23 results on '"Boral AL"'
Search Results
2. Bortezomib in multiple myeloma.
- Author
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Cecchi M, Caccese E, Messori A, Vandenbroucke JP, Kroep JR, Richardson PG, Boral AL, and Anderson KC
- Published
- 2005
3. Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF © ) and determination of a threshold score for moderate symptoms.
- Author
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Shields AL, Taylor F, Lamoureux RE, Padilla B, Severson K, Green T, Boral AL, Akin C, Siebenhaar F, and Mar B
- Subjects
- Humans, Female, Middle Aged, Male, Quality of Life, Prospective Studies, Symptom Assessment, Psychometrics, Mastocytosis, Systemic diagnosis
- Abstract
Background: The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (©Blueprint Medicines Corporation), a 12-item daily diary that assesses 11 signs and symptoms of indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), was psychometrically evaluated among patients with ISM. Additionally, thresholds of the ISM-SAF total symptom score (TSS) to distinguish patients with moderate to severe symptoms from those with mild symptoms were evaluated., Methods: The ISM-SAF was completed daily as an electronic diary in a prospective, observational study utilizing an online survey of patients with ISM in the United States. Descriptive statistics, psychometric analyses, and analyses to estimate ISM-SAF TSS clinical cutoff values were conducted., Results: A total of 103 patients (81.6% female; mean age = 50.2 [± 12.6]) with a self-reported diagnosis of ISM or SSM (58 of whom also had a medically documented diagnosis) contributed to the analyses. Psychometric analysis supported the trustworthiness of the biweekly TSS, which was reliable (α > 0.8, ICC > 0.9), construct-valid, and able to distinguish among clinically distinct groups as specified by the Patient Global Impression of Severity, 12-item Short-Form Health Survey, and Mastocytosis Quality of Life Questionnaire (p < 0.01). A biweekly ISM-SAF TSS from 21 to 28 begins to distinguish the moderately to severely symptomatic ISM/SSM patients from mildly symptomatic patients., Conclusion: The biweekly TSS of ISM-SAF was reliable, construct-valid, and able to distinguish among clinically distinct groups. A cut-off value of 28 is a conservative threshold that can be used for screening purposes in future clinical studies to identify patients with at least a moderate severity of ISM symptoms., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
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4. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.
- Author
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Griesinger F, Curigliano G, Thomas M, Subbiah V, Baik CS, Tan DSW, Lee DH, Misch D, Garralda E, Kim DW, van der Wekken AJ, Gainor JF, Paz-Ares L, Liu SV, Kalemkerian GP, Houvras Y, Bowles DW, Mansfield AS, Lin JJ, Smoljanovic V, Rahman A, Kong S, Zalutskaya A, Louie-Gao M, Boral AL, and Mazières J
- Subjects
- Humans, Proto-Oncogene Proteins c-ret genetics, Pyrazoles therapeutic use, Pyrimidines adverse effects, Adolescent, Adult, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Background: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study., Patients and Methods: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety., Results: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs., Conclusions: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending., Competing Interests: Disclosure FG has consulted or provided expert opinion for Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda; has received fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda; and has received funding for scientific research from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda. GC has consulted and/or had advisory roles for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Foundation Medicine, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seattle Genetics; served on speakers’ bureaus for Daiichi Sankyo, Foundation Medicine, Lilly, Novartis, Pfizer, Roche/Genentech, and Samsung; received travel, accommodations, and expenses from Pfizer, Roche/Genentech; received honoraria from Ellipses Pharma and research funding from Merck; and is supported by the OPTIMA [grant number 101034347]. MT has received honoraria for scientific meetings (self) from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; advisory-board honoraria (self) from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; travelling support (self) from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; and has received research funding (institution) from AstraZeneca, BMS, Roche, and Takeda. VS reports research funding/grant support for clinical trials from AbbVie, Agensys, Alfa-sigma, Altum, Amgen, Bayer, Berg Health, Biotherapeutics, Blueprint Medicines Corporation, Boston Biomedical, Boston Pharmaceuticals, Celgene, D3, Dragonfly Therapeutics, Exelixis, Fujifilm, GSK, Idera Pharma, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, Nanocarrier, National Comprehensive Cancer Network, NCI-CTEP, Novartis, Northwest Biotherapeutics, Pfizer, PharmaMar, Roche/Genentech, Takeda, Turning Point Therapeutics, UT MD Anderson Cancer Center, and Vegenics; travel support from ASCO, ESMO, Helsinn, Incyte, Novartis, and PharmaMar; consultancy/advisory board participation for Helsinn, Incyte, Loxo Oncology/Eli Lilly, MedImmune, Novartis, R-Pharma US, QED Pharma; and other relationship with Medscape. CSB has received consulting fees from AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Turning Point Therapeutics, Guardant, Regeneron, Silverback, and Takeda; and has received research funding to their institution from AbbVie, AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Genentech Inc., Janssen, Lilly, Loxo Oncology, Novartis, Pfizer, Rain Therapeutics, Spectrum Pharmaceuticals, and Turning Point Therapeutics. DSWT has consulted and/or had advisory roles for AstraZeneca, Bayer, Lilly, Loxo Oncology, Merrimack, Novartis, Pfizer, and Takeda; received honoraria from Boehringer Ingelheim, Merck, and Roche; and research funding to their institution from AstraZeneca, Bayer, GSK, and Novartis. DHL has received personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, CJ Healthcare, Genexine, Janssen, Lilly, Merck, Menarini, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, and Takeda; and non-financial support from Blueprint Medicines Corporation and Takeda. DM has consulted and/or had advisory roles at scientific meetings for AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi, and Takeda (institution, no personal honoraria). EG has consulted and/or had advisory roles for Alkermes, BMS, Boehringer Ingelheim, Ellipses Pharma, Janssen, NeoMed, Roche, Seattle Genetics, TFS, Thermo Fisher Scientific; served on speakers’ bureaus for MSD, Roche, and Thermo Fisher Scientific; received travel and accommodation expenses from BMS, Glycotope GmbH, Menarini, and MSD; research funding to their institution from Novartis, Roche, and Thermo Fisher Scientific; and is supported by a grant from the ‘la Caixa’ Foundation [grant number LCF/PR/CE07/50610001]. DWK has received travel and accommodation expenses from Amgen and Daiichi Sankyo; and research funding to their institution from Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. AJvdW reports research funding/grant support for clinical trials from AstraZeneca [grant number ESR-16-12212], Boehringer Ingelheim, Pfizer, Roche, and Takeda [grant number 2019N0853/2020N0366]; and consultancy/advisory board participation for AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Pfizer, Roche, and Takeda. JFG has an immediate family member who is an employee of Ironwood Pharmaceuticals; has consulted and/or had advisory roles for Agios, Amgen, Array BioPharma, Blueprint Medicines Corporation, BMS, Genentech, Gilead Sciences, Jounce Therapeutics, Lilly, Loxo Oncology, Merck, Mirati, Silverback Therapeutics, GlydeBio, Moderna Therapeutics, Oncorus, Regeneron, Takeda, and Theravance; has stock and ownership in Ironwood Pharmaceuticals; has received honoraria from ARIAD, Incyte, Merck, Novartis, Pfizer, and Takeda; and research funding from Adaptimmune, ALX Oncology, ARIAD, Array BioPharma, AstraZeneca, Blueprint Medicines Corporation, BMS, Genentech, Jounce Therapeutics, Merck, Novartis, and Tesaro. LPA has a leadership role in ALTUM Sequencing and Genomica; served on speakers’ bureaus for AstraZeneca, BMS, Lilly, MSD Oncology, Merck Serono, Pfizer, Roche/Genentech; received travel, accommodation, and expenses from AstraZeneca, BMS, MSD, Pfizer, Roche, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Blueprint Medicines Corporation, BMS, Celgene, Ipsen, Lilly, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Servier, and Takeda; research funding to their institution from AstraZeneca, BMS, Kura Oncology, MSD, and PharmaMar; other relationships with Roche; and an immediate family member has other relationships with Amgen, Ipsen, Merck Novartis, Pfizer, Sanofi, Servier, and Roche. SVL served as a consultant or advisory board member to Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines Corporation, BMS, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; received research funding (to institution) from Alkermes, Bayer, Blueprint Medicines Corporation, BMS, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT Therapeutics, Turning Point Therapeutics; and is supported by the National Cancer Institute [grant number UM1CA186691]. GPK received research grants from Blueprint Medicines Corporation, Merck, AbbVie, Takeda, Daiichi, and Cullinan. DWB served on an advisory board for Blueprint Medicines Corporation. ASM received research funding from DoD, Mark Foundation, NIH, Novartis, and Verily; honoraria to institution for participation in advisory boards: AbbVie, BeiGene, BMS, Genentech, Inc., Janssen; travel support from: Roche; is a non-remunerated member of the Mesothelioma Applied Research Foundation Board of Directors; and is supported by the Mark Foundation for Cancer Research ASPIRE Award, the National Cancer Institute [grant number R21 CA251923], and Department of Defense Concept Award [grant number W81XWH-22-1-0021]. JJL served as a compensated consultant or advisory board member for Genentech, C4 Therapeutics, Blueprint Medicines Corporation, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, and Turning Point Therapeutics; received honorarium and travel support from Pfizer; received institutional research funding from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; and received CME funding from OncLive, MedStar Health, and Northwell Health. VSm is an employee and/or equity holder of F. Hoffmann-La Roche, Ltd. AR is an employee and/or equity holder of F. Hoffmann-La Roche, Ltd and equity holder of Merck/MSD. SK is a former employee and/or equity holder of F. Hoffmann-La Roche, Ltd. AZ, MLG and ALB are employees and/or equity holders of Blueprint Medicines Corporation. JM has provided expertise for Amgen, AstraZeneca, Blueprint Medicines Corporation, BMS, Daiichi Sankyo, Hengrui, MSD, Novartis, Pierre Fabre, Roche, and Takeda; and received research funding from AstraZeneca, BMS, Pierre Fabre, and Roche. YH has declared no conflicts of interest. Data sharing The anonymized derived data from this study that underlie the results reported in this article will be made available, beginning 12 months and ending 5 years after this article’s publication, to any investigators who sign a data access agreement and provide a methodologically sound proposal to medinfo@blueprintmedicines.com. The trial protocol will also be made available, as will a data fields dictionary., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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5. Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) in a phase 2 clinical study.
- Author
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Padilla B, Shields AL, Taylor F, Li X, Mcdonald J, Green T, Boral AL, Lin HM, Akin C, Siebenhaar F, and Mar B
- Subjects
- Female, Humans, Male, Middle Aged, Psychometrics, Pyrazoles, Pyrroles, Quality of Life, Reproducibility of Results, Severity of Illness Index, Surveys and Questionnaires, Symptom Assessment, Triazines, Mastocytosis, Systemic diagnosis
- Abstract
Background: Indolent systemic mastocytosis (ISM) is a rare, clonal mast cell neoplasm characterized by severe, unpredictable symptoms. The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) items compose a Total Symptom Score (TSS), Gastrointestinal Symptom Score (GSS), and Skin Symptom Score (SSS) to assess symptom severity. This study evaluated the psychometric performance of ISM-SAF among ISM patients., Methods: In PIONEER, a Phase 2 trial evaluating safety and efficacy of selective kinase inhibitor avapritinib in patients with ISM, the 12-item ISM-SAF was administered daily. Psychometric evaluation of score reliability, validity, and clinical interpretation was conducted using the trial data., Results: Thirty-eight patients contributed to analyses (78.9% female; mean age = 49). Baseline internal consistency reliability (α) for bi-weekly TSS, GSS, and SSS was 0.86, 0.83, and 0.82, respectively. Test-retest reliability among patients exhibiting no change in Patient Global Impression of Symptom Severity (PGIS) between Baseline and Day 15 exceeded 0.74 universally. Construct validity and known-groups analysis showed moderate to strong ISM-SAF score correlation (r = 0.382-0.881) to supportive patient-reported questionnaires (e.g., PGIS and Mastocytosis Quality of Life Questionnaire) symptom and skin scores, and ability to distinguish among clinically unique groups. Correlations of ISM-SAF and other assessment change scores reflect evidence of score sensitivity. Clinically important difference and response estimates were 7-10 and 19, respectively., Discussion: ISM-SAF produced reliable, construct-valid, sensitive scores when administered in PIONEER to patients in the target population. Results of this study support the use of the ISM-SAF as a reliable and valid measure to evaluate disease symptomology in ISM patients. Trial registration ClinicalTrials.gov, NCT03731260. Registered 10 October 2018, https://clinicaltrials.gov/ct2/show/study/NCT03731260 ., (© 2021. The Author(s).)
- Published
- 2021
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6. Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF © .
- Author
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Taylor F, Akin C, Lamoureux RE, Padilla B, Green T, Boral AL, Mazar I, Mar B, Shields AL, and Siebenhaar F
- Subjects
- Humans, Patient Reported Outcome Measures, Surveys and Questionnaires, Mastocytosis, Systemic diagnosis
- Abstract
Background: Advanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations. To fill that gap, this study documents the development and content validity of instruments evaluating signs and symptoms of systemic mastocytosis., Methods: A review of peer-reviewed literature, advice meetings with clinical therapeutic area experts, patient concept elicitation interviews, concept selection and questionnaire construction meetings, and patient cognitive debriefing interviews were conducted, and regulatory feedback was incorporated., Results: For AdvSM, 26 sign- and symptom-level concepts were identified in literature, 39 by clinicians, and 33 by patients. For ISM/SSM, 38 sign- and symptom-level concepts were identified in the literature, 39 by clinicians, and 57 by patients. Two patient-reported instruments, the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) and Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF)(©Blueprint Medicines Corporation), were developed based on consolidated findings. Cognitive debriefing interviews with AdvSM and ISM patients showed the AdvSM-SAF and ISM-SAF were understood and interpreted as intended by the majority of patients., Conclusion: The AdvSM-SAF and ISM-SAF are content-valid tools measuring symptoms from AdvSM and ISM patients' perspective., (© 2021. The Author(s).)
- Published
- 2021
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7. Psychometric evaluation of the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF).
- Author
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Taylor F, Li X, Yip C, Padilla B, Mar B, Green T, Oren R, Boral AL, Lin HM, Shields AL, and Gotlib J
- Subjects
- Female, Follow-Up Studies, Humans, Male, Mastocytosis, Systemic epidemiology, Middle Aged, Prognosis, Reproducibility of Results, Surveys and Questionnaires, United Kingdom epidemiology, United States epidemiology, Mastocytosis, Systemic diagnosis, Mastocytosis, Systemic psychology, Psychometrics methods, Quality of Life, Severity of Illness Index, Symptom Assessment methods
- Abstract
Background: The Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) was developed to evaluate symptoms of advanced systemic mastocytosis (AdvSM). This study aimed to psychometrically evaluate AdvSM-SAF scores and provide score interpretation guidelines., Methods: The 10-item AdvSM-SAF was administered daily (scored as a seven-day average) in EXPLORER, an open-label Phase 1 study in AdvSM. Score distribution, reliability, construct-related validity, sensitivity to change, and interpretation guidelines were evaluated for AdvSM-SAF items, gastrointestinal symptom score (GSS), skin symptom score (SSS), and total symptom score (TSS)., Results: Thirty-one patients contributed to the analyses. At Baseline, the GSS, SSS, and TSS had adequate internal consistency (α > 0.7) and test-retest reliability (intraclass correlation coefficients >0.7). AdvSM-SAF scores were moderately to strongly correlated with variables as expected, and distinguished among clinically distinct groups. Observed relationships between change scores in the AdvSM-SAF and other assessments reflect evidence that AdvSM-SAF scores change in concert with other assessments designed to measure similar constructs. The magnitude of AdvSM-SAF weekly TSS mean change scores based on different anchor groupings was as expected (improvement > stable > worsening). Candidate clinically meaningful between-group difference estimates (GSS = 2-4, SSS = 2-3, and TSS = 4-7 points) and within-person change estimates (GSS = 6-9, SSS = 1-4, TSS = 9-14) for AdvSM-SAF weekly scores were generated., Conclusion: The AdvSM-SAF produced reliable, construct-valid, and sensitive scores when administered in the target patient population. These results, along with its strong development history and evidence of content validity, indicate that the AdvSM-SAF is fit for the purpose of measuring treatment benefit in individuals with AdvSM., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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8. Ceritinib in patients with advanced anaplastic lymphoma kinase-rearranged anaplastic large-cell lymphoma.
- Author
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Richly H, Kim TM, Schuler M, Kim DW, Harrison SJ, Shaw AT, Boral AL, Yovine A, and Solomon B
- Subjects
- Adult, Anaplastic Lymphoma Kinase, Female, Humans, Lymphoma, Large-Cell, Anaplastic genetics, Male, Middle Aged, Receptor Protein-Tyrosine Kinases genetics, Treatment Outcome, Young Adult, Antineoplastic Agents therapeutic use, Lymphoma, Large-Cell, Anaplastic drug therapy, Pyrimidines therapeutic use, Sulfones therapeutic use
- Published
- 2015
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9. Ceritinib in ALK-rearranged non-small-cell lung cancer.
- Author
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Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, and Engelman JA
- Subjects
- Adult, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, Female, Humans, Lung Neoplasms genetics, Lung Neoplasms mortality, Male, Maximum Tolerated Dose, Middle Aged, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Pyrimidines adverse effects, Pyrimidines pharmacokinetics, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Recombination, Genetic, Sulfones adverse effects, Sulfones pharmacokinetics, Treatment Outcome, Young Adult, Carcinoma, Non-Small-Cell Lung drug therapy, Drug Resistance, Neoplasm genetics, Lung Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Pyrimidines administration & dosage, Receptor Protein-Tyrosine Kinases genetics, Sulfones administration & dosage
- Abstract
Background: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies., Methods: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib., Results: A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5)., Conclusions: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).
- Published
- 2014
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10. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.
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Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, Li J, Tompkins C, Pferdekamper A, Steffy A, Cheng J, Kowal C, Phung V, Guo G, Wang Y, Graham MP, Flynn S, Brenner JC, Li C, Villarroel MC, Schultz PG, Wu X, McNamara P, Sellers WR, Petruzzelli L, Boral AL, Seidel HM, McLaughlin ME, Che J, Carey TE, Vanasse G, and Harris JL
- Subjects
- Acyltransferases, Animals, Axin Protein antagonists & inhibitors, Blotting, Western, Cell Line, Tumor, Cloning, Molecular, High-Throughput Screening Assays, Humans, Mice, Mutagenesis, Phosphorylation drug effects, Pyrazines therapeutic use, Pyridines therapeutic use, Radioligand Assay, Rats, Receptors, Notch genetics, Reverse Transcriptase Polymerase Chain Reaction, Membrane Proteins antagonists & inhibitors, Neoplasms drug therapy, Pyrazines pharmacology, Pyridines pharmacology, Wnt Signaling Pathway drug effects
- Abstract
Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.
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- 2013
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11. Potential biomarkers of bortezomib activity in mantle cell lymphoma from the phase 2 PINNACLE trial.
- Author
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Goy A, Bernstein SH, McDonald A, Pickard MD, Shi H, Fleming MD, Bryant B, Trepicchio W, Fisher RI, Boral AL, and Mulligan G
- Subjects
- Adult, Aged, Aged, 80 and over, Bortezomib, Cyclin-Dependent Kinase Inhibitor p27, Female, Humans, Intracellular Signaling Peptides and Proteins metabolism, Male, Middle Aged, NF-kappa B metabolism, Proteasome Endopeptidase Complex metabolism, Retrospective Studies, Survival Rate, Treatment Outcome, Antineoplastic Agents therapeutic use, Biomarkers, Tumor metabolism, Boronic Acids therapeutic use, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell metabolism, Pyrazines therapeutic use
- Abstract
Immunohistochemical analyses of archival tumor specimens were used for pre-planned exploratory analyses of protocol-specified candidate biomarkers of bortezomib activity in 73 patients with relapsed/refractory mantle cell lymphoma in the phase 2 PINNACLE study. Consistent with other studies, elevated Ki-67 was a marker of poor prognosis, demonstrating significant associations with shorter time to progression and overall survival. Elevated NF-kappaB p65 and low PSMA5 expression demonstrated a trend for better response and were significantly associated with longer time to progression; elevated NF-kappaB p65 demonstrated a trend toward longer overall survival. This is consistent with myeloma clinical genomics research, suggesting biomarker relevance across tumor types. Elevated p27 was significantly associated with longer overall survival. Overall survival analyses by International Prognostic Index and Mantle Cell Lymphoma International Prognostic Index confirmed differential prognosis by both scores. These biomarkers data begin to illuminate bortezomib's mechanism of action in lymphoma.
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- 2010
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12. Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma.
- Author
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de Vos S, Goy A, Dakhil SR, Saleh MN, McLaughlin P, Belt R, Flowers CR, Knapp M, Hart L, Patel-Donnelly D, Glenn M, Gregory SA, Holladay C, Zhang T, and Boral AL
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Murine-Derived, Boronic Acids administration & dosage, Bortezomib, Feasibility Studies, Female, Humans, Male, Middle Aged, Pyrazines administration & dosage, Rituximab, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Lymphoma, B-Cell, Marginal Zone drug therapy, Lymphoma, Follicular drug therapy
- Abstract
Purpose: To determine overall response rate (ORR), time to progression (TTP), and duration of response (DOR) with twice-weekly/weekly bortezomib plus rituximab, and evaluate safety/tolerability, in patients with relapsed or refractory CD20(+) follicular lymphoma (FL) or marginal-zone lymphoma., Patients and Methods: Patients were randomly assigned (minimization method) to bortezomib 1.3 mg/m(2) twice weekly (days 1, 4, 8, and 11; 21-day cycle, five cycles; arm A) or bortezomib 1.6 mg/m(2) weekly (days 1, 8, 15, and 22; 35-day cycle, three cycles; arm B) plus rituximab 375 mg/m(2) weekly for 4 weeks (both arms). Response/progression was determined by International Workshop Response Criteria using oncologist/radiologist-adjudicated data from independent radiology review and investigator assessment., Results: Eighty-one patients (arm A, n = 41; arm B, n = 40) were enrolled. Dose-intensity was higher in arm A; mean total bortezomib received was similar between arms (18.5 and 17.1 mg/m(2)). In arm A, ORR was 49% (14% complete response [CR]/CR unconfirmed [CRu]), median TTP was 7.0 months, and median DOR was not reached. In arm B, ORR was 43% (10% CR/CRu), and median TTP/DOR were 10.0/9.3 months. The weekly combination regimen seemed better tolerated. Grade 3 or worse adverse events seemed more common in arm A (54%) versus arm B (35%), including thrombocytopenia (10% v 0%) and peripheral neuropathy (10% v 5%), but diarrhea seemed less frequent (7% v 15%). No grade 4 toxicities were reported in arm B., Conclusion: Both bortezomib plus rituximab regimens seem feasible in relapsed or refractory indolent lymphomas. The more convenient weekly combination regimen is being compared with single-agent rituximab in an ongoing phase III study in relapsed FL.
- Published
- 2009
- Full Text
- View/download PDF
13. Phase I study of the c-raf-1 antisense oligonucleotide ISIS 5132 in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.
- Author
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Fidias P, Pennell NA, Boral AL, Shapiro GI, Skarin AT, Eder JP Jr, Kwoh TJ, Geary RS, Johnson BE, Lynch TJ, and Supko JG
- Subjects
- Adult, Aged, Carboplatin administration & dosage, Carboplatin adverse effects, Carboplatin pharmacokinetics, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Paclitaxel administration & dosage, Paclitaxel adverse effects, Paclitaxel pharmacokinetics, Thionucleotides adverse effects, Thionucleotides pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Proto-Oncogene Proteins c-raf antagonists & inhibitors, Thionucleotides administration & dosage
- Abstract
Background: A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC)., Patients and Methods: Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m(2) and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC(fp)) of 5 mg . min/ml (dose level 1). The carboplatin dose was then increased to AUC(fp) 6 mg . min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m(2) (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion., Results: Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC(fp) 6 mg . min/ml, paclitaxel 175 mg/m(2), and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum., Conclusion: ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study.
- Published
- 2009
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14. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline.
- Author
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Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Bladé J, Boccadoro M, Cavenagh JD, Boral AL, Esseltine DL, Wen PY, Amato AA, Anderson KC, and San Miguel J
- Subjects
- Aged, Antineoplastic Agents adverse effects, Boronic Acids adverse effects, Bortezomib, Clinical Protocols, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multiple Myeloma complications, Multiple Myeloma mortality, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases diagnosis, Pyrazines adverse effects, Recurrence, Statistics, Nonparametric, Survival Rate, Antineoplastic Agents therapeutic use, Boronic Acids therapeutic use, Multiple Myeloma drug therapy, Peripheral Nervous System Diseases drug therapy, Pyrazines therapeutic use
- Abstract
The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline. Overall, 124/331 patients (37%) had treatment-emergent peripheral neuropathy, including 30 (9%) with grade >or=3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade >or=3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose-modification guidelines. Of patients with grade >or=2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade >or=2 peripheral neuropathy. Bortezomib-associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome.
- Published
- 2009
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15. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study.
- Author
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Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Nasta S, O'Connor OA, Shi H, Boral AL, and Fisher RI
- Subjects
- Aged, Antineoplastic Agents adverse effects, Boronic Acids adverse effects, Bortezomib, Female, Humans, Male, Middle Aged, Pyrazines adverse effects, Survival Rate, Treatment Outcome, Antineoplastic Agents therapeutic use, Boronic Acids therapeutic use, Lymphoma, Mantle-Cell drug therapy, Pyrazines therapeutic use
- Abstract
Background: We previously reported results of the phase 2, multicenter PINNACLE study, which confirmed the substantial single-agent activity of bortezomib in patients with relapsed or refractory mantle cell lymphoma (MCL)., Materials and Methods: We report updated time-to-event data, in all patients and by response to treatment, after extended follow-up (median 26.4 months)., Results: Median time to progression (TTP) was 6.7 months. Median time to next therapy (TTNT) was 7.4 months. Median overall survival (OS) was 23.5 months. In responding patients, median TTP was 12.4 months, median duration of response (DOR) was 9.2 months, median TTNT was 14.3 months, and median OS was 35.4 months. Patients achieving complete response had heterogeneous disease characteristics; among these patients, median TTP and DOR were not reached, and median OS was 36.0 months. One-year survival rate was 69% overall and 91% in responding patients. Median OS from diagnosis was 61.1 months, after median follow-up of 63.7 months. Activity was seen in patients with refractory disease and patients relapsing following high-intensity treatment. Toxicity was generally manageable., Conclusions: Single-agent bortezomib is associated with lengthy responses and notable survival in patients with relapsed or refractory MCL, with considerable TTP and TTNT in responding patients, suggesting substantial clinical benefit.
- Published
- 2009
- Full Text
- View/download PDF
16. The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma.
- Author
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Niesvizky R, Richardson PG, Rajkumar SV, Coleman M, Rosiñol L, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Boral AL, Esseltine DL, Anderson KC, and Bladé J
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Bortezomib, Chi-Square Distribution, Clinical Trials, Phase III as Topic, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Protease Inhibitors therapeutic use, Randomized Controlled Trials as Topic, Recurrence, Remission Induction, Time, Treatment Outcome, Antineoplastic Agents administration & dosage, Boronic Acids administration & dosage, Multiple Myeloma drug therapy, Protease Inhibitors administration & dosage, Pyrazines administration & dosage
- Abstract
Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone in relapsed myeloma assessed the relationship between quality of response to bortezomib (n = 315) and clinical benefit. Treatment-free interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n = 31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n = 159). CR was associated with significantly longer median TFI (24.1 vs. 6.9/6.4 months) and TTAT (27.1 vs. 13.6/14 months) versus VGPR/PR. Median TTP was similar in CR, VGPR and PR cohorts; median OS was not reached. Patients achieving MR appeared to have prolonged median TFI (3.8 vs. 2.3 months), TTAT (8.7 vs. 6.2 months), TTP (4.9 vs. 2.8 months) and OS (24.9 vs. 18.7 months) versus NR. In conclusion, bortezomib had substantial activity in relapsed myeloma patients; CR may be a surrogate marker for significant clinical benefit with bortezomib. MR appeared to be valid as a separate response category in this setting.
- Published
- 2008
- Full Text
- View/download PDF
17. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study.
- Author
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San-Miguel JF, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Bladé J, Boccadoro M, Cavenagh JD, Neuwirth R, Boral AL, Esseltine DL, and Anderson KC
- Subjects
- Aged, Antineoplastic Agents administration & dosage, Antineoplastic Agents toxicity, Boronic Acids toxicity, Bortezomib, Dexamethasone administration & dosage, Dexamethasone toxicity, Drug-Related Side Effects and Adverse Reactions, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Pyrazines toxicity, Renal Insufficiency pathology, Survival Analysis, Treatment Outcome, Boronic Acids administration & dosage, Multiple Myeloma complications, Multiple Myeloma drug therapy, Pyrazines administration & dosage, Renal Insufficiency mortality
- Abstract
Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30-50, 51-80 and >80 ml min(-1)). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl < or =50 ml min(-1) (severe-to-moderate) and >50 ml min(-1) (no/mild impairment). Response rates with bortezomib were similar (36-47%) and time to response rapid (0.7-1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl < or =50 vs >50 ml min(-1) (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl < or =50 vs >50 ml min(-1). These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.
- Published
- 2008
- Full Text
- View/download PDF
18. Bortezomib-induced tumor lysis syndrome in multiple myeloma.
- Author
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Sezer O, Vesole DH, Singhal S, Richardson P, Stadtmauer E, Jakob C, Boral AL, Esseltine DL, and Mehta J
- Subjects
- Bortezomib, Cell Proliferation, Chromosome Deletion, Dexamethasone administration & dosage, Female, Humans, Male, Multiple Myeloma genetics, Protease Inhibitors pharmacology, Proteasome Inhibitors, Recurrence, Treatment Outcome, Tumor Lysis Syndrome pathology, Antineoplastic Agents therapeutic use, Boronic Acids therapeutic use, Multiple Myeloma drug therapy, Pyrazines therapeutic use, Tumor Lysis Syndrome diagnosis
- Abstract
Tumor lysis syndrome (TLS) is exceedingly rare in multiple myeloma because of the relatively slow proliferation and response of the malignant cells. Bortezomib is a novel agent that inhibits proteasome and has shown activity against multiple myeloma. We report 8 episodes of TLS seen in 7 patients with bortezomib therapy, with or without dexamethasone, among 496 patients treated on 3 phase II multicenter studies. Biochemical abnormalities resolved with supportive therapy in 6 patients (including hemodialysis in 2) but proved fatal in 1. Clinicians should be alert for TLS in patients with myeloma with significant disease burden treated with bortezomib because of the potential for rapid onset of cell lysis with this agent.
- Published
- 2006
- Full Text
- View/download PDF
19. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma.
- Author
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Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Stadtmauer EA, O'Connor OA, Shi H, Boral AL, and Goy A
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Boronic Acids adverse effects, Bortezomib, Drug Resistance, Neoplasm, Female, Humans, Lymphoma, Mantle-Cell pathology, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Pyrazines adverse effects, Treatment Outcome, Antineoplastic Agents therapeutic use, Boronic Acids therapeutic use, Lymphoma, Mantle-Cell drug therapy, Pyrazines therapeutic use
- Abstract
Purpose: Evaluate response rate, duration of response (DOR), time-to-progression (TTP), overall survival (OS), and safety of bortezomib treatment in patients with relapsed or refractory mantle cell lymphoma (MCL)., Patients and Methods: Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 of a 21-day cycle, for up to 17 cycles. Response and progression were determined using International Workshop Response Criteria, both using data from independent radiology review and by the investigators. Primary efficacy analyses were based on data from independent radiology review., Results: In total, 155 patients were treated. Median number of prior therapies was one (range, one to three). Response rate in 141 assessable patients was 33% including 8% complete response (CR)/unconfirmed CR. Median DOR was 9.2 months. Median TTP was 6.2 months. Results by investigator assessments were similar. Median OS has not been reached after a median follow-up of 13.4 months. The safety profile of bortezomib was similar to previous experience in relapsed multiple myeloma. The most common adverse events grade 3 or higher were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). Death from causes that were considered to be treatment related was reported for 3% of patients., Conclusion: These results confirm the activity of bortezomib in relapsed or refractory MCL, with predictable and manageable toxicities. Bortezomib provides significant clinical activity in terms of durable and complete responses, and may therefore represent a new treatment option for this population with usually very poor outcome. Studies of bortezomib-based combinations in MCL are ongoing.
- Published
- 2006
- Full Text
- View/download PDF
20. Translational research: walking the bridge between idea and cure--seventeenth Bruce F. Cain Memorial Award lecture.
- Author
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Chabner BA, Boral AL, and Multani P
- Subjects
- Antineoplastic Agents therapeutic use, Clinical Trials as Topic, Combined Modality Therapy, Genetic Techniques, Humans, Neoplasms genetics, Neoplasms pathology, Neoplasms physiopathology, Neoplasms therapy, Research
- Abstract
Advances in the understanding of normal and malignant cell biology are allowing the development of biologically targeted drugs directed at specific differences between host and tumor. The array of potential new targets is vast, but drugs currently in development are targeted at cell-cycle regulators, growth factors and their receptors, signal transduction intermediates, angiogenesis, and the mechanisms that mediate apoptosis and DNA repair. Recent results raise the possibility that novel biologically targeted agents, perhaps in combination with traditional cytotoxic agents, may finally cure cancer. However, the development of a biologically targeted drug raises unique challenges in the design of clinical trials to demonstrate its efficacy, and despite the promising preclinical data that exist for most of the agents in development, the clinical trial remains the critical, final step across the bridge from basic research to clinical application. In this review, we discuss some of the challenges in the clinical development of biologically targeted agents and the implications for clinical trial design.
- Published
- 1998
21. Clinical evaluation of biologically targeted drugs: obstacles and opportunities.
- Author
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Boral AL, Dessain S, and Chabner BA
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Humans, Neoplasms, Experimental drug therapy, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic pathology, Oligonucleotides, Antisense therapeutic use, Antineoplastic Agents pharmacology, Neoplasms drug therapy
- Abstract
Recent insights into the molecular mechanisms of cancer have indicated that a variety of fundamental cellular processes are dysregulated in malignant cells. These processes include cell cycle control, signal transduction pathways, apoptosis, telomere stability, angiogenesis, and interactions with the extracellular matrix. Remarkable advances in molecular genetics, enzymology, and medicinal chemistry have permitted the design of compounds that modulate some of these processes with specificity that was unimaginable a decade ago. As these novel, biologically targeted compounds enter the clinic, they will require a strategy for clinical evaluation and development different from that used commonly for cytotoxic antineoplastic agents. This review examines the development of cancer drugs directed against angiogenesis, metastasis, signal transduction, telomerase, and molecular message (antisense), outlines strategies for the clinical testing of agents directed at these processes, and contrasts these efforts with traditional approaches to cancer drug testing.
- Published
- 1998
- Full Text
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22. Relative importance of elements within the SL3-3 virus enhancer for T-cell specificity.
- Author
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LoSardo JE, Boral AL, and Lenz J
- Subjects
- Animals, Base Sequence, DNA-Binding Proteins metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Repetitive Sequences, Nucleic Acid, Transcription, Genetic genetics, Tumor Cells, Cultured, Enhancer Elements, Genetic, Gammaretrovirus genetics, T-Lymphocytes metabolism
- Abstract
Elements within the enhancer of T-lymphomagenic SL3-3 virus were examined for their contributions to transcriptional activity in T lymphocytes and non-T cells. A region containing two sequences homologous to the enhancer core consensus sequence and a sequence homologous to the binding site for factor LVb was found to have the largest effect on activity. Evidence was obtained that suggests that the activity of this region was greater in T lymphocytes than in non-T cells and that multiple elements within it were necessary for activity. A second region, containing sequences homologous to the binding site of factor NF-I and the glucocorticoid response element, had about a twofold effect on transcription in both T lymphocytes and non-T cell lines. The twofold effect was seen whether the region containing the cores and LVb site was present or not. These results indicate that the most important region for the specificity of SL3-3 enhancer activity and, presumably, for viral leukemogenicity comprises the core elements and the LVb site. DNA-protein-binding studies demonstrated that one cellular factor, S/A-CBF, bound to both core elements, while a second cellular factor, S-CBF, bound to only one of them. In combination with earlier studies, this indicates that cells contain multiple factors that bind to the critical region.
- Published
- 1990
- Full Text
- View/download PDF
23. Identification of the SL3-3 virus enhancer core as a T-lymphoma cell-specific element.
- Author
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Boral AL, Okenquist SA, and Lenz J
- Subjects
- Animals, DNA Probes, DNA, Viral metabolism, Nuclear Proteins metabolism, Plasmids, Repetitive Sequences, Nucleic Acid, Tumor Cells, Cultured, Enhancer Elements, Genetic, Leukemia Virus, Murine genetics, Lymphoma microbiology, T-Lymphocytes microbiology
- Abstract
Transient expression assays were used to determine the sequences within the long terminal repeat (LTR) that define the high activity in T-lymphoma cells of the leukemogenic SL3-3 virus in comparison with that of the nonleukemogenic Akv virus. Each of these viruses contains sequences related to the consensus element, the enhancer core. The SL3-3 and Akv enhancer cores differ at a single base pair. Substitution of the Akv core element into the SL3-3 LTR decreased expression in T-lymphoma cells but not in other cell types. Likewise, substitution of the SL3-3 core sequence into the Akv LTR increased expression in T-lymphoma cells but not in other types of hematopoietic cells. These data indicate that the SL3-3 enhancer core sequence functions better than that of Akv in T-lymphoma cells, but in other hematopoietic cell types the two are approximately equivalent. Competition DNA-protein binding assays were used to assess what nuclear factors from T-lymphoma lines and non-T lines bound to the SL3-3 and Akv core elements. Factors were detected that bound specifically to either the SL3-3 or Akv core but not to the other. Another factor was detected that bound equally well to both. However, none of these factors was specific to T-lymphoma cells.
- Published
- 1989
- Full Text
- View/download PDF
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