Abstract CT096: Phase 1b study of ramucirumab (RAM) in combination with fluoropyrimidine and platinum-based agents in Japanese patients (pts) with metastatic gastric/gastroesophageal junction adenocarcinoma (mGC)

2017 ◽  
Author(s):  
Shigenori Kadowaki ◽  
Kohei Shitara ◽  
Daisuke Sakai ◽  
Tomohiro Nishina ◽  
Reigetsu Yoshikawa ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Japanese Patients ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Phase 1B

scholarly journals Safety and tolerability of andecaliximab as monotherapy and in combination with an anti-PD-1 antibody in Japanese patients with gastric or gastroesophageal junction adenocarcinoma: a phase 1b study

2022 ◽  
Vol 10 (1) ◽  
pp. e003518
Author(s):  
Akie Kimura Yoshikawa ◽  
Kensei Yamaguchi ◽  
Kei Muro ◽  
Atsuo Takashima ◽  
Takashi Ichimura ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Her2 Status ◽  
Clinical Activity ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Programmed Death 1 ◽  
Phase 1B

BackgroundMatrix metalloproteinase 9 (MMP9) is implicated in protumorigenic processes. Targeting either stromal or epithelial MMP9 reduces the incidence of metastasis. Andecaliximab is a monoclonal antibody that targets MMP9 with high affinity and selectivity. However, no study has examined whether the inhibition of T-cell programmed death 1 (PD-1) in the presence of andecaliximab increases activated lymphocyte infiltration into the tumor, thereby increasing antitumor activity more than that in anti-PD-1 monotherapy. In this study, we assessed the safety, pharmacokinetics (PK), exploratory biomarkers, and preliminary efficacy of andecaliximab as monotherapy and in combination with nivolumab in Japanese patients with advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma.MethodsThis phase 1b study comprised four cohorts enrolling Japanese patients with gastric or GEJ adenocarcinoma. This paper concerns cohorts 1 and 4; cohorts 2 and 3 will be reported subsequently. Cohort 1 enrolled patients with human epidermal growth factor receptor 2 (HER2)-negative tumors (n=8) who received andecaliximab monotherapy (800 mg by intravenous infusion every 2 weeks (Q2W)), and cohort 4 enrolled patients irrespective of their HER2 status (n=10) who received 800 mg of andecaliximab in combination with nivolumab Q2W. Safety, dose-limiting toxicities (DLTs), PK, pharmacodynamics, and biomarkers were assessed in both cohorts.ResultsPK of andecaliximab in Japanese patients with gastric or GEJ adenocarcinoma was similar to that reported in non-Japanese patients with advanced solid tumors. Andecaliximab monotherapy and in combination with nivolumab demonstrated no DLTs in cohort 1 and 4, respectively. Toxicities were manageable and well tolerated in both cohorts. The median progression-free survival was 1.4 months (90% CI, 0.5 to 5.4) and 4.6 months (90% CI, 0.9 to not reached) in cohorts 1 and 4, respectively. The objective response rate was 50% (90% CI, 22% to 78%) in cohort 4, and in some patients, the combination therapy was effective regardless of the biomarker status.ConclusionsThe andecaliximab–nivolumab combination demonstrated a manageable safety profile and promising clinical activity in patients with advanced gastric adenocarcinoma.NCT02862535.

ZW25, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3145-TPS3145
Author(s):  
Do-Youn Oh ◽  
Hyun Cheol Chung ◽  
Young Hyuck Im ◽  
Chia Jui Yen ◽  
Yee Chao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Gastroesophageal Junction ◽  
Single Agent ◽  
Tolerability Profile ◽  
First Line ◽  
Her2 Positive ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Treatment Naïve ◽  
Phase 1B

TPS3145 Background: ZW25 is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action, including activation of ADCC and inhibition of ligand-dependent and -independent cellular growth. ZW25 is well tolerated and showed single-agent antitumor activity in patients (pts) with advanced HER2-positive cancers. Previous reports suggested that tislelizumab, an investigational anti-PD-1 antibody engineered to minimize binding of FcgR on macrophages in order to abrogate antibody-dependent phagocytosis, was generally well tolerated and had antitumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. Combining HER2-targeted agents with chemotherapy has resulted in improved survival; the highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort phase 1B/2 study is designed to evaluate ZW25 plus chemotherapy ± tislelizumab as first-line therapy in pts (n≈50) with HER2-positive metastatic breast cancer (mBC; cohort 1) or advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). In cohort 1, pts with HER2-positive (IHC3+ or ISH amplified) mBC must be treatment-naïve for metastatic disease and will receive intravenous (IV) ZW25 30 mg/kg plus docetaxel 75 mg/m2 IV once every 3 weeks (Q3W). In cohort 2, treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive ZW25 30 mg/kg plus tislelizumab 200 mg IV and chemotherapy (CAPOX regimen: capecitabine 1000 mg/m2 twice daily and oxaliplatin 130 mg/m2 IV) Q3W. A safety lead-in phase is designed for the first six pts in cohort 2, followed by dose expansion after a safety monitoring committee review. Primary endpoints are the safety/tolerability profile and objective response rate; secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: Registered, NCT number pending will provide as soon as available .

Zanidatamab, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2656-TPS2656
Author(s):  
Keun Wook Lee ◽  
Young-Hyuck Im ◽  
Keun Seok Lee ◽  
Jae Yong Cho ◽  
Do-Youn Oh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Metastatic Breast ◽  
First Line ◽  
Her2 Positive ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Treatment Naïve ◽  
Phase 1B ◽  
Anti Tumor Activity

TPS2656 Background: Zanidatamab is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action including enhanced binding, clustering, receptor internalization and downregulation; this results in inhibition of ligand-dependent and -independent proliferation and potent activation of antibody-dependent cellular cytotoxicity. Zanidatamab monotherapy is well tolerated and has shown promising anti-tumor activity in patients (pts) with pre-treated advanced HER2-positive cancers, and was well tolerated in a Phase I trial (NCT02892123). Tislelizumab is an investigational anti-programmed death-1 (PD-1) antibody engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, which is a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. Tislelizumab is well tolerated and has anti-tumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. The highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort Phase 1B/2 study (NCT04276493) is designed to evaluate zanidatamab as a first-line therapy with chemotherapy in pts with HER2-positive metastatic breast cancer (mBC; cohort 1) or with chemotherapy + tislelizumab in pts with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). Weight-based dosing (cohorts 1a and 2a) and flat dosing (cohorts 1b and 2b) regimens of zanidatamab are being investigated. In cohort 1 (n = 20), pts with treatment-naïve HER2-positive (IHC3+ or ISH amplified) mBC will receive intravenous (IV) zanidatamab 30 mg/kg (cohort 1a) or 1800 mg (cohort 1b), plus IV docetaxel 75 mg/m2 once every 3 weeks (Q3W). In cohort 2 (n = 30), treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive IV zanidatamab 30 mg/kg (cohort 2a), or 1800 mg (pts < 70kg; cohort 2b) or 2400 mg (pts ≥ 70kg; cohort 2b), plus IV tislelizumab 200 mg and chemotherapy (CAPOX regimen: oral capecitabine 1000 mg/m2 twice daily [days 1–14] and IV oxaliplatin 130 mg/m2 [day 1]) Q3W. For cohort 2 there is a six pt safety lead-in phase, followed by dose expansion after approval by the safety monitoring committee. Primary endpoints are the safety profile and objective response rate. Secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: NCT02892123.

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