A phase I study of olaparib in combination with capecitabine-based chemoradiation (CRT) in patients (pts) with locally advanced pancreatic cancer (LAPC)
| العنوان: | A phase I study of olaparib in combination with capecitabine-based chemoradiation (CRT) in patients (pts) with locally advanced pancreatic cancer (LAPC) |
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| المؤلفون: | Elaine McCartney, Martin Eatock, Alanna Morton, Chantevy Pou, Caroline Kelly, David McIntosh, Peter Houston, Anthony J. Chalmers, Susie Cooke, Fiona Thomson, T.R. Jeffry Evans, Claire N. Harrison, A. Duffton, Derek Grose, Miranda Ashton, Jill Graham, Alan Bilsland, Liz-Anne Lewsley, Colin Purcell |
| المصدر: | Journal of Clinical Oncology. 38:709-709 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | DNA single strand, Cancer Research, business.industry, Phase i study, Olaparib, Locally advanced pancreatic cancer, Capecitabine, chemistry.chemical_compound, Oncology, Base Excision Repair Pathway, chemistry, Cancer research, Medicine, In patient, business, medicine.drug |
| الوصف: | 709 Background: Olaparib is a potent inhibitor of PARP-1, which has a critical role in signalling DNA single strand breaks (SSB) as part of the base excision repair pathway, and may have radio-sensitizing effects due to impaired resolution of radiation induced SSB. We hypothesize that O may potentiate the effects of X-CRT in pts with LAPC. Methods: Eligible pts with LAPC, ECOG < 1, tumor diameter < 6cm, with stable disease (SD) or response after 12 weeks’ induction chemotherapy, were treated with 1 of 4 escalating doses of O given bid po starting on day -3, and then in combination with X (830 mg/m2 bid) and radiation (50·4 Gy in 28 fractions) all administered Mon-Fri. Dose limiting toxicities (DLT) were determined on clinical and lab toxicity assessments (NCI-CTC AE v4.03) performed weekly from the start of O until completion of O plus X-CRT (i.e. 6 weeks). Dose escalation continued with a rolling-six design until the Maximum Tolerated Dose (MTD) was reached. Blood samples for PK analyses of O and PD measurement (inhibition of PARP activity) were collected on day -3 (O monotherapy) and during week 1 of O + X-CRT. Results: 18 pts, (9 m, 9 f, ECOG 0/1 [n=6/12]), age range 49-81 (median=70) years, with histologic (14) or cytologic (4) proven LAPC, had received induction chemotherapy with gemcitabine [GEM] (n=2), GEM + X (12), or FOLFIRINOX (3) with partial response (n=4) or stable disease (14). Pts received 50 (3), 100 (4), 150 (6), or 200 (5) mgs bid of O with X+CRT. DLTs were observed in 2 pts (both at 200mgs bid): 1 pt with grade 3 nausea (on optimal anti-emetics) and grade 3 fatigue, 1 pt with grade 3 anorexia. 6 pts were subsequently recruited at 150mgs bid with no DLTs. No pts had complete response, 2 pts had partial response (1 pt each at 100 and 150 mgs bid) and 1 pt (at 100 mgs bid) had progressive disease; the remaining 14 pts had SD. Conclusions: The recommended dose (RP2) of O is 150mgs bid when given in combination with X + CRT in LAPC. Recruitment of up to 12 pts with borderline operable LAPC at the RP2 is ongoing. PK analyses of O, PD studies (PARP inhibition – PBMCs; cytokeratin 18 – serum; γH2AX foci – hair follicles), and exploratory predictive marker studies (tumor – NGS; RNA exome sequencing) are ongoing. Clinical trial information: ISRCTN10361292. |
| تدمد: | 1527-7755 0732-183X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::d892180fc8369736edaf8170c7557b50 https://doi.org/10.1200/jco.2020.38.4_suppl.709 |
| رقم الأكسشن: | edsair.doi...........d892180fc8369736edaf8170c7557b50 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
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