| 11. |
|
|
| 12. |
- Thellenberg-Karlsson, Camilla, 1972-, et al.
(författare)
-
A randomised, double-blind, dose-finding, phase II multicentre study of ODX in the treatment of patients with castration-resistant prostate cancer and skeletal metastases
- 2023
-
Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 181, s. 198-207
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: This study aimed to assess the efficacy and safety of ODX, a novel, cytotoxic, bone-targeting drug candidate, in castration-resistant prostate cancer bone metastatic disease.Methods: Patients with progressive disease were randomised to ten cycles of ODX, intravenous infusion Q2W (3, 6, and 9 mg/kg, respectively). The primary objective was to assess the relative change from baseline in bone alkaline phosphatase (B-ALP) and serum-aminoterminal-propeptide of Type I procollagen (S-P1NP) at 12 weeks. The inclusion criteria selected were broad, and a double-blind design was used to ensure objective recruitment of patients for the assessment of efficacy. None of the patients received bone-protecting agents during the ODX treatment period.Results: Fifty-five 21,20 and 14) patients were randomised to ODX (3, 6 and 9 mg/kg), respectively. The lower number of patients in arm 3 was due to too low a recruitment rate towards the end of the study. The median treatment time were 14, 13 and 14 weeks, respectively. The decrease in B-ALP at 12 weeks in study arms 3, 6 and 9 mg/kg was seen in 6/15 (40%), 8/12 (67%) and 5/12 (42%) patients, respectively, whereas the corresponding numbers for P1NP were 8/15 (53%), 8/12 (67%), and 4/12 (33%), respectively. The median decrease in B-ALP and P1NP at 12 weeks for study arms 3, 6 and 9 mg/kg were 37%, 14% and 43%, respectively, and 51%, 40% and 64%, respectively. The decrease in serum C-terminal telopeptide at 12 weeks was seen in the vast majority of patients and in about one-third of patients in bone scan index. ODX was well tolerated, and no drug-related serious adverse events occurred. There were no significant differences between study arms regarding efficacy and safety.Conclusions: ODX was well tolerated and demonstrated inhibitory effects on markers related to the vicious cycle in bone at all three doses. The reduction in metastatic burden, assessed with bone scan index, supports this finding. Studies with continued ODX treatment until disease progression are being planned (ClinicalTrials.gov Identifier: NCT02825628).
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Berglund, Åke, et al.
(författare)
-
First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies
- 2015
-
Ingår i: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 33:6, s. 1232-1241
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. Methods This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). Results In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. Conclusions In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.
|
|
| 18. |
- Blennow Nordström, Erik, et al.
(författare)
-
Combined use of the Montreal Cognitive Assessment and Symbol Digit Modalities Test improves neurocognitive screening accuracy after cardiac arrest : A validation sub-study of the TTM2 trial
- 2024
-
Ingår i: Resuscitation. - 0300-9572. ; 202
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: To assess the merit of clinical assessment tools in a neurocognitive screening following out-of-hospital cardiac arrest (OHCA).Methods: The neurocognitive screening that was evaluated included the performance-based Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT), the patient-reported Two Simple Questions (TSQ) and the observer-reported Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE-CA). These instruments were administered at 6-months in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. We used a comprehensive neuropsychological test battery from a TTM2 trial sub-study as a gold standard to evaluate the sensitivity and specificity of the neurocognitive screening.Results: In our cohort of 108 OHCA survivors (median age = 62, 88% male), the most favourable cut-off scores were: MoCA < 26; SDMT z ≤ -1; IQCODE-CA ≥ 3.04. The MoCA (sensitivity 0.64, specificity 0.85) and SDMT (sensitivity 0.59, specificity 0.83) had a higher classification accuracy than the TSQ (sensitivity 0.28, specificity 0.74) and IQCODE-CA (sensitivity 0.42, specificity 0.60). When using the cut-points for MoCA or SDMT in combination to identify neurocognitive impairment, sensitivity improved (0.81, specificity 0.74), area under the curve = 0.77, 95% CI [0.69, 0.85]. The most common unidentified impairments were within the episodic memory and executive functions domains, with fewer false negative cases on the MoCA or SDMT combined.Conclusion: The MoCA and SDMT have acceptable diagnostic accuracy for screening for neurocognitive impairment in an OHCA population, and when used in combination the sensitivity improves. Patient and observer-reports correspond poorly with neurocognitive performance.ClinicalTrials.gov Identifier: NCT03543371.
|
|
| 19. |
|
|
| 20. |
- Blennow Nordström, Erik, et al.
(författare)
-
Neuropsychological outcome after cardiac arrest : results from a sub-study of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial
- 2023
-
Ingår i: Critical Care. - : BioMed Central (BMC). - 1364-8535 .- 1466-609X. ; 27:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA.METHODS: This was a prospective case-control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes.RESULTS: Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ - 1 (at least borderline-mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ - 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = - 0.37, 95% confidence intervals [- 0.61, - 0.12]), verbal (MD = - 0.34 [- 0.62, - 0.07]), and visual/constructive functions (MD = - 0.26 [- 0.47, - 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = - 0.44 [- 0.82, - 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance.CONCLUSIONS: In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue.TRIAL REGISTRATION: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018.
|
|
