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.

Phase II, Randomized, Double-Blind Study of Two Dose Levels of Arzoxifene in Patients With Locally Advanced or Metastatic Breast Cancer

2003 ◽  
Vol 21 (6) ◽  
pp. 1007-1014 ◽  
Author(s):  
Aman Buzdar ◽  
Joyce A. O’Shaughnessy ◽  
Daniel J. Booser ◽  
John E. Pippen ◽  
Stephen E. Jones ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Double Blind Study ◽  
Double Blind ◽  
Dose Levels

Purpose: To select a daily dose of arzoxifene ( LY353381 ), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR). Patients and Methods: This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity. Results: Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P > .05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P > .05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study. Conclusion: Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.

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 .

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