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
AI Summary:
Olaparib can be safely combined with hypofractionated brain radiation therapy and is well tolerated in patients unsuitable for radical chemoradiation.AI Topics:
Purpose
Patients with glioblastoma who are older or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiation therapy (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 and Materials
Phase 1 of the PARADIGM trial was a 3+3 dose-escalation study testing olaparib in combination with radiation therapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 years or older (World Health Organization PS 0-1) or aged 18 to 69 years with PS 2. The primary outcome was the recommended phase 2 dose of olaparib. Secondary endpoints included safety and tolerability, overall survival, and progression-free survival. Effects on cognitive function were assessed via the Mini Mental State Examination.
Results
Of 16 eligible patients (56.25% male; median age, 71.5 years [range, 44-78]; 75% PS 0-1), 1 dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the recommended phase 2 dose was determined as 200 mg twice daily. Median overall survival and progression-free survival were 10.8 months (80% CI, 7.3-11.4) and 5.5 months (80% CI, 3.9-5.9), respectively. Mini Mental State Examination plots indicated that cognitive function was not adversely affected by the olaparib–radiation therapy combination.
Conclusions
Olaparib can be safely combined with hypofractionated brain radiation therapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomized phase 2 study and support future trials of PARP inhibitors in combination with radiation therapy 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 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 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 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 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 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 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
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 listJames, Allan
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 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 listNowicki, Stefan
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 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 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
See full publications listAvailable under License Creative Commons Attribution.
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