dc.contributor.author | Yap, TA | |
dc.contributor.author | O'Carrigan, B | |
dc.contributor.author | Penney, MS | |
dc.contributor.author | Lim, JS | |
dc.contributor.author | Brown, JS | |
dc.contributor.author | de Miguel Luken, MJ | |
dc.contributor.author | Tunariu, N | |
dc.contributor.author | Perez-Lopez, R | |
dc.contributor.author | Rodrigues, DN | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Hare, B | |
dc.contributor.author | McDermott, K | |
dc.contributor.author | Khalique, S | |
dc.contributor.author | Williamson, CT | |
dc.contributor.author | Natrajan, R | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Banerji, U | |
dc.contributor.author | Pollard, J | |
dc.contributor.author | Lopez, J | |
dc.contributor.author | de Bono, JS | |
dc.date.accessioned | 2020-07-06T08:55:16Z | |
dc.date.issued | 2020-06-22 | |
dc.identifier.citation | Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2020, 38 (27), pp. 3195 - 3204 | |
dc.identifier.issn | 0732-183X | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3802 | |
dc.identifier.eissn | 1527-7755 | |
dc.identifier.doi | 10.1200/jco.19.02404 | |
dc.description.abstract | PURPOSE: Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS: This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS: Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION: To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed. | |
dc.format | Print-Electronic | |
dc.format.extent | 3195 - 3204 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC CLINICAL ONCOLOGY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-04-20 | |
rioxxterms.versionofrecord | 10.1200/jco.19.02404 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | |
pubs.issue | 27 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine (de Bono Prostate) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine (de Bono Prostate) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.publication-status | Published | |
pubs.volume | 38 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicine (de Bono Prostate) | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Functional Genomics | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Natrajan, Rachael | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Lord, Christopher | |
dc.contributor.icrauthor | Banerji, Udai | |
dc.contributor.icrauthor | De Bono, Johann | |