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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Metastatic Gastric Adenocarcinoma, Second Line, Chemotherapy

Intervention / Treatment
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* Drug: nal-IRI /Experimental
* Drug: Ramucirumab /Experimental
* Drug: Trifluridine/Tipiracil /Experimental


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically or cytologically confirmed metastatic gastric adenocarcinoma patients have received only first line of systemic therapy, including recurrence during adjuvant therapy or within 6 months after the completion of adjuvant treatment. ECOG(Eastern Cooperative Oncology Group) performance status 0 or 1 patients with HER2/neu-positive tumor must be exposure to Herceptin treatment at least one measurable disease according to the RECIST version 1.1; patients are aged 20 to 80 years; patients have a life expectancy ≥ 3 months; patients have adequate renal function with defined as serum creatinine ≤ 1.5 times the upper limit of normal (ULN) or Ccr ≥ 40 mL/min; 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. 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) patients have International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN; 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+; patients with childbearing potential shall have effective contraception for both the patient and his or her partner during the study; female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of protocol therapy; the ability to understand and willingness and to sign a written informed consent document. Exclusion Criteria: patient can't take oral drugs; known hypersensitivity to irinotecan, fluoropyrimidine, or ramucirumab; receipt of surgery within the past 4 weeks before study enrollment; ≥ grade 2 diarrhea and ascites concurrent severe infection with intravenous systemic antibiotics treatment; 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; patients have a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation; 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; patients have a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy; 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; patients have uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management; patients have experienced any grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy; 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; patients are receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted; previously received prior nal-IRI (ONIVYDE®) or TAS-102 (LONSURF®) or ramucirumab therapy another previous malignancy diagnosed within the past 5 years except for nonmelanoma skin cancer or stage I cervical cancer; pregnant or breastfeeding women.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b/II<br>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<br>* infusional 50/60/70 mg/m2 over 90 minutes day 1, every 14 days.<br>* Other names: ONIVYDE;Drug: Ramucirumab /Experimental<br>* infusional 8mg/kg over 60 minutes day 1, every 14 days.<br>* Other names: Cyramza;Drug: Trifluridine/Tipiracil /Experimental<br>* oral 30 mg/m2/b.i.d. day 1-5, every 14 days.<br>* Other names: LONSURF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine MTD (maximum tolerated dose) of nal-IRI (ONIVYDE) | 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) | 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) | •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) | • 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) | 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 | •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 | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nal-IRI (ONIVYDE), TAS-102 (LONSURF), Ramucirumab (Cyramza)