Serum Profile of microRNAs Linked to Bone Metabolism During Sequential Treatment for Postmenopausal Osteoporosis

2020 ◽  
Vol 105 (8) ◽  
pp. e2885-e2894 ◽  
Author(s):  
Maria P Yavropoulou ◽  
Athanasios D Anastasilakis ◽  
Polyzois Makras ◽  
Athanasios Papatheodorou ◽  
Martina Rauner ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Sequential Treatment ◽  
Single Center ◽  
Open Label ◽  
Relative Expression ◽  
Naive Group ◽  
Subgroup Analyses ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Sequential Treatments

Abstract Context Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment. Objective To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis. Design Observational, open label, nonrandomized clinical trial. Setting A single-center outpatient clinic. Patients and Interventions Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6). Main Outcome Measures Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment. Results Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P < 0.001) and 6 months (FC 0.34, P < 0.001), and miR-338-3p and miR-2861 at 6 months (FC 0.31, P = 0.041; FC 0.52, P = 0.016, respectively) in the whole cohort. In subgroup analyses, Dmab decreased the relative expression of miR-21a-5p, miR-29a-3p, miR-338-3p, and miR-2861 at 3 months (FC 0.13, P < 0.001; FC 0.68, P = 0.044; FC 0.46, P = 0.012; and FC 0.16, P < 0.001, respectively) and 6 months (FC 0.1, P < 0.001; FC 0.52, P < 0.001; FC 0.04, P = 0.006; and FC 0.2, P < 0.001, respectively) only within the TPTD group. Conclusions TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction.

scholarly journals SUN-LB65 Circulating Micrornas Linked to Bone Metabolism Are Affected by Sequential Anti Osteoporotic Treatment in Postmenopausal Osteoporosis

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Maria Yavropoulou ◽  
Polyzois Makras ◽  
Athanasios Anastasilakis ◽  
Athanasios Papatheodorou ◽  
Martina Rauner ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Subsequent Treatment ◽  
Fold Change ◽  
Transcriptional Level ◽  
Open Label ◽  
Relative Expression ◽  
Teriparatide Treatment ◽  
Long Term Treatment ◽  
Treatment Naïve ◽  
Previously Treated

Abstract Depending on osteoporosis severity a long-term treatment, often in the form of a sequential regimen, may be required. The expression of microRNAs (miRs) related to bone metabolism in the serum is potentially affected by anti-osteoporotic treatment. Here, we investigated the effect of sequential treatments on microRNA expression profile in the serum. Methods: This is an observational, open label, non-randomized clinical trial that included 37 postmenopausal women with osteoporosis who were treated with denosumab (Dmab) for 1 year. Patients had been previously treated for 2 years with either teriparatide (n=20), or zolendronate (n=6), or were treatment-naïve (n=11). We evaluated changes in the relative serum expression of selected miRs linked to bone metabolism at 3 and 12 months of Dmab treatment at each group separately. Results: In the group of patients who were previously treated with teriparatide, the relative expressions of miR-21a-5p, miR-29a, and miR-2861 were significantly decreased at both 3 months (fold change 0.13, p<0.001 for miR-21a-5p; fold change 0.68, p=0.044 for miR-29a; fold change 0.16, p<.0001 for miR-2861), and 12 months (fold change 0.09, p<0.001 for miR-21a-5p; fold change 0.65, p=0.044 for miR-29a; fold change 0.19, p<0.001 for miR-2861) of Dmab treatment. The relative expression of miR-23a-3p was also significantly decreased (fold change 0.65, p<0.001) at 12 months of Dmab treatment. The relative expression of miRs was not changed among patients previously treated with zolendronate. No change was also observed during Dmab treatment in previously treatment-naïve osteoporotic women. Conclusions: The expression of circulatings miRs linked to bone metabolism during Dmab treatment is depended on previous treatment status. Patients previously on teriparatide treatment present alterations of the relative expression of miRs related to the expression of key osteoblastic genes such as RUNX-2 (miR-23), collagen type 1 (miR-29a) and HDAC5 gene (miR-2861) during subsequent treatment with Dmab Our data suggest that teriparatide may influence the subsequent anti-resorptive effect of Dmab on bone metabolism at post-transcriptional level.

281 JAVELIN Medley VEGF: phase 2 study of avelumab + axitinib in patients with previously treated non-small cell lung cancer (NSCLC) or treatment naive, cisplatin-ineligible urothelial cancer (UC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A307-A307
Author(s):  
Gabriella Galffy ◽  
Iwona Lugowska ◽  
Elena Poddubskaya ◽  
Byoung Chul Cho ◽  
Myung-Ju Ahn ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Maintenance Treatment ◽  
Locally Advanced ◽  
Small Cell Lung ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Open Label Phase ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Grade 3

BackgroundAvelumab, a human anti–PD-L1 monoclonal antibody, has shown a manageable safety profile and antitumor activity in multiple tumor types, including platinum-resistant metastatic or recurrent NSCLC,1 and is approved for patients with locally advanced or metastatic UC who have progressed after ≥1 previous line of platinum-based chemotherapy2 3 and as maintenance treatment for those who have not progressed with platinum-based chemotherapy.4 JAVELIN Medley VEGF (NCT03472560) evaluated the efficacy and safety of avelumab + axitinib, a potent inhibitor of VEGFR 1, 2, and 3, in patients with advanced or metastatic NSCLC or UC.MethodsEligible patients with NSCLC had received ≥1 prior platinum-containing therapy and ≤2 prior lines of systemic therapy for locally advanced or metastatic disease; patients with UC were treatment naive in the locally advanced or metastatic setting and ineligible for cisplatin-containing chemotherapy. Patients were immune checkpoint inhibitor naïve and received avelumab 800 mg intravenously every 2 weeks + axitinib 5 mg orally twice daily. The primary endpoint was confirmed objective response (OR) per investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS) and safety. PD-L1 expression was assessed in baseline tumor samples (Ventana SP263 assay). Data have not undergone standard quality checks and are subject to change due to COVID-19–related healthcare burden.ResultsA total of 41 patients with NSCLC and 20 with UC received avelumab + axitinib. The confirmed OR rate was 31.7% (95% CI, 18.1–48.1) in the NSCLC cohort and 10% (95% CI, 1.2–31.7) in the UC cohort (all partial responses); 16 patients (39.0%) and 5 (25.0%) had stable disease, respectively. Responses were observed regardless of PD-L1 expression status. Median PFS was 5.5 months (95% CI, 2.5–7.0) in the NSCLC cohort and 2.3 months (95% CI, 1.8–5.6) in the UC cohort. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 24 patients (58.5%) in the NSCLC cohort; the most common was hypertension (n=7 [17.1%]). Grade ≥3 TRAEs occurred in 9 patients (45.0%) in the UC cohort; the most common were amylase increased, asthenia, decreased appetite, and palmar-plantar erythrodysesthesia syndrome (n=2 [10%] each). One patient in each cohort experienced a TRAE that led to death (gastric perforation and urinary bladder hemorrhage).ConclusionsAvelumab + axitinib showed antitumor activity and a manageable safety profile in patients with advanced or metastatic NSCLC or UC consistent with findings from studies of each drug alone and in combination.Trial RegistrationNCT03472560Ethics ApprovalThe study was approved by each site’s independent ethics committee.ConsentN/AReferencesGulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 2017;18:599–610.Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 2018;19:51–64.Bavencio(avelumab) injection. [package insert] Darmstadt, Germany: Merck KGaA; 2019.US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed August 19, 2020.

Addition of Low-Dose Decitabine to Anti–PD-1 Antibody Camrelizumab in Relapsed/Refractory Classical Hodgkin Lymphoma

2019 ◽  
Vol 37 (17) ◽  
pp. 1479-1489 ◽  
Author(s):  
Jing Nie ◽  
Chunmeng Wang ◽  
Yang Liu ◽  
Qingming Yang ◽  
Qian Mei ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Hodgkin Lymphoma ◽  
Cell Function ◽  
Response Duration ◽  
High Response Rate ◽  
Open Label ◽  
Classic Hodgkin Lymphoma ◽  
Open Label Phase ◽  
Treatment Naïve ◽  
Previously Treated

PURPOSE Anti–programmed death-1 (PD-1) monotherapy induces a high response rate in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but complete remission (CR) is infrequently observed. As decitabine is known to boost T-cell function, we assessed the safety and efficacy of anti–PD-1 camrelizumab alone versus decitabine-primed camrelizumab in patients with relapsed/refractory cHL. METHODS This two-arm, open-label, phase II study enrolled patients with relapsed/refractory cHL who had received at least two lines of previous therapy. Anti–PD-1 treatment-naïve patients were randomly assigned (1:2) to camrelizumab (200 mg) monotherapy or decitabine (10 mg/d, days 1 to 5) plus camrelizumab (200 mg, day 8) combination therapy every 3 weeks. Patients who were previously treated with anti–PD-1 were assigned combination therapy. Primary end point was CR rate and safety. RESULTS Overall, 86 patients were enrolled and evaluated for response, with a median follow-up of 14.9 months. In anti–PD-1–naïve patients, CR rate was 32% (six of 19 patients) with camrelizumab monotherapy versus 71% (30 of 42 patients) who were administered decitabine plus camrelizumab ( P = .003). At the time of analysis, the response duration rate at 6 months was 76% on camrelizumab monotherapy versus 100% on decitabine plus camrelizumab. For patients who were previously treated with anti–PD-1, 28% achieved CR and 24% partial response after decitabine plus camrelizumab. Ten patients maintained a response at more than 6 months and 81% of responders were estimated to have a response at more than 1 year. For both treatments, the most common adverse events were clinically inconsequential cherry hemangiomas and leukocytopenia that were self-limiting. CONCLUSION CR rate in patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade was significantly higher with decitabine plus camrelizumab than with camrelizumab alone. Decitabine plus camrelizumab may reverse resistance to PD-1 inhibitors in patients with relapsed/refractory cHL.

A multi-center, open-label study to evaluate the safety and efficacy of pentostatin, cytoxan, and rituxan (PCR) in the treatment of previously untreated or treated, stage III or IV, low-grade CLL

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17508-17508
Author(s):  
R. R. Mena ◽  
R. Robles ◽  
M. Auerbach ◽  
M. Moezi ◽  
D. Headley
Keyword(s):  
Low Grade ◽  
Open Label ◽  
Eligibility Criteria ◽  
Bulky Disease ◽  
Clinical Evaluations ◽  
Treatment Naïve ◽  
Grade Ii ◽  
Previously Treated ◽  
Intent To Treat ◽  
Anti Cd20

17508 Background: The decision to treat indolent CLL is often based on progressive bulky disease, worsening symptoms, and increasing hematological variations. When treatment is indicated, these lymphoproliferative disorders are sensitive to combination immunochemotherapies utilizing pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody. PCR represents a promising new approach in the treatment of patients with low grade CLL. Methods: Eligibility criteria allow previously treated and treatment-naïve patients diagnosed with low-grade stage II/III/IV CLL (modified Rai classification). Treatment consisted of intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for a total of up to 10 cycles. Clinical evaluations (including CT scan) were performed after cycles 2, 4, 6, 8, and 10 (if necessary). Results: The intent-to-treat (ITT) population consisted of 80 CLL patients (median age 64, range 35–83) who received a total of 368 cycles (median 5 per patient). ECOG status at enrollment was 0 (68.4%), 1 (27.6%) and 2 (3.9%). The overall response rate of the 59 evaluable patients was 61% (CR 6.8%, Cru 16.9%, PR 37.3%). 7 cases of grade 4 neutropenia, 2 cases of grade 4 respiratory distress, and 1 case of grade 4 anemia were reported. 5 deaths, all in elderly patients (>70 years old), have been recorded, due to acute respiratory failure, myocardial infarction, pulmonary edema, sepsis, and one unknown cause of death. Conclusions: This immunochemotherapeutic regimen is active in Grade II/III/IV CLL and the incidence of significant toxicities was low with deaths occurring only in elderly (>80 YO) patients. The presented results are preliminary and this study is currently on-going. No significant financial relationships to disclose.

A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9508-9508 ◽  
Author(s):  
Georgina V. Long ◽  
Victoria Atkinson ◽  
Alexander M. Menzies ◽  
Serigne Lo ◽  
Alexander David Guminski ◽  
...  
Keyword(s):  
Antitumour Activity ◽  
Braf Inhibitor ◽  
Local Therapy ◽  
Progression Free Survival ◽  
Leptomeningeal Disease ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Treatment Naïve ◽  
Secondary Endpoints ◽  
Previously Treated

9508 Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]

scholarly journals Open-Label, Expanded Access Study of Taliglucerase Alfa in Patients with Gaucher Disease Requiring Enzyme Replacement Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3755-3755
Author(s):  
David J. Kuter ◽  
Michael Wajnrajch ◽  
Betina Hernandez ◽  
Rong Wang ◽  
Raul Chertkoff ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Research Funding ◽  
Hemoglobin Concentration ◽  
Open Label ◽  
Expanded Access ◽  
Platelet Counts ◽  
Enzyme Replacement ◽  
Treatment Naïve ◽  
Previously Treated

Abstract Taliglucerase alfa, an enzyme replacement therapy (ERT) approved in several countries for the treatment of adult and pediatric patients with Type 1 Gaucher disease, is the first FDA-approved plant cell-expressed recombinant therapeutic protein for humans. PB-06-004 (NCT00962260) was a multicenter, open-label, expanded access study designed to follow the safety of taliglucerase alfa in patients with Gaucher disease who required ERT and who were previously treated with imiglucerase but had a dose reduction or discontinued due to a shortage of imiglucerase. Eligible patients (aged ≥18 years) with Type 1 Gaucher disease received taliglucerase alfa every 2 weeks for ³9 months at a dose equivalent to their previous imiglucerase dose, before it was reduced or discontinued (Part A), and had the option of continuing treatment for up to 33 months (Part B); a later amendment allowed treatment-naïve patients. Fifty-eight patients received treatment (55.2% male, mean age 46.1 years, mean bi-weekly dose 35.2 U/kg, mean duration 17.8 months); 51 patients previously received ERT, 7 were treatment-naïve. Thirty-six patients completed the study. Hemoglobin concentration and platelet counts were also explored. Most adverse events (AEs) were mild or moderate in severity and not related to taliglucerase alfa; treatment-related AEs were mild and transient in nature. In previously treated patients, mean (SE) hemoglobin concentration was 13.0 (0.3) g/dL at baseline, 13.4 (0.2) g/dL at 9 months, and 13.4 (0.2) g/dL at last follow-up; mean (SE) platelet count was 179,242 (15,344)/mm3 at baseline, 209,727 (17,157)/mm3 at 9 months, and 215,242 (17,867)/mm3 at last follow-up. In treatment-naïve patients, mean hemoglobin concentration and platelet counts increased. In conclusion, taliglucerase alfa was well tolerated for up to 33 months of treatment and demonstrated a durable therapeutic effect, as evidenced by stable or improved hemoglobin concentration and platelet counts in this expanded access study. Disclosures Kuter: BMS: Research Funding; Bioverativ: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Protalex: Research Funding; Novartis: Consultancy; Principia: Research Funding; Amgen Inc.: Consultancy; Argenx: Consultancy; ONO: Consultancy; Syntimmune: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wajnrajch:Pfizer Inc: Employment. Hernandez:Pfizer Inc: Employment. Wang:Pfizer Inc: Employment. Chertkoff:Protalix Biotherapeutics: Employment. Zimran:Pfizer Inc: Honoraria; Shire: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.

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