A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of GS-5745 combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4139-TPS4139 ◽  
Author(s):  
Johanna C. Bendell ◽  
Alexander Starodub ◽  
Xi Huang ◽  
Julia D. Maltzman ◽  
Zev A. Wainberg ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Cycle ◽  
Day Treatment ◽  
Gastroesophageal Junction ◽  
Controlled Study ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Primary Tumor Site

TPS4139 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 blocks paracrine signaling and metastasis and alters the tumor immune microenvironment. GS-5745 (800 mg q 2 weeks) with mFOLFOX6 was examined in a Phase 1b study in 40 patients with gastric and GEJ adenocarcinoma (GS-US-296-0101), and demonstrated encouraging activity without added toxicity (10% CR, median PFS 10.7 mo (Shah et al ASCO GI 2017, a108)). Decreased free MMP9 suggested inhibition of MMP9 enzymatic activity by GS-5745. These data support the hypothesis that GS-5745 treatment inhibits MMP9 activity and that the inhibition may lead to improved clinical outcomes. Methods: This phase 3, randomized, double-blind, multicenter study investigates the efficacy and safety of GS-5745 combined with mFOLFOX6 in subjects with untreated gastric and GEJ adenocarcinoma. Total of 430 eligible subjects with advanced gastric and GEJ cancer will be randomized in a 1:1 manner to mFOLFOX6 plus GS-5745 or mFOLFOX6 plus placebo. Stratification factors include ECOG status (0 v 1), geographic region (Latin America v All other countries), and primary tumor site (gastric v GEJ). CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. mFOLFOX6 will be administered on Days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles followed thereafter by leucovorin (LV) and 5-fluorouracil (5-FU) dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. GS-5745/placebo 800 mg will be infused on Days 1 and Day 15 of each 28 day cycle until disease progression. Primary endpoint is OS, and secondary endpoints include PFS, ORR (RECIST 1.1), and safety. The study is designed to have an 85% power to detect clinically meaningful improvement in overall survival at the one-sided significance level of 0.025. The association of exploratory biomarkers with study drug response will also be evaluated. Enrollment opened Oct. 2015. Clinical trial information: NCT02545504.

A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of GS-5745 combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS217-TPS217
Author(s):  
Johanna C. Bendell ◽  
Alexander Starodub ◽  
Xi Huang ◽  
Julia D. Maltzman ◽  
Zev A. Wainberg ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Cycle ◽  
Day Treatment ◽  
Gastroesophageal Junction ◽  
Controlled Study ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Primary Tumor Site

TPS217 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. GS-5745 (800 mg every 2 weeks) with mFOLFOX6 was examined in a Phase 1b study in 40 patients with gastric and GEJ adenocarcinoma (GS-US-296-0101), and demonstrated encouraging activity without added toxicity. Additionally, decreased serum biomarkers suggested inhibition of MMP9 enzymatic activity by these agents. These data support the hypothesis that GS-5745 treatment inhibits MMP9 activity and that the inhibition may lead to improved clinical outcomes. Methods: This phase 3, randomized, double-blind, multicenter study investigates the efficacy and safety of GS-5745 combined with mFOLFOX6 in subjects with untreated gastric and GEJ adenocarcinoma. Total of 430 eligible subjects with advanced gastric and GEJ cancer will be randomized in a 1:1 manner to mFOLFOX6 plus GS-5745 or mFOLFOX6 plus placebo. Stratification factors include ECOG status (0 v 1), geographic region (Latin America v All other countries), and primary tumor site (gastric v GEJ). CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. mFOLFOX6 will be administered on Days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles followed thereafter by leucovorin (LV) and 5-fluorouracil (5-FU) dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. GS-5745/placebo 800 mg will be infused on Days 1 and Day 15 of each 28 day cycle until disease progression. Primary endpoint is OS, and secondary endpoints include PFS, ORR (RECIST 1.1), and safety. The study is designed to have an 85% power to detect clinically meaningful improvement in overall survival at the one-sided significance level of 0.025. The association of exploratory biomarkers with study drug response will also be evaluated. Enrollment opened Oct. 2015. Clinical trial information: NCT02545504.

A phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of andecaliximab combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma (GAMMA-1).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 4-4 ◽  
Author(s):  
Manish A. Shah ◽  
Eduardo Patricio Yanez Ruiz ◽  
Gyorgy Bodoky ◽  
Alexander Starodub ◽  
David Cunningham ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Cycle ◽  
Day Treatment ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Phase Iii ◽  
Controlled Study ◽  
Efficacy And Safety ◽  
First Line ◽  
Double Blind

4 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. A phase I/Ib study of mFOLFOX6 + ADX revealed encouraging antitumor activity in patients (pts) with gastric or gastroesophageal junction (GEJ) adenocarcinoma (median first-line, progression-free survival [PFS] of 9.9 months). Methods: This phase 3, randomized, double-blind, multicenter study investigated the efficacy and safety of mFOLFOX6 with/without ADX in pts with untreated HER2-negative gastric or GEJ adenocarcinoma. Randomization was 1:1 to mFOLFOX6 + ADX or mFOLFOX6 + placebo (PBO). Oxaliplatin was administered on Days 1 and 15 of each 28-day treatment cycle (total of 6 cycles), followed by leucovorin and 5-fluorouracil dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. ADX/PBO 800 mg was infused on Days 1 and 15 of each 28-day cycle until disease progression. The study had 85% power (one-sided significance of 0.025) to detect a hazard ratio of 0.7 for overall survival (OS) by intention-to-treat analysis using the log-rank test. Secondary endpoints were PFS, objective response rate (ORR, RECIST 1.1), and safety. Results: Between September 2015 and May 2017, 432 pts were randomized; 218 pts to ADX and 214 pts to PBO. Median (95% CI) OS was 12.5 (11.2, 14.0) vs 11.8 (10.3, 13.5) months in the ADX and PBO groups, respectively (HR 0.93 [0.74, 1.18], two-sided p=0.56). Median PFS was 7.5 vs 7.1 months in the ADX and PBO groups, respectively (HR 0.84 [0.672, 1.038], two-sided p=0.10). Median investigator assessed ORR was 50.5% vs 41.1% in the ADX and PBO groups, respectively (two-sided p=0.049). The most common treatment-emergent adverse events were nausea, diarrhea, neutropenia, and fatigue. There were no meaningful differences in the safety profile of the ADX vs PBO groups. Subgroup analysis is ongoing. Conclusion: Additionof ADX to mFOLFOX6 does not improve OS in pts with untreated HER2-negative gastric or GEJ adenocarcinoma. Clinical trial information: NCT02545504.

scholarly journals 111 Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P301) Assessing Efficacy and Safety of Extended-Release Viloxazine in Children with ADHD

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 272-272 ◽  
Author(s):  
Azmi Nasser ◽  
Joseph T. Hull ◽  
Fatima A. Chowdhry ◽  
Toyin Adewole ◽  
Tesfaye Liranso ◽  
...  
Keyword(s):  
Clinical Global Impression ◽  
Extended Release ◽  
Rating Scale ◽  
Controlled Study ◽  
Average Score ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
T Score ◽  
Total Average

Abstract:Study Objective:SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P301) evaluated the efficacy and safety of once-daily SPN-812 at doses of 100 and 200 mg compared to placebo in children ages 6-11yrs with ADHD.Method:Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, a Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. This investigation was conducted at 34 study sites in the United States. Subjects (N=477) were randomized 1:1:1 to placebo:100 mg SPN-812:200 mg SPN-812. The 6-week treatment period included up to 1 week of titration and 5 weeks of maintenance (intent-to-treat population: N=460; placebo=155, 100 mg=147, 200 mg=158). The primary efficacy endpoint was the change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) scores at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and in Weiss Functional Impairment Rating Scale-Parent Version (WFIRS-P) total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical exams, electrocardiograms, and the Columbia-Suicide Severity Rating Scale.Results:Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 100 mg and 200 mg SPN-812 treatment groups beginning at week 1 (p=0.0004, p=0.0244; respectively) through EOS (p=0.0004, p<0.0001; respectively). Significant improvement at EOS for both 100 mg and 200 mg SPN-812 compared to placebo was also observed in CGI-I score (p=0.0020, p<0.0001; respectively), Connors 3-PS Composite T-score (p=0.0003, p=0.0002; respectively), and in WFIRS-P total average score (p=0.0019, p=0.0002, respectively). The most common (≥5%) treatment-related AEs reported were somnolence, decreased appetite, and headache.Conclusions:In this study, SPN-812 at 100 mg and 200 mg doses met the primary and secondary objectives with statistical significance. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).Funding Acknowledgements:This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.

scholarly journals 112 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P302): Efficacy and Safety of Extended-Release Viloxazine in Adolescents with ADHD

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 272-273 ◽  
Author(s):  
Azmi Nasser ◽  
Joseph T. Hull ◽  
Fatima A. Chowdhry ◽  
Toyin Adewole ◽  
Tesfaye Liranso ◽  
...  
Keyword(s):  
Clinical Global Impression ◽  
Extended Release ◽  
Rating Scale ◽  
Controlled Study ◽  
Average Score ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
T Score ◽  
Total Average

Abstract:Study Objective:SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P302) evaluated the efficacy and safety of once-daily SPN-812 at doses of 200 and 400 mg compared to placebo in adolescents ages 12-17yrs with ADHD.Method:Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. This investigation was conducted at 34 study sites in the United States. Subjects (N=310) were randomized 1:1:1 to placebo:200 mg SPN-812:400 mg SPN-812. The treatment period included up to 1 week of titration and 5 weeks of maintenance (intent-to-treat population: N=301; placebo=104, 200 mg=94, 400 mg=103). The primary efficacy endpoint was change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) score at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and Weiss Functional Impairment Rating Scale-Parent Form (WFIRS-P) total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical exams, electrocardiograms, and the Columbia-Suicide Severity Rating Scale.Results:Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 200 mg and 400 mg SPN-812 treatment group at EOS (p=0.0232, p=0.0091; respectively). Significant improvement in CGI-I score at EOS for both 200 mg and 400 mg SPN-812 compared to placebo was also observed (p=0.0042, p=0.0003; respectively). No significant change was observed at either dose compared to placebo in the Conners 3-PS Composite T-score (p=0.6854, p=0.0518; respectively), or the WFIRS-P total average score (p=0.2062, p=0.0519; respectively). The most common (≥5%) treatment-related AEs were somnolence, decreased appetite, fatigue, headache, and nausea.Conclusions:In this study, SPN-812 met the primary objective for both the 200 and 400 mg doses, and a key secondary objective (CGI-I) for both the 200 and 400 mg doses. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).Funding Acknowledgements:This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.

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