Ramucirumab (Cyramza), Nal-IRI (ONIVYDE) and Trifluridine/Tipiracil (Lonsurf) in Second Line Metastatic Gastric Cancer .

June 25, 2023 updated by: National Health Research Institutes, Taiwan

A Phase Ib/II Study of Ramucirumab (Cyramza®), Nal-IRI (ONIVYDE®) and Trifluridine/Tipiracil (Lonsurf®) in Second Line Metastatic Gastric Cancer (COOL Study).

Primary Objectives

  • In phase 1b cohort, to determine MTD (maximum tolerated dose) of nal-IRI (ONIVYDE®) in combination with Ramucirumab (Cyramza®) and TAS-102 (LONSURF®)
  • In phase II cohort, to evaluate disease objective response rate (ORR) of Ramucirumab (Cyramza®), nal-IRI (ONIVYDE®) in combination with TAS-102 (LONSURF®) Secondary Objectives
  • To evaluate disease control rate (DCR)
  • To evaluate progression-free survival (PFS)
  • To evaluate overall survival (OS)
  • To assess the safety profile
  • To study the blood biomarkers

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

  • Eligible patients will be treated with infusional nal-IRI (ONIVYDE®, free form) 50/60/70 mg/m2 over 90 minutes day 1, Ramucirumab 8 mg/kg over 60 minutes day 1, in combination with oral TAS-102 (LONSURF®) 30 mg/m2/b.i.d. day 1-5, every 14 days.
  • Every 14 days count as one cycle.
  • Patients will be treated until disease progression, unacceptable toxicity or other condition meeting the off-study criteria.
  • Scheme of phase 1b: dose Level 0 to 2 will be tested with the following dose levels:
  • Dose level 0= Ramucirumab(Cyramza®) 8mg/kg on day 1, nal-IRI (ONIVYDE®, free form) 50 mg/m2 on day 1 plus Trifluridine/Tipiracil (Lonsurf®) 30mg/m2 on day 1-5, q2wk
  • Dose level 1= Ramucirumab(Cyramza®) 8mg/kg on day 1, nal-IRI (ONIVYDE®, free form) 60 mg/m2 on day 1 plus Trifluridine/Tipiracil (Lonsurf®) 30mg/m2 on day 1-5, q2wk
  • Dose level 2= Ramucirumab(Cyramza®) 8mg/kg on day 1, nal-IRI (ONIVYDE®, free form) 70 mg/m2 on day 1 plus Trifluridine/Tipiracil (Lonsurf®) 30mg/m2 on day 1-5, q2wk
  • Adaptive phase IB cohort:
  • 3+3 dose escalation will be applied for phase Ib cohort. All treated patients of MTD dose level in phase 1b cohort will be incorporated into phase II cohort for final analysis. No intra-patient dose escalation is allowed during DLT period. Patients could only have dose modification after the DLT period. G-CSF prophylaxis is not allowed in DLT period.
  • Dose escalation rule: Two to six patients will be enrolled in each cohort depending on cases with DLTs. The starting dose is dose level 0. If none of the first 3 patients experiences DLT, then dose escalation will proceed to the next cohort of patients. If only 1 of 3 patients developed DLT, the cohort will be expanded to 6 patients. If more than 1 patient developed DLT at a certain dose level/group, the dose level/group is considered intolerable to the patients. If no more than 1 out of 6 patients experience DLT, the dose level/group is considered tolerable. A minimum of 6 evaluable patients will be treated at the MTD. The MTD at which no more than 1 of the 6 patients experience DLT will be determined for the phase II cohort. Based on results from phase IB cohort, MTD will be determined. All treated population in MTD cohort will be incorporated into phase II cohort for final analysis.

Study Type

Interventional

Enrollment (Estimated)

45

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. histologically or cytologically confirmed metastatic gastric adenocarcinoma
  2. patients have received only first line of systemic therapy, including recurrence during adjuvant therapy or within 6 months after the completion of adjuvant treatment.
  3. ECOG(Eastern Cooperative Oncology Group) performance status 0 or 1
  4. patients with HER2/neu-positive tumor must be exposure to Herceptin treatment
  5. at least one measurable disease according to the RECIST version 1.1;
  6. patients are aged 20 to 80 years;
  7. patients have a life expectancy ≥ 3 months;
  8. patients have adequate renal function with defined as serum creatinine ≤ 1.5 times the upper limit of normal (ULN) or Ccr ≥ 40 mL/min;
  9. patients with adequate hepatic function as defined by a total bilirubin ≤1.5 times the ULN, and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times the ULN or 5 times the ULN in the setting of liver metastases.
  10. patients have adequate bone marrow function, defined as an absolute neutrophil count ≥ 1500/mm3, hemoglobin ≥9 g/dL, and platelet count ≥ 100,000/mm3 (transfusion or G-CSF support before enrollment is allowed)
  11. patients have International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN;
  12. patients' urinary protein is ≤1+ on dipstick or routine urinalysis or a 24-hour urine collection for protein must demonstrate <1000 mg of protein if urine dipstick or routine analysis is ≥ 2+;
  13. patients with childbearing potential shall have effective contraception for both the patient and his or her partner during the study;
  14. female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of protocol therapy;
  15. the ability to understand and willingness and to sign a written informed consent document.

Exclusion Criteria:

  1. patient can't take oral drugs;
  2. known hypersensitivity to irinotecan, fluoropyrimidine, or ramucirumab;
  3. receipt of surgery within the past 4 weeks before study enrollment;
  4. ≥ grade 2 diarrhea and ascites
  5. concurrent severe infection with intravenous systemic antibiotics treatment;
  6. patients have experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy;
  7. patients have a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation;

  8. patients have:

    • cirrhosis at a level of Child-Pugh B (or worse) or
    • cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis;
  9. patients have a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy;
  10. patients have undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy. Patients have elective or planned major surgery to be performed during the course of the clinical trial;
  11. patients have uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management;
  12. patients have experienced any grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy;
  13. patients have a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy;
  14. patients are receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted;
  15. previously received prior nal-IRI (ONIVYDE®) or TAS-102 (LONSURF®) or ramucirumab therapy
  16. another previous malignancy diagnosed within the past 5 years except for nonmelanoma skin cancer or stage I cervical cancer;
  17. pregnant or breastfeeding women.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Phase 1b/II
  • Infusional nal-IRI (ONIVYDE, free form) 50/60/70 mg/m2 over 90 minutes day 1.
  • Infusional Ramucirumab(Cyramza)8 mg/kg over 60 minutes day 1.
  • oral Trifluridine/Tipiracil TAS-102 (LONSURF) 30 mg/m2/b.i.d. day 1-5.
  • Every 14 days count as one cycle.
Drug: nal-IRI /Experimental
infusional 50/60/70 mg/m2 over 90 minutes day 1, every 14 days.
Other Names:
  • ONIVYDE
Drug: Ramucirumab /Experimental
infusional 8mg/kg over 60 minutes day 1, every 14 days.
Other Names:
  • Cyramza
Drug: Trifluridine/Tipiracil /Experimental
oral 30 mg/m2/b.i.d. day 1-5, every 14 days.
Other Names:
  • LONSURF

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To determine MTD (maximum tolerated dose) of nal-IRI (ONIVYDE)
Time Frame: Phase I last patient in has been treated for 28 days.
All treated patients of MTD dose level in phase 1b cohort will be incorporated into phase II cohort for final analysis.
Phase I last patient in has been treated for 28 days.
To evaluate disease objective response rate (ORR)
Time Frame: Whichever occurs first assessed up to 24 months.
Based on results from phase Ib cohort, MTD will be determined. All treated population in MTD cohort will be incorporated into phase II cohort for final analysis.
Whichever occurs first assessed up to 24 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
•To evaluate disease control rate (DCR)
Time Frame: The time from registration to death from any cause assessed up to 24 months.
•Patients will be treated until disease progression, unacceptable toxicity or other condition meeting the off-study criteria.
The time from registration to death from any cause assessed up to 24 months.
•To evaluate progression-free survival (PFS)
Time Frame: The time from registration to occurrence of progression based on the tumor response assessment by scheduled or un- scheduled CT scan or MRI. (whichever occurs first assessed up to 24 months)
• objective tumor response according to RECIST v1.1 guidelines.
The time from registration to occurrence of progression based on the tumor response assessment by scheduled or un- scheduled CT scan or MRI. (whichever occurs first assessed up to 24 months)
•To evaluate overall survival (OS)
Time Frame: The time from registration to death from any cause assessed up to 24 months.
the time from the date of first study treatment to the date of patient death, due to any cause, or to the last date the patient was known to be alive.
The time from registration to death from any cause assessed up to 24 months.
•To assess the safety profile
Time Frame: The time from registration to death from every 14 days assessed up to 24 months.
•Safety evaluations: physical examination, vital signs, body weight, ECOG performance status, clinical laboratory values (biochemistry, hematology, and urinalysis), and any adverse event (AE) graded by using CTCAE v5.0 if applicable.
The time from registration to death from every 14 days assessed up to 24 months.
•To study the blood biomarkers
Time Frame: The time from baseline on day 1.
  • To evaluate the drug sensitivity of circulating tumor cells to, including but not limited to irinotecan, fluorouracil and ramucirumab.
  • Patients enrolled in both phase Ib and phase II parts will participate in biomarker study
The time from baseline on day 1.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Health Research Institutes, Taiwan

Collaborators

China Medical University Hospital
Chang Gung Memorial Hospital
Kaohsiung Medical University Chung-Ho Memorial Hospital
Taipei Veterans General Hospital, Taiwan
National Cheng-Kung University Hospital

Investigators

  • Principal Investigator: Nai-Jung Chiang, MD-PhD, National Health Research Institutes, Taiwan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2023

Primary Completion (Estimated)

August 31, 2025

Study Completion (Estimated)

December 31, 2025

Study Registration Dates

First Submitted

June 14, 2023

First Submitted That Met QC Criteria

June 25, 2023

First Posted (Actual)

July 3, 2023

Study Record Updates

Last Update Posted (Actual)

July 3, 2023

Last Update Submitted That Met QC Criteria

June 25, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • T1223

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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