paola-1 clinicaltrials gov

Crossover between the trial groups was not planned. ), German Society of Gynecologic Oncology (AGO) (J.S., U.C., F.M., N.G., P.B., A.B., P.H. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15:852-861. The outcome of first-line treatment at screening was determined according to the electronic case-report form. The most common adverse events and the incidence of associated grade 3 or higher adverse events for the entire maintenance treatment period are shown in Table 2 and Table S5. Cancer Res 2010;70:8045-8054. ), Institut Curie, Hpital Claudius Rgaud (M.R. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644. Details of the statistical analyses are provided in the Supplementary Appendix. However, owing to late diagnosis with advanced-stage disease, the vast majority of patients have a relapse (after a median of 10 to 18 months),1,2 despite being treated with cytoreductive surgery and platinum-based chemotherapy.3, The addition of the antiangiogenic agent bevacizumab to carboplatin plus paclitaxel, followed by bevacizumab alone, is a standard option in patients with newly diagnosed advanced ovarian cancer.1,2,4-7 Recently, in the phase 3 SOLO1 trial, the poly(adenosine diphosphateribose) polymerase (PARP) inhibitor olaparib provided a substantial progression-free survival benefit as maintenance monotherapy in patients with newly diagnosed advanced ovarian cancer whose tumors had a BRCA1 or BRCA2 mutation (BRCA mutation) and who had a complete or partial clinical response after platinum-based chemotherapy (hazard ratio for disease progression or death, 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001).8. The data include patients with anemia, a decreased hemoglobin level, a decreased hematocrit, a decreased red-cell count, erythropenia, macrocytic anemia, normochromic anemia, normochromic normocytic anemia, or normocytic anemia. The baseline characteristics were well balanced between the trial groups (Table 1 and Tables S2 through S4). N Engl J Med 2011;365:2473-2483. 22. Anderson Cancer Center Madrid (A.G.-M.), Grupo Espaol de Investigacin en Cncer de Ovario (GEICO) (A.G.-M., E.M.G.A. CA-125 denotes cancer antigen 125, CR complete response, ECOG Eastern Cooperative Oncology Group, FIGO International Federation of Gynecology and Obstetrics, NED no evidence of disease, PR partial response, and ULN upper limit of the normal range. This article was updated on February 19, 2020, at NEJM.org. Patients with other nonmucinous epithelial ovarian cancers were eligible, provided they had a deleterious germline BRCA1 or BRCA2 mutation. NEW! S3B.). A total of 535 of the 537 patients assigned to olaparib plus bevacizumab (olaparib group) and 267 of the 269 patients assigned to placebo plus bevacizumab (placebo group) received the trial intervention; 2 patients in each group withdrew before receiving the trial intervention (Fig. 21. Among the patients without a tumor BRCA mutation (prespecified subgroup analysis) (Panel B), the KaplanMeier estimate of the percentage of patients who were free from disease progression and death at 24 months was 33% in the olaparib-plus-bevacizumab group and 23% in the placebo-plus-bevacizumab group. ), Centre Eugne Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hpital Priv du Confluent, Nantes (A.L. 8. Ann Oncol 2019;30:551-557. OConnor MJ. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Stat Med 1997;16:2349-2380. There was no evidence of a meaningful difference in health-related quality of life between the trial groups. 13. The most common serious adverse event that occurred at a higher incidence with placebo plus bevacizumab than with olaparib plus bevacizumab was hypertension (35 patients [13%] in the placebo group and 48 patients [9%] in the olaparib group). 1. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). 12. all in France; the Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, and Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Naples (S.P. **Partial response was defined as radiologic evidence of disease, an abnormal CA-125 level, or both. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. Cnaan A, Laird NM, Slasor P. Using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data. The PAOLA-1 population was representative of the majority of patients with advanced ovarian cancer because patient selection was not restricted on the basis of surgical outcome or BRCA mutation status. The hazard ratio and associated 95% confidence interval were calculated with the use of a stratified Cox proportional-hazards model. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. A list of the PAOLA-1 principal investigators is provided in the Supplementary Appendix, available at NEJM.org. Serious adverse events occurred in 31% of the patients in both trial groups (Table S6). ), and Arbeitsgemeinschaft Gynkologische Onkologie Study Group (AGO)Austria (R.B., A.R. all in Austria; Saitama Medical University International Medical Center, Hidaka (K.F. Clinical complete response was defined as the disappearance of all measurable or assessable disease and normalization of CA-125 levels. Karam A, Ledermann JA, Kim JW, et al. In patients with HRD-negative tumors or whose tumor HRD status was unknown (total, 419 patients), the median progression-free survival was 16.9 months in the olaparib group and 16.0 months in the placebo group (hazard ratio for disease progression or death, 0.92; 95% CI, 0.72 to 1.17) (Fig. From July 2015 through September 2017, a total of 806 patients underwent randomization. NEW! Ann Oncol 2019;30:672-705. Administering maintenance olaparib in addition to bevacizumab to patients with newly diagnosed advanced ovarian cancer who were receiving standard treatment including bevacizumab resulted in a significant progression-free survival benefit, with a substantial benefit in patients with HRD-positive tumors. After discontinuation of the intervention, patients could receive other treatments at the investigators discretion. Lancet Oncol 2015;16:928-936. A hierarchical-testing procedure was used to control for type I error at 5% for progression-free survival, second progressionfree survival, and overall survival, in that order. Patients were eligible irrespective of previous surgical outcome (residual macroscopic disease or no residual macroscopic disease after upfront or interval surgery). ); Tampere University and University Hospital, Tampere, Finland (J.M. J Clin Oncol 2019;37:Suppl:5505-5505. abstract. NA denotes not available. S3C). The trial was performed in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines under the auspices of an independent data monitoring committee. 3. CA-125 denotes cancer antigen 125, and HRD homologous-recombination deficiency. ), Essen, Universittsklinikum Carl Gustav Carus, Technische Universitt Dresden, Dresden (U.C. The most trusted, influential source of new medical knowledge and clinical best practices in the world. ), Health Services and Performance Research Lab (EA 7425 HESPER), University Claude Bernard Lyon 1 (I.R.-C.), and Centre Hospitalier Lyon-Sud (B.Y. Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. Lancet Oncol 2014;15:1207-1214. The most common adverse event (all grades) that occurred at a higher incidence among patients receiving placebo plus bevacizumab than among those receiving olaparib plus bevacizumab was hypertension (Table 2). ), University of MilanBicocca and European Institute of Oncology IRCCS, and Mario Negri Gynecologic Oncology Group (MANGO) (N.C.), and Fondazione IRCCS Istituto Nazionale Tumori and MITO (D.L. December 19, 2019N Engl J Med 2019; 381:2416-2428 ); and CharitMedical University of Berlin (Campus Virchow Klinikum), Berlin (J.S. S2) were consistent with the results of the primary analysis (median, 26.1 months in the olaparib group and 18.3 months in the placebo group; hazard ratio for disease progression or death, 0.63; 95% CI, 0.51 to 0.77). 10. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper. Tumor HRD status was determined with the use of the myChoice HRD Plus assay (Myriad Genetic Laboratories). Subgroup Analysis of Progression-free Survival. The mean global health statusquality of life score at baseline was 68.6 in the olaparib group and 67.1 in the placebo group. Data regarding second progressionfree survival and overall survival are currently immature. ), and Institut Curie, Hpital Ren Huguenin, Saint Cloud (C.D.) Overall survival data are immature. Oza AM, Cook AD, Pfisterer J, et al. All the patients provided written informed consent. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. In this trial, the progression-free survival benefit seen with olaparib plus bevacizumab in patients with BRCA-mutated tumors (hazard ratio for disease progression or death, 0.31; 95% CI, 0.20 to 0.47) is consistent with that observed in the SOLO1 trial (hazard ratio, 0.30; 95% CI, 0.23 to 0.41),8 despite the improved outcome of the control group in our trial (median progression-free survival, 21.7 months with placebo plus bevacizumab in the PAOLA-1 trial and 13.8 months with placebo in the SOLO1 trial), which may be due to the addition of bevacizumab or to differences in patient selection.22 Caution is needed when comparing outcomes between patients in the SOLO1 trial and patients with BRCA-mutated tumors in the PAOLA-1 trial because of differences between the two trials, including in baseline characteristics (Table S3). The primary end point was the time from randomization until investigator-assessed disease progression or death. In this analysis, we used the electronic case-report form data set, except for the prespecified HRD analysis, which used the Myriad myChoice Plus HRD test. 9. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. J Clin Oncol 2019;37:2317-2328. Int J Gynecol Cancer 2010;20:476-478. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. After first-line treatment with platinumtaxane chemotherapy plus bevacizumab, patients were required to have no evidence of disease or to have had a clinical complete or partial response (definitions in Table 1). HRD negative was defined as an HRD score of less than 42. Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Eur J Cancer 2012;48:1713-1721. all in Italy; M.D. The adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. (For details on the FIGO staging system, see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The primary end point was the time from randomization until investigator-assessed disease progression or death. Among the patients with HRD-positive tumors without a BRCA mutation (prespecified subgroup analysis) (Panel D), the KaplanMeier estimate of the percentage of patients who were free from disease progression and death at 24 months was 52% in the olaparib-plus-bevacizumab group and 26% in the placebo-plus-bevacizumab group. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). The most common adverse events (all grades) that occurred at a higher incidence among patients receiving olaparib plus bevacizumab than among those receiving placebo plus bevacizumab were fatigue, nausea, and anemia (. For the hazard ratios, the size of the circle is proportional to the number of events. Results of the analysis of progression-free survival as assessed by blinded independent review (Fig. Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: a randomized controlled chemotherapy-free study NSGO-AVANOVA2/ENGOT-OV24. Safety data were summarized in the safety analysis set (all patients who received at least one dose of olaparib or placebo). The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. ), Universittsklinikum Ulm, Ulm (N.G. 4. 14. KaplanMeier Estimates of Investigator-Assessed Progression-free Survival, According to Tumor, In patients with tumors positive for HRD (tumor score of 42 on the myChoice HRD Plus assay or tumor. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. La et Napolon Bullukian, Lyon 69008, France, or at [emailprotected]. Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The duration of investigator-assessed progression-free survival was significantly longer in the olaparib group than in the placebo group (median, 22.1 months vs. 16.6 months; hazard ratio for disease progression or death, 0.59; 95% CI, 0.49 to 0.72; P<0.001) (Figure 1). The median time until the first subsequent treatment for all patients was 24.8 months in the olaparib group and 18.5 months in the placebo group (hazard ratio, 0.59; 95% CI, 0.49 to 0.71). S4). The authors attest to the accuracy and completeness of the data and to the adherence of the trial to the protocol (available at NEJM.org). After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The most common serious adverse event that occurred at a higher incidence with olaparib plus bevacizumab than with placebo plus bevacizumab was anemia (34 patients [6%] in the olaparib group and 1 patient [<1%] in the placebo group). Lancet Oncol 2017;18:1274-1284. The adjusted mean change from baseline was 1.33 points (95% CI, 2.47 to 0.19) in the olaparib group (498 patients) and 2.89 points (95% CI, 4.52 to 1.26) in the placebo group (246 patients) (Fig. 11. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Patients were eligible irrespective of previous surgical outcome (residual macroscopic disease or no residual macroscopic disease after upfront or interval surgery). The dashed horizontal line indicates the median value. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

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