A phase II, open-label, randomized study to evaluate the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4141-TPS4141 ◽  
Author(s):  
Manish A. Shah ◽  
Jean-Philippe Metges ◽  
Patrick Youngwhan Chun ◽  
Victoria Smith ◽  
Julia D. Maltzman ◽  
...  
Keyword(s):  
T Cell ◽  
Performance Status ◽  
Randomized Study ◽  
Gastroesophageal Junction ◽  
Cell Polarization ◽  
Phase Iii ◽  
Matrix Remodeling ◽  
Cell Trafficking ◽  
Efficacy And Safety ◽  
Open Label

TPS4141 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. Results from the ATTRACTION-2 Phase III trial showed the PD-1 inhibitor nivolumab significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in patients with heavily pre-treated advanced gastric or gastroesophageal junction cancer. Preclinical studies indicate that selective inhibition of MMP9 can inhibit immune-suppressive myeloid cell polarization, regulatory T cell generation, desmoplasia, and the destruction of ligands for CXCR3 (a critical chemokine receptor that enables effector T cell trafficking). In combination with a checkpoint inhibitor, CD8+, CD4+ and CD44+ cytotoxic T cells are significantly increased in a checkpoint-refractory model, suggesting that MMP9 inhibition could relieve immune suppression. Methods: This phase 2, open-label, randomized study investigates the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in patients with unresectable or recurrent gastric or gastroesophageal adenocarcinoma. 120 patients will be randomized to either GS-5745 800mg IV + nivolumab 3mg/kg IV, or nivolumab alone. Treatment will be administered every 2 weeks and stratified by PD-L1 status. CT will be performed every 8 weeks to evaluate response. The primary endpoint of the study is ORR; secondary endpoints include PFS, OS, and occurrence of adverse events. Key inclusion criteria: metastatic or inoperable adenocarcinoma of the stomach or GEJ which has progressed after ≥1 prior systemic therapy, ECOG performance status ≤1, RECISTv1.1 measureable disease, archival tissue adequate for PD-L1 evaluation. Exploratory biomarkers correlated with study drug response will also be evaluated. Enrollment opened September 2016. Clinical trial information: NCT02864381.

Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 337-337 ◽  
Author(s):  
David Cunningham ◽  
Istvan Lang ◽  
Vito Lorusso ◽  
Janja Ocvirk ◽  
Dongbok Shin ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Statistical Significance ◽  
Performance Status ◽  
Randomized Study ◽  
Single Agent ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
First Line ◽  
Open Label ◽  
Phase Iii Trial

337 Background: Elderly patients (pts) comprise the majority of pts diagnosed with mCRC, although they are in general underrepresented in clinical trials. AVEX, an open-label phase III trial, evaluated the efficacy and safety of cape ± bev in elderly pts with previously untreated mCRC. Methods: Pts ≥70 years with mCRC, for whom single-agent chemotherapy was deemed appropriate, were randomized 1:1 to receive first-line cape (1000 mg/m2 bid days 1–14) as monotherapy or in combination with bev (7.5 mg/kg) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), and safety. The study was powered to show a difference in PFS, but not OS, between treatment arms. PFS and OS estimates were calculated using Kaplan-Meier methods. Results: 280 pts across 10 countries were randomized to cape + bev (n=140) and cape alone (n=140). Median age at enrollment was 76 years (range, 70–87), and 91.1% of pts had an ECOG performance status of 0–1. Baseline pt and disease characteristics were well balanced between arms. Bev + cape was associated with significantly prolonged PFS compared with cape alone (median of 9.1 vs 5.1 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p<0.001). The ORR was also significantly improved in the bev + cape arm (19.3% vs 10.0%; p=0.042). OS was longer in pts treated with bev + cape vs cape alone, although this difference did not reach statistical significance (median of 20.7 vs 16.8 months; HR, 0.79; 95% CI, 0.57–1.09; p=0.182). Grade ≥3 adverse events occurred in 59.0% vs 44.1% of pts in the bev + cape and cape arm, respectively. Treatment was in general well tolerated and the safety profile consistent with previously reported data for bev + cape. Conclusions: This is the first randomized study prospectively evaluating bev specifically in elderly pts with mCRC. Based on the efficacy and safety results, bev plus cape might be an optimal treatment approach to improve outcomes in elderly pts. Clinical trial information: NCT00484939.

ROCHOP study: A phase III randomized study of CHOP compared to romidepsin-CHOP in untreated peripheral T-cell lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS8616-TPS8616 ◽  
Author(s):  
Richard Delarue ◽  
Pier Luigi Zinzani ◽  
Mark S. Hertzberg ◽  
Won Seog Kim ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Performance Status ◽  
Randomized Study ◽  
Total Duration ◽  
Progression Free Survival ◽  
Phase Iii ◽  
T Cell Lymphomas ◽  
Ann Arbor ◽  
Efficacy Parameters

TPS8616 Background: Peripheral T-cell lymphomas (PTCL) account for 10-15% of lymphomas. They share an aggressive clinical behaviour and a poor prognosis when treated by CHOP-like regimen which is nevertheless consider as a standard because others regimens failed to demonstrate survival advantage. Romidepsin is a histone deacetylase inhibitor with promising results in PTCL. First trials showed a response rate of 38% in heavily pre-treated PTCL patients. These results were confirmed with 15% of patients reaching a CR/CRu, 89% of them without disease progression at 13 months. Adverse events include gastrointestinal, hematologic and asthenic conditions. A phase I study of romidepsin combined with CHOP was conducted by LYSA. A total of 18 patients were included. The recommended dose was 12 mg/m² administered at day 1 and day 8 of each cycle. Methods: Ro-CHOP study is an international phase III study comparing 6 cycles of CHOP21 with 6 cycles of romidepsin-CHOP21 (EUDRACT 2012-001580-68). Primary endpoint is Progression-Free Survival assessed independently. Secondary objectives include overall survival, other efficacy parameters, analysis of response rate according to 18FDG-PET, safety, quality of life and biological ancillary studies. A total of 420 subjects aged from 18 to 80 years will be enrolled in the study. Main inclusion criteria are untreated PTCL whatever Ann Arbor stage and a performance status of 0-2. Main exclusion criteria are other subtypes of lymphoma, HTLV1 positivity, any cardiac abnormality, poor renal, hepatic and marrow functions unless related to lymphoma. Patients are randomized 1:1 between the two regimens. A stratification is performed with IPI score, age and histology. The first patient has been included in January 2013. A recruitment of 10.5 patients per month is anticipated, with a total duration of the study of 60 months. An update on enrolment will be presented at the meeting. Clinical trial information: 2012-001580-68.

Efficacy and safety of nivolumab (NIVO) in patients with advanced melanoma (MEL) and poor prognostic factors who progressed on or after ipilimumab (IPI): Results from a phase II study (CheckMate 172).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9524-9524 ◽  
Author(s):  
Dirk Schadendorf ◽  
Paolo Antonio Ascierto ◽  
John B. A. G. Haanen ◽  
Enrique Espinosa ◽  
Lev V. Demidov ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Brain Metastases ◽  
Phase Ii ◽  
Response Rate ◽  
Performance Status ◽  
Objective Response ◽  
Safety Data ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Open Label

9524 Background: In the phase III CheckMate 037 study, NIVO improved the objective response rate and progression-free survival with less toxicity vs chemotherapy in patients (pts) with MEL who progressed after prior IPI treatment. We report the first efficacy and updated safety data from pts with MEL in CheckMate 172, including those with rare melanoma subtypes (uveal, mucosal), brain metastases, or an ECOG performance status (PS) of 2. Methods: In this ongoing phase II, single-arm, open-label, multicenter study, pts with MEL who progressed on or after IPI were treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity (NCT02156804). We report efficacy and updated safety data from 734 treated pts with ≥1 year of follow-up (database lock: November 2016). Results: Of 734 pts, 50% had LDH>ULN, 7% ECOG PS 2, 66% M1c disease, 15% a history of brain metastases, and 23% received ≥3 prior therapies. Overall, 593 pts (81%) received more than 4 doses of NIVO. Overall, response rate at 12 weeks was 32%, with a complete response in 1% (Table). The 1-year overall survival (OS) rate was 63%. Any grade and grade 3/4 treatment-related adverse events (AEs) occurred in 66% and 17% of pts, respectively. Discontinuations due to treatment-related AEs occurred in 4% of pts. The most common treatment-related select (potentially immune-related) AEs were diarrhea (12%), hypothyroidism (9%), and pruritus (7%). Conclusions: CheckMate 172 is the largest study of NIVO efficacy and safety in pts with MEL who progressed on or after IPI. NIVO demonstrated a safety profile consistent with that of prior clinical trials. Efficacy outcomes were encouraging in some difficult-to-treat subgroups of pts with poor prognostic factors, such as mucosal melanoma and brain metastases. Clinical trial information: NCT02156804. [Table: see text]

A phase II, open-label, randomized study to evaluate the efficacy and safety of andecaliximab combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 75-75 ◽  
Author(s):  
Manish A. Shah ◽  
Jean-Philippe Metges ◽  
David Cunningham ◽  
Kai-Keen Shiu ◽  
Lucjan Wyrwicz ◽  
...  
Keyword(s):  
Randomized Study ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Tolerability Profile ◽  
Efficacy And Safety ◽  
Open Label ◽  
T Cell Infiltration ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Kaplan Meier

75 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). Preclinical studies suggest that MMP9 inhibition relieves immune suppression and promotes T-cell infiltration to potentiate checkpoint blockade. Methods: Phase 2, open-label, randomized study of the efficacy and safety of ADX + nivolumab (NIVO) vs. NIVO alone in patients with pre-treated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients were randomized to either ADX 800 mg IV + NIVO 3 mg/kg IV, or NIVO 3 mg/kg IV alone, and stratified by tumor PD-L1 status. Treatment was administered every 2 weeks. Re-staging CT scans were performed every 8 weeks to evaluate response. Primary endpoint: objective response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Of the 144 patients randomized, 141 were treated, 109 (76%) completed tumor assessment. 81% of patients were white, with 69% male and a mean (SD) age of 59 (12) years. ORR (95% CI) was 11.1% (4.9–20.7%) in patients receiving ADX + NIVO, and 6.9% (2.3–15.5%) in those receiving NIVO alone, p = 0.6. Kaplan-Meier estimated median (95% CI) PFS was 1.8 (1.8–2.0) months in patients receiving ADX + NIVO, and 1.9 (1.7–1.9) months in those receiving NIVO alone, p = 0.2. Kaplan-Meier estimated median (95% CI) OS was 7.2 (5.2–9.1) months in patients receiving ADX + NIVO, and 5.9 (3.5–8.6) months in those receiving NIVO alone, p = 0.4. AEs leading to treatment discontinuation occurred in 1 patient in the ADX + NIVO group, and in 1 patient in NIVO-only group. PD-L1 and mismatch repair deficient subgroup analyses will be presented. Exploratory biomarker analyses will be submitted separately. Conclusions: Addition of ADX to NIVO did not improve ORR, PFS, or OS compared with NIVO alone in patients with pre-treated metastatic gastric or GEJ adenocarcinoma. Combination of ADX with NIVO had a favorable safety and tolerability profile. Clinical trial information: NCT02864381.

A phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4025-4025 ◽  
Author(s):  
Rui-hua Xu ◽  
Guo-ping Sun ◽  
Hui-shan Lu ◽  
Liu Yun Peng ◽  
Jian-ming Xu ◽  
...  
Keyword(s):  
Group Performance ◽  
Performance Status ◽  
Gastroesophageal Junction ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
Controlled Study ◽  
Control Group ◽  
Time To Failure ◽  
Open Label ◽  
Gastroesophageal Junction Adenocarcinoma

4025 Background: A combination of S-1 and cisplatin (DDP) has been shown to be effective and safe for the first-line treatment of advanced gastric cancer in Japan. This is the first randomized phase III trial to compare S-1 plus DDP with 5-fluorouracil (5-Fu) plus DDP in Asia. Methods: This is an open-label, multicenter, phase 3, randomized controlled study. Patients with gastric or gastro-oesophageal junction adenocarcinoma were eligible for inclusion. Patients were randomly assigned in a 1:1 ratio to receive S-1 plus DDP (experiment group) or 5-Fu plus DDP (control group) for 6 cycles. In the experiment group, the dose of S-1 was 80 mg/m2/day, po, twice daily on day 1-21 and DDP was 20mg/m2 iv on day 1-4, repeat every 5 weeks. In the control group, 5-Fu was given as 0.8g/m2/d CI 120h ,and the dose of DDP was the same with the experiment group, while repeat every 4 weeks. Allocation was by block randomization stratified by Eastern Cooperative Oncology Group performance status, sites of metastasis and prior gastrectomy. The primary endpoint was time to progression (TTP). Secondary end points included time to failure (TTF), overall survival (OS), and quality of life. Results: Totally 255 patients were enrolled into the study, of whom 236 were included in the analysis (n=120; n=116). Median TTP was 5.51 months (95% CI 4.59-6.26) in those assigned to experiment group compared with 4.62 months (95% CI 4.00-6.33) in the control group (hazard ratio [HR] 1.03; 95%CI 0.76-1.39, p=0.86). In the experiment and control groups, response rates were 22.5% vs 21.5%; P=0.86. Median OS was 10.00 months (95% CI 8.59-14.52) in the experiment group compared with 10.46 months (8.92-13.84) in the control group (HR 1.05; 95%CI 0.71-1.54, p=0.82). The most common adverse events in both groups were anemia (S-1 plus cisplatin, 80.17% vs 5-Fu plus cisplatin, 71.19%), leukopenia (71.90% vs 62.71%), neutropenia (68.60% vs 55.93%), nausea (50.41% vs 60.17%), thrombocytopenia (44.63% vs 26.27%), vomiting (42.98% vs 42.37%) and anorexia (38.02% vs 41.53%). Conclusions: S-1 plus DDP is an effective and tolerable option for patients with advanced gastric or gastro-oesophageal junction adenocarcinoma. Clinical trial information: NCT01198392.

Phase III trial of a 3-weekly versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOS study.

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA4024-LBA4024 ◽  
Author(s):  
Min-Hee Ryu ◽  
Eishi Baba ◽  
Kyung Hee Lee ◽  
Narikazu Boku ◽  
Young Iee Park ◽  
...  
Keyword(s):  
Performance Status ◽  
Gastroesophageal Junction ◽  
Dose Intensity ◽  
Phase Iii ◽  
Weekly Schedule ◽  
Line Treatment ◽  
First Line ◽  
Open Label ◽  
Ecog Performance Status ◽  
First Line Treatment

LBA4024 Background: 5-weekly S-1 plus cisplatin (SP5: S-1 80-120 mg/body/day on D1-21, cisplatin 60 mg/m2 on D8, every 5 weeks) has become a standard first-line chemotherapy for AGC in Japan based on the SPIRITS trial (Lancet Oncol. 2008;9:215). To strengthen the low-dose intensity of cisplatin in this SP5 for greater efficacy, a 3-weekly S-1 plus cisplatin (SP3: S-1 80 mg/m2/day on D1-14, cisplatin 60 mg/m2on D1, every 3 weeks) has been developed in Korea (Cancer Chemother Pharmacol. 2008;61:837). Methods: This SOS study was a multicenter, randomized, open-label, phase III study to evaluate whether SP3 was non-inferior/superior to SP5 in terms of progression-free survival (PFS) determined by a blinded central radiology review according to RECIST v1.1. Patients (pts) with metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma and with no prior chemotherapy were randomized 1:1 to receive either SP3 or SP5 until disease progression or unacceptable toxicities. Results: Between February 2009 and January 2012, a total of 625 pts were randomized from 42 sites in Korea and Japan. Median age was 59.6 years. 99% of pts had ECOG performance status 0-1. 16% of pts had prior gastrectomy. 62% of pts had measurable lesions. With a median follow-up of 34.7 months (range, 14.2-48.8) in surviving pts, SP3 was significantly noninferior and superior to SP5 in PFS (median 5.5 months vs. 4.9 months; HR 0.82, 95% CI 0.68-0.99, p=0.0418). Overall response rate (ORR) was also better with SP3 than with SP5 (60% vs. 50%, p=0.029). However, OS of both groups was equivalent (median 14.1 vs. 13.9 months; HR 0.99, 95% CI 0.81-1.21, p=0.9068). Treatment was well tolerated in both arms, while SP3 was associated with more frequent G3/4 anemia (19% vs. 9%) and neutropenia (39% vs. 9%). Dose intensity was higher in SP3 than in SP5 for both agents (median 331 vs. 317 mg/m2/week for S-1, p<0.001; median 18 vs. 12 mg/m2/week for cisplatin, p<0.001). Conclusions: SP3 was noninferior and superior to SP5 in terms of PFS and ORR. However, considering the small benefit in PFS and no difference in OS, both SP3 and SP5 can be recommended for the first-line treatment of AGC. Clinical trial information: NCT00915382.

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