Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
AI Summary:
Olaparib can be safely combined with hypofractionated brain radiotherapy and is well tolerated in patients unsuitable for radical chemoradiation.AI Topics:
Background
: Patients with glioblastoma who are elderly or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiotherapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain.
Methods
: Phase I of the PARADIGM trial was a 3+3 dose escalation study testing olaparib in combination with radiotherapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 or over (WHO PS 0-1) or aged 18-69 with PS 2. The primary outcome was the recommended phase 2 dose (RP2D) of olaparib. Secondary endpoints included safety and tolerability, overall survival (OS) and progression free survival (PFS). Effects on cognitive function were assessed by mini-mental state examination (MMSE).
Results
: Of 16 eligible patients (56.25% male, median age 71.5 [range 44-78 years], 75% PS 0-1), one dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the RP2D was determined as 200 mg twice daily. Median OS and PFS were 10.8 months (80% CI: 7.3-11.4) and 5.5 months (80% CI: 3.9-5.9) respectively. MMSE plots indicated that cognitive function was not adversely affected by the olaparib-radiotherapy combination.
Conclusions
: Olaparib can be safely combined with hypofractionated brain radiotherapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomised phase II study and support future trials of PARP inhibitors in combination with radiotherapy for patients with brain tumors.
Derby, Sarah
Author
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony J. (2024) Concurrent olaparib and radiation therapy in older patients with newly diagnosed glioblastoma: the phase 1 dose-escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listJackson, Mark R.
Author
Vens, C. and van Luijk, P. and Vogelius, R.I. and El Naqa, I. and Humbert-Vidan, L. and von Neubeck, C. and Gomez-Roman, N. and Bahn, E. and Brualla, L. and Böhlen, T.T. and Ecker, S. and Koch, R. and Handeland, A. and Pereira, S. and Possenti, L. and Rancati, T. and Todor, D. and Vanderstraeten, B. and Van Heerden, M. and Ullrich, W. and Jackson, M. and Alber, M. and Marignol, L. and ESTRO DREAM team (2024) A joint physics and radiobiology DREAM team vision - towards better response prediction models to advance radiotherapy. Radiotherapy and Oncology, 196: 110277. ISSN 0167-8140
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony J. (2024) Concurrent olaparib and radiation therapy in older patients with newly diagnosed glioblastoma: the phase 1 dose-escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listWilliams, Karin
Author
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony J. (2024) Concurrent olaparib and radiation therapy in older patients with newly diagnosed glioblastoma: the phase 1 dose-escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listStobo, Jamie
Author
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony J. (2024) Concurrent olaparib and radiation therapy in older patients with newly diagnosed glioblastoma: the phase 1 dose-escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listKelly, Caroline
Author
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Pennel, Kathryn A.F. and Hatthakarnkul, Phimmada and Wood, Colin S. and Lian, Guang-Yu and Al-Badran, Sara and Quinn, Jean A. and Legrini, Assya and Inthagard, Jitwadee and Alexander, Peter G. and van Wyk, Hester and Kurniawan, Ahmad and Hashmi, Umar and Gillespie, Michael A. and Mills, Megan and Ammar, Aula and Hay, Jennifer and Andersen, Ditte and Nixon, Colin and Rebus, Selma and Chang, David K. and Kelly, Caroline and Harkin, Andrea and Graham, Janet and Church, David and Tomlinson, Ian and Saunders, Mark and Iveson, Tim and Lannagan, Tamsin R. M. and Jackstadt, Rene and Maka, Noori and Horgan, Paul G. and Roxburgh, Campbell S. D. and Sansom, Owen J. and McMillan, Donald C. and Steele, Colin W. and Jamieson, Nigel B. and Park, James H. and Roseweir, Antonia K. and Edwards, Joanne (2024) JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors. Journal of Experimental and Clinical Cancer Research, 43: 64. ISSN 1756-9966
Frei, Anja L. and McGuigan, Anthony and Sinha, Ritik R.A.K. and Jabbar, Faiz and Gneo, Luciana and Tomasevic, Tijana and Iveson, Tim and Saunders, Mark P. and Oien, Karin A. and Maka, Noori and Pezzella, Francesco and Campo, Leticia and Browne, Molly and Glaire, Mark and Kildal, Wanja and Danielsen, Havard E. and Hay, Jennifer and Edwards, Joanne and Sansom, Owen and Kelly, Caroline and Tomlinson, Ian and Kerr, Rachel and Kerr, David and Domingo, Enric and TransSCOT consortium and Church, David N. and Koelze, Viktor H. (2024) Multiplex analysis of intratumoural immune infiltrate and prognosis in patients with stage II–III colorectal cancer from the SCOT and QUASAR 2 trials: A retrospective analysis. Lancet Oncology, 25 (2). pp. 198-211. ISSN 1470-2045
See full publications listSweeting, Lorna
Author
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listShad, Shumaila
Author
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Ferguson, Jenny and Tsim, Selina and Kelly, Caroline and Alexander, Laura and Shad, Shumaila and Neilly, Mark and Tate, Matthew and Zahra, Baryab and Saleh, Merna and Cowell, Gordon and Banks, Elspeth and Grundy, Seamus and Corcoran, John and Downer, Nicola and Stanton, Andrew and Evison, Matthew and Rahman, Najib and Maskell, Nick and Blyth, Kevin (2023) Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY): Protocol of a prospective, multicentre, observational study. BMJ Open Respiratory Research, 10: e001771. ISSN 2052-4439
See full publications listHerbert, Christopher
Author
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony J. (2024) Concurrent olaparib and radiation therapy in older patients with newly diagnosed glioblastoma: the phase 1 dose-escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listShort, Susan C.
Author
Boele, Florien and Rosenlund, Lena and Nordentoft, Sara and Melhuish, Sara and Nicklin, Emma and Rydén, Isabelle and Williamson, Aoife and Donders-Kamphuis, Marike and Preusser, Matthias and Le Rhun, Emilie and Kiesel, Barbara and Minniti, Giuseppe and Furtner, Julia and Dirven, Linda and Taphoorn, Martin and Galldiks, Norbert and Rudà, Roberta and Chalmers, Anthony and Short, Susan C. and Piil, Karin and the Nurse and Allied Health Professionals Committee and the Disparity and Inclusion Committee of EANO (2024) Inequalities in access to neuro-oncology supportive care and rehabilitation: a survey of healthcare professionals’ perspectives. Neuro-Oncology Practice, 11 (4). pp. 484-493. ISSN 2054-2577
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony J. (2024) Concurrent olaparib and radiation therapy in older patients with newly diagnosed glioblastoma: the phase 1 dose-escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listWilliamson, Aoife
Author
Williamson, Aoife and Houston, Peter and Paterson, Jennifer and Chalmers, Anthony J. and McLoone, Philip and Fullerton, Natasha and Foo, Sin Yee and James, Allan and Nowicki, Stefan (2024) Dosimetric comparison of hippocampal sparing technologies in patients with low grade glioma. Neuro-Oncology Advances, 6 (1): vdae131. ISSN 2632-2498
Boele, Florien and Rosenlund, Lena and Nordentoft, Sara and Melhuish, Sara and Nicklin, Emma and Rydén, Isabelle and Williamson, Aoife and Donders-Kamphuis, Marike and Preusser, Matthias and Le Rhun, Emilie and Kiesel, Barbara and Minniti, Giuseppe and Furtner, Julia and Dirven, Linda and Taphoorn, Martin and Galldiks, Norbert and Rudà, Roberta and Chalmers, Anthony and Short, Susan C. and Piil, Karin and the Nurse and Allied Health Professionals Committee and the Disparity and Inclusion Committee of EANO (2024) Inequalities in access to neuro-oncology supportive care and rehabilitation: a survey of healthcare professionals’ perspectives. Neuro-Oncology Practice, 11 (4). pp. 484-493. ISSN 2054-2577
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listJames, Allan
Author
Williamson, Aoife and Houston, Peter and Paterson, Jennifer and Chalmers, Anthony J. and McLoone, Philip and Fullerton, Natasha and Foo, Sin Yee and James, Allan and Nowicki, Stefan (2024) Dosimetric comparison of hippocampal sparing technologies in patients with low grade glioma. Neuro-Oncology Advances, 6 (1): vdae131. ISSN 2632-2498
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listNowicki, Stefan
Author
Williamson, Aoife and Houston, Peter and Paterson, Jennifer and Chalmers, Anthony J. and McLoone, Philip and Fullerton, Natasha and Foo, Sin Yee and James, Allan and Nowicki, Stefan (2024) Dosimetric comparison of hippocampal sparing technologies in patients with low grade glioma. Neuro-Oncology Advances, 6 (1): vdae131. ISSN 2632-2498
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listBulbeck, Helen
Author
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
Derby, Sarah and Jackson, Mark R. and Williams, Karin and Stobo, Jamie and Kelly, Caroline and Sweeting, Lorna and Shad, Shumaila and Herbert, Christopher and Short, Susan C. and Williamson, Aoife and James, Allan and Nowicki, Stefan and Bulbeck, Helen and Chalmers, Anthony J. (2024) Concurrent olaparib and radiation therapy in older patients with newly diagnosed glioblastoma: the phase 1 dose-escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, 118 (5). pp. 1371-1378. ISSN 0360-3016
See full publications listChalmers, Anthony
Author
Williamson, Aoife and Houston, Peter and Paterson, Jennifer and Chalmers, Anthony J. and McLoone, Philip and Fullerton, Natasha and Foo, Sin Yee and James, Allan and Nowicki, Stefan (2024) Dosimetric comparison of hippocampal sparing technologies in patients with low grade glioma. Neuro-Oncology Advances, 6 (1): vdae131. ISSN 2632-2498
Jackson, Mark R. and Richards, Amanda R. and Oladipupo, Abdul-Basit Ayoola and Chahal, Sandeep K. and Caragher, Seamus and Chalmers, Anthony J. and Gomez-Roman, Natividad (2024) ClonoScreen3D - a novel three-dimensional clonogenic screening platform for identification of radiosensitizers for glioblastoma. International Journal of Radiation Oncology, Biology, Physics, 120 (1). pp. 162-177. ISSN 0360-3016
Boele, Florien and Rosenlund, Lena and Nordentoft, Sara and Melhuish, Sara and Nicklin, Emma and Rydén, Isabelle and Williamson, Aoife and Donders-Kamphuis, Marike and Preusser, Matthias and Le Rhun, Emilie and Kiesel, Barbara and Minniti, Giuseppe and Furtner, Julia and Dirven, Linda and Taphoorn, Martin and Galldiks, Norbert and Rudà, Roberta and Chalmers, Anthony and Short, Susan C. and Piil, Karin and the Nurse and Allied Health Professionals Committee and the Disparity and Inclusion Committee of EANO (2024) Inequalities in access to neuro-oncology supportive care and rehabilitation: a survey of healthcare professionals’ perspectives. Neuro-Oncology Practice, 11 (4). pp. 484-493. ISSN 2054-2577
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