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.

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.

Phase III study of first-line zolbetuximab + CAPOX versus placebo + CAPOX in Claudin 18.2+/HER2−advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: GLOW.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4648-TPS4648
Author(s):  
Manish A. Shah ◽  
Jaffer A. Ajani ◽  
Salah-Eddin Al-Batran ◽  
Yung-Jue Bang ◽  
Daniel Catenacci ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Controlled Study ◽  
Her2 Status ◽  
First Line ◽  
Double Blind ◽  
Junction Protein

TPS4648 Background: Gastric cancer is the fourth leading cause of cancer death worldwide. Capecitabine + oxaliplatin (CAPOX) is a standard first-line treatment for advanced gastric cancer. Claudin (CLDN)18.2 has emerged as a promising targetable biomarker. In healthy tissue, CLDN18.2, a tight junction protein, is confined to gastric mucosa (ie, cells in the pit and base regions of gastric glands). Upon malignant transformation, structural loss in gastric or gastroesophageal junction (G/GEJ) adenocarcinoma cells may allow antibodies more access to previously unavailable CLDN18.2. Zolbetuximab is a chimeric IgG1 monoclonal antibody that specifically binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Results of a phase 2 study (NCT01630083) showed prolonged survival of patients with CLDN18.2-positive (CLDN18.2+) advanced G/GEJ adenocarcinoma treated with zolbetuximab + epirubicin, oxaliplatin, and capecitabine (EOX) vs EOX alone. Methods: This phase 3, double-blind, placebo-controlled study (NCT03653507) will enroll ~500 adult patients from global sites. Patients are required to have CLDN18.2+/HER2− locally advanced unresectable or metastatic G or GEJ adenocarcinoma that is radiographically evaluable per RECIST v1.1. Patients are not permitted to have received prior treatment with chemotherapy for advanced or metastatic G or GEJ adenocarcinoma. Patients will be randomly assigned 1:1 to receive either zolbetuximab plus CAPOX or placebo plus CAPOX. Randomization will be stratified by region (Asia vs non-Asia), number of metastatic sites (0 to 2 vs ≥3), and prior gastrectomy (yes vs no). Zolbetuximab will be administered at a loading dose of 800 mg/m2 IV on Cycle 1 Day 1 followed by 600 mg/m2 IV every 3 weeks. Central testing of tumor tissue will determine CLDN18.2 and HER2 status (if unknown); patients will be considered CLDN18.2+ if ≥75% of tumor cells demonstrate moderate-to-strong membranous immunohistochemical staining. The primary objective is to compare progression-free survival between treatment arms. Secondary endpoints are overall survival; objective response rate; duration of response; and the safety/tolerability, pharmacokinetics, and immunogenicity of zolbetuximab. As of January 31, 2020, 127 sites were active and open to enrollment. Clinical trial information: NCT03653507 .

A randomized, double-blind, placebo-controlled phase III study of cisplatin plus a fluoropyrimidine with or without ramucirumab as first-line therapy in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (RAINFALL, NCT02314117).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS178-TPS178 ◽  
Author(s):  
Charles S. Fuchs ◽  
Josep Tabernero ◽  
Salah-Eddin Al-Batran ◽  
Ian Chau ◽  
David H. Ilson ◽  
...  
Keyword(s):  
Disease Progression ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Safety Analysis ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Type I ◽  
Line Treatment ◽  
First Line ◽  
Double Blind

TPS178 Background: Ramucirumab, a human IgG1 monoclonal antibody directed to the ectodomain of VEGFR-2, prevents ligand binding to the receptor, blocking activation of downstream receptor-mediated pathways. Ramucirumab has demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) in 2 phase III registration studies (REGARD, RAINBOW) in patients in second-line treatment of gastric cancer. This global phase III trial will compare PFS in patients with HER2-negative, metastatic gastric or GEJ adenocarcinoma receiving ramucirumab with cisplatin/capecitabine (or 5-FU) versus placebo with cisplatin/capecitabine (or 5-FU) as first-line treatment. The trial is conducted in 137 sites in the Americas, Europe and Japan and is currently open to enrollment. Methods: Eligible patients will be randomized to receive ramucirumab (8mg/kg on days 1 and 8, based upon population pharmacokinetic modelling) or placebo with cisplatin/capecitabine every 21-day cycle until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary endpoint is PFS; OS is the key secondary endpoint. Efficacy will be considered at 3 analysis points: futility analysis for PFS, primary analysis of PFS & final analysis of OS. A gatekeeping strategy will be used to assess PFS and OS. The OS endpoint will only be tested if the PFS test is significant to control Type I error at 5% across both endpoints. An exposure/safety analysis will be done after 60 patients have started the 3rd cycle. The study has 90% power to demonstrate a PFS advantage assuming HR = 0.70 and 80% power to demonstrate an OS advantage assuming HR = 0.77. Other secondary endpoints include PFS2 (the time from randomization to disease progression after the start of additional systemic anticancer treatment, or death from any cause, whichever occurs first), objective response rate, safety and quality of life. As of 9/11/2015, 128 patients have been enrolled in 19 countries. The 1st exposure/safety analysis is underway. Clinical trial information: NCT02314117.

REGARD: A phase III, randomized, double-blinded trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. LBA5-LBA5 ◽  
Author(s):  
Charles S. Fuchs ◽  
Jiri Tomasek ◽  
Jae Yong Cho ◽  
Filip Dumitru ◽  
Rodolfo Passalacqua ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Disease Progression ◽  
Gastroesophageal Junction ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Vegf Receptor ◽  
First Line ◽  
Double Blind ◽  
Cancer Pathogenesis ◽  
Line Therapy

LBA5 Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or placebo (PL) plus BSC every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Eligible patients had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. The Hazard Ratio (HR) for OS was 0.776 (95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent of grade ≥ 3 adverse events (AEs) were: hypertension (7.2% RAM; 2.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.1% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), fatigue (4.2% RAM; 3.5% PL), decreased appetite (3.4% RAM; 3.5% PL) and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab conferred a statistically significant benefit in OS and PFS compared to PL in metastatic gastric or GEJ adenocarcinoma following progression on 1st-line therapy with an acceptable safety profile. Clinical trial information: NCT00917384.

Phase III LEAP-010 study: first-line pembrolizumab with or without lenvatinib in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6589-TPS6589 ◽  
Author(s):  
Lillian L. Siu ◽  
Barbara Burtness ◽  
Ezra E.W. Cohen ◽  
Kevin Joseph Harrington ◽  
Lisa F. Licitra ◽  
...  
Keyword(s):  
Disease Progression ◽  
Tumor Imaging ◽  
Performance Status ◽  
Objective Response ◽  
Phase Iii ◽  
First Line ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Multikinase Inhibitor ◽  
End Points

TPS6589 Background: The PD-1 inhibitor pembrolizumab is currently approved as first-line monotherapy for patients with R/M HNSCC whose tumors express PD-L1 combined positive score (CPS) ≥1. In a phase 1b/2 trial (NCT02501096) of pembrolizumab plus lenvatinib (multikinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRa, RET, and KIT) in solid tumors, the combination demonstrated promising antitumor activity and a manageable safety profile in patients with HNSCC. LEAP-010 (NCT04199104) is a randomized, double-blind, placebo-controlled, phase 3 study that will evaluate the efficacy and safety of first-line pembrolizumab with or without lenvatinib in patients with PD-L1–positive R/M HNSCC. Methods: Key eligibility criteria include histologically confirmed R/M HNSCC incurable by local therapies, PD-L1–positive tumor (CPS ≥1) as determined by central laboratory, measurable disease as assessed by blinded independent central review (BICR) per RECIST v1.1, and ECOG performance status (PS) 0 or 1. Patients will be randomly assigned 1:1 to pembrolizumab plus lenvatinib or pembrolizumab plus placebo. Randomization will be stratified by PD-L1 status defined by tumor proportion score ( < 50% vs ≥50%), human papillomavirus status for oropharynx cancer (positive vs negative), and ECOG PS (0 or 1). Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles (~2 years) and oral lenvatinib 20 mg or placebo once daily; patients may continue to receive lenvatinib or placebo after pembrolizumab treatment is complete. Treatment will continue until BICR-verified disease progression or unacceptable toxicity. Pembrolizumab retreatment (second course) for 17 additional cycles will be allowed for eligible patients who stop pembrolizumab and subsequently experience BICR-verified disease progression. These patients could have stopped treatment with stable disease, partial response, or complete response or after 35 cycles of pembrolizumab for reasons other than disease progression or toxicity. Tumor imaging assessment will be performed at week 6, then every 6 weeks until 1 year, and thereafter every 9 weeks. Primary end points are objective response rate and progression-free survival, assessed by BICR per RECIST v1.1, and overall survival. Secondary end points are duration of response and safety and tolerability. Recruitment is ongoing; planned enrollment is ~500 patients. Clinical trial information: NCT04199104 .

RAINBOW-Asia: A randomized, multicenter, double-blind, phase III study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line chemotherapy with platinum and fluoropyrimidine.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 199-199
Author(s):  
Rui-hua Xu ◽  
Yan-Qiao Zhang ◽  
Hongming Pan ◽  
Ji Feng Feng ◽  
Tao Zhang ◽  
...  
Keyword(s):  
Disease Progression ◽  
Chinese Population ◽  
Performance Status ◽  
Gastroesophageal Junction ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
First Line ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Line Chemotherapy

199 Background: Ramucirumab (RAM), a fully human IgG1 monoclonal antibody targeting vascular endothelial growth factor receptor 2, has been approved in combination with paclitaxel (PTX) in patients with advanced gastric cancer in the second-line setting outside of China in around 80 countries based on the significant overall survival (OS) benefit in the global phase 3 RAINBOW study. RAINBOW-Asia was a bridging study of RAINBOW to evaluate the efficacy and safety of RAM in a predominantly Chinese population. Methods: Patients with advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who experienced disease progression on first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomized at a 2:1 ratio to receive RAM (8 mg/kg) on day 1 and 15 plus PTX (80 mg/m²) on day 1, 8, and 15 of a 28-day cycle or placebo (PL) plus PTX. Randomization was stratified by ECOG Performance Status (0 versus 1) and peritoneal metastases (yes versus no). The co-primary endpoints were PFS and OS. Results: From Mar 2017 to Jun 2020, 440 pts were randomized (RAM+PTX: 294; PL+PTX: 146). Median PFS was significantly improved with RAM+PTX compared to PL+PTX (4.14m vs. 3.15m; HR = 0.765 [95% CI: 0.613 to 0.955]; p = 0.0184). Median OS was 8.71m with RAM+PTX and 7.92m with PL+PTX (HR = 0.963 [95% CI: 0.771 to 1.203]; p = 0.7426). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurring in > 5% of patients with RAM+PTX were: neutrophil count decreased (54.3% RAM+PTX; 38.6% PL+PTX), white blood cell count decreased (43.3% vs. 29.0%), anaemia (15.7% vs. 16.6%), hypertension (7.2% vs. 6.2%), and febrile neutropenia (6.1% vs. 0.7%). Conclusions: The combination of RAM+PTX as 2nd-line therapy demonstrated a statistically significant PFS benefit, and OS benefit consistent with RAINBOW study in a predominantly Chinese population with advanced gastric and GEJ cancer. The safety profile of RAM was consistent with previous studies. No new safety signal was observed. Clinical trial information: NCT02898077.

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