Combining Cyramza, ONIVYDE, and Lonsurf as a second-line treatment for metastatic gastric cancer

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

This trial tests whether adding nal-IRI (ONIVYDE) and trifluridine/tipiracil (Lonsurf) to ramucirumab (Cyramza) helps people with metastatic gastric cancer who progressed after one prior systemic therapy.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 45 (estimated)
• Ages: 20 Years to 80 Years
• Sex: All
• Sponsor: National Health Research Institutes, Taiwan (Academic / other)
• Drugs / interventions: ramucirumab
• Locations: 1 site (Taipei, Taiwan/Taipei)
• Trial ID: NCT05927857 on ClinicalTrials.gov

What this trial studies

This is an open-label Phase 1b/2 interventional trial that begins with a 3+3 dose-escalation (phase 1b) to find the maximum tolerated dose of nal-IRI when given with fixed-dose ramucirumab and oral trifluridine/tipiracil on a 14-day schedule. Patients treated at the identified MTD will roll into the Phase 2 cohort to measure objective response rate, with secondary endpoints of disease control rate, progression-free survival, overall survival, safety, and blood biomarker analysis. Planned nal-IRI dose levels are 50, 60, and 70 mg/m2 iv on day 1, with ramucirumab 8 mg/kg iv on day 1 and TAS-102 30 mg/m2 orally days 1–5 every two weeks. Treatment continues until disease progression, unacceptable toxicity, or other off-study criteria.

Who should consider this trial

Good fit: Ideal candidates are adults aged 20–80 with histologically confirmed metastatic gastric adenocarcinoma who have received only one prior systemic therapy, have ECOG 0–1, measurable disease by RECIST 1.1, and adequate organ function.

Not a fit: Patients with poor performance status (ECOG >1), more than one prior systemic therapy, significant organ dysfunction, or contraindications to the study drugs are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, this combination could increase tumor response and extend the time without progression for patients needing second-line therapy.

How similar studies have performed: Ramucirumab has proven benefit in second-line gastric cancer when combined with paclitaxel, but combining nal-IRI and trifluridine/tipiracil with ramucirumab is a novel approach without established evidence of improved outcomes.

Eligibility criteria

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 non melanoma skin cancer or stage I cervical cancer;
17. pregnant or breast feeding women.

Where this trial is running

Taipei, Taiwan/Taipei

• Taipei Veterans General Hospital — Taipei, Taiwan/Taipei, Taiwan (Recruiting)

Study contacts

• Principal investigator: Nai-Jung Chiang, MD-PhD — National Health Research Institutes, Taiwan
• Study coordinator: Chien-Ya Hung, BS

Conditions Metastatic Gastric Adenocarcinoma; Second Line; Chemotherapy; nal-IRI; TAS-102; Ramucirumab