UMIN-CTR Clinical Trial

Public title

Phase I/II multicenter trial of paclitaxel, ramucirumab and nivolumab for metastatic gastric cancer patients who progressed on chemotherapy with fluoropyrimidine plus platinum

Acronym

Phase I/II trial of paclitaxel, ramucirumab and nivolumab for advanced gastric cancer patients

Scientific Title

Phase I/II multicenter trial of paclitaxel, ramucirumab and nivolumab for metastatic gastric cancer patients who progressed on chemotherapy with fluoropyrimidine plus platinum

Scientific Title:Acronym

Phase I/II trial of paclitaxel, ramucirumab and nivolumab for advanced gastric cancer patients

Region

Japan

Condition

Gastric cancer

Classification by specialty

Gastroenterology

Hematology and clinical oncology

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

Phase I: To determine Maximum Tolerated Dose: MTD, Dose Limiting Toxicity: DLT, Recommended Dose: RD of paclitaxel, ramucirumab and nivolumab

Phase II: To evaluate efficacy of paclitaxel, ramucirumab and nivolumab at RD level

Basic objectives2

Safety

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Explanatory

Developmental phase

Phase I,II

Primary outcomes

Phase I: DLT
Phase II: 6 months progression -free survival

Key secondary outcomes

Phase I: Safety
Phase II: Overall response rate: ORR, Disease control rate: DCR, Progression-free survival: PFS, Overall survival: OS

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Level1
Paclitaxel: 80 mg/m2 day1, 8, 15
Ramucirumab:8 mg/kg div day1, 15
Nivolumab: 3 mg/kg div day1, 15
28 days 1 course

Level0
Paclitaxel: 80 mg/m2 day1, 8, 15
Ramucirumab:8 mg/kg div day1, 15
Nivolumab: 1 mg/kg div day1, 15
28 days 1 course

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

1) Histologically diagnosed as adenocarcinoma (papillary adenocarcinoma, tubular adenocarcinoma, poorly differentiated adenocarcinoma), signet ring cell carcinoma, mucinous carcinoma, hepatoid adenocarcinoma.
2) Unresectable gastric cancer including esophago-gastric junctional cancer)
3) No massive ascites that needs drainage.
4) No brain metastasis
5) To be able to take oral intake
6) Aged 20 years or over
7) ECOG PS 0 or 1
8) One or more measurable lesions
9) Prior chemotherapy with fluoropyrimidine and platinum
10) Adequate organ function
1. Neutrophil count: 1,500/mm3 or above
2. Platelet count: 100,000/mm3 or above
3. Hemoglobin: 8.0 g/dL or above
4. AST(GOT):100 IU/L or less
5. ALT(GPT):100 IU/L or less
6. Total bilirubin: 1.5 mg/dL or less
7. Creatinin: 1.5 mg/dL or less
8. PT-INR: 1.5 or less
9. i. Urinary protein (-) or (1+)
ii. Urinary protein (2+) or more : Measure proteinuria for 24 hours and urinary protein 1g or less / 24 hour
11) Blood pressure under control
12) Written informed consent

Key exclusion criteria

1) Prior therapy with anti PD-1/PD-L1/CTLA-4 antibody or treatment targeting T cell
2) Chemotherapy within 14 days prior to enrollment
3) Treatment under investigation within 28 days prior to enrollment
4) Prednisolone 10mg or more/immunosuppressing therapy within 14 days prior to enrollment
5) Other active cancer
6) Active infecton
7) Fever of 38 Centigrade or above
8) Pregnancy
9) HBsAg+ or HCVAb+
10) HIV-1 Ab+ or HIV-2 Ab+ or HTLV-1 Ab+
11) Serious comorbidity
12) Consent to contraception

Target sample size

43

Name of lead principal investigator

1st name	Takako
Middle name
Last name	Nakajima

Organization

St. Marianna University School of Medicine Hospital

Division name

Department of Clinical Oncology

Zip code

216-8511

Address

2-16-1 Sugao Miyamae-ku Kawasaki Kanagawa

TEL

044-977-8111

Email

tnakajima@marianna-u.ac.jp

Name of contact person

1st name	Yuko
Middle name
Last name	Tanno

Organization

St. Marianna University School of Medicine

Division name

Department of Clinical Oncology

Zip code

216-8511

Address

2-16-1 Sugao Miyamae-ku Kawasaki Kanagawa

TEL

044-977-8111

Homepage URL

Email

kenkyug-rinshoshuyou@googlegroups.com

Institute

St. Marianna University School of Medicine Hospital
Department of Clinical Oncology

Institute

Department

Personal name

Organization

ONO PHARMACEUTICAL CO., LTD.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

St. Marianna University School of Medicine Hospital

Address

2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan

Tel

044-977-8111

Email

k-sienbu.mail@marianna-u.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

聖マリアンナ医科大学病院　　腫瘍内科　
千葉県がんセンター　臨床試験推進部　
愛知県がんセンター中央病院 薬物療法部　　　
独立行政法人国立病院機構四国がんセンター 消化器内科　　

Date of disclosure of the study information

2017

Year

02

Month

03

Day

URL releasing protocol

http://www.oncology-mari.com/outline

Publication of results

Published

URL related to results and publications

https://clincancerres.aacrjournals.org/content/27/4/1029

Number of participants that the trial has enrolled

43

Results

Forty-three patients were enrolled. The recommended dose was determined as level 1. The overall response rate was 37.2% (95% CI, 23.0%-53.5%) and the 6-month PFS rate was 46.5% (80% CI, 36.4%-55.8%; P = 0.067). Median survival time was 13.1 months (95% CI, 8.0-16.6 months). Nivolumab with paclitaxel plus ramucirumab demonstrated promising antitumor activity as second-line treatment for AGC.

Results date posted

2021

Year

08

Month

09

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

2021

Year

02

Month

28

Day

Baseline Characteristics

A total of 43 patients were enrolled between February 2017 and July 2018, and all patients were included in the FAS. The majority of patients were male, with an age range of 38-78 years. Twenty-two patients (51.2%) had PS of 0, TPS was positive in six patients (14.0%), and CPS was　>1 in 26 patients (60.5%) and >10 in seven patients (16.3%). MMR and EBER were positive in zero and 4 patients (9.3%), respectively.

Participant flow

Six patients in phase 1 and 37 patients in phase 2 were enrolled. At the primary analysis (January 2019, median follow-up time of 8.2 months), 23 PFS events (53.5%) had occurred. At final analysis with a median follow-up time of 23.2 months (95%CI, 17.4-28.0), thirty-two OS events (74.4%) occurred.

Adverse events

Thirty-nine (90.7%) patients experienced grade >3 treatment-related AEs. The most common grade >3 AE was neutrophil count decrease (33 patients, 76.7%), while febrile neutropenia was observed in seven patients (16.3%). Fourteen (32.6%) patients experienced grade >3 immune-related AEs. There was one treatment-related death from thrombocytopenia.

Outcome measures

DLTs (febrile neutropenia and neutropenia over a period of 8 days) were observed in two of six patients in level 1, and the RD was determined at level 1. All patients included in the phase 2 part were treated at the RD.　 Six-month PFS was 46.5% (80% CI, 36.4-55.8; P = 0.067), which means primary endpoint was met. OS at 12 and 18 months was 55.8% (95% CI, 39.8-69.1) and 32.1% (95% CI, 18.2-46.8), respectively.
Median PFS was 5.1 months (95% CI, 4.5-6.5 months): 6.4 months (95% CI, 4.2-7.9 months) in patients with CPS >1 and 5.1 months (95% CI, 2.6-6.7 months) in patients with CPS <1; 6.4 months (95% CI, 1.0-6.9 months) in patients with CPS >5 and 5.9 months (95% CI, 4.6-6.9 months) in patients with CPS <5; 6.7 months (95% CI, 1.0-8.8 months) in patients with CPS >10 and 5.5 months (95% CI, 4.2-6.7 months) in patients with CPS <10; and 5.8 months (95% CI, 4.2-7.9 months) in patients with PS 0 and 4.9 months (95% CI, 3.2-6.4 months) in patients with PS 1.
Thirty-two OS events (74.4%) occurred and median survival time was 13.1 months (95% CI, 8.0-16.6 months): 13.8 months (95% CI, 8.0-19.5 months) in patients with CPS >1 and 8.0 months (95% CI, 4.8-24.1 months) in patients with CPS <1; 13.1 months (95% CI, 5.1 months-not reached) in patients with CPS >5 and 14.9 months (95% CI, 7.4-19.5 months) in patients with CPS <5; 13.8 months (95% CI, 8.0 months-not reached) in patients with CPS >10 and 13.0 months (95% CI, 7.1-18.6 months) in patients with CPS <10; and 14.4 months (95% CI, 7.7-28.0 months) in patients with PS 0 and 8.0 months (95% CI, 4.8-16.6 months) in patients with PS 1.
　　DCR was 83.7% (95% CI, 69.3-93.2). ORR was 37.2% (95% CI, 23.0-53.5): 46.2% (95% CI, 26.6-66.6) in patients with CPS >1 and 30.8% (95% CI, 9.1-61.4) in patients with CPS <1; and 45.5% (95% CI, 24.4-67.8) in patients with PS 0 and 28.6% (95% CI, 11.3-52.5) in patients with PS 1.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2017

Year

01

Month

20

Day

Date of IRB

2016

Year

12

Month

12

Day

Anticipated trial start date

2017

Year

02

Month

03

Day

Last follow-up date

2019

Year

07

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

2021

Year

02

Month

28

Day

Other related information

Registered date

2017

Year

02

Month

01

Day

Last modified on

2021

Year

08

Month

09

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000029783