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
* 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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
45
infusional 50/60/70 mg/m2 over 90 minutes day 1, every 14 days.
infusional 8mg/kg over 60 minutes day 1, every 14 days.
oral 30 mg/m2/b.i.d. day 1-5, every 14 days.
Taipei Veterans General Hospital
Taipei, Taiwan/Taipei, Taiwan
RECRUITINGTo 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.
Time frame: 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.
Time frame: Whichever occurs first assessed up to 24 months.
•To evaluate disease control rate (DCR)
•Patients will be treated until disease progression, unacceptable toxicity or other condition meeting the off-study criteria.
Time frame: 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.
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)
•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.
Time frame: 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.
Time frame: 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
Time frame: The time from baseline on day 1.
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