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  • 1
    Online Resource
    Online Resource
    Adjuvant nab -Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 11 ( 2023-04-10), p. 2007-2019
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 11 ( 2023-04-10), p. 2007-2019
    Abstract: This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR] , 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7] ), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.22.01134
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial
    Elsevier BV ; 2021
    In:  The Lancet Oncology Vol. 22, No. 7 ( 2021-07), p. 931-945
    Details
    In: The Lancet Oncology, Elsevier BV, Vol. 22, No. 7 ( 2021-07), p. 931-945
    Type of Medium: Online Resource
    ISSN: 1470-2045
    URL: Article
    DOI: 10.1016/S1470-2045(21)00152-2
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2049730-1
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  • 3
    Online Resource
    Online Resource
    Phase 3 VERACITY clinical study of sabizabulin in men with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor targeting agent.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS5102-TPS5102
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS5102-TPS5102
    Abstract: TPS5102 Background: Sabizabulin is a first-in-class, oral agent that inhibits microtubule polymerization disrupting the cytoskeleton and arresting cellular proliferation. A Phase 1b/2 clinical study was conducted to establish the MTD and evaluate the preliminary efficacy in men with metastatic castrate resistant prostate cancer (mCRPC) who progressed on at least one androgen receptor targeting agent (ARTA). The most common AEs reported were mild to moderate diarrhea, fatigue, nausea, and vomiting with no clinically relevant neurotoxicity or neutropenia. In the Phase 1b/2, the median radiographic progression free survival for the 63mg dose (n = 55) was 11.4 months (range 6-36+ months) in the Phase 1b portion including responses 〉 2.75 years. The Phase 3 reformulation which had improved bioavailability is 32mg PO qd. Methods: VERACITY is an ongoing Phase 3 multicenter, randomized, active-control study designed to evaluate sabizabulin in the treatment of mCRPC who have progressed on at least one ARTA. Patients on the study will be chemotherapy naive. Subjects (n = 245) are being randomized in a 2:1 ratio to receive sabizabulin (32 mg/d oral) or active control (alternative ARTA) and will remain on study until radiographic progression-free survival (rPFS). Randomization will be stratified by: measurable disease vs bone-only disease and by prior exposure to ARTA (progressed on one vs more than one prior ARTA). The primary efficacy endpoint of the study is median rPFS. Secondary endpoints include: objective response rate (ORR), duration of objective response, overall survival and time to intravenous (IV) chemotherapy. The Phase 3, VERACITY registration clinical trial is current ongoing in approximately 45 clinical sites with enrollment anticipated to be completed in 2022 and with unblinded results presented in 2023 Based upon the Phase 1b/2 clinical trial, sabizabulin daily chronic oral dosing has a favorable safety profile, is feasible to administer chronically, and has significant and durable antitumor activity. mCRPC that has progressed following ARTAs and prior to taxane chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that may add to the armamentarium for the treatment of mCRPC following progression on ARTA’s. Clinical trial information: NCT04844749.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS5102
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    CD46 targeted 212Pb alpha particle radioimmunotherapy for prostate cancer treatment
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Experimental & Clinical Cancer Research Vol. 42, No. 1 ( 2023-03-11)
    Details
    In: Journal of Experimental & Clinical Cancer Research, Springer Science and Business Media LLC, Vol. 42, No. 1 ( 2023-03-11)
    Abstract: We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212 Pb, an in vivo generator of alpha-emitting 212 Bi and 212 Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212 Pb-TCMC-YS5. We characterized 212 Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212 Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) 212 Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi 212 Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212 Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.
    Type of Medium: Online Resource
    ISSN: 1756-9966
    URL: Article
    DOI: 10.1186/s13046-023-02636-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2430698-8
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  • 5
    Online Resource
    Online Resource
    Patterns of Cancer Progression of Metastatic Hormone-sensitive Prostate Cancer in the ECOG3805 CHAARTED Trial
    Elsevier BV ; 2020
    In:  European Urology Oncology Vol. 3, No. 6 ( 2020-12), p. 717-724
    Details
    In: European Urology Oncology, Elsevier BV, Vol. 3, No. 6 ( 2020-12), p. 717-724
    Type of Medium: Online Resource
    ISSN: 2588-9311
    URL: Article
    DOI: 10.1016/j.euo.2020.07.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2945338-0
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  • 6
    Online Resource
    Online Resource
    Phase 3 VERACITY clinical study of sabizabulin in men with metastatic castrate resistant prostate cancer who have progressed on an androgen receptor targeting agent.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. TPS217-TPS217
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. TPS217-TPS217
    Abstract: TPS217 Background: Sabizabulin is a first-in-class, oral agent that inhibits microtubule polymerization disrupting the cytoskeleton and arresting cellular proliferation. In prostate cancer, targeted inhibition of microtubule polymerization further blocks the transport of the androgen receptor into the nucleus. A phase 1b/2 clinical study was conducted to establish the MTD and evaluate the preliminary efficacy in men with metastatic castrate resistant prostate cancer (mCRPC) who progressed on at least one androgen receptor targeting agent (ARTA). The most common AEs reported were mild to moderate diarrhea, fatigue, nausea, and vomiting with no clinically relevant neurotoxicity or neutropenia. In the phase 1b/2, in all evaluable patients that would qualify for the VERACITY study (n=26), the ORR was 23.1%. Median radiographic progression free survival was 〉 12 months (range 6-28+ months) in the phase 1b portion including responses 〉 two years. The revised formulation for use in the Phase 3 study, with improved bioavailability, is 32mg PO qd. Methods: VERACITY is an ongoing phase 3 multicenter, randomized, active-control study designed to evaluate sabizabulin in the treatment of mCRPC who have progressed on at least one ARTA. Patients on the study will be chemotherapy naive. Subjects (n=245) are being randomized in a 2:1 ratio to receive sabizabulin (32 mg/d oral) or active control (alternative ARTA) and will remain on study until radiographic progression-free survival (rPFS). Randomization will be stratified by: measurable disease vs. bone-only disease and by prior exposure to ARTA (progressed on one vs more than one prior ARTA). The primary efficacy endpoint of the study is median rPFS. Secondary endpoints include: objective response rate (ORR), duration of objective response, overall survival and time to intravenous (IV) chemotherapy. The phase 3, VERACITY registration clinical trial is current ongoing in approximately 45 clinical sites with enrollment anticipated to be completed in 2022 and with unblinded results presented in 2023. Based upon the phase 1b/2 clinical trial, sabizabulin daily chronic oral dosing has a favorable safety profile, is feasible to administer chronically, and has significant and durable antitumor activity. Metastatic prostate cancer that has become refractory to newer generation ARTAs and prior to IV chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that will add to the armamentarium for the treatment of metastatic castration and ARTA resistant prostate cancer. Clinical trial information: NCT04844749.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.TPS217
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 7
    Online Resource
    Online Resource
    A phase 1/2a, open-label, multicenter study of intramuscular (IM) abiraterone decanoate (PRL-02) depot in patients with advanced prostate cancer (NCT04729114).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS5090-TPS5090
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS5090-TPS5090
    Abstract: TPS5090 Background: PRL-02 is a long-acting IM formulation of a lipophilic abiraterone prodrug being developed for the treatment of patients with metastatic castration-sensitive (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). In nonclinical models, PRL-02 has a longer effective half-life and duration of action compared to oral abiraterone acetate (AA), due to slow release of the prodrug into circulation. PRL-02 is expected to provide greater abiraterone bioavailability and less variability in pharmacokinetics than oral AA. Based upon results in non-human primate models, PRL-02 should provide efficacy (e.g., testosterone [T] suppression) comparable to oral AA, but with lower abiraterone peak plasma concentrations and overall exposures, potentially leading to a superior therapeutic index and safety profile. The current trial is a phase 1/2a, open-label, dose escalation and subsequent dose expansion study of PRL-02 in men with metastatic prostate cancer. Study Objectives: The primary objective of this study is to determine a recommended phase 2 dose (RP2D) of PRL-02 that provides adequate T suppression up to 84 days. The secondary objectives of this study include the evaluation of safety and tolerability, the pharmacokinetic profile following IM administration and the pharmacodynamic effects of PRL-02. Methods: The phase 1 portion (Dose Escalation) is a standard 3+3 design intended to identify a RP2D that adequately suppresses T up to 84 days. The phase 2a portion (Dose Expansion) will confirm the safety, tolerability and pharmacodynamic effects of the RP2D. Main inclusion criteria are orchiectomy or ongoing GnRH analogue therapy for at least 3 months and a screening T level 〈 50 ng/dL but 〉 2 ng/dL. Prior treatment with abiraterone (or any other CYP17 inhibitor) and current treatment with enzalutamide or any other AR blocking agents are excluded. Patients will undergo scheduled periodic assessments of T levels. Patients may remain on study unless their T is 〉 1 ng/dL on two sequential determinations starting on Day 28 through Day 77 of the first dosing cycle. In phase 1, three patients will initially be enrolled at each dose. The starting dose is 180 mg (i.e., 1.0 mL of PRL-02) and dose escalation will proceed with a modified Fibonacci sequence. If none of the patients in a cohort experience a dose-limiting toxicity (DLT), the dose will be escalated in the next cohort of 3 patients. A DLT is defined as a drug-related Grade 3 or higher toxicity on the Common Terminology Criteria for Adverse Events v5.0, or meets drug-induced liver injury criteria, occurring during the first 28 days following the first dose. In phase 2a, 12 mCSPC and 12 mCRPC patients will be enrolled to receive up to 4 cycles of PRL-02 at the RP2D. The results of this phase 1/2a study will be presented at a future ASCO conference. Clinical trial information: NCT04729114.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.TPS5090
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 8
    Online Resource
    Online Resource
    Clinical Cancer Advances 2021: ASCO's Report on Progress Against Cancer
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 10 ( 2021-04-01), p. 1165-1184
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 10 ( 2021-04-01), p. 1165-1184
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.20.03420
    RVK:
    XA 52760
    RVK:
    XA 10000
    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
    Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 5 ( 2021-03-01), p. 1305-1315
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 5 ( 2021-03-01), p. 1305-1315
    Abstract: We recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [89Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models. Experimental Design: [89Zr]DFO-YS5 was prepared and its in vitro binding affinity for CD46 was measured. ImmunoPET imaging was conducted in male athymic nu/nu mice bearing DU145 [AR−, CD46+, prostate-specific membrane antigen–negative (PSMA−)] or 22Rv1 (AR+, CD46+, PSMA+) tumors, and in NOD/SCID gamma mice bearing patient-derived adenocarcinoma xenograft, LTL-331, and neuroendocrine prostate cancers, LTL-331R and LTL-545. Results: [89Zr]DFO-YS5 binds specifically to the CD46-positive human prostate cancer DU145 and 22Rv1 xenografts. In biodistribution studies, the tumor uptake of [89Zr] DFO-YS5 was 13.3 ± 3.9 and 11.2 ± 2.5 %ID/g, respectively, in DU145 and 22Rv1 xenografts, 4 days postinjection. Notably, [89Zr]DFO-YS5 demonstrated specific uptake in the PSMA- and AR-negative DU145 model. [89Zr] DFO-YS5 also showed uptake in the patient-derived LTL-331 and -331R models, with particularly high uptake in the LTL-545 neuroendocrine prostate cancer tumors (18.8 ± 5.3, 12.5 ± 1.8, and 32 ± 5.3 %ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days postinjection). Conclusions: [89Zr]DFO-YS5 is an excellent PET imaging agent across a panel of prostate cancer models, including in both adenocarcinoma and neuroendocrine prostate cancer, both cell line- and patient-derived xenografts, and both PSMA-positive and -negative tumors. It demonstrates potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in prostate cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-3310
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 10
    Online Resource
    Online Resource
    Association between baseline body mass index and survival in men with metastatic hormone‐sensitive prostate cancer: ECOG‐ACRIN CHAARTED E3805
    Wiley ; 2022
    In:  The Prostate Vol. 82, No. 12 ( 2022-09), p. 1176-1185
    Details
    In: The Prostate, Wiley, Vol. 82, No. 12 ( 2022-09), p. 1176-1185
    Abstract: E3805 (CHAARTED) is a phase 3 trial demonstrating improved survival for men with metastatic hormone‐sensitive prostate cancer (mHSPC) randomized to treatment with docetaxel (D) and androgen‐deprivation therapy (ADT) versus ADT alone. We assessed the association of baseline body mass index (BMI) and metformin exposure with quality of life (QOL) and prostate cancer outcomes including survival in patients enrolled in the CHAARTED study. Methods We performed a posthoc exploratory analysis of the CHAARTED trial of men with mHSPC randomized to treatment with ADT with or without D between 2006 and 2012. Cox proportional hazards models and Kruskal–Wallis test were used to evaluate the association between BMI with QOL and prostate cancer outcomes and between metformin exposure and survival. Results In 788 of 790 enrolled patients with prospectively recorded baseline BMI and metformin exposure status, lower BMI was not associated with survival, but was associated with high volume disease ( p   〈  0.0001) and poorer baseline QOL on functional assessment of cancer therapy–prostate ( p  = 0.008). Only 68 patients had prevalent metformin exposure at baseline in the CHAARTED trial. Four groups were identified: ADT + D + metformin ( n  = 39); ADT + D ( n  = 357); ADT + metformin ( n  = 29); and ADT alone ( n  = 363). Baseline clinicopathologic characteristics were similar between groups. In this small exploratory multivariable analysis, metformin exposure was not associated with survival (hazard ratio: 1.15; 95% confidence interval: 0.81–1.63, p  = 0.44). Conclusions There was no link between baseline BMI and survival, but lower baseline BMI was associated with features of greater cancer burden and poorer QOL.
    Type of Medium: Online Resource
    ISSN: 0270-4137 , 1097-0045
    URL: Issue
    URL: Article
    DOI: 10.1002/pros.v82.12
    DOI: 10.1002/pros.24369
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1494709-2
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