scholarly journals Comparison of biosimilar Tigerase and Pulmozyme in long-term symptomatic therapy of patients with cystic fibrosis and severe pulmonary impairment (subgroup analysis of a Phase III randomized open-label clinical trial (NCT04468100))

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261410
Author(s):  
Elena L. Amelina ◽  
Stanislav A. Krasovsky ◽  
Nina E. Akhtyamova-Givirovskaya ◽  
Nataliya Yu. Kashirskaya ◽  
Diana I. Abdulganieva ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Randomized Study ◽  
Phase Iii ◽  
Study Phase ◽  
Symptomatic Therapy ◽  
Open Label ◽  
Pulmonary Impairment ◽  
Severe Impairment ◽  
Safety Parameters ◽  
Efficacy Parameters

Background Patients with cystic fibrosis (CF) need costly medical care and adequate therapy with expensive medicinal products. Tigerase® is the first biosimilar of dornase alfa, developed by the lead Russian biotechnology company GENERIUM. The aim of the manuscript to present post hoc sub-analysis of patients’ data with cystic fibrosis and severe pulmonary impairment of a larger comparative study (phase III open label, prospective, multi-centre, randomized study (NCT04468100)) of a generic version of recombinant human DNase Tigerase® to the only comparable drug, Pulmozyme® Methods In the analyses included subgroup of 46 severe pulmonary impairment patients with baseline FEV1 level 40–60% of predicted (23 patients in each treatment group) out of 100 patients registered in the study phase III open label, prospective, multi-center, randomized study (NCT04468100), and compared efficacy endpoints (FEV1, FVC, number and time of exacerbations, body weight, St.George’s Respiratory Questionnaire) as well as safety parameters (AEs, SAEs, anti-drug antibody) within 24 treatment weeks. Results All outcomes were comparable among the studied groups. In the efficacy dataset, the similar mean FEV1 and mean FVC changes for 24 weeks of both treatment groups were observed. The groups were also comparable in safety, all the secondary efficacy parameters and immunogenicity. Conclusions The findings from this study support the clinical Tigerase® biosimilarity to Pulmozyme® administered in CF patients with severe impairment of pulmonary function.

CONTACT-01: A phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9134-TPS9134
Author(s):  
Joel W. Neal ◽  
Palak Kundu ◽  
Tomohiro Tanaka ◽  
Ida Enquist ◽  
Sid Patel ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Phase Iii ◽  
Clinical Activity ◽  
Open Label ◽  
Eligibility Criteria ◽  
Recist 1.1 ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Previously Treated

TPS9134 Background: Patients with mNSCLC who progress on anti–PD-L1/PD-1 therapy administered in combination with or after platinum-based chemotherapy (PBC) are mainly treated with docetaxel or pemetrexed monotherapy. These therapies only have modest clinical activity, leaving a high unmet medical need. Cabozantinib, a tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment and may enhance the efficacy of PD-L1/PD-1 inhibitors, offering a promising second/third-line therapeutic opportunity for patients with mNSCLC. In a Phase Ib multi-cohort study (COSMIC-021; NCT03170960), cabozantinib plus atezolizumab (anti–PD-L1) showed an acceptable safety profile and promising efficacy (ORR: 27%; mDOR: 5.7 mo [range: 2.6-6.9]; disease control rate [CR + PR + SD]: 83%) in 30 patients with mNSCLC who had progressed after prior anti–PD-L1/PD-1 therapy plus chemotherapy (Neal et al. J Clin Oncol 2020). The Phase III CONTACT-01 study will further evaluate the efficacy and safety of atezolizumab plus cabozantinib versus docetaxel monotherapy in patients with mNSCLC who have progressed during or after prior treatment with anti–PD-L1/PD-1 therapy and PBC. Methods: CONTACT-01 (NCT04471428) is a Phase III, multi-center, randomized, open-label study that will enroll ≈350 patients from 150 to 200 sites internationally. Key eligibility criteria include histologically or cytologically confirmed mNSCLC, disease progression with concurrent or sequential anti–PD-L1/PD-1 treatment and PBC, measurable disease (RECIST 1.1), ECOG PS of 0-1 and the availability of tissue specimens for centralized PD-L1 testing or known PD-L1 status using a health authority–approved PD-L1 assay. Patients with NSCLC previously treated with cabozantinib, docetaxel or anti–PD-L1/PD-1 + VEGFR TKIs are excluded. Patients with known sensitizing EGFR/ALK mutations and active or untreated CNS metastases are also excluded. Patients will be randomized 1:1 to receive either atezolizumab (1200 mg IV every 3 weeks) + cabozantinib (40 mg orally once daily) or docetaxel (75 mg/m2 IV every 3 weeks). The primary endpoint is OS. Secondary endpoints include investigator-assessed PFS, ORR and DOR per RECIST 1.1; TTD in patient-reported physical function and global health status (EORTC QLQ-C30); investigator-assessed PFS rates at 6 months and 1 year; OS rates at 1 and 2 years; safety and PK. Clinical trial information: NCT04471428.

A Comparison of Sevoflurane with Halothane for Paediatric Day Case Surgery

1997 ◽  
Vol 25 (6) ◽  
pp. 643-649 ◽  
Author(s):  
S. M. Walker ◽  
R. D. Haugen ◽  
A. Richards
Keyword(s):  
Randomized Study ◽  
Phase Iii ◽  
Breath Holding ◽  
Day Case ◽  
Open Label ◽  
Day Case Surgery ◽  
Inhalational Induction ◽  
Rapid Induction ◽  
Respiratory Events ◽  
Case Surgery

A phase III, open label, randomized study was conducted in 50 patients comparing halothane and sevoflurane for paediatric day case surgery. A graded inhalational induction resulted in only slightly more rapid induction with sevoflurane (3.34±0.92 versus 3.85±1.02 minutes; P>0.05). In children receiving sevoflurane, systolic blood pressure decreased to a lesser extent during induction (14.3±19.2 versus 26.9±10.9 percent decrease from resting values; P<0.01) and heart rate was maintained. Respiratory events (coughing, breath-holding, bronchospasm, laryngospasm) were more common during induction with halothane, and excitement more common in children receiving sevoflurane. Emergence times were significantly more rapid in children who had received sevoflurane (21.4±10.9 versus 33.1 ±13.7 minutes; P<0.01). Objective pain/discomfort scores were higher in patients receiving sevoflurane at 10, 20, 30 and 40 minutes after arrival in the recovery room, and the incidence of excitement during emergence was higher in this group. It is concluded that sevoflurane is well tolerated for inhalational induction and has an improved cardiovascular profile compared to halothane. Emergence was significantly more rapid following sevoflurane.

A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 11-11 ◽  
Author(s):  
Yung-Jue Bang
Keyword(s):  
Randomized Study ◽  
Asian Population ◽  
Phase Iii ◽  
Weekly Paclitaxel ◽  
Line Treatment ◽  
Second Line ◽  
Her2 Positive ◽  
Open Label ◽  
Significant Prolongation ◽  
The Difference

11 Background: The use of trastuzumab has been established as the standard first-line treatment of HER2 positive (+) AGC. However, the role of anti-HER2 agents in the second-line treatment of HER2+ AGC has not been clearly established yet. TyTAN is the first randomized study to compare the efficacy and safety of adding lapatinib (L) to paclitaxel (P) vs P alone in the second-line treatment of HER2+ AGC. Methods: Eligibility required patients (pts) with AGC, amplification of HER2 by fluorescence in situ hybridization (FISH), and one prior regimen containing fluoropyrimidines and/or cisplatin. Pts were randomized 1:1 to L (1500mg QD) and P (80mg/m2, Day 1, 8, 15 q4w) or P alone. The treatments were given until disease progression or unacceptable toxicity. Stratification variables were prior trastuzumab treatment and gastrectomy status. Primary endpoint was overall survival (OS). Results: From March 2008 to June 2011, 1923 pts were screened and 430 pts were HER2+ AGC. 261 out of 430 pts were enrolled. All pts were from Asian countries: Japan (100), China (95), Korea (46), and Taiwan (20). Median OS was 11.0 months for L+P and 8.9 months for P alone in the intent-to-treat (ITT) population (HR 0.84; p=0.2088). In a pre-planned subgroup analysis, median OS in HER2 immunohistochemistry (IHC) 3+ subgroup was 14.0 months for L+P and 7.6 months for P alone (HR 0.59; p=0.0176). The endpoints in efficacy and AEs of special interest for L+P are summarized below (Table). Conclusions: Although OS was prolonged in L+P arm by 2 months, the difference was not statistically significant. HER2 IHC 3+ subgroup demonstrated statistically significant prolongation of OS by adding L. Clinical trial information: NCT00486954. [Table: see text]

scholarly journals One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study

2020 ◽  
Vol 11 ◽  
pp. 204062072096613
Author(s):  
Hubert Schrezenmeier ◽  
Austin Kulasekararaj ◽  
Lindsay Mitchell ◽  
Flore Sicre de Fontbrune ◽  
Timothy Devos ◽  
...  
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Controlled Trial ◽  
Randomized Study ◽  
Phase Iii ◽  
Complement Inhibitor ◽  
Open Label ◽  
Evaluation Period ◽  
Open Label Extension ◽  
Primary Evaluation ◽  
Long Acting

Background: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment. Methods: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics. Results: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab–ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab–ravulizumab, 64.5%; eculizumab–ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time. Conclusion: In adult, complement inhibitor–naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control. Trial registration: ClinicalTrials.gov identifier, NCT02946463

A phase III, open-label, randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes: Subgroup analyses.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1049-1049 ◽  
Author(s):  
Peter Andrew Kaufman ◽  
Javier Cortes ◽  
Ahmad Awada ◽  
Louise Yelle ◽  
Edith A. Perez ◽  
...  
Keyword(s):  
Randomized Study ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Her2 Status ◽  
Open Label ◽  
Eribulin Mesylate ◽  
Prior Chemotherapy ◽  
Metastatic Setting ◽  
Subgroup Analyses

1049^ Background: This phase III study, comparing eribulin versus capecitabine, showed a non-significant trend for superior overall survival (OS; hazard ratio [HR] 0.88 [95% confidence interval (CI) 0.77, 1.00]; p = 0.056) but not progression-free survival (PFS; HR 1.08 [95% CI 0.93, 1.25]; p = 0.31). Pre-specified exploratory subgroup analyses previously presented showed that patients with triple-negative, ER-negative or HER2-negative disease may have a greater benefit in OS with eribulin compared with capecitabine. Here we present further pre-specified exploratory analyses of OS and PFS. Methods: Patients (eribulin n=554; capecitabine n=548) with locally advanced or MBC had received ≤3 prior chemotherapy regimens (≤2 for advanced disease), including an anthracycline and a taxane. Patients were randomized (stratified for geographic region and HER2 status) 1:1 to 21-day cycles of eribulin mesylate 1.4 mg/m2 i.v. on days 1 and 8 or capecitabine 1.25 g/m2BID orally on days 1-14. Further pre-specified exploratory subgroups included: age; receptor status; number and setting of prior chemotherapy regimen(s); sites of disease; number of organs involved; and time to progression after last chemotherapy. Results: From analyses for OS, patients with only non-visceral disease (HR 0.51; 95% CI 0.33, 0.80), with >2 organs involved (HR 0.75; 95% CI 0.62, 0.90), who had progressed >6 months after last chemotherapy (HR 0.70; 95% CI 0.52, 0.95), or who had received an anthracycline and/or a taxane in the metastatic setting (HR 0.84; 95% CI 0.72, 0.98), appeared to benefit more from treatment with eribulin compared with capecitabine. For OS, in no subgroup was a trend favoring capecitabine seen. Data for other pre-specified subgroups for both OS and PFS will be presented. Conclusions: In addition to patients with triple-, ER-, or HER2-negative disease, further pre-specified exploratory analyses suggest that other patient subgroups may particularly benefit from treatment with eribulin; further studies are warranted to address these hypotheses. Clinical trial information: NCT00337103.

ROCHOP study: A phase III randomized study of CHOP compared to romidepsin-CHOP in untreated peripheral T-cell lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS8616-TPS8616 ◽  
Author(s):  
Richard Delarue ◽  
Pier Luigi Zinzani ◽  
Mark S. Hertzberg ◽  
Won Seog Kim ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Performance Status ◽  
Randomized Study ◽  
Total Duration ◽  
Progression Free Survival ◽  
Phase Iii ◽  
T Cell Lymphomas ◽  
Ann Arbor ◽  
Efficacy Parameters

TPS8616 Background: Peripheral T-cell lymphomas (PTCL) account for 10-15% of lymphomas. They share an aggressive clinical behaviour and a poor prognosis when treated by CHOP-like regimen which is nevertheless consider as a standard because others regimens failed to demonstrate survival advantage. Romidepsin is a histone deacetylase inhibitor with promising results in PTCL. First trials showed a response rate of 38% in heavily pre-treated PTCL patients. These results were confirmed with 15% of patients reaching a CR/CRu, 89% of them without disease progression at 13 months. Adverse events include gastrointestinal, hematologic and asthenic conditions. A phase I study of romidepsin combined with CHOP was conducted by LYSA. A total of 18 patients were included. The recommended dose was 12 mg/m² administered at day 1 and day 8 of each cycle. Methods: Ro-CHOP study is an international phase III study comparing 6 cycles of CHOP21 with 6 cycles of romidepsin-CHOP21 (EUDRACT 2012-001580-68). Primary endpoint is Progression-Free Survival assessed independently. Secondary objectives include overall survival, other efficacy parameters, analysis of response rate according to 18FDG-PET, safety, quality of life and biological ancillary studies. A total of 420 subjects aged from 18 to 80 years will be enrolled in the study. Main inclusion criteria are untreated PTCL whatever Ann Arbor stage and a performance status of 0-2. Main exclusion criteria are other subtypes of lymphoma, HTLV1 positivity, any cardiac abnormality, poor renal, hepatic and marrow functions unless related to lymphoma. Patients are randomized 1:1 between the two regimens. A stratification is performed with IPI score, age and histology. The first patient has been included in January 2013. A recruitment of 10.5 patients per month is anticipated, with a total duration of the study of 60 months. An update on enrolment will be presented at the meeting. Clinical trial information: 2012-001580-68.

A phase II, open-label, randomized study to evaluate the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4141-TPS4141 ◽  
Author(s):  
Manish A. Shah ◽  
Jean-Philippe Metges ◽  
Patrick Youngwhan Chun ◽  
Victoria Smith ◽  
Julia D. Maltzman ◽  
...  
Keyword(s):  
T Cell ◽  
Performance Status ◽  
Randomized Study ◽  
Gastroesophageal Junction ◽  
Cell Polarization ◽  
Phase Iii ◽  
Matrix Remodeling ◽  
Cell Trafficking ◽  
Efficacy And Safety ◽  
Open Label

TPS4141 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 is expected to block paracrine signaling and metastasis and to alter the immune microenvironment within the tumor. Results from the ATTRACTION-2 Phase III trial showed the PD-1 inhibitor nivolumab significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in patients with heavily pre-treated advanced gastric or gastroesophageal junction cancer. Preclinical studies indicate that selective inhibition of MMP9 can inhibit immune-suppressive myeloid cell polarization, regulatory T cell generation, desmoplasia, and the destruction of ligands for CXCR3 (a critical chemokine receptor that enables effector T cell trafficking). In combination with a checkpoint inhibitor, CD8+, CD4+ and CD44+ cytotoxic T cells are significantly increased in a checkpoint-refractory model, suggesting that MMP9 inhibition could relieve immune suppression. Methods: This phase 2, open-label, randomized study investigates the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in patients with unresectable or recurrent gastric or gastroesophageal adenocarcinoma. 120 patients will be randomized to either GS-5745 800mg IV + nivolumab 3mg/kg IV, or nivolumab alone. Treatment will be administered every 2 weeks and stratified by PD-L1 status. CT will be performed every 8 weeks to evaluate response. The primary endpoint of the study is ORR; secondary endpoints include PFS, OS, and occurrence of adverse events. Key inclusion criteria: metastatic or inoperable adenocarcinoma of the stomach or GEJ which has progressed after ≥1 prior systemic therapy, ECOG performance status ≤1, RECISTv1.1 measureable disease, archival tissue adequate for PD-L1 evaluation. Exploratory biomarkers correlated with study drug response will also be evaluated. Enrollment opened September 2016. Clinical trial information: NCT02864381.

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