A phase II randomized study of telaglenastat, a glutaminase (GLS) inhibitor, versus placebo, in combination with pembrolizumab (Pembro) and chemotherapy as first-line treatment for KEAP1/NRF2-mutated non-squamous metastatic non-small cell lung cancer (mNSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9627-TPS9627
Author(s):  
Ferdinandos Skoulidis ◽  
Joel W. Neal ◽  
Wallace L. Akerley ◽  
Paul K. Paik ◽  
Thales Papagiannakopoulos ◽  
...  
Keyword(s):  
Phase Ii ◽  
Target Genes ◽  
Randomized Study ◽  
Standard Of Care ◽  
Glutamine Metabolism ◽  
Double Blind Study ◽  
Double Blind ◽  
Nrf2 Pathway ◽  
Mutational Status ◽  
Mutational Activation

TPS9627 Background: Mutational activation of the KEAP1/NRF2 pathway occurs in >20% of NSCLC patients (pts). KEAP1/NRF2 activation protects tumor cells from diverse forms of oxidative stress and promotes tumor growth and survival. In pts w/ advanced NSCLC, mutation of the KEAP1/NRF2 pathway is associated w/ dramatically reduced survival and poor outcomes following standard-of-care therapy. These tumors have increased dependence on GLS-mediated conversion of glutamine to glutamate due to upregulation of NRF2 target genes involved in glutamine metabolism. Telaglenastat (CB-839), an investigational, first-in-class, potent, oral GLS inhibitor, has demonstrated preclinical activity in KEAP1/NRF2-mutated NSCLC cell lines and xenograft models. This study will evaluate the safety and efficacy of telaglenastat + standard-of-care pembro and chemotherapy as 1L therapy for KEAP1/NRF2-mutated non-squamous mNSCLC (NCT04265534). Methods: This phase II, randomized, multicenter, double-blind study will enroll ~120 pts with histologically or cytologically documented stage IV non-squamous NSCLC w/ KEAP1 or NRF2 mutation, no prior systemic therapy for mNSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, and no EGFR, ALK, ROS, or other actionable mutation w/ available approved therapy in 1L setting. KEAP1 or NRF2 mutations will be determined by next generation sequencing (NGS), and study-provided liquid biopsy NGS will be available. Pts will be randomized 1:1 to receive telaglenastat (800 mg BID PO) or placebo, in combination with pembro, carboplatin, and pemetrexed at standard doses on day 1 of each 21-day cycle. Pts will be stratified by STK11/LKB1 mutational status and M stage of cancer (M1a-b vs M1c). The study will include an initial safety run-in period (n=12; 1 cycle). Co-primary endpoints are safety and investigator-assessed progression-free survival (RECIST v1.1). Secondary endpoints include overall response rate, duration of response, overall survival, and efficacy analysis in the subgroup of pts w/ biochemical confirmation of KEAP1/NRF2 pathway activation. Findings of this novel NGS biomarker-selected study will inform the efficacy and safety profile of telaglenastat + standard-of-care chemoimmunotherapy for 1L treatment of KEAP1/NRF2-mutated, non-squamous mNSCLC. Clinical trial information: NCT04265534 .

scholarly journals Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE–CF™ 1 – a randomised, Phase II study

2021 ◽  
pp. 2100746
Author(s):  
Christopher H. Goss ◽  
Isabelle Fajac ◽  
Raksha Jain ◽  
Wolfgang Seibold ◽  
Abhya Gupta ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Phase Ii ◽  
Clinical Effect ◽  
Quality Criteria ◽  
Standard Of Care ◽  
Double Blind Study ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Dose Levels ◽  
Epithelial Sodium Channel Enac

BackgroundInhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated preclinical efficacy and safety already demonstrated in humans.ObjectiveWe present results from BALANCE-CF™ 1, a Phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF.ResultsInitially, 28 randomised subjects (n=14 each BI 1265162 200 µg BID, placebo BID) were assessed at an interim futility analysis. Compared with placebo, numerical changes of –0.8% (95%CI –6.6, 4.9) in ppFEV1 and +2.1 units (95%CI –2.4, 6.5) in LCI were observed in the active group, meeting a predefined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg BID dose versus placebo) were not supportive of relevant clinical effect. LCI change was also not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in CFQ-R Respiratory Domain was observed in the 200 µg BID dose group versus placebo. BI 1265162 up to 200 µg BID was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers.ConclusionBI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.

Phase II randomized, double-blind, study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients hcrn GI14-198.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS475-TPS475
Author(s):  
Walid Labib Shaib ◽  
Bert O'Neil ◽  
Bassel F. El-Rayes ◽  
Steven J. Cohen ◽  
Tina Ashley Khair ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
De Novo ◽  
Advanced Pancreatic Cancer ◽  
Standard Of Care ◽  
Double Blind Study ◽  
Current Standard ◽  
Double Blind ◽  
Angiogenic Therapy ◽  
Pancreas Adenocarcinoma

TPS475 Background: The prognosis of pancreas adenocarcinoma (PCA) remains poor. A chemotherapy backbone is the current standard of care in PCA. The choice of a chemotherapeutic backbone may impact the efficacy of anti-angiogenic therapy in PCA. Ramucirumab has increased activity with fluoropyrimidines (5FU) because 5FU increases VEGF expression. Methods: This is a double-blind, placebo controlled Phase II study. Subjects will receive either Ramucirumab or a placebo followed by mFOLFIRINOX every two weeks of a 28 day cycle until progression or discontinuation for other reasons. The primary endpoint of this clinical trial is nine month PFS defined as the time from enrollment to the time of progression or death. Among the key inclusion criteria, subjects must have recurrent or metastatic pancreas adenocarcinoma (PCA) with no prior first-line systemic treatment, ECOG PS 0-1, adequate organ function, no DVT, PE or other thromboembolism within three months of randomization. Total number of patient enrolled as of September 19, 2018 is 48 of 85 at eight sites; 27 male (56%), 42 Caucasians (87.5%), three African American (6.2%), one Asian (2%). Median age is 63 (40 - 76). Majority of patients (41) had de novo metastatic disease and six with recurrent disease after surgery. Regimen has been tolerated well with no unanticipated events. Clinical trial information: NCT02581215.

scholarly journals Baricitinib-associated changes in global gene expression during a 24-week phase II clinical systemic lupus erythematosus trial implicates a mechanism of action through multiple immune-related pathways

2020 ◽  
Vol 7 (1) ◽  
pp. e000424
Author(s):  
Thomas Dörner ◽  
Yoshiya Tanaka ◽  
Michelle A Petri ◽  
Josef S Smolen ◽  
Daniel J Wallace ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phase Ii ◽  
Lupus Erythematosus ◽  
Target Genes ◽  
Janus Kinase ◽  
Double Blind Study ◽  
Double Blind ◽  
Baseline Serum ◽  
Network Analyses ◽  
Serum Cytokines

ObjectiveTo characterise the molecular pathways impacted by the pharmacologic effects of the Janus kinase (JAK) 1 and JAK2 inhibitor baricitinib in SLE.MethodsIn a phase II, 24-week, randomised, placebo-controlled, double-blind study (JAHH), RNA was isolated from whole blood in 274 patients and analysed using Affymetrix HTA2.0 array. Serum cytokines were measured using ultrasensitive quantitative assays.ResultsGene expression profiling demonstrated an elevation of STAT1, STAT2 and multiple interferon (IFN) responsive genes at baseline in patients with SLE. Statistical and gene network analyses demonstrated that baricitinib treatment reduced the mRNA expression of functionally interconnected genes involved in SLE including STAT1-target, STAT2-target and STAT4-target genes and multiple IFN responsive genes. At baseline, serum cytokines IFN-α, IFN-γ, interleukin (IL)-12p40 and IL-6 were measurable and elevated above healthy controls. Treatment with baricitinib significantly decreased serum IL-12p40 and IL-6 cytokine levels at week 12, which persisted through week 24.ConclusionBaricitinib treatment induced significant reduction in the RNA expression of a network of genes associated with the JAK/STAT pathway, cytokine signalling and SLE pathogenesis. Baricitinib consistently reduced serum levels of two key cytokines implicated in SLE pathogenesis, IL-12p40 and IL-6.

scholarly journals Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis

Neurology ◽  
2018 ◽  
Vol 90 (16) ◽  
pp. e1425-e1434 ◽  
Author(s):  
Karen Hewett ◽  
Donald B. Sanders ◽  
Richard A. Grove ◽  
Christine L. Broderick ◽  
Todd J. Rudo ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Lupus Erythematosus ◽  
B Lymphocyte ◽  
Randomized Study ◽  
Treatment Phase ◽  
Standard Of Care ◽  
Double Blind Study ◽  
Double Blind ◽  
Treatment Groups ◽  
Significant Difference

ObjectiveTo investigate the efficacy and safety of belimumab, a fully human immunoglobulin G1λ monoclonal antibody against B-lymphocyte stimulator, in participants with generalized myasthenia gravis (MG) who remained symptomatic despite standard of care (SoC) therapy.MethodsEligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo in this phase II, placebo-controlled, multicenter, double-blind study (NCT01480596; BEL115123). Participants received SoC therapies throughout the 24-week treatment phase and 12-week follow-up period. The primary efficacy endpoint was mean change from baseline in the Quantitative Myasthenia Gravis (QMG) scale at week 24; safety assessments included the frequency and severity of adverse events (AEs) and serious AEs.ResultsForty participants were randomized (placebo n = 22; belimumab n = 18). The mean change in QMG score from baseline at week 24 was not significantly different for belimumab vs placebo (p = 0.256). There were no statistically significant differences between treatment groups for secondary endpoints, including the MG Composite and MG–Activity of Daily Living scores. Acetylcholine receptor antibody levels decreased over time in both treatment groups. No unexpected AEs were identified and occurrence was similar in the belimumab (78%) and placebo (91%) groups. One participant receiving placebo died (severe sepsis) during the treatment phase.ConclusionsThe primary endpoint was not met for belimumab in participants with generalized MG receiving SoC. There was no significant difference in mean change in the QMG score at week 24 for belimumab vs placebo. The safety profile of belimumab was consistent with previous systemic lupus erythematosus studies.Classification of evidenceThis study provides Class I evidence that for participants with generalized MG, belimumab did not significantly improve QMG score compared with placebo.

Benefits of immunonutrition in patients with head and neck cancer receiving chemoradiation: A phase II randomized, double-blind study

2021 ◽  
Author(s):  
Tanadech Dechaphunkul ◽  
Tippawan Arundon ◽  
Ponpis Raungkhajon ◽  
Rungarun Jiratrachu ◽  
Sarayut Lucien Geater ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Phase Ii ◽  
Neck Cancer ◽  
Blind Study ◽  
Double Blind Study ◽  
Double Blind

scholarly journals Rifabutin-Containing Triple Therapy (RHB-105) for Eradication of Helicobacter pylori: Randomized ERADICATE Hp Trial

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 685 ◽  
Author(s):  
Ira N. Kalfus ◽  
David Y. Graham ◽  
Dennis S. Riff ◽  
Raymond M. Panas
Keyword(s):  
Helicobacter Pylori ◽  
Eradication Rate ◽  
Study Drug ◽  
Standard Of Care ◽  
Empiric Therapy ◽  
World Health ◽  
Double Blind Study ◽  
Double Blind ◽  
Treatment Naïve ◽  
H Pylori

Due to increasing resistance to commonly used antibiotics, the World Health Organization and Food and Drug Administration have advocated the development of new therapeutic regimens for Helicobacter pylori (H. pylori). This phase three, double-blind study (ERADICATE Hp) randomized (2:1) treatment-naïve adults with H. pylori infection and dyspepsia to RHB-105 (an all-in-one combination of omeprazole 40 mg, amoxicillin 1000 mg, and rifabutin 50 mg) or an identically-appearing placebo, both administered every 8 h for 14 days. The H. pylori eradication rate with RHB-105, using a modified intent-to-treat (mITT) population of subjects who received ≥1 dose of study drug and had test-of-eradication performed 28–35 days post-completion of therapy, was compared (one-sample Z-test) to a literature-derived comparator rate of 70% and success rate with physician-selected standard-of-care given to placebo failures. The mITT H. pylori eradication rate (95% CI) with RHB-105 of 89.4% (82.0–96.8%) was greater than both the literature-derived comparator rate (P < 0.001) and the standard-of-care rate of 63.0% (44.8–81.1%) (P = 0.006). Adverse events with an incidence ≥5% for RHB-105 were diarrhea (12.7%), headache (11.9%), chromaturia (9.3%), abdominal tenderness (6.8%), and dizziness (5.1%). No leukopenia was noted. RHB-105 (Talicia®) proved to be a safe and effective empiric therapy for H. pylori eradication.

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