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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO)
    Abstract: Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) 〉 6 months. Immunotherapy may be synergistic with bevacizumab and chemotherapy. PATIENTS AND METHODS ATALANTE/ENGOT-ov29 (ClinicalTrials.gov identifier: NCT02891824 ), a placebo-controlled double-blinded randomized phase III trial, enrolled patients with recurrent epithelial OC, one to two previous chemotherapy lines, and PFI 〉 6 months. Eligible patients were randomly assigned 2:1 to atezolizumab (1,200 mg once every 3 weeks or equivalent) or placebo for up to 24 months, combined with bevacizumab and six cycles of chemotherapy doublet, stratified by PFI, PD-L1 status, and chemotherapy regimen. Coprimary end points were investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) and PD-L1–positive populations (alpha .025 for each population). RESULTS Between September 2016 and October 2019, 614 patients were randomly assigned: 410 to atezolizumab and 204 to placebo. Only 38% had PD-L1–positive tumors. After 3 years' median follow-up, the PFS difference between atezolizumab and placebo did not reach statistical significance in the ITT (hazard ratio [HR], 0.83; 95% CI, 0.69 to 0.99; P = .041; median 13.5 v 11.3 months, respectively) or PD-L1–positive (HR, 0.86; 95% CI, 0.63 to 1.16; P = .30; median 15.2 v 13.1 months, respectively) populations. The immature overall survival (OS) HR was 0.81 (95% CI, 0.65 to 1.01; median 35.5 v 30.6 months with atezolizumab v placebo, respectively). Global health-related quality of life did not differ between treatment arms. Grade ≥3 adverse events (AEs) occurred in 88% of atezolizumab-treated and 87% of placebo-treated patients; grade ≥3 AEs typical of immunotherapy were more common with atezolizumab (13% v 8%, respectively). CONCLUSION ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1–positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Oncology Pharmacy Practice, SAGE Publications
    Abstract: Chemotherapy-induced nausea and vomiting (CINV) is one of the adverse events that most affects oncologic patients’ quality of life. Carboplatin AUC ≥ 4 belongs to agents with high emetic risk (moderate risk in ASCO guidelines). We aimed to compare the effectiveness of netupitant/palonosetron and dexamethasone triple combination (TC) therapy versus ondansetron and dexamethasone double combination (DC) therapy as antiemetic prophylaxis in patients with carboplatin AUC ≥ 4. As a secondary endpoint, in TC group we evaluated the effectiveness of changing NEPA administration timing from 1 h to 15 min before chemotherapy. Methods Open-label prospective study conducted in a tertiary-care hospital in patients receiving carboplatin AUC ≥ 4. CINV was evaluated using MASCC antiemetic tool, in acute ( 〈 24 h) and delayed phase (24–120 h). Results were analyzed using χ 2 test. Results Two-hundred four completed questionnaires (CQ) were analyzed (76 in DC and 128 in TC). The proportion of patients who remained emesis-free was superior for TC-treated group compared to DC, either in acute (99.2% vs 92.1%, p = 0.0115) and delayed phase (97.6% vs 90.7%, p = 0.043). Likewise, a higher proportion of TC-treated patients compared to DC remained nausea-free for the first 24 h after treatment (90.6% vs 71%, p = 0.0004) and between 24 and 120 h (82.3% vs 62.7%, p = 0.0025). The change of NEPA administration time showed similar effectiveness in terms of CINV control (81.6% vs 74.5%, p = 0.70). Conclusions TC showed superiority in early and delayed CINV control in carboplatin AUC ≥ 4 regimens, with no significant differences among cancer types. Change in NEPA administration timing has beneficial implications; it allows NEPA to be administered at hospitals before chemotherapy session.
    Type of Medium: Online Resource
    ISSN: 1078-1552 , 1477-092X
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2023
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    SSG: 15,3
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e17598-e17598
    Abstract: e17598 Background: Rucaparib is a PARP inhibitor (PARPi) approved as maintenance therapy for platinum (Pt)-sensitive recurrent high-grade ovarian cancer (HGOC), and as treatment for BRCA-mutant HGOC patients. To date, there is little evidence about the efficacy and safety of rucaparib after prior exposure to PARPi. This subanalysis aims to describe the patients’ characteristics and treatment outcomes with rucaparib in women who were included in the rucaparib early access program (RAP) in Spain and had received a prior PARPi. Methods: A retrospective study was conducted by GEICO at 22 hospitals in Spain to analyze data of 51 women treated within the RAP (600 mg BID). Adult women with HGOC, fallopian tube, or primary peritoneal cancer, who had received at least one prior PARPi before rucaparib were analyzed. Patients’ characteristics, medical history, safety, efficacy, and dosing data were collected. Results: A total of 14 women, with a median age of 63 years old (42-78) were included in this subanalysis. Of them, 92.9% were diagnosed of epithelial ovarian cancer and 78.6% had mutations in BRCA1/ 2 genes. The median number of lines before rucaparib was 5 (3-8), while the number of lines before the first PARPi was 3 (2-5). Except for one woman who had received 2 prior PARPis before rucaparib, the others had received just 1. Most patients were given olaparib as the first PARPi (n = 12, 85.8%), while niraparib was the initial PARPi in the remaining cases (n = 2, 14.3%). The outcomes of the treatment with rucaparib in these patients are outlined in table 1. Rucaparib was given as maintenance therapy in 1 patient and as treatment in 13 patients, 12 of them being Pt-resistant. The progression-free survival (PFS) ranged from 0.23 to 9.12 months. Adverse events (AE) of any grade were detected in 78.6% of patients, whereas AE of grade ≥3 affected 28.6% of women. Rucaparib dose was interrupted in 57.1% and reduced in 42.9% of patients. Only 1 patient discontinued rucaparib due to toxicity. No new safety signals were detected. Conclusions: This is one of the first real-word studies reporting the use of rucaparib after treatment with another PARPi. Even in these heavily pre-treated patients who had received prior PARPi, rucaparib efficacy has been notable in some cases, and its safety profile is consistent with that reported in previous clinical trials. Future studies should focus on the selection of patients who could benefit from rucaparib after prior PARPi exposure. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 4
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. LB-C18-LB-C18
    Abstract: Background: ABTL0812 is a first-in-class antitumor drug whose mechanism of action relies on the inhibition of PI3K/Akt/mTOR (PAM) pathway by upregulation of TRIB3 levels, an endogenous inhibitor of Akt activity that prevents Akt phosphorylation. Preclinical studies showed good efficacy of ABTL0812 in xenograft models with high safety margin. Here we describe the First-in-Human (FiH) Phase I/Ib clinical trial of ABTL0812 in patients with advanced solid tumors (NCT02201823). Methods: ABTL0812 was dosed daily, by the oral route, in 28-day cycles. The study included a 4-cohort dose escalation, in a 3+3 dose escalating design, followed by an expansion cohort. The trial objectives were to determine safety and tolerability, to evaluate signs of efficacy, to determine drug pharmacokinetics (PK) in plasma and to analyze inhibition of Akt phosphorylation in platelets by MSD® as pharmacodynamic (PD) biomarker. Pretreatment tumor biopsies were analyzed by next generation sequencing to identify mutations in a panel of 50 cancer-related genes. Results: Fifteen patients were recruited in the escalation part and 14 patients in the expansion cohort (February 2014 to May 2015). No dose-limiting-toxicities were detected and the recommended Phase II was 1300 mg tid based on PK/PD modeling. The median number of previous chemotherapy lines was 2 (range 0-11). The profile of ABTL0812 grade 1-2 related adverse events (AEs) included asthenia, nausea/vomiting and throat burning (34%, 31% and 24% of patients, respectively). Only one case of grade 3-4 AE (elevated hepatic enzymes) appeared. ABTL0812 half-life was short (3-5 h), which supported the increase in the administration schedule from once to twice and finally to three times a day. Biomarker analysis showed inhibition of Akt phosphorylation with increasing doses, with average 90% inhibition in the expansion cohort; furthermore it correlated with C-trough plasma levels. Five patients had stable disease (SD) for at least 16 weeks: 1 endometrial cancer (62 weeks), 1 cholangiocarcinoma (35 weeks, ongoing on Sep 15th, 2015), 2 colorectal cancer (28 and 22 weeks) and 1 lung adenocarcinoma (16 weeks). The median time to progression in the expansion cohort was 11 weeks (range 1-≥35 weeks). Interestingly, the tumor biopsy from the patient with endometrial cancer had activating mutations in Akt1 (E17K) and PIK3CA (R88Q). The tumor from the patient with colorectal cancer (28 weeks SD) showed deleterious mutations in TP53 (R248W) and APC (Q1469Ter). None of these samples included major mutations in Ras. Conclusions: ABTL0812 is a PAM pathway inhibitor acting by a novel mechanism of action that involves upregulation of TRIB3 levels. The FiH Phase I/Ib study in patients with advanced solid tumors showed excellent tolerability and safety profile and demonstrated dose-dependent inhibition of Akt phosphorylation. ABTL0812 treatment induced several long term disease stabilizations (5/29), being the best responder a patient with endometrial cancer (68 weeks) with activating mutations in Akt1 and PIK3CA. Based on these data, a Phase II clinical trial in patients with endometrial cancer is planned. Citation Format: Laura Vidal, Lydia Gaba, Ivan Victoria, Marta Gil-Martin, Berta Laquente, Marc Cortal, Merce Brunet, Pilar Paredes, Mariana Gomez-Ferreria, Jose Alfon, Carles Domenech, Pedro Gascon. First-in-Human Clinical Trial of ABTL0812, a Compound that Inhibits PI3K/Akt/mTOR Pathway by Upregulating TRIB3, in Patients with Advanced Solid Tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C18.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 5
    In: European Journal of Cancer, Elsevier BV, Vol. 91 ( 2018-03), p. 116-124
    Type of Medium: Online Resource
    ISSN: 0959-8049
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
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    detail.hit.zdb_id: 1468190-0
    detail.hit.zdb_id: 82061-1
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  • 6
    In: European Urology, Elsevier BV, Vol. 70, No. 5 ( 2016-11), p. 709-713
    Type of Medium: Online Resource
    ISSN: 0302-2838
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
    detail.hit.zdb_id: 1482253-2
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  • 7
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2022-11-08)
    Abstract: Rucaparib is a poly(ADP-ribose) polymerase inhibitor approved in Europe as maintenance therapy for recurrent platinum-sensitive (Pt-S) ovarian cancer (OC). The Rucaparib Access Programme (RAP) was designed to provide early access to rucaparib for the above-mentioned indication, as well as for patients with BRCA -mutated Pt-S or platinum-resistant (Pt-R) OC and no therapeutic alternatives. Methods: In this observational, retrospective study we analysed the efficacy and safety of rucaparib within the RAP in Spain. Hospitals associated with the Spanish Ovarian Cancer Research Group (GEICO) recruited patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with rucaparib 600 mg twice daily as maintenance or treatment (Pt-S/Pt-R) in the RAP. Baseline characteristics, efficacy, and safety data were collected. Results: Between July 2020 and February 2021, 51 patients treated in 22 hospitals in the RAP were included in the study. Eighteen patients with a median of 3 (range, 1–6) prior treatment lines received rucaparib as maintenance; median progression-free survival (PFS) for this group was 9.1 months (95% confidence interval [CI], 4.2–11.6 months). Among 33 patients (median 5 [range, 1–9] prior treatment lines) who received rucaparib as treatment, 7 and 26 patients had Pt-S and Pt-R disease, respectively. Median PFS was 10.6 months (95% CI, 2.5 months-not reached) in the Pt-S group and 2.2 months (95% CI, 1.1–3.2 months) in the Pt-R group. Grade ≥ 3 treatment-emergent adverse events were reported in 39% of all patients, the most common being anaemia (12% and 15% in the maintenance and treatment groups, respectively). At data cut-off, 5 patients remained on treatment. Conclusion Efficacy results in these heavily pre-treated patients were similar to those from previous trials. The safety profile of rucaparib in real life was predictable and manageable.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041352-X
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3060-3060
    Abstract: 3060 Background: Genetic profiling (GP) is essential not only for understanding tumor biology but also helps to identify potential genes for targeted therapies. At the same time, selected CT provide an individual genomic profile panel during the pre-screening phase. Here, we demonstrate our experience using these panels. Methods: We selected 14 CT from our Early Drug Development Clinical Trial Unit at Hospital Clinic of Barcelona that included analysis of gene panels in tumor (Foundation One, ArcherDX, Therascreen and Sophia Genetics) or plasma (Resolution Bioscience ctDx). These panels analyzed mutations, fusions, amplifications, microsatellite instability (MSI) and tumor mutational burden (TMB), among others. We collected information about types of cancers, molecular alterations and therapies chosen according to the results of GP. The platform OncoKB (Chakravarty JCO PO, 2017) was used to define genes with potential target therapies and levels of evidence (LE) for those targets (from LE 1 –FDA-recognized biomarker predictive of response to an FDA-approved drug- to LE 4 –Compelling biological evidence supports the biomarker as being predictive of response to a drug). Descriptive statistics were used. Results: From March 2017 to January 2021 we analyzed samples from 410 patients (pts) with CNS (19.3%), urothelial (18.3%), prostate (17.6%), breast (15.4%), ovarian (9.3%), esophageal and gastric (5.4%), colorectal (4.4%), pancreas (2.7%), endometrial (2.4%), cholangiocarcinoma (1.2%), cervix (1%), HNSCC (1%), renal (1%), lung (0.5%), liver (0.2%) fallopian tube (0.2%) and paraganglioma (0.2%). 352 pts (85.8%) had at least 1 genetic alteration. The most frequently altered genes were TP53 (153 pts, 46.2%), INSR (19 pts, 22.8%), TERT (76 pts, 22%), CDKN2A (65 pts, 19.9%), FAM175A (11 pts, 19.3%), CDKN2B (54 pts, 18.1%), MLL2 (53 pts, 17.7%), PTEN (52 pts, 16%), MTAP (45 pts, 15.7%), PIK3CA (52 pts, 15%) and ATM (55 pts, 14.4%). TMB ranged from 0 to 76.9 mut/Mb (median 2.5 mut/Mb). MSI was found in 3 pts (1.5%). 196 pts (47.1%) had an OncoKB LE 1 alteration, 105 pts (25.6%) if we restrict the options to their specific cancer type. 16 pts (3.9%) received a matched therapy: 6 pts received an off-label drug, 6 pts were included in the same CT for which the pre-screening was performed and 4 pts were included in a different CT. Additionally, 13 pts (3.2%) received a matched therapy either with OncoKB LE 4 (5 pts received an off-label drug and 3 were included in a different CT) or not included in OncoKB (8 pts included in the same CT of the pre-screening). As a whole, 29 pts (7.1%) received a matched drug according to their genomic results. Conclusions: Comprehensive gene panel testing offered through CT allows the identification of targets to enroll pts, although the recruitment was 1.5%. However, 7.1% of the pts received a matched therapy due to the molecular information of these gene panels.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 9
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 7_suppl ( 2017-03-01), p. 66-66
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 7_suppl ( 2017-03-01), p. 66-66
    Abstract: 66 Background: Anti-PD1 antibodies (Abs) Nivolumab (Nivo) and Pembrolizumab (Pembro) have both demonstrated to improve the overall survival (OS) in patients (pts) with advanced or metastatic melanoma (MM) in the first line setting. We previously reported that an increase in absolute eosinophil counts (AEC) of 100/mm3 over baseline at week 3 and an AEC 〉 400/mm3 at week 12 during anti-PD1 treatment (tmt) might identify pts with MM most likely to experience long-term disease control (1) . AEC could serve as an important marker allowing the detection of those patients who may benefit from the therapy with anti-PD1 Abs. Methods: This retrospective observational study included pts with MM who received anti-PD1 tmt in a single institution. The objective was to identify whether an increase over the upper limit of normal AEC ( 〉 400/mm3) at any time during the tmt could predict better outcomes. Blood tests were performed before every tmt administration. Progression free survival (PFS) and OS were evaluated. Descriptive statistics were used to analyze patient baseline characteristics. PFS and OS were estimated by the Kaplan-Meier method. Results: From March 2013 to February 2016, 50 pts were treated with anti-PD1 Abs (39 pts with Pembro and 11 pts with Nivo). Median age was 58 years (33-84). 72% had received previous systemic tmt for MM, 64% had stage M1c disease, and 50% had elevated LDH levels. BRAF V600 mutations were observed in 34%. The median time to increase AEC 〉 400/mm2 was 42 (14-196) days. Pts who experienced an increase 〉 400/mm3 at 12 weeks demonstrated better outcomes in terms of PFS (21,9 [95% CI: 11,1-32,6] vs. 7,5 [95% CI: 4,3-10,7] months, p=0.017) and OS (38,0 [95% CI: 30,8-45,1] vs. 20,5 [95% CI: 15,7-25,3] months, p=0.025) compared with those who did not. Moreover, according to our previous results, pts with an increase of at least 100/mm3 in AEC over the baseline at 12 weeks also showed better OS (32,5 [95% CI: 26,3-38,8] vs. 16,3 [95% CI: 11,1-21,6] months, p=0.008). Conclusions: An increase in AEC of 100/mm3 over baseline and an absolute AEC 〉 400/mm3 at week 12 during anti-PD1 tmt might identify pts with MM most likely to experience clinical benefit with anti-PD1 Abs which could be relevant for pts management.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 10
    In: Oncotarget, Impact Journals, LLC, Vol. 6, No. 12 ( 2015-04-30), p. 10604-10616
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2015
    detail.hit.zdb_id: 2560162-3
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