A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study): Safety evaluation.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4525-4525
Author(s):  
Daisuke Takahari ◽  
Hirokazu Shoji ◽  
Keiko Minashi ◽  
Hiroki Hara ◽  
Keisho Chin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Safety Evaluation ◽  
Sensory Neuropathy ◽  
Complete Response ◽  
Preliminary Evaluation ◽  
Her2 Positive ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

4525 Background: Addition of an anti-PD-1 antibody to trastuzumab (Tmab) reportedly enhances ADCC activity of Tmab, leading to an additive antitumor effect. We investigated the safety and tolerability of nivolumab (Nivo) plus Tmab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for pts with HER2-positive (+) advanced gastric cancer (AGC). Here, we report the safety evaluation results. Methods: This open-label, phase 1b study was conducted at four centers in Japan. The study consisted of safety (n = 12) and expansion (n = 24–30) parts. Chemotherapy-naïve pts aged ≥ 20 years with histopathologically confirmed HER2+ AGC and measurable lesions were eligible. In the safety evaluation, pts were assigned to cohort 1 or 2 in sequence. Pts received Nivo (360 mg, day 1), Tmab (course 1: 8 mg/kg; course 2–: 6 mg/kg, day 1), Ox (130 mg/m2, day 1) and either S-1 (40 mg/m2 bid, days 1–14; cohort 1) or Cape (1000 mg/m2 bid, days 1–14; cohort 2) every 3 weeks until disease progression or unacceptable toxicity. The primary purpose of the safety evaluation was to determine the toxicity and tolerability of this combination therapy. An independent data and safety monitoring committee assessed the tolerability of the study treatments before starting the second treatment course. A preliminary evaluation of tumor response on the cut-off date (December 16, 2019) was also performed. Results: From November 2018 to August 2019, 12 pts with HER2+ AGC were enrolled in the safety part (six pts each in cohorts 1 and 2). During the 1st course, all 12 pts experienced at least one adverse event (AE). The most common AEs were peripheral sensory neuropathy (PSN) (n = 4) and leukocytopenia (n = 3) in cohort 1 and PSN (n = 5) and anorexia (n = 4) in cohort 2. AEs of grade ≥ 3 were observed in only one pt in cohort 1 (grade 3 neutropenia). No pt suspended or discontinued study treatments due to AEs. One pt in cohort 1 reduced dose of S-1 due to grade 2 erythema and continued the subsequent courses with the dose. After a median follow-up of 6.1 (range, 3.1–13.3) months, one pt from cohort 1 achieved a complete response, eight pts (four in each cohort) achieved a partial response, and three pts (one in cohort 1 and two in cohort 2) showed stable disease. No progressive disease was observed. Conclusions: Both Nivo plus Tmab and either S-1 or Cape plus Ox are tolerable in pts with HER2+ AGC. Both cohorts 1 and 2 have progressed to the expansion part of the study. Clinical trial information: 000034222 .

Value of FGFR2 expression for advanced gastric cancer patients receiving pazopanib plus CapeOX (capecitabine and oxaliplatin).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 65-65
Author(s):  
Seung Kim ◽  
Young-Woong Won ◽  
Jung Hoon Kim ◽  
Joon Ho Park
Keyword(s):  
Gastric Cancer ◽  
Treatment Outcomes ◽  
Advanced Gastric Cancer ◽  
Complete Response ◽  
Open Label ◽  
Prognostic Analysis ◽  
Tumor Tissues ◽  
Significant Difference ◽  
Open Label Phase ◽  
Gastric Cancer Patients

65 Background: The aim of this study was to use immunohistochemistry (IHC) to determine the effect of FGFR2 and VEGFR2 expression on treatment outcomes for patients with metastatic or recurrent advanced gastric cancer (AGC) receiving a combination of pazopanib with CapeOx (capecitabine and oxaliplatin). Methods: We conducted a single-arm, open-label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx in 66 patients with metastatic or recurrent AGC (ClinicalTrials.gov NCT01130805). IHC analysis of FGFR2 and VEGFR2 was possible in 54 patients (81.8%). Results: Among 54 patients, the median age was 51.5 years (range, 23–72 years). Most patients were men (59.3%). Seven patients (13.5%) had tumor tissues that expressed FGFR2 by IHC. No patients had tumors that expressed VEGFR2. Among 7 patients with tumors with FGFR2 expression, 6 achieved partial response (PR) with a 85.7% response rate and one patient with stable disease. Among 47 patients with tumors without FGFR2 expression, one had complete response and 27 had PR (59.5%). A significant difference in PFS was seen between patients who were positive and negative for FGFR2 using IHC (8.5 vs. 5.6 months, p = 0.050). By prognostic analysis for PFS, only FGFR2 status by IHC (positive vs. negative) had significant prognostic value for predicting PFS. Conclusions: FGFR2 expression by IHC might be a useful biomarker for predicting treatment outcomes of patients with metastatic or recurrent AGC treated with a combination of pazopanib and CapeOx.

scholarly journals Phase II Prospective Study of Trastuzumab in Combination with S-1 and Oxaliplatin (SOX100) Therapy for HER2-Positive Advanced Gastric Cancer

2021 ◽  
Author(s):  
Yoshinori Mori ◽  
Hiromi Kataoka ◽  
Masahide Ebi ◽  
Kazunori Adachi ◽  
Yoshiharu Yamaguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Rate ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Growth Factor Receptor ◽  
Sensory Neuropathy ◽  
Progression Free Survival ◽  
Her2 Positive ◽  
Grade 3 ◽  
Peripheral Sensory

Abstract Purpose The standard first-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) is trastuzumab in combination with cisplatin and fluoropyrimidines. We evaluated the efficacy and safety of S-1 and oxaliplatin (100 mg/m2) (SOX100) combined with trastuzumab, a monoclonal antibody against HER2 for HER2-positive AGC.Methods In this single-arm, multicenter phase II study, patients with HER2-positive AGC received S-1 (80–120 mg per day) orally on days 1–14, oxaliplatin (100 mg/m2) intravenously on day 1, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. Results A total of 25 patients from six centers were enrolled from December 2015 to March 2020. In the 25 patients evaluable for analysis, the 1-year survival rate was 70.8% [90% confidence interval (CI) = 55.5%–86.1%], whereas the median OS, PFS, and ORR were 17.8 (95% CI 10.5–22.9) months, 7.6 (95% CI 5.0–10.9) months, and 75.0 (95% CI 53.3–90.2) %, respectively. Major grade 3/4 adverse events included anorexia (20%), anemia (16%), peripheral sensory neuropathy (16%), and diarrhea (15%). Conclusion SOX100 combined with trastuzumab was effective with a favorable safety profile in patients with HER2-positive AGC.

Feasibility study of TAS-118 plus oxaliplatin as perioperative chemotherapy for patients with locally advanced gastric cancer (APOLLO-11).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 205-205
Author(s):  
Daisuke Takahari ◽  
Manabu Ohashi ◽  
Atsuo Takashima ◽  
Takuro Mizukami ◽  
Naoki Ishizuka ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Locally Advanced ◽  
Dose Intensity ◽  
Complete Response ◽  
Free Survival ◽  
D2 Gastrectomy ◽  
Locally Advanced Gastric Cancer ◽  
Grade 3

205 Background:TAS-118 (S-1 and leucovorin) + oxaliplatin (L-OHP) improved overall survival (OS) compared to S-1 + cisplatin for patients (pts) with advanced gastric cancer (GC) (Kang, Lancet Oncol. 2020). This study investigated the feasibility of peri (pre and post)-operative (op) chemotherapy (chemo) with TAS-118 ± L-OHP in pts with locally advanced resectable GC. While it was reported that pre-op TAS-118 + L-OHP followed by D2 gastrectomy was well tolerated and showed promising efficay (Takahari, ASCO-GI. 2020), the recommended post-op chemo regimen, TAS-118 or TAS-118 + L-OHP, has yet to be determined. Methods:Eligible pts with GC of clinical T3-4N1-3M0 were enrolled. The protocol treatment consisted of pre-op chemo with 4 courses of TAS-118 (40-60 mg/body, orally, twice daily, 7 days) + L-OHP (85 mg/m2, intravenously, day 1) in a 2-week cycle, and gastrectomy with D2 lymphadenectomy, followed by post-op chemo with 12 courses of TAS-118 (step 1) and 8 courses of TAS-118 + L-OHP (step 2). Step 2 was started if the dose-limiting toxicity (DLT) occurred in < 6 of 10 pts in step 1. Up to 20 pts were included in the analysis of feasibility after a recommended regimen was determined. Results:Between December 2016 and February 2019, 45 pts were enrolled. The numbers of pts with cT3/4a and cN1/2/3 were 13/32 and 25/17/3, respectively. Excluding 14 pts (4 achieving pathological complete response, 4 not satisfying the criteria for post-op chemo, 3 physician judgement or pt withdrawal, 2 progressive disease, 1 adverse event [AE]), 31 pts (11/20 in step 1/2) received the post-op chemo. No DLT was observed in either step. The post-op chemo completion rate was 90.9% (95% CI, 63.6-99.5) in step 1 and 80.0% (95% CI, 59.9-92.9) in step 2. The median relative dose intensity of TAS-118 in step 1 was 83.3%, and those of TAS-118 and L-OHP in step 2 were 69.9% and 74.3%, respectively. One pt in step 2 discontinued post-op chemo due to AE. Grade ³ 3 AEs observed in ≥ 10% of pts were weight loss in both step 1 and step 2 (2 in each), and hypokalemia (n = 3) and neutropenia (n = 2) in step 2. At 1-year follow-up after the last pt was enrolled, recurrence-free survival and OS rates were 91.1% (95% CI, 78.0-96.6) and 100%, respectively at 12 months, and 69.1% (95% CI, 49.6-82.3) and 95.5% (95% CI, 71.9-99.3), respectively at 24 months. Conclusions:Taken together with the feasibility and efficacy of pre-op chemo, peri-op chemo with TAS-118 + L-OHP with D2 gastrectomy was well tolerated and showed promising efficacy. Clinical trial information: UMIN000024688.

Chemoradiotherapy for highly advanced gastric cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 121-121
Author(s):  
Mai Tsutsui ◽  
Tsunehiro Takahashi ◽  
Yoshiro Saikawa ◽  
Hirofumi Kawakubo ◽  
Norihito Wada ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Radiation Therapy ◽  
Lymph Nodes ◽  
Advanced Gastric Cancer ◽  
Multidisciplinary Treatment ◽  
Multimodality Treatment ◽  
Complete Response ◽  
Technological Advancement ◽  
Regional Lymph Nodes ◽  
Grade 3

121 Background: Although the prognosis of early gastric cancer is favorable, the treatment for advanced cases still have difficulty in achieving satisfactory results. Thus, more effective multimodality treatment should be established. Chemoradiotherapy has become a standard treatment for gastric cancer especially as an adjuvant therapy while radiotherapy has been expected as one of the modalities against highly advanced gastric cancer. Methods: Patients with advanced gastric cancer who were treated with chemotherapy of S-1 and cisplatin plus radiation were analyzed retrospectively. Concurrent radiation therapy (5 days/week) at 2 Gy/day was started with chemotherapy and repeated daily on days 1–5, 8–12, 15–19 and 22–26. Irradiation was planned using a computed tomography (CT) simulator for two rectangular portals with a pair of 45-degree wedge filters and was targeted at the primary tumor and surrounding lesions, including lymph nodes. Results: A total 109 patients were treated with chemoradiotherapy between 2002 and 2013 at our institute. The median age was 64 years. Histological type included 45 differentiated and undifferentiated 64 subtypes. The TNM stage before the treatment was diagnosed as IIIA: 11; IIIB: 10; IIIC: 14; IV: 74. Of the 98 evaluable patients, 69 patients had partial responses while no patients had a complete response, resulting in an overall response rate of 70%. Progressive disease (PD) occurred in 2 patients (4%). The most frequent adverse events more than grade 3 were hematologic toxicities, including leukocytopenia (47%), neutropenia (25%), and thrombocytopenia (24%). Non-hematologic toxicities such as general fatigue, renal-related events, and gastrointestinal toxicities were manageable with no treatment-related death. The median survival time was 537 days. Conclusions: While there were disadvantages of radiotherapy including the difficulty of confirming the area of irradiation due to peristaltic movement, risk of perforation and ulceration, recent technological advancement of radiation therapy has enabled pinpoint accuracy in treatment of primary gastric lesions and regional lymph nodes. There has been much anticipation that chemoradiotherapy will be a part of multidisciplinary treatment for advanced cancer.

Oxaliplatin, irinotecan, and cetuximab in advanced gastric cancer. First efficacy results of a multicenter phase II trial (AGMT Gastric-2) of the Arbeitsgemeinschaft Medikamentoese Tumortherapie (AGMT)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4538-4538
Author(s):  
E. Woell ◽  
R. Greil ◽  
W. Eisterer ◽  
M. Fridrik ◽  
B. Grünberger ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Treatment Options ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Multicenter Phase ◽  
Grade 3 ◽  
Line Setting

4538 Background: Patients (pts.) suffering from advanced gastric cancer have still a poor prognosis and treatment options are limited. In our previous phase II trial (AGMT-Gastric-1) we could show that the combination of oxaliplatin and irinotecan was well tolerated and showed an objective response rate of 58% (Anticancer Res 28:2901–2906, 2008). This chemotherapy regimen was tested in combination with cetuximab in a multicenter phase II trial. Methods: Oxaliplatin 85 mg/m2 biweekly and irinotecan 125 mg/m2 biweekly were combined with cetuximab 400 mg/m2 loading dose and subsequently weekly 250 mg/m2. 51 patients with histological proven unresectable and/or metastatic gastric adenocarcinoma were treated in a first line setting. Median age: 62 years (range 19–79 years), PS 0: 25 patients, PS 1+2 26 patients, single metastatic site: 24 patients, multiple metastases: 27 patients. Results: Frequently reported adverse events (more than 20% of pts.) were predominantly grade 1 or 2 and included neutropenia (35% of pts.), thrombocytopenia (33%), anemia (73%), nausea (45%), diarrhea (57%), alopecia (22%), and fatigue (37%). Grade 3 and 4 toxicities included neutropenia in 9/1 pts., thrombocytopenia in 1/0 pts., anemia in 3/1 pts., nausea in 2/0 pts., and diarrhea in 7/2 pts. Sensory neuropathy occurred mostly as grade 1 and 2 in 37% of pts., in 7 pts. grade 3 neurotoxicity was observed. Acneiform skin rash grade 1 / 2 / 3 / 4 was reported in 31% / 20% / 6% / 2% of pts. respectively. 16 pts. went off-study due to neutropenia (n=5), nausea/vomiting (n=1), diarrhea (n=1), progressive disease (n=3), toxic colon (n=2), and allergic reaction to cetuximab at first (n=2), second (n=1) or third infusion (n=1). 35 patients are assessable for response with 1 pt. (3%) showing a CR, 21 pts. (60%) a PR, 7 pts. (20%) a SD and PD in 6 pts. (17%). A disease control rate was achieved in 83%. Median time to progression was 24.8 weeks (n=29), median overall survival 38.1 weeks (n=32). Conclusions: The combination of oxaliplatin and irinotecan with cetuximab is feasible, safe and active in advanced gastric cancer. [Table: see text]

A phase ll study of new combination regimen with trastuzumab, S-1, and CDDP in HER2-positive advanced gastric cancer (HERBIS-1).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4072-4072
Author(s):  
Keisuke Koeda ◽  
Naotoshi Sugimoto ◽  
Junji Tanaka ◽  
Masahiro Tsuda ◽  
Wataru Okamoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Advanced Gastric Cancer ◽  
Response Rate ◽  
Progression Free Survival ◽  
New Combination ◽  
Combination Regimen ◽  
Her2 Positive ◽  
Threshold Response ◽  
Grade 3

4072 Background: S-1, a novel oral fluoropyrimidine, plus cisplatin (SP) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer. ToGA study demonstrated that trastuzumab (T-mab) combination regimen improved the overall survival of patients with HER2-positive advanced gastric cancer. However, there was no study evaluating the efficacy and the safety of T-mab in combination with S-1 plus cisplatin (SP) regimen. Therefore, we planned this study to examine the efficacy and the safety of the SP plus T-mab. Methods: Patients confirmed to be HER2-positive by IHC and/or FISH (IHC 3+ or IHC 2+ and FISH positive) received S-1 at 80 mg/m2 po, day 1-14, and cisplatin 60 mg/m2 iv, day 1 plus trastuzumab 8 mg/kg iv, day 1 (6 mg/kg iv, d1 from 2nd course), repeated every 3 weeks until disease progression. Primary endpoint was response rate (RR). Secondary endpoints were progression-free survival, overall survival and safety. The threshold response rate was defined as 35%, and the expected rate was set at 50% with a 80% power and a 1-sided alpha value of 0.1 and the calculated sample size was 50 patients. Results: A total of 56 patients (median age 66) were enrolled in this study. The efficacy and the safety analyses were conducted in the full analysis set of 53 patients. (Two patients were excluded for ineligibility and one was for no treatment). The confirmed RR assessed by the independent review committee was 67.9% (95% CI: 53.7 – 80.1), and the disease control rate was 94.3%. The median PFS was 7.1 months (95% CI: 6.0 – 10.1). The median OS was not reached. (The median follow-up time: 9.2 months) The main grade 3/4 adverse events were as follows: neutropenia 34%, leucopenia 8%, anorexia 23%, diarrhea 8%, hypoalbuminemia 4%, vomiting 6%, and increased creatinine 6%. Conclusions: This tri-week regimen with SP plus T-mab showed promising results in patients with HER2-positive advanced gastric cancer. Clinical trial information: UMIN000005739.

Anlotinib and irinotecan for advanced Ewing sarcoma after failure of standard therapy: A multicenter, two-cohort, single-arm, open label, phase Ib/II trial (NCT03416517).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11012-11012
Author(s):  
Jie Xu ◽  
Lu Xie ◽  
Wei Guo ◽  
Xiaodong Tang ◽  
Rongli Yang ◽  
...  
Keyword(s):  
Phase Ii ◽  
Ewing Sarcoma ◽  
Initial Level ◽  
Objective Response ◽  
Complete Response ◽  
Fixed Dose ◽  
Open Label ◽  
Phase Ib ◽  
Open Label Phase ◽  
Grade 3

11012 Background: Both protracted irinotecan and anti-angiogenesis therapy have shown promising results in Ewing sarcoma. We did this phase Ib/II trial to first define the proper dose of irinotecan in combination with anlotinib in Ewing sarcoma and then evaluate efficacy. Methods: Patients diagnosed with recurrent or refractory Ewing sarcoma were enrolled and sub-classified into cohort A (≥16y) or cohort B ( < 16y). In the dose-defining phase Ib portion, anlotinib was given at a fixed dose of 12mg D1-14every 21 days, while the de-escalated 3+3 design was used to detect the recommended dose of irinotecan in each cohort from an initial level of 20mg/m2/d dx5x2. Recommended phase 2 dose (RP2D) was defined as the highest dose at which no more than 30% patients experience a DLT in the first two courses. In the next dose-expanding phase II portion, the primary endpoint was objective response rate at 12 weeks (ORR12w). A conventional two-stage study design model was used. Results: 41 patients were enrolled with 29 in cohort A and 12 in cohort B. For cohort A, first 5 patients were treated at initial level in phase Ib portion, two of whom subsequently experienced delayed diarrhea as dose-limiting toxicity (DLT). Additional six patients were then treated at a lower dose of 15mg/m2. Since no more DLT was recorded, it was used as RP2D. 23/24 patients in cohort A phase II were available for response evaluation at 12 weeks, with one complete response (CR), 14 partial response (PR) (including one CMR who has a negative PET/CT scan but still abnormal lesions in MR scan), 2 stable disease (SD) and 6 progressive disease (PD). ORR12wwas 62.5%. For cohort B, no DLT was noticed in the first six patients treated at the initial level which was used as RP2D later. Finally, 12 patients were included in cohort B. ORR12wwas 83.3% with two CR, 8 PR (including one CMR) and two PD. Although effective, cohort B were closed because of slow enrollment. Most common grade 3/4 adverse events were diarrhea, abdominal pain and neutropenia. The genotype of UGT1A1*1 and UGT1A1*28 were not associated with the risk of diarrhea. Conclusions: The combination of irinotecan and anlotinib demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in advanced Ewing sarcoma. Clinical trial information: NCT03416517.

Bortezomib With or Without Irinotecan in Relapsed or Refractory Colorectal Cancer: Results From a Randomized Phase II Study

2008 ◽  
Vol 26 (14) ◽  
pp. 2320-2326 ◽  
Author(s):  
Peter S. Kozuch ◽  
Caio Max Rocha-Lima ◽  
Tomislav Dragovich ◽  
Howard Hochster ◽  
Bert H. O'Neil ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Sensory Neuropathy ◽  
Primary Objective ◽  
Response To Treatment ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

PurposeTo evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC).Patients and MethodsPatients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m2(arm A) or bortezomib 1.3 mg/m2plus irinotecan 125 mg/m2(arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability.ResultsA preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade ≥ 3 adverse events reported, per patient, during the study were fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B.ConclusionBortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.

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