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A phase II study of Trastuzumab with S-1 plus Oxaliplatin for HER2 positive advanced gastric cancer (Herceptin with
SOX for Gastric Cancer) (HIGHSOX study)

HIGHSOX study (HIGHSOX study)

75

The baseline characteristics of the enrolled 75 patients were as follows; :Age (median,years);64 :ECOG PS(0/1);57/18 :unresectable/recurrent;66/9 :Gastric/EGJ;64/11 :differentiated(tub1,tub 2)/undifferentiated(por,sig);46/29 :Metastatic site(LNs/liver/peritoneum/lung/bone/others);40/35/20/9/3/8 :IHC 2+/3+;20/55

A total of 75 patients were enrolled between June 2015 and January 2018 as scheduled in 10 investigational sites in Japan(the number of patients enrolled in each site is not shown).No patient discontinued the study treatment after the start of the study and all of the 75 patients were included in the Full Analysis Set(FAS).

A total of 14 patients reported adverse events (AE) during the study period (from the start of the study to March 26, 2019). All AEs but one (Anemia), as shown below, occurred in each one patient. Anemia was reported in two patients. Disease progression; Surgical site infection; Hepatic infection (Liver abscess): Pulmonary embolism; Fever; Gastrointestinal disorders (Inguinal hernia); Anemia; Blood bilirubin increased; Diarrhea; Gastric hemorrhage; Lung infection; Musculoskeletal and connective tissue disorder (Lumbar disc herniation); Pneumonitis.

Primary endpoint: Response Rate(N=75): CR:1(1.3%),PR:52(69.3%),SD:17(22.7%),PD:4(5.3%),NE:1(1.3%). Secondary endpoints: Progression Free Survival:PFS(N=75): PD or death events occurred in 66 patients.Median PFS time was 8.8 months(95% CI 7.3-11.8). :6month PFS 69.3%(95% CI 57.6-78.4) :12month PFS 37.3%(95% CI 26.5-48.1) :24month PFS 21.3%(95% CI 12.9-31.2) :36month PFS 11.2%(95% CI 5.2-19.9) Overall Survival:OS(N=75): After median follow up of 20.6 months,death event occurred in 52 patients (no death was reported within 30 days after enrollment). Median OS time was 20.6 months (95% CI 15.9-29.2) :12month OS 76.0% (95% CI 64.6-84.1) :24month OS 46.7% (95% CI 35.1-57.4) :36month OS 30.0% (95% CI 19.6-41.0) Safety (AE frequency and severity): During the study period,a total of 14 serious AEs were reported,as shown in the number 9 above.Of these,one was disease progression.No drug-related death was reported.Other AEs are shown below including those reported in 30 days after the last dose when the patient discontinued the study treatment by the 8th course. Grade 3 or worse hematological AEs including neutropenia,anemia and thrombocytopenia were reported in 10.7%,6.7%,and 1.3% of patients,respectively.No febrile neutropenia was observed. The most commonly observed non-hematological AE was PSN (any grade 84%;grade 3 or worse 16%).Grade 3 or worse gastrointestinal toxicities including diarrhea,anorexia,and nausea/vomiting were observed in 6.7%,5.3%,and 4.0% of patients,respectively.The proportion of patients experiencing grade 3 or worse hepatic AEs included 2.7% and 4.0% for AST increase and ALT increased, respectively. There was few AEs of creatinine increase which is most commonly seen in patients receiving combination therapies with CDDP,leaving no patient with grade 3 or worse. No grade 3 or worse infusion-related reactions and heart failure,which are frequently reported in patients with combination treatments with Tmab. Overall,the data suggest that SOX Tmab combination therapy is well tolerated.Both frequency and severity of AEs reported in this study were less compared with those seen in the previously reported studies evaluating Tmab-based chemotherapy in patients with HER2-positive advanced gastric cancer.

Results from this phase 2 study suggest that trastuzumab with SOX is well tolerated and has promising efficacy, offering one possibility of new treatment option as a first-line chemo therapy for patients with HER2-positive advanced gastric cancer.

Sept. 30, 2020

May. 08, 2019

https://doi.org/10.1007/s10120-019-00973-5

No

none

https://jrct.mhlw.go.jp/latest-detail/jRCTs051180196

Takahari Daisuke

The Cancer Institute Hospital of JFCR

3-8-31 Ariake, Koto-ku, Tokyo

daisuke.takahari@jfcr.or.jp

Takahari Daisuke

The Cancer Institute Hospital of JFCR

3-8-31, Ariake, Koto-ku, Tokyo

+81-3-3520-0111

daisuke.takahari@jfcr.or.jp

Complete

May. 15, 2015

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1) Histologically proven advanced or recurrent adenocarcinoma
2) No prior therapy except for adjuvant chemotherapy of S-1 finished more than 6 months before
3) With measurable lesions by RECIST version 1.1
4) HER2 positive (IHC 3+ or IHC 2 + and ISH +)
5) Age 20 - 75
6) ECOG PS 0 or 1
7) No symptomatic cerebral lesions
8) Adequate organ functions
9) LVEF (Left Ventricular Ejection Fraction) > 50 %
10) No abnormal findings in ECG
11) Possible for oral intake
12) With an expected survival longer than 3 months
13) Wth written Informed consent

1) Could not administrate S-1, oxaliplatin, and trastuzumab
2) Pregnant and/or nursing women or men who wish to have children in future
3) With active infectious disease
4) HBs antigen positive
5) With a history or current symptoms of heart failure, uncontrollable arrhythmia, angina pectoris, valvular disease, and uncontrollable hypertension
6) With interstitial pneumonia, pulmonary fibrosis, heart failure, renal failure, hepatic failure, uncontrollable diabetes mellitus
7) With dyspnea at rest
8) With active bleeding from gastric cancer / ulcer
9) With severe diarrhea
10) With severe sensory neuropathy
11) With active double cancers excluding carcinoma in situ and/or prior curative cancer with relapse free for more than 5 years
12) Under meditation of flucytosine, phenytoin,or warfarin
13) Under continuous meditation of steroids
14) Judged to be unfit to participate in this study by investigator

Both

HER2 positive unresectable advanced gastric cancer

HIGHSOX: S-1; 80 mg/day, 100 mg/day, 120 mg/day [day1-day15], Oxaliplatin; 130mg/m2 [day1], Trastuzumab; first: 8mg/kg(body), After the second time: 6mg/kg(body) [day1]: The treatment will be repeated every 3 weeks, untill the disease progression, unacceptable toxicity, tumor resection, or consent withdrawel.

Response Rate

Progression free survival,
Overall survival,
Safety

+81-73-441-0714

Feb. 27, 2019

None