhard, David M. Wilson, Sonny Gunawan, Li-Tain Yeh, Zancong Shen, Jeffrey N. Miner, Cory Iverson, Diane P. Leffingwell, Lawrence Garbo, Morris Sherman, Aram F. Hezel, Joe J. Stephenson, Carlos H.R. Becerra, Fadi Braiteh, Anthony El-Khoueiry, Donald A. Richards, and Alex A. Adjei
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CTC enumeration and pERK analysis in course 1
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- 2023
6. Supplementary Figure 1 from A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer
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Neil J. Clendeninn, Heiko Krissel, Prabhu Rajagopalan, Kimberly J. Manhard, David M. Wilson, Sonny Gunawan, Li-Tain Yeh, Zancong Shen, Jeffrey N. Miner, Cory Iverson, Diane P. Leffingwell, Lawrence Garbo, Morris Sherman, Aram F. Hezel, Joe J. Stephenson, Carlos H.R. Becerra, Fadi Braiteh, Anthony El-Khoueiry, Donald A. Richards, and Alex A. Adjei
- Abstract
pERK levels in hair follicles by dose level and course
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- 2023
7. Supplementary Table 4 from A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer
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Neil J. Clendeninn, Heiko Krissel, Prabhu Rajagopalan, Kimberly J. Manhard, David M. Wilson, Sonny Gunawan, Li-Tain Yeh, Zancong Shen, Jeffrey N. Miner, Cory Iverson, Diane P. Leffingwell, Lawrence Garbo, Morris Sherman, Aram F. Hezel, Joe J. Stephenson, Carlos H.R. Becerra, Fadi Braiteh, Anthony El-Khoueiry, Donald A. Richards, and Alex A. Adjei
- Abstract
Refametinib geometric mean (% coefficient of variation) single-dose pharmacokinetic data on day 1 of course 1
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- 2023
8. Supplementary Table 6 from A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer
- Author
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Neil J. Clendeninn, Heiko Krissel, Prabhu Rajagopalan, Kimberly J. Manhard, David M. Wilson, Sonny Gunawan, Li-Tain Yeh, Zancong Shen, Jeffrey N. Miner, Cory Iverson, Diane P. Leffingwell, Lawrence Garbo, Morris Sherman, Aram F. Hezel, Joe J. Stephenson, Carlos H.R. Becerra, Fadi Braiteh, Anthony El-Khoueiry, Donald A. Richards, and Alex A. Adjei
- Abstract
Sorafenib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2
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- 2023
9. Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations
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Heiko Maacke, Helen Evans, Michael Thomas, Philippe L. Bedard, Martijn P. Lolkema, Filip Janku, Joe J. Stephenson, Daniel Shao-Weng Tan, Jordi Rodon, Aditya Bardia, Cristiana Sessa, Yongjian Sun, Mrinal M. Gounder, Patricia LoRusso, and Martin Schuler
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0301 basic medicine ,MAPK/ERK pathway ,Neuroblastoma RAS viral oncogene homolog ,Adult ,Male ,Cancer Research ,Combination therapy ,Morpholines ,Buparlisib ,Medizin ,Phase Ib ,Aminopyridines ,New Drug Development and Clinical Pharmacology ,medicine.disease_cause ,Binimetinib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ovarian cancer ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Protein Kinase Inhibitors ,Response Evaluation Criteria in Solid Tumors ,EGFR inhibitors ,Aged ,business.industry ,MEK inhibitor ,RAS/RAF ,Middle Aged ,3. Good health ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Benzimidazoles ,Female ,KRAS ,business - Abstract
Background This multicenter, open‐label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3‐kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations. Materials and Methods Eighty‐nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0‐2. Binimetinib and buparlisib combinations were explored in patients with KRAS‐, NRAS‐, or BRAF‐mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)‐mutant, advanced non‐small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS‐ or BRAF‐mutant ovarian cancer; or advanced non‐small cell lung cancer with KRAS mutation. Results At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF‐mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies. Conclusion Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose‐limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies. Implications for Practice Because dysregulation of the mitogen‐activated protein kinase (MAPK) and the phosphatidylinositol 3‐kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single‐agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways., This article reports on the safety and efficacy of binimetinib and buparlisib combination therapy in patients with advanced solid tumors harboring selected genomic alterations in the RAS/RAF pathway.
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- 2019
10. Diagnostic accuracy and performance of artificial intelligence in measuring left atrial volumes and function on multiphasic CT in patients with atrial fibrillation.
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Aquino GJ, Chamberlin J, Yacoub B, Kocher MR, Kabakus I, Akkaya S, Mercer M, Waltz J, Fiegel M, Leaphart N, Jacob A, Gulsun MA, Gilkes J, Stephenson J, Sharma P, Sahbaee P, Schoepf J, Zimmerman S, Field ME, Agha AM, and Burt JR
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- Aged, Artificial Intelligence, Heart Atria diagnostic imaging, Humans, Middle Aged, Retrospective Studies, Tomography, X-Ray Computed methods, Atrial Fibrillation diagnostic imaging
- Abstract
Objectives: To evaluate the effectiveness of a novel artificial intelligence (AI) algorithm for fully automated measurement of left atrial (LA) volumes and function using cardiac CT in patients with atrial fibrillation., Methods: We included 79 patients (mean age 63 ± 12 years; 35 with atrial fibrillation (AF) and 44 controls) between 2017 and 2020 in this retrospective study. Images were analyzed by a trained AI algorithm and an expert radiologist. Left atrial volumes were obtained at cardiac end-systole, end-diastole, and pre-atrial contraction, which were then used to obtain LA function indices. Intraclass correlation coefficient (ICC) analysis of the LA volumes and function parameters was performed and receiver operating characteristic (ROC) curve analysis was used to compare the ability to detect AF patients., Results: The AI was significantly faster than manual measurement of LA volumes (4 s vs 10.8 min, respectively). Agreement between the manual and automated methods was good to excellent overall, and there was stronger agreement in AF patients (all ICCs ≥ 0.877; p < 0.001) than controls (all ICCs ≥ 0.799; p < 0.001). The AI comparably estimated LA volumes in AF patients (all within 1.3 mL of the manual measurement), but overestimated volumes by clinically negligible amounts in controls (all by ≤ 4.2 mL). The AI's ability to distinguish AF patients from controls using the LA volume index was similar to the expert's (AUC 0.81 vs 0.82, respectively; p = 0.62)., Conclusion: The novel AI algorithm efficiently performed fully automated multiphasic CT-based quantification of left atrial volume and function with similar accuracy as compared to manual quantification. Novel CT-based AI algorithm efficiently quantifies left atrial volumes and function with similar accuracy as manual quantification in controls and atrial fibrillation patients., Key Points: • There was good-to-excellent agreement between manual and automated methods for left atrial volume quantification. • The AI comparably estimated LA volumes in AF patients, but overestimated volumes by clinically negligible amounts in controls. • The AI's ability to distinguish AF patients from controls was similar to the manual methods., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)
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- 2022
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11. First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors.
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Papadopoulos KP, Gluck L, Martin LP, Olszanski AJ, Tolcher AW, Ngarmchamnanrith G, Rasmussen E, Amore BM, Nagorsen D, Hill JS, and Stephenson J Jr
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- Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal blood, Dose-Response Relationship, Drug, Female, Humans, Interleukin-1 blood, Macrophage Colony-Stimulating Factor blood, Macrophage Colony-Stimulating Factor genetics, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms genetics, Neoplasms pathology, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor blood, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor immunology, Treatment Outcome, Antibodies, Monoclonal administration & dosage, Drug-Related Side Effects and Adverse Reactions pathology, Neoplasms drug therapy, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor antagonists & inhibitors
- Abstract
Purpose: Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820. Experimental Design: Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal. Results: Twenty-five patients received ≥1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose-limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade ≥3 treatment-related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%). Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. Clin Cancer Res; 23(19); 5703-10. ©2017 AACR ., (©2017 American Association for Cancer Research.)
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- 2017
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12. Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer.
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Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, Schelman WR, Stephenson J Jr, Chiorean EG, Rosen PJ, Ulrich B, Dragovich T, Del Prete SA, Rarick M, Eng C, Kroll S, and Ryan DP
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Disease Progression, Disease-Free Survival, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging, Nitroimidazoles administration & dosage, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Phosphoramide Mustards administration & dosage, Proportional Hazards Models, Time Factors, Treatment Outcome, United States, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy
- Abstract
Purpose: TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer., Patients and Methods: Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety., Results: Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation., Conclusion: PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979)., (© 2014 by American Society of Clinical Oncology.)
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- 2015
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13. Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer.
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Tebbutt N, Kotasek D, Burris HA, Schwartzberg LS, Hurwitz H, Stephenson J, Warner DJ, Chen L, Hsu CP, and Goldstein D
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Camptothecin administration & dosage, Camptothecin analogs & derivatives, Colorectal Neoplasms metabolism, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Fluorouracil administration & dosage, Humans, Indoles administration & dosage, Indoles pharmacokinetics, Leucovorin administration & dosage, Male, Middle Aged, Niacinamide administration & dosage, Niacinamide analogs & derivatives, Niacinamide pharmacokinetics, Oligonucleotides, Organoplatinum Compounds administration & dosage, Panitumumab, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms drug therapy
- Abstract
Purpose: This study assessed the safety, efficacy, and pharmacokinetics of motesanib, a multitargeted small molecule angiogenesis inhibitor, with and without panitumumab, in combination with FOLFIRI or FOLFOX in patients with metastatic colorectal cancer (mCRC)., Methods: This open-label, phase 1b, two-part, multicenter study in patients with mCRC and ≤1 prior treatment evaluated escalating doses (50, 75, 100, or 125 mg QD, 75 mg BID) of motesanib with panitumumab and chemotherapy (Part 1) and the target dose of motesanib with chemotherapy (Part 2)., Results: At 17 sites in the USA and Australia, 119 patients were enrolled between December 2004 and February 2010. In Part 1 [motesanib plus panitumumab/FOLFIRI (n = 36) or plus panitumumab/FOLFOX (n = 17)], all motesanib doses tested were tolerated and 125 mg QD was deemed the target dose. Following toxicity results for combination therapy in other trials, panitumumab was withdrawn from the study. Part 2 evaluated motesanib 125 mg with chemotherapy [FOLFIRI (n = 37); FOLFOX (n = 29)]. The primary endpoint, objective response rate in patients with measurable disease by RECIST, was 20 % overall and was higher among patients receiving first-line (27 % overall; FOLFOX, 24 %; FOLFIRI, 27 %) compared with second-line therapy (14 % overall; FOLFOX, 0 %; FOLFIRI, 20 %). The most common adverse events were diarrhea, nausea, fatigue, and hypertension. We observed a low rate of cholecystitis [3 of 119 (2.5 %)], a known adverse event of motesanib and other small molecule VEGF inhibitors., Conclusions: Motesanib 125 mg QD in combination with FOLFIRI or FOLFOX chemotherapy was tolerated and demonstrated modest efficacy in first-/second-line mCRC.
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- 2015
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14. Sequential ofatumumab and lenalidomide for the treatment of relapsed and refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.
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Costa LJ, Fanning SR, Stephenson J Jr, Afrin LB, Kistner-Griffin E, Bentz TA, and Stuart RK
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- Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Drug Combinations, Drug Resistance, Neoplasm drug effects, Female, Humans, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Neutropenia chemically induced, Thalidomide adverse effects, Thalidomide therapeutic use, Thrombocytopenia chemically induced, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Immunologic Factors therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Thalidomide analogs & derivatives
- Abstract
Ofatumumab is a fully human anti-CD20 monoclonal antibody with enhanced antibody dependent and complement dependent cytotoxicity. Lenalidomide induces T cell and natural killer (NK) cell activation and in vitro enhances clearance of chronic lymphocytic leukemia (CLL) cells by monoclonal antibodies. We performed a multi-center, phase 2 trial of sequential treatment with ofatumumab and lenalidomide in patients with advanced, relapsed and refractory (R/R) CLL, consisting of ofatumumab 2000 mg intravenously on day 1 and lenalidomide 10 mg on days 8-28, for up to six cycles. Twenty-one subjects were included with median age of 63 years and two prior lines of therapy. The overall response rate was 47.6% and 23.8% had stable disease. Median overall survival was 21.5 months. Neutropenia and thrombocytopenia were the most frequent adverse events. Tumor flare reaction occurred in 43% of subjects. Intracycle sequential ofatumumab plus lenalidomide is active in high-risk R/R CLL and well tolerated except for frequent cytopenias.
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- 2015
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15. An innovative, multi-arm, complete phase 1b study of the novel anti-cancer agent tasisulam in patients with advanced solid tumors.
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Jotte RM, Von Hoff DD, Braiteh F, Becerra CR, Richards DA, Smith DA, Garbo L, Stephenson J, Conkling PR, Robert-Vizcarrondo F, Chen J, Turner PK, Chow KH, Tai DF, and Ilaria R Jr
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Benzamides administration & dosage, Benzamides adverse effects, Benzamides blood, Benzamides pharmacokinetics, Cisplatin administration & dosage, Cisplatin adverse effects, Dacarbazine administration & dosage, Dacarbazine adverse effects, Dacarbazine analogs & derivatives, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine analogs & derivatives, Docetaxel, Erlotinib Hydrochloride, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms metabolism, Quinazolines administration & dosage, Quinazolines adverse effects, Sulfonamides administration & dosage, Sulfonamides adverse effects, Sulfonamides blood, Sulfonamides pharmacokinetics, Taxoids administration & dosage, Taxoids adverse effects, Temozolomide, Young Adult, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasms drug therapy
- Abstract
Background: This phase Ib study used a parallel, multi-arm design to examine tasisulam-sodium (hereafter tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development., Methods: Patients received escalating doses of tasisulam (3 + 3 schema; target Cmax 300-400 μg/mL) every 28 days plus 1,000 mg/m(2) gemcitabine HCl (days 1 and 15), 60 mg/m(2) docetaxel, 200 mg/m(2)/day temozolomide, 75 mg/m(2) cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*μg/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*μg/mL for gemcitabine and erlotinib)., Results: A total of 234 patients were enrolled. The safety profile of tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade ≥3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm., Conclusions: The multi-arm design allowed the efficient determination of the maximum tolerated dose of tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.
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- 2015
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16. Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer.
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Van Cutsem E, Eng C, Nowara E, Swieboda-Sadlej A, Tebbutt NC, Mitchell E, Davidenko I, Stephenson J, Elez E, Prenen H, Deng H, Tang R, McCaffery I, Oliner KS, Chen L, Gansert J, Loh E, Smethurst D, and Tabernero J
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Female, Follow-Up Studies, Humans, Liver Neoplasms mortality, Liver Neoplasms secondary, Male, Middle Aged, Mutation genetics, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Panitumumab, Prognosis, Proto-Oncogene Proteins p21(ras), Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms drug therapy, Liver Neoplasms drug therapy, Neoplasm Recurrence, Local drug therapy, Proto-Oncogene Proteins genetics, ras Proteins genetics
- Abstract
Purpose: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC., Experimental Design: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work., Results: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints., Conclusions: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC., (©2014 American Association for Cancer Research.)
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- 2014
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17. Effects of Esomeprazole on the Pharmacokinetics of Lapatinib in Breast Cancer Patients.
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Koch KM, Im YH, Kim SB, Urruticoechea Ribate A, Stephenson J, Botbyl J, Cartee L, Holshouser J, and Ridgway D
- Abstract
The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate., (© 2013, The American College of Clinical Pharmacology.)
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- 2013
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18. A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors.
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Heath EI, Infante J, Lewis LD, Luu T, Stephenson J, Tan AR, Kasubhai S, LoRusso P, Ma B, Suttle AB, Kleha JF, Ball HA, and Dar MM
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- Adult, Aged, Algorithms, Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors pharmacokinetics, Anti-Bacterial Agents pharmacokinetics, Aza Compounds pharmacokinetics, Blood Pressure drug effects, Confidence Intervals, Double-Blind Method, Electrocardiography, Ambulatory, Female, Fluoroquinolones, Heart Rate drug effects, Humans, Indazoles, Long QT Syndrome chemically induced, Long QT Syndrome physiopathology, Male, Middle Aged, Moxifloxacin, Neoplasms drug therapy, Neoplasms physiopathology, Pyrimidines administration & dosage, Pyrimidines pharmacokinetics, Quinolines pharmacokinetics, Sulfonamides administration & dosage, Sulfonamides pharmacokinetics, Young Adult, Angiogenesis Inhibitors adverse effects, Heart Conduction System drug effects, Neoplasms complications, Pyrimidines adverse effects, Sulfonamides adverse effects
- Abstract
Purpose: As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer., Methods: This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2-8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms., Results: Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90% confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90% CI: -2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval., Conclusions: Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.
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- 2013
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19. Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors.
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Nemunaitis J, Mita A, Stephenson J, Mita MM, Sarantopoulos J, Padmanabhan-Iyer S, Nanda N, Gleich L, Benichou AC, and Craig A
- Subjects
- Adult, Aged, Antineoplastic Agents, Phytogenic adverse effects, Antineoplastic Agents, Phytogenic pharmacokinetics, Female, Half-Life, Harringtonines adverse effects, Harringtonines blood, Harringtonines pharmacokinetics, Hematologic Neoplasms pathology, Homoharringtonine, Humans, Injections, Subcutaneous, Long QT Syndrome chemically induced, Male, Middle Aged, Neoplasms pathology, Neutropenia chemically induced, Thrombocytopenia chemically induced, Tissue Distribution, Antineoplastic Agents, Phytogenic administration & dosage, Harringtonines administration & dosage, Hematologic Neoplasms drug therapy, Neoplasms drug therapy
- Abstract
Purpose: Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated efficacy and safety in phase 1/2 trials in patients previously treated with ≥1 tyrosine kinase inhibitor. This study assessed pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers., Methods: Omacetaxine 1.25 mg/m(2) SC was administered BID, days 1-14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity. Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites. Adverse events, including QT interval prolongation, were recorded. Tumor response was assessed at cycle 2 completion., Results: Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients. Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 h, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m(2). Plasma concentration versus time data demonstrated biexponential decay; mean steady-state terminal half-life was 7 h. Concentrations of inactive metabolites 4'-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively. Urinary excretion of unchanged omacetaxine accounted for <15 % of the dose. Grade 3/4 drug-related adverse events included thrombocytopenia (48 %) and neutropenia (33 %). Two grade 2 increases in QTc interval (>470 ms) were observed and were not correlated with omacetaxine plasma concentration. No objective responses were observed., Conclusions: Omacetaxine is well absorbed after SC administration. Therapeutic plasma concentrations were achieved with 1.25 mg/m(2) BID, supporting clinical development of this dose and schedule.
- Published
- 2013
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20. MG98, a second-generation DNMT1 inhibitor, in the treatment of advanced renal cell carcinoma.
- Author
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Amato RJ, Stephenson J, Hotte S, Nemunaitis J, Bélanger K, Reid G, and Martell RE
- Subjects
- Adult, Aged, Carcinoma, Renal Cell mortality, DNA (Cytosine-5-)-Methyltransferase 1, Disease-Free Survival, Humans, Kidney Neoplasms mortality, Middle Aged, Oligodeoxyribonucleotides adverse effects, Thionucleotides adverse effects, Carcinoma, Renal Cell drug therapy, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, Kidney Neoplasms drug therapy, Oligodeoxyribonucleotides therapeutic use, Thionucleotides therapeutic use
- Abstract
Background: In carcinogenesis, methylation of DNA promoter regions results in inactivation of tumor-suppressing genes. MG98 was designed to inhibit DNA methyltransferases enzyme 1 production., Methods: This multicenter study explored two schedules of MG98 with Interferon-α-2β to identify schedule and dose for patients with metastatic RCC., Results: Doses of IFN 9 MIU/MG98 125 mg/m(2) for a continuous schedule and IFN 9 MIU/MG98 200 mg/m(2) for an intermittent schedule were considered the MTDs. Treatment resulted in one PR and eight SD., Conclusion: MG98 combined with IFN was safe and resulted in clinical activity.
- Published
- 2012
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21. Phase I/II trial of custirsen (OGX-011), an inhibitor of clusterin, in combination with a gemcitabine and platinum regimen in patients with previously untreated advanced non-small cell lung cancer.
- Author
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Laskin JJ, Nicholas G, Lee C, Gitlitz B, Vincent M, Cormier Y, Stephenson J, Ung Y, Sanborn R, Pressnail B, Nugent F, Nemunaitis J, Gleave ME, Murray N, and Hao D
- Subjects
- Adenocarcinoma mortality, Adenocarcinoma secondary, Adult, Aged, Carboplatin administration & dosage, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung secondary, Carcinoma, Squamous Cell mortality, Carcinoma, Squamous Cell secondary, Cisplatin administration & dosage, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Female, Follow-Up Studies, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Oligonucleotides, Antisense therapeutic use, Survival Rate, Treatment Outcome, Gemcitabine, Adenocarcinoma drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Squamous Cell drug therapy, Lung Neoplasms drug therapy, Neoplasm Recurrence, Local drug therapy, Thionucleotides therapeutic use
- Abstract
Purpose: Clusterin (CLU), an antiapoptotic, stress-associated protein, confers resistance to therapy when overexpressed. This trial tested custirsen (OGX-011), an inhibitor of CLU protein production, combined with gemcitabine/platinum in patients with advanced non-small cell lung cancer (NSCLC)., Patients and Methods: This was a single-arm, multicenter, phase I/II study in chemotherapy-naive stage IIIB/IV NSCLC. Custirsen was infused during a loading dose period and weekly in combination with gemcitabine (1250 mg/m) on days 1 and 8 and with cisplatin (75 mg/m) or carboplatin (area under the curve 5) on day 1 of each 21-day cycle. Ten patients were treated in a phase I lead-in and 71 in the phase II component. The primary efficacy endpoint was response rate, with exploratory analyses of other efficacy outcomes and biomarker relationships., Results: Eighty-one patients received custirsen and were included in the primary analysis. The median age was 61 years; 82% had stage IV disease. Overall response was 25 of 81 (31%; 95% confidence interval 21-42). The 1- and 2-year survivals were 54 and 30%, respectively. Toxicity of the combination was not appreciably different from what is reported for gemcitabine/platinum combinations. Custirsen treatment decreased serum CLU levels in 95% of patients evaluated. Patients who achieved a minimum median CLU level for the population of ≤38 μg/ml during treatment had a median survival of 27.1 compared with 16.1 months for patients who did not (p = 0.02)., Conclusion: Based on the above results, a randomized phase 3 trial to evaluate the survival benefit of custirsen in patients with NSCLC is warranted.
- Published
- 2012
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22. A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma.
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Hwang TH, Moon A, Burke J, Ribas A, Stephenson J, Breitbach CJ, Daneshmand M, De Silva N, Parato K, Diallo JS, Lee YS, Liu TC, Bell JC, and Kirn DH
- Subjects
- Adult, Aged, Female, Humans, Male, Melanoma pathology, Middle Aged, Neoplasm Metastasis, Poxviridae physiology, Transgenes, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Melanoma therapy, Oncolytic Virotherapy, Poxviridae genetics
- Abstract
JX-594 is a targeted and granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In order to study the mechanisms-of-action (MOA) of JX-594 in humans, a mechanistic proof-of-concept clinical trial was performed at a low dose equivalent to ≤10% of the maximum-tolerated dose (MTD) in other clinical trials. Ten patients with previously treated stage IV melanoma were enrolled. Tumors were injected weekly for up to nine total treatments. Blood samples and tumor biopsies were analyzed for evidence of transgene activity, virus replication, and immune stimulation. The β-galactosidase (β-gal) transgene was expressed in all patients as evidenced by antibody induction. Six patients had significant induction of GM-CSF-responsive white blood cell (WBC) subsets such as neutrophils (25-300% increase). JX-594 replication and subsequent shedding into blood was detectable in five patients after cycles 1-9. Tumor biopsies demonstrated JX-594 replication, perivascular lymphocytic infiltration, and diffuse tumor necrosis. Mild flu-like symptoms were the most common adverse events. In sum, JX-594 replication, oncolysis, and expression of both transgenes were demonstrated; replication was still evident after multiple cycles. These findings have implications for further clinical development of JX-594 and other transgene-armed oncolytic viruses.
- Published
- 2011
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23. Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer.
- Author
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Trump DL, Payne H, Miller K, de Bono JS, Stephenson J 3rd, Burris HA 3rd, Nathan F, Taboada M, Morris T, and Hubner A
- Subjects
- Adenocarcinoma physiopathology, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Bone Neoplasms drug therapy, Bone Neoplasms physiopathology, Bone Neoplasms secondary, Cohort Studies, Docetaxel, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Humans, Leukopenia chemically induced, Male, Middle Aged, Neutropenia chemically induced, Pain physiopathology, Prostatic Neoplasms surgery, Pyrrolidines adverse effects, Pyrrolidines pharmacokinetics, Taxoids adverse effects, Taxoids pharmacokinetics, Treatment Outcome, Adenocarcinoma drug therapy, Adenocarcinoma secondary, Antineoplastic Agents administration & dosage, Endothelin A Receptor Antagonists, Orchiectomy, Prostatic Neoplasms pathology, Pyrrolidines administration & dosage, Taxoids therapeutic use
- Abstract
Background: This two-part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer., Methods: Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Patients received once-daily oral zibotentan 10 mg (initial cohort) or 15 mg in combination with docetaxel 75 mg/m(2) (administered on day 1 of each 21-day cycle) for up to 10 cycles. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized 2:1 to receive zibotentan (at the highest tolerated dose identified in part A) plus docetaxel or placebo plus docetaxel., Results: Six patients were enrolled in part A (n = 3, zibotentan 10 mg; n = 3, zibotentan 15 mg). No dose-limiting toxicity was observed, thus zibotentan 15 mg in combination with docetaxel was evaluated in part B (n = 20, zibotentan plus docetaxel; n = 11, placebo plus docetaxel). CTCAE grade ≥3, most commonly neutropenia or leucopenia, were reported in 10 (50%) and nine (82%) patients in the zibotentan and placebo groups, respectively. One (17%) patient receiving placebo achieved complete response, two (22%) patients receiving zibotentan achieved partial response and stable disease occurred in six (67%) and three (50%) patients receiving zibotentan and placebo, respectively., Conclusions: The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development., (Copyright © 2011 Wiley-Liss, Inc.)
- Published
- 2011
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24. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans.
- Author
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Breitbach CJ, Burke J, Jonker D, Stephenson J, Haas AR, Chow LQ, Nieva J, Hwang TH, Moon A, Patt R, Pelusio A, Le Boeuf F, Burns J, Evgin L, De Silva N, Cvancic S, Robertson T, Je JE, Lee YS, Parato K, Diallo JS, Fenster A, Daneshmand M, Bell JC, and Kirn DH
- Subjects
- Adult, Aged, Aged, 80 and over, DNA, Viral blood, Female, Gene Expression Regulation, Enzymologic, Humans, Infusions, Intravenous, Male, Middle Aged, Neoplasms pathology, Neoplasms surgery, Neoplasms virology, Organisms, Genetically Modified physiology, Transgenes genetics, beta-Galactosidase genetics, beta-Galactosidase metabolism, Neoplasms therapy, Oncolytic Virotherapy, Oncolytic Viruses physiology, Poxviridae physiology
- Abstract
The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.
- Published
- 2011
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25. A phase I study of the chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer.
- Author
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Kummar S, Copur MS, Rose M, Wadler S, Stephenson J, O'Rourke M, Brenckman W, Tilton R, Liu SH, Jiang Z, Su T, Cheng YC, and Chu E
- Subjects
- Adult, Aged, Animals, Antineoplastic Combined Chemotherapy Protocols adverse effects, Camptothecin administration & dosage, Camptothecin adverse effects, Camptothecin analogs & derivatives, Camptothecin pharmacokinetics, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Drugs, Chinese Herbal adverse effects, Drugs, Chinese Herbal pharmacokinetics, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Fluorouracil pharmacokinetics, Half-Life, Humans, Irinotecan, Leucovorin administration & dosage, Leucovorin adverse effects, Leucovorin pharmacokinetics, Male, Mice, Middle Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Colorectal Neoplasms drug therapy, Drugs, Chinese Herbal administration & dosage, Phytotherapy methods
- Abstract
PHY906 is a novel Chinese herbal preparation that has been used in the Orient for over 1800 years to treat a wide range of gastrointestinal side effects including diarrhea, abdominal cramps, vomiting, fever, and headache. Preclinical and clinical studies were conducted to further investigate the biologic and clinical activities of this herbal medicine. To ensure standardization and maintain interbatch reliability of PHY906, high performance liquid chromatography (HPLC) was used to establish a "chemical fingerprint" of PHY906. In vivo preclinical studies using the murine Colon 39 tumor model showed that PHY906 protected against the weight loss associated with irinotecan treatment. In the presence of PHY906, mice were able to tolerate otherwise lethal doses of irinotecan. Significantly improved antitumor activity and overall survival were observed in animals treated with the combination of irinotecan and PHY906 versus irinotecan alone. The combination of PHY906 with irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) also resulted in at least additive antitumor activity with no increased host toxicity. Based on these in vivo studies, a phase I multicenter, double-blind, randomized, placebo-controlled, dose escalation, cross-over study of PHY906 as a modulator of the weekly, bolus regimen of irinotecan, 5-FU, and LV (IFL) in the first-line treatment of patients with advanced colorectal cancer (CRC) was conducted. The specific objectives of this clinical trial were to determine the safety and tolerability of PHY906 when administered concomitantly with the bolus, weekly IFL regimen. Treatment with PHY906 did not alter the pharmacokinetics of 5-FU, irinotecan, or the irinotecan metabolite SN-38., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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26. Safety and pharmacokinetics of motesanib in combination with panitumumab and gemcitabine-Cisplatin in patients with advanced cancer.
- Author
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Burris H, Stephenson J, Otterson GA, Stein M, McGreivy J, Sun YN, Ingram M, Ye Y, and Schwartzberg LS
- Abstract
Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin. Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m(2)) and cisplatin (75 mg/m(2)) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response. Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases.
- Published
- 2011
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27. A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma.
- Author
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Weber JS, Samlowski WE, Gonzalez R, Ribas A, Stephenson J, O'Day S, Sato T, Dorr R, Grenier K, and Hersh E
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Female, Humans, Male, Maximum Tolerated Dose, Melanoma pathology, Middle Aged, Neoplasm Metastasis, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dacarbazine administration & dosage, Hexanones administration & dosage, Melanoma drug therapy
- Abstract
Background: Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy., Methods: Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks., Results: There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports., Conclusions: Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study., (Copyright (c) 2010 American Cancer Society.)
- Published
- 2010
- Full Text
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28. Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma.
- Author
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Eager RM, Cunningham CC, Senzer NN, Stephenson J Jr, Anthony SP, O'Day SJ, Frenette G, Pavlick AC, Jones B, Uprichard M, and Nemunaitis J
- Subjects
- Adult, Aged, Disease Progression, Disease-Free Survival, Female, Humans, Male, Middle Aged, Prognosis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Boronic Acids administration & dosage, Cisplatin administration & dosage, Dipeptides administration & dosage, Melanoma drug therapy, Skin Neoplasms drug therapy
- Abstract
Background: Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties., Methods: This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75-100 mg/m2 cisplatin combined with 300-400 mcg talabostat bid for 6, 21-day cycles. The primary endpoint was overall response. The rate of complete responses, duration of overall objective response, progression-free survival (PFS), and overall survival were the secondary endpoints., Results: Six objective partial responses were recorded in the 74 patients (8.1%) in the intention-to-treat population. Five of these responses involved the 40 evaluable patients (12.5%). Thirty-one percent of patients reported SAEs to the combination of talabostat and cisplatin., Conclusion: Acceptable tolerability was observed in the intention-to-treat population and antitumor activity was observed in 12.5% of evaluable patients, which is not greater than historical expectation with cisplatin alone.
- Published
- 2009
- Full Text
- View/download PDF
29. Induction of immune responses and clinical efficacy in a phase II trial of IDM-2101, a 10-epitope cytotoxic T-lymphocyte vaccine, in metastatic non-small-cell lung cancer.
- Author
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Barve M, Bender J, Senzer N, Cunningham C, Greco FA, McCune D, Steis R, Khong H, Richards D, Stephenson J, Ganesa P, Nemunaitis J, Ishioka G, Pappen B, Nemunaitis M, Morse M, Mills B, Maples PB, Sherman J, and Nemunaitis JJ
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung immunology, Epitopes, T-Lymphocyte immunology, Female, Humans, Male, Middle Aged, Remission Induction, Cancer Vaccines immunology, Cancer Vaccines therapeutic use, Carcinoma, Non-Small-Cell Lung prevention & control, Carcinoma, Non-Small-Cell Lung secondary, Lung Neoplasms immunology, Lung Neoplasms prevention & control, T-Lymphocytes, Cytotoxic immunology
- Abstract
Purpose: Generation of broad cytotoxic T-lymphocyte responses against multiple epitopes and tumor-associated antigens (TAAs) may provide effective immunotherapy in patients with cancer. We evaluated a single-vial peptide vaccine consisting of nine HLA-A2 supertype-binding epitopes (two native and seven analog epitopes modified for optimal HLA binding or T-cell receptor stimulation) covering five TAAs and the universal helper pan-DR epitope, formulated as a stable emulsion with incomplete Freund's adjuvant (Montanide ISA 51; Seppic SA, Paris, France). The clinical efficacy, safety, and multiepitope immunogenicity of IDM-2101 was evaluated in patients with stage IIIB or IV non-small-cell lung cancer (NSCLC)., Patients and Methods: A total of 63 patients were enrolled who were positive for HLA-A2. End points included survival, safety, and immune response. IDM-2101 (previously EP-2101) was administered every 3 weeks for the first 15 weeks, then every 2 months through year 1, then quarterly through year 2, for a total of 13 doses. Epitope-specific cytotoxic and helper T-lymphocyte immunogenic responses were measured by the interferon gamma enzyme-linked immunosorbent spot assay., Results: No significant adverse events were noted. Low-grade erythema and pain at the injection site were the most common adverse effects. One-year survival in the treated patients was 60%, and median survival was 17.3 months. One complete and one partial response were identified. Survival was longer in patients demonstrating an immune response to epitope peptides (P < .001)., Conclusion: IDM-2101 was well tolerated, and evidence of efficacy was suggested.
- Published
- 2008
- Full Text
- View/download PDF
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