Clinical trial NCT05927857: Ramucirumab (Cyramza), Nal-IRI (ONIVYDE) and Trifluridine/Tipiracil (Lonsurf) in Second Line Metastatic Gastric Cancer .
Official title: A Phase Ib/II Study of Ramucirumab (Cyramza®), Nal-IRI (ONIVYDE®) and Trifluridine/Tipiracil (Lonsurf®) in Second Line Metastatic Gastric Cancer (COOL Study).
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastatic Gastric Adenocarcinoma
Second Line
Chemotherapy
Keywords: nal-IRI (ONIVYDE)
TAS-102 (LONSURF)
Ramucirumab (Cyramza)
Lead sponsor: National Health Research Institutes, Taiwan
Sponsor class: OTHER
Collaborators: name: Taipei Veterans General Hospital, Taiwan
name: China Medical University Hospital
name: National Cheng-Kung University Hospital
name: Kaohsiung Medical University Chung-Ho Memorial Hospital
name: Chang Gung Memorial Hospital
First posted: 2023-07-03
Enrollment: 45
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

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.

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 nonmelanoma skin cancer or stage I cervical cancer;
17. pregnant or breastfeeding women.

Primary outcomes:
measure: To determine MTD (maximum tolerated dose) of nal-IRI (ONIVYDE)
timeFrame: Phase I last patient in has been treated for 28 days.
measure: To evaluate disease objective response rate (ORR)
timeFrame: Whichever occurs first assessed up to 24 months.
Secondary outcomes:
measure: •To evaluate disease control rate (DCR)
timeFrame: The time from registration to death from any cause assessed up to 24 months.
measure: •To evaluate progression-free survival (PFS)
timeFrame: 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)
measure: •To evaluate overall survival (OS)
timeFrame: The time from registration to death from any cause assessed up to 24 months.
measure: •To assess the safety profile
timeFrame: The time from registration to death from every 14 days assessed up to 24 months.
measure: •To study the blood biomarkers
timeFrame: The time from baseline on day 1.
Other outcomes:
Locations:
Study officials:
affiliation: National Health Research Institutes, Taiwan
name: Nai-Jung Chiang, MD-PhD
role: PRINCIPAL_INVESTIGATOR
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