36 results on '"van der Wijngaart H"'
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2. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs
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van der Velden, D.L., Hoes, L.R., van der Wijngaart, H., van Berge Henegouwen, J.M., van Werkhoven, E., Roepman, P., and Schilsky, R.L.
- Subjects
Antineoplastic agents -- Usage ,Medical protocols -- Evaluation ,Antimitotic agents -- Usage ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available.sup.1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit--defined as complete or partial response, or as stable disease beyond 16 weeks--of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making. Clinical benefit was observed in 34% of a cohort of 215 patients with cancer who received treatment with anticancer drugs outside of their approved label, in the Drug Rediscovery protocol trial., Author(s): D. L. van der Velden [sup.1] [sup.2] , L. R. Hoes [sup.1] [sup.2] [sup.3] , H. van der Wijngaart [sup.2] [sup.3] [sup.4] , J. M. van Berge Henegouwen [sup.2] [...]
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- 2019
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3. 124P Durvalumab in advanced, pre-treated microsatellite instability-high solid tumors: Results of a tumor-agnostic DRUP trial cohort
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Geurts, B.S., primary, Battaglia, T., additional, van Berge Henegouwen, J.M., additional, Zeverijn, L.J., additional, Hoes, L.R., additional, van der Wijngaart, H., additional, de Wit, G.F., additional, Roepman, P., additional, Jansen, A., additional, de Leng, W., additional, van der Noort, V., additional, Opdam, F.L., additional, Bins, A.D., additional, de Groot, J.W.B., additional, Labots, M., additional, Gelderblom, H., additional, Verheul, H.M.W., additional, and Voest, E.E., additional
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- 2022
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4. 257P Efficacy of pembrolizumab in pre-treated breast cancer harboring high mutational load 140-290 – results from the Drug Rediscovery Protocol (DRUP)
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Zeverijn, L.J., primary, Geurts, B.S., additional, van Berge Henegouwen, J.M., additional, Hoes, L.R., additional, van der Wijngaart, H., additional, de Wit, G.F., additional, Roepman, P., additional, Jansen, A., additional, de Leng, W., additional, van der Noort, V., additional, Van Ommen-Nijhof, A., additional, Gelderblom, H., additional, Verheul, H.M.W., additional, and Voest, E.E., additional
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- 2022
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5. Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer
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van Berge Henegouwen, J.M., primary, Jebbink, M., additional, Hoes, L.R., additional, van der Wijngaart, H., additional, Zeverijn, L.J., additional, van der Velden, D.L., additional, Roepman, P., additional, de Leng, W.W.J., additional, Jansen, A.M.L., additional, van Werkhoven, E., additional, van der Noort, V., additional, van der Wekken, A.J., additional, de Langen, A.J., additional, Voest, E.E., additional, Verheul, H.M.W., additional, Smit, E.F., additional, and Gelderblom, H., additional
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- 2022
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6. Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature
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Apotheek O&O&O, Cancer, MS Medische Oncologie, van Berge Henegouwen, J M, van der Wijngaart, H, Zeverijn, L J, Hoes, L R, Meertens, M, Huitema, A D R, Devriese, L A, Labots, M, Verheul, H M W, Voest, E E, Gelderblom, H, Apotheek O&O&O, Cancer, MS Medische Oncologie, van Berge Henegouwen, J M, van der Wijngaart, H, Zeverijn, L J, Hoes, L R, Meertens, M, Huitema, A D R, Devriese, L A, Labots, M, Verheul, H M W, Voest, E E, and Gelderblom, H
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- 2022
7. Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer
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Divisie Beeld & Oncologie, Pathologie Pathologen staf, Cancer, Pathologie Moleculair, Externen Med. Onco, van Berge Henegouwen, J M, Jebbink, M, Hoes, L R, van der Wijngaart, H, Zeverijn, L J, van der Velden, D L, Roepman, P, de Leng, W W J, Jansen, A M L, van Werkhoven, E, van der Noort, V, van der Wekken, A J, de Langen, A J, Voest, E E, Verheul, H M W, Smit, E F, Gelderblom, H, Divisie Beeld & Oncologie, Pathologie Pathologen staf, Cancer, Pathologie Moleculair, Externen Med. Onco, van Berge Henegouwen, J M, Jebbink, M, Hoes, L R, van der Wijngaart, H, Zeverijn, L J, van der Velden, D L, Roepman, P, de Leng, W W J, Jansen, A M L, van Werkhoven, E, van der Noort, V, van der Wekken, A J, de Langen, A J, Voest, E E, Verheul, H M W, Smit, E F, and Gelderblom, H
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- 2022
8. 1261P Trastuzumab/pertuzumab combination therapy in advanced pre-treated HER2-mutated non-small cell lung cancer: Results of a DRUP trial cohort
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van Berge Henegouwen, J., primary, Jebbink, M., additional, Hoes, L., additional, van der Wijngaart, H., additional, Zeverijn, L., additional, van der Velden, D., additional, Roepman, P., additional, de Leng, W., additional, Jansen, A., additional, van Werkhoven, E., additional, van der Noort, V., additional, van der Wekken, A.J., additional, Burgers, S., additional, Smit, E.F., additional, Verheul, H., additional, Voest, E., additional, and Gelderblom, H., additional
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- 2021
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9. 1710P Protocol waivers and consequences on treatment safety and efficacy in the Drug Rediscovery Protocol (DRUP)
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Zeverijn, L.J., van Berge Henegouwen, J.M., Geurts, B.S., de Wit, G.F., Hoes, L., van der Wijngaart, H., van der Noort, V., Huitema, A.D.R., De Vos, F.Y.F.L., Grunberg, K., Bloemendal, H., Verheul, H.M.W., Voest, E.E., and Gelderblom, H.
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- 2023
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10. Landelijke studie naar competenties van opleiders kindergeneeskunde en hun functie als rolmodel
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Shabo, G., van der Wijngaart, H., Sana, S., Scherpbier, A. J., and Gemke, R. J. B. J.
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- 2010
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11. 595P Abdominal events in targeted therapies: Report from the Drug Rediscovery Protocol (DRUP)
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Zeverijn, L.J., primary, Hoes, L.R., additional, van der Wijngaart, H., additional, van Berge Henegouwen, J.M., additional, Gelderblom, H., additional, Verheul, H.M.W., additional, and Voest, E.E., additional
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- 2020
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12. 594P The Drug Rediscovery Protocol (DRUP): Results of the first 500 treated patients
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Hoes, L.R., primary, van der Wijngaart, H., additional, van Berge Henegouwen, J.M., additional, Zeverijn, L.J., additional, van der Velden, D.L., additional, Roepman, P., additional, de Leng, W., additional, Jansen, A.M.L., additional, van Werkhoven, E., additional, Huitema, A., additional, Smit, E.F., additional, Van Herpen, C., additional, Labots, M., additional, Hoeben, A., additional, Morreau, H., additional, Lolkema, M.P., additional, Cuppen, E., additional, Gelderblom, H., additional, Verheul, H.M.W., additional, and Voest, E.E., additional
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- 2020
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13. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs
- Author
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van der Velden, D L, Hoes, L R, van der Wijngaart, H, van Berge Henegouwen, J M, van Werkhoven, E, Roepman, P, Schilsky, R L, de Leng, W W J, Huitema, A D R, Nuijen, B, Nederlof, P M, van Herpen, C M L, de Groot, D J A, Devriese, L A, Hoeben, A, de Jonge, M J A, Chalabi, M, Smit, E F, de Langen, A J, Mehra, N, Labots, M, Kapiteijn, E, Sleijfer, S, Cuppen, E, Verheul, H M W, Gelderblom, H, Voest, E E, van der Velden, D L, Hoes, L R, van der Wijngaart, H, van Berge Henegouwen, J M, van Werkhoven, E, Roepman, P, Schilsky, R L, de Leng, W W J, Huitema, A D R, Nuijen, B, Nederlof, P M, van Herpen, C M L, de Groot, D J A, Devriese, L A, Hoeben, A, de Jonge, M J A, Chalabi, M, Smit, E F, de Langen, A J, Mehra, N, Labots, M, Kapiteijn, E, Sleijfer, S, Cuppen, E, Verheul, H M W, Gelderblom, H, and Voest, E E
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- 2019
14. Personalised reimbursement : a risk-sharing model for biomarker-driven treatment of rare subgroups of cancer patients
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van Waalwijk van Doorn-Khosrovani, S B, Pisters-van Roy, A, van Saase, L, van der Graaff, M, Gijzen, J, Sleijfer, S, Hoes, L R, van Berge Henegouwen, J M, van der Wijngaart, H, van der Velden, D L, van Werkhoven, E, Retel, V P, van Harten, W H, Huitema, A D R, Timmers, L, Gelderblom, H, Verheul, H M W, Voest, E E, van Waalwijk van Doorn-Khosrovani, S B, Pisters-van Roy, A, van Saase, L, van der Graaff, M, Gijzen, J, Sleijfer, S, Hoes, L R, van Berge Henegouwen, J M, van der Wijngaart, H, van der Velden, D L, van Werkhoven, E, Retel, V P, van Harten, W H, Huitema, A D R, Timmers, L, Gelderblom, H, Verheul, H M W, and Voest, E E
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- 2019
15. Personalised reimbursement: a risk-sharing model for biomarker-driven treatment of rare subgroups of cancer patients
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Cancer, Apotheek Onderzoek, van Waalwijk van Doorn-Khosrovani, S B, Pisters-van Roy, A, van Saase, L, van der Graaff, M, Gijzen, J, Sleijfer, S, Hoes, L R, van Berge Henegouwen, J M, van der Wijngaart, H, van der Velden, D L, van Werkhoven, E, Retel, V P, van Harten, W H, Huitema, A D R, Timmers, L, Gelderblom, H, Verheul, H M W, Voest, E E, Cancer, Apotheek Onderzoek, van Waalwijk van Doorn-Khosrovani, S B, Pisters-van Roy, A, van Saase, L, van der Graaff, M, Gijzen, J, Sleijfer, S, Hoes, L R, van Berge Henegouwen, J M, van der Wijngaart, H, van der Velden, D L, van Werkhoven, E, Retel, V P, van Harten, W H, Huitema, A D R, Timmers, L, Gelderblom, H, Verheul, H M W, and Voest, E E
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- 2019
16. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs
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Pathologie Pathologen staf, Cancer, Apotheek Onderzoek, MS Medische Oncologie, CMM Groep Cuppen, CMM, Externen Med. Onco, van der Velden, D L, Hoes, L R, van der Wijngaart, H, van Berge Henegouwen, J M, van Werkhoven, E, Roepman, P, Schilsky, R L, de Leng, W W J, Huitema, A D R, Nuijen, B, Nederlof, P M, van Herpen, C M L, de Groot, D J A, Devriese, L A, Hoeben, A, de Jonge, M J A, Chalabi, M, Smit, E F, de Langen, A J, Mehra, N, Labots, M, Kapiteijn, E, Sleijfer, S, Cuppen, E, Verheul, H M W, Gelderblom, H, Voest, E E, Pathologie Pathologen staf, Cancer, Apotheek Onderzoek, MS Medische Oncologie, CMM Groep Cuppen, CMM, Externen Med. Onco, van der Velden, D L, Hoes, L R, van der Wijngaart, H, van Berge Henegouwen, J M, van Werkhoven, E, Roepman, P, Schilsky, R L, de Leng, W W J, Huitema, A D R, Nuijen, B, Nederlof, P M, van Herpen, C M L, de Groot, D J A, Devriese, L A, Hoeben, A, de Jonge, M J A, Chalabi, M, Smit, E F, de Langen, A J, Mehra, N, Labots, M, Kapiteijn, E, Sleijfer, S, Cuppen, E, Verheul, H M W, Gelderblom, H, and Voest, E E
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- 2019
17. Drug Rediscovery Protocol: Expanded use of existing anticancer drugs
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Voest, E.E., primary, van der Velden, D.L., additional, Hoes, L., additional, Van Der Wijngaart, H., additional, Van Berge Henegouwen, M., additional, Van Werkhoven, E., additional, Roepman, P., additional, Huitema, A.D.R., additional, van Herpen, C., additional, de Groot, D.J., additional, Devriese, L., additional, de Jonge, M.J.A., additional, Chalabi, M., additional, Smit, E.F., additional, Mehra, N., additional, Labots, M., additional, Sleijfer, S., additional, Cuppen, E., additional, Verheul, H.M.W., additional, and Gelderblom, H., additional
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- 2019
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18. Personalised reimbursement: a risk-sharing model for biomarker-driven treatment of rare subgroups of cancer patients
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van Waalwijk van Doorn-Khosrovani, S.B., primary, Pisters-van Roy, A., additional, van Saase, L., additional, van der Graaff, M., additional, Gijzen, J., additional, Sleijfer, S., additional, Hoes, L.R., additional, van Berge Henegouwen, J.M., additional, van der Wijngaart, H., additional, van der Velden, D.L., additional, van Werkhoven, E., additional, Retel, V.P., additional, van Harten, W.H., additional, Huitema, A.D.R., additional, Timmers, L., additional, Gelderblom, H., additional, Verheul, H.M.W., additional, and Voest, E.E., additional
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- 2019
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19. Expanding the use of approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP)
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Voest, E., primary, van der Velden, D., additional, Hoes, L., additional, Bloemendal, H., additional, Grunberg, K., additional, Huitema, A.D.R., additional, Lugtenburg, E., additional, De Vos, F., additional, van Herpen, C., additional, de Groot, D.J.A., additional, Hamberg, P., additional, Smit, E., additional, Cuppen, E., additional, Steeghs, N., additional, Sleijfer, S., additional, Verheul, H., additional, Gelderblom, H., additional, and van der Wijngaart, H., additional
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- 2017
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20. Expanding the use of approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP)
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van der Velden, D., primary, Hoes, L., additional, van der Wijngaart, H., additional, Bloemendal, H., additional, Grunberg, K., additional, Huitema, A., additional, Lugtenburg, E., additional, De Vos, F., additional, Herpen, C.M.L., additional, de Groot, D.J., additional, Hamberg, P., additional, Smit, E., additional, Cuppen, E., additional, Steeghs, N., additional, Sleijfer, S., additional, Verheul, H.M., additional, Gelderblom, H., additional, and Voest, E., additional
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- 2017
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21. LBA27 - Drug Rediscovery Protocol: Expanded use of existing anticancer drugs
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Voest, E.E., van der Velden, D.L., Hoes, L., Van Der Wijngaart, H., Van Berge Henegouwen, M., Van Werkhoven, E., Roepman, P., Huitema, A.D.R., van Herpen, C., de Groot, D.J., Devriese, L., de Jonge, M.J.A., Chalabi, M., Smit, E.F., Mehra, N., Labots, M., Sleijfer, S., Cuppen, E., Verheul, H.M.W., and Gelderblom, H.
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- 2019
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22. 2O - Expanding the use of approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP)
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Voest, E., van der Velden, D., Hoes, L., Bloemendal, H., Grunberg, K., Huitema, A.D.R., Lugtenburg, E., De Vos, F., van Herpen, C., de Groot, D.J.A., Hamberg, P., Smit, E., Cuppen, E., Steeghs, N., Sleijfer, S., Verheul, H., Gelderblom, H., and van der Wijngaart, H.
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- 2017
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23. LBA59_PR - Expanding the use of approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP)
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van der Velden, D., Hoes, L., van der Wijngaart, H., Bloemendal, H., Grunberg, K., Huitema, A., Lugtenburg, E., De Vos, F., Herpen, C.M.L., de Groot, D.J., Hamberg, P., Smit, E., Cuppen, E., Steeghs, N., Sleijfer, S., Verheul, H.M., Gelderblom, H., and Voest, E.
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- 2017
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24. Bariatric surgery does not cure all type 2 diabetes
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Jadoon, K. A., primary, Van der Wijngaart, H. A., additional, and Olczak, S. A, additional
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- 2009
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25. The Innate Immune Landscape of dMMR/MSI Cancers Predicts the Outcome of Nivolumab Treatment: Results from the Drug Rediscovery Protocol.
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Zeverijn LJ, Geurts BS, Battaglia TW, van Berge Henegouwen JM, de Wit GF, Hoes LR, van der Wijngaart H, van der Noort V, Roepman P, de Leng WWJ, Jansen AML, Chalabi M, van Herpen CML, Devriese LA, Erdkamp FLG, Labots M, de Jonge MJA, Kerver ED, Bins AD, Leek LVM, Notohardjo JCL, van den Eertwegh AJM, Wessels LFA, Verheul HMW, Gelderblom H, van de Haar J, and Voest EE
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- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Antineoplastic Agents, Immunological therapeutic use, Biomarkers, Tumor genetics, DNA Mismatch Repair, Immune Checkpoint Inhibitors therapeutic use, Prognosis, Treatment Outcome, Prospective Studies, Immunity, Innate drug effects, Microsatellite Instability, Neoplasms drug therapy, Neoplasms immunology, Neoplasms genetics, Neoplasms mortality, Nivolumab therapeutic use, Nivolumab administration & dosage
- Abstract
Purpose: The treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid mismatch repair deficiency/microsatellite-instable (dMMR/MSI) tumors, and in-depth biomarker analyses were performed to inform precision immunotherapy approaches., Patients and Methods: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol, a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response or stable disease ≥16 weeks). Whole-genome sequencing and RNA sequencing were performed on pretreatment tumor biopsies., Results: A total of 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% [95% confidence interval (CI), 53-70], with an objective response in 45% (95% CI, 36-54). After a median follow-up of 14.5 months (95% CI, 13-19), the median progression-free survival was 18 months (95% CI, 9-not reached), and the median overall survival was not reached. Whereas CB was not, or only weakly, associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, in which markers of adaptive immunity dominated the biomarker landscape., Conclusions: Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of a good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor type-specific biomarkers for guiding immunotherapy., (©2024 American Association for Cancer Research.)
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- 2024
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26. Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol.
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Geurts BS, Zeverijn LJ, Leek LVM, van Berge Henegouwen JM, Hoes LR, van der Wijngaart H, van der Noort V, van de Haar J, van Ommen-Nijhof A, Kok M, Roepman P, Jansen AML, de Leng WWJ, de Jonge MJA, Hoeben A, van Herpen CML, Westgeest HM, Wessels LFA, Verheul HMW, Gelderblom H, and Voest EE
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Antineoplastic Agents, Immunological therapeutic use, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized administration & dosage, Biomarkers, Tumor genetics, Mutation, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology, Neoplasms immunology, Whole Genome Sequencing
- Abstract
Purpose: To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing-based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234)., Patients and Methods: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer cohort harboring a TML of 140 to 290, cohort B: tumor-agnostic cohort harboring a TML of 140 to 290, and cohort C: tumor-agnostic cohort harboring a TML >290. Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint was clinical benefit [CB; objective response or stable disease (SD) ≥16 weeks]. Pretreatment tumor biopsies were obtained for whole-genome sequencing and RNA sequencing., Results: Seventy-two evaluable patients with 26 different histotypes were enrolled. The CB rate was 13% in cohort A [3/24 with partial response (PR)], 21% in cohort B (3/24 with SD; 2/24 with PR), and 42% in cohort C (4/24 with SD; 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohorts A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, whereas in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated., Conclusions: Although pembrolizumab lacked activity in cohort A, cohorts B and C met the study's primary endpoint. Further research is warranted to refine the selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity. See related commentary by Hsu and Yen, p. 3652., (©2024 American Association for Cancer Research.)
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- 2024
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27. Maximizing Treatment Opportunities: Assessing Protocol Waivers' Impact on Safety and Outcome in the Drug Rediscovery Protocol.
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van Berge Henegouwen JM, Zeverijn LJ, Geurts BS, Hoes LR, van der Wijngaart H, van der Noort V, Huitema ADR, de Vos FYF, Grünberg K, Bloemendal HJ, Verheul HMW, Voest EE, and Gelderblom H
- Subjects
- Humans, Female, Male, Middle Aged, Aged, Treatment Outcome, Adult, Research Design, Patient Selection, Immunotherapy methods, Immunotherapy adverse effects, Molecular Targeted Therapy adverse effects, Molecular Targeted Therapy methods, Neoplasms drug therapy
- Abstract
Purpose: Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain. In the Drug Rediscovery Protocol (DRUP), protocol exceptions are frequently requested and occasionally granted. Here we describe the impact of these waivers on treatment safety and efficacy., Experimental Design: DRUP is a multicenter, nonrandomized clinical basket trial treating patients with therapy-refractory cancer with molecularly targeted and immunotherapies outside their registered indications (NCT02925234). Here, all granted waivers were revised, analyzed in terms of safety and efficacy outcome, and comparedwithoutcomes of includedpatientswho didnot receive awaiver., Results: Between September 1, 2016, and September 1, 2021, protocol waivers were granted for 82 patients (8%) of 1,019 included patients in DRUP. Most waivers (45%) were granted for general- or drug-related eligibility criteria; other categories were out-of-window testing, treatment, and testing exceptions. Serious adverse event rate was similar between patients who received a waiver (pW) and patients who did not (pNW): 39% vs. 41%, respectively (P = 0.81). The clinical benefit (either objective response or stable disease ≥ 16 weeks) rate of pW was 40% versus 33% in pNW (P = 0.43)., Conclusions: Safety and clinical benefit were preserved in patients for whom a waiver was granted. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options. See related commentary by Waqar and Govindan, p. 3655., (©2024 American Association for Cancer Research.)
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- 2024
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28. Characterization of discordance between mismatch repair deficiency and microsatellite instability testing may prevent inappropriate treatment with immunotherapy.
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Geurts BS, Zeverijn LJ, van Berge Henegouwen JM, van der Wijngaart H, Hoes LR, de Wit GF, Spiekman IA, Battaglia TW, van Beek DM, Roepman P, Jansen AM, de Leng WW, Broeks A, Labots M, van Herpen CM, Gelderblom H, Verheul HM, Snaebjornsson P, and Voest EE
- Subjects
- Humans, Female, Male, Middle Aged, Aged, Immunotherapy methods, Whole Genome Sequencing, Adult, Biomarkers, Tumor genetics, Neoplasms genetics, Neoplasms therapy, Neoplasms pathology, Aged, 80 and over, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Colorectal Neoplasms therapy, Microsatellite Instability, DNA Mismatch Repair, Immune Checkpoint Inhibitors therapeutic use
- Abstract
In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS. Therefore, we aimed to evaluate the discordance rate between routine dMMR/MSI diagnostics and WGS and to further characterize discordant cases. We assessed patients enrolled in DRUP with dMMR/MSI-positive tumors identified by routine diagnostics, who were treated with immune checkpoint blockade (ICB) and for whom WGS data were available. Patient and tumor characteristics, study treatment outcomes, and material from routine care were retrieved from the patient medical records and via Palga (the Dutch Pathology Registry), and were compared with WGS results. Initially, discordance between routine dMMR/MSI diagnostics and WGS was observed in 13 patients (13/121; 11%). The majority of these patients did not benefit from ICB (11/13; 85%). After further characterization, we found that in six patients (5%) discordance was caused by dMMR tumors that did not harbor an MSI molecular phenotype by WGS. In six patients (5%), discordance was false due to the presence of multiple primary tumors (n = 3, 2%) and misdiagnosis of dMMR status by immunohistochemistry (n = 3, 2%). In one patient (1%), the exact underlying cause of discordance could not be identified. Thus, in this group of patients limited to those initially diagnosed with dMMR/MSI tumors by current routine diagnostics, the true assay-based discordance rate between routine dMMR/MSI-positive diagnostics and WGS was 5%. To prevent inappropriate ICB treatment, clinicians and pathologists should be aware of the risk of multiple primary tumors and the limitations of different tests. © 2024 The Pathological Society of Great Britain and Ireland., (© 2024 The Pathological Society of Great Britain and Ireland.)
- Published
- 2024
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29. Candidate biomarkers for treatment benefit from sunitinib in patients with advanced renal cell carcinoma using mass spectrometry-based (phospho)proteomics.
- Author
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van der Wijngaart H, Beekhof R, Knol JC, Henneman AA, de Goeij-de Haas R, Piersma SR, Pham TV, Jimenez CR, Verheul HMW, and Labots M
- Abstract
The tyrosine kinase inhibitor sunitinib is an effective first-line treatment for patients with advanced renal cell carcinoma (RCC). Hypothesizing that a functional read-out by mass spectrometry-based (phospho, p-)proteomics will identify predictive biomarkers for treatment outcome of sunitinib, tumor tissues of 26 RCC patients were analyzed. Eight patients had primary resistant (RES) and 18 sensitive (SENS) RCC. A 78 phosphosite signature (p < 0.05, fold-change > 2) was identified; 22 p-sites were upregulated in RES (unique in RES: BCAR3, NOP58, EIF4A2, GDI1) and 56 in SENS (35 unique). EIF4A1/EIF4A2 were differentially expressed in RES at the (p-)proteome and, in an independent cohort, transcriptome level. Inferred kinase activity of MAPK3 (p = 0.026) and EGFR (p = 0.045) as determined by INKA was higher in SENS. Posttranslational modifications signature enrichment analysis showed that different p-site-centric signatures were enriched (p < 0.05), of which FGF1 and prolactin pathways in RES and, in SENS, vanadate and thrombin treatment pathways, were most significant. In conclusion, the RCC (phospho)proteome revealed differential p-sites and kinase activities associated with sunitinib resistance and sensitivity. Independent validation is warranted to develop an assay for upfront identification of patients who are intrinsically resistant to sunitinib., (© 2023. The Author(s).)
- Published
- 2023
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30. Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials.
- Author
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Zeverijn LJ, Looze EJ, Thavaneswaran S, van Berge Henegouwen JM, Simes RJ, Hoes LR, Sjoquist KM, van der Wijngaart H, Sebastian L, Geurts BS, Lee CK, de Wit GF, Espinoza D, Roepman P, Lin FP, Jansen AML, de Leng WWJ, van der Noort V, Leek LVM, de Vos FYFL, van Herpen CML, Gelderblom H, Verheul HMW, Thomas DM, and Voest EE
- Subjects
- Humans, Female, Cyclins, Australia, Precision Medicine, Aminopyridines therapeutic use, Cyclin D, Cyclin-Dependent Kinase 4, Protein Kinase Inhibitors pharmacology, Cyclin-Dependent Kinase 6, DNA Helicases, Nuclear Proteins, Neoplasms drug therapy, Breast Neoplasms drug therapy
- Abstract
The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible., (© 2023 UICC.)
- Published
- 2023
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31. Advancing wide implementation of precision oncology: A liquid nitrogen-free snap freezer preserves molecular profiles of biological samples.
- Author
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van der Wijngaart H, Jagga S, Dekker H, de Goeij R, Piersma SR, Pham TV, Knol JC, Zonderhuis BM, Holland HJ, Jiménez CR, Verheul HMW, Vanapalli S, and Labots M
- Subjects
- Humans, Precision Medicine, Freezing, RNA, Cryopreservation methods, Neoplasms genetics
- Abstract
Purpose: In precision oncology, tumor molecular profiles guide selection of therapy. Standardized snap freezing of tissue biospecimens is necessary to ensure reproducible, high-quality samples that preserve tumor biology for adequate molecular profiling. Quenching in liquid nitrogen (LN
2 ) is the golden standard method, but LN2 has several limitations. We developed a LN2 -independent snap freezer with adjustable cold sink temperature. To benchmark this device against the golden standard, we compared molecular profiles of biospecimens., Methods: Cancer cell lines and core needle normal tissue biopsies from five patients' liver resection specimens were used to compare mass spectrometry (MS)-based global phosphoproteomic and RNA sequencing profiles and RNA integrity obtained by both freezing methods., Results: Unsupervised cluster analysis of phosphoproteomic and transcriptomic profiles of snap freezer versus LN2 -frozen K562 samples and liver biopsies showed no separation based on freezing method (with Pearson's r 0.96 (range 0.92-0.98) and >0.99 for K562 profiles, respectively), while samples with +2 h bench-time formed a separate cluster. RNA integrity was also similar for both snap freezing methods. Molecular profiles of liver biopsies were clearly identified per individual patient regardless of the applied freezing method. Two to 25 s freezing time variations did not induce profiling differences in HCT116 samples., Conclusion: The novel snap freezer preserves high-quality biospecimen and allows identification of individual patients' molecular profiles, while overcoming important limitations of the use of LN2 . This snap freezer may provide a useful tool in clinical cancer research and practice, enabling a wider implementation of (multi-)omics analyses for precision oncology., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)- Published
- 2023
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32. Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours.
- Author
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Geurts BS, Battaglia TW, van Berge Henegouwen JM, Zeverijn LJ, de Wit GF, Hoes LR, van der Wijngaart H, van der Noort V, Roepman P, de Leng WWJ, Jansen AML, Opdam FL, de Jonge MJA, Cirkel GA, Labots M, Hoeben A, Kerver ED, Bins AD, Erdkamp FGL, van Rooijen JM, Houtsma D, Hendriks MP, de Groot JB, Verheul HMW, Gelderblom H, and Voest EE
- Subjects
- Humans, Biomarkers, Microsatellite Instability, Brain Neoplasms
- Abstract
Background: In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile., Patients and Methods: Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses., Results: Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB., Conclusion: Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings., Trial Registration: Clinical trial registration: NCT02925234. First registration date: 05/10/2016., (© 2023. The Author(s).)
- Published
- 2023
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33. Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment.
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Hoes LR, van Berge Henegouwen JM, van der Wijngaart H, Zeverijn LJ, van der Velden DL, van de Haar J, Roepman P, de Leng WJ, Jansen AML, van Werkhoven E, van der Noort V, Huitema ADR, Gort EH, de Groot JWB, Kerver ED, de Groot DJ, Erdkamp F, Beerepoot LV, Hendriks MP, Smit EF, van der Graaf WTA, van Herpen CML, Labots M, Hoeben A, Morreau H, Lolkema MP, Cuppen E, Gelderblom H, Verheul HMW, and Voest EE
- Subjects
- Genomics methods, Humans, Molecular Targeted Therapy methods, Precision Medicine, Neoplasms drug therapy, Neoplasms genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers., Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency-approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks)., Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup., Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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34. Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types.
- Author
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van der Wijngaart H, Hoes LR, van Berge Henegouwen JM, van der Velden DL, Zeverijn LJ, Roepman P, van Werkhoven E, de Leng WWJ, Jansen AML, Mehra N, Robbrecht DGJ, Labots M, de Groot DJA, Hoeben A, Hamberg P, Gelderblom H, Voest EE, and Verheul HMW
- Subjects
- BRCA1 Protein genetics, Humans, Phthalazines adverse effects, Piperazines therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Ovarian Neoplasms drug therapy
- Abstract
Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type., Patients and Methods: Patients with treatment-refractory BRCA1/2- mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model., Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2 , while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types., Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non- BRCA -associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay., (©2021 American Association for Cancer Research.)
- Published
- 2021
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35. Optimal treatment of opioid induced constipation in daily clinical practice - an observational study.
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Neefjes ECW, van der Wijngaart H, van der Vorst MJDL, Ten Oever D, van der Vliet HJ, Beeker A, Rhodius CA, van den Berg HP, Berkhof J, and Verheul HMW
- Subjects
- Aged, Analgesics, Opioid therapeutic use, Constipation etiology, Female, Fentanyl adverse effects, Fentanyl therapeutic use, Humans, Laxatives therapeutic use, Male, Middle Aged, Naltrexone analogs & derivatives, Naltrexone therapeutic use, Narcotic Antagonists therapeutic use, Neoplasms complications, Neoplasms drug therapy, Oxycodone adverse effects, Oxycodone therapeutic use, Pain Management adverse effects, Pain Management methods, Prospective Studies, Quaternary Ammonium Compounds therapeutic use, Retrospective Studies, Surveys and Questionnaires, Analgesics, Opioid adverse effects, Constipation drug therapy
- Abstract
Background: Opioids are prescribed in over 40% of patients with advanced cancer, but side effects occur frequently. In this study we evaluated the development and treatment of opioid induced constipation (OIC), and OIC resolving effect of methylnaltrexone for different opioid subtypes in daily clinical practice., Methods: Patients with cancer using opioids were included in a retrospective chart analysis. Baseline characteristics, data on opioid use, laxative use, and OIC were collected. Patients with OIC who were prescribed methylnaltrexone, were included in a prospective observational trial (NCT01955213)., Results: Thirty-nine of 327 patients (pts) with cancer who were treated with opioids suffered from OIC (overall prevalence 12%; 95%-CI: 8-15%). The prevalence of OIC was similar in patients treated with oxycodone or fentanyl (12 of 81 pts. vs. 18 of 110 pts., RR 0.9; 95%CI 0.4-2.0). The morphine equivalent daily dose did not significantly differ between opioid subtypes (fentanyl 89 mg (IQR 60-180) vs. oxycodone 40 mg (40-80), P = 0.231). Twenty-two individual patients (7%) were admitted for OIC. Most effective laxatives in admitted patients were enemas, methylnaltrexone, or 4-l polyethylene-glycol solution. In the prospective observational study, the effect of methylnaltrexone could be evaluated in 23 patients. Eleven patients achieved the primary endpoint of ≥2 laxation responses out of the first four doses methylnaltrexone, independent of opioid subtype., Conclusions: OIC is a burdensome clinical problem independent of opioid subtype. Timely intensification of prophylactic laxative treatment, especially when opioid doses increase, may help to prevent OIC. Clinically overt OIC requires a more intensive laxative regimen with for example methylnaltrexone., Trial Registration: NCT01955213 .
- Published
- 2019
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36. A 73-year-old male with jaundice and acute kidney injury. Bile cast nephropathy.
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van der Wijngaart H, van Dam B, van den Berg JG, Krul-Poel YH, Klemt-Kropp M, and Bax WA
- Subjects
- Acute Kidney Injury diagnosis, Aged, Bile metabolism, Biopsy, Diagnosis, Differential, Humans, Jaundice diagnosis, Jaundice metabolism, Male, Acute Kidney Injury etiology, Jaundice complications, Kidney Tubules, Proximal pathology
- Published
- 2014
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