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Metronomic Capecitabine, Oxaliplatin and UGT1A1 Genotype-directed Irinotecan in Metastatic Pancreatic Cancer Patients

Primary Purpose

Metastatic Pancreatic Cancer

Status
Not yet recruiting
Phase
Phase 2
Locations
Singapore
Study Type
Interventional
Intervention
Low Dose OXIRI (LD-OXIRI)
Sponsored by
National Cancer Centre, Singapore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Pancreatic Cancer focused on measuring Low Dose OXIRI (LDOXIRI), Pancreatic Cancer, Irinotecan, Oxaliplatin, Capecitabine, Pharmacokinetics, Metronomic Chemotherapy, UGT1A1

Eligibility Criteria

21 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: The patient must meet all of the inclusion criteria to participate in the study. Aged above 21 Histopathological diagnosis of pancreatic cancer Advanced disease not amenable to curative resection (locally advanced or metastatic disease) Measureable disease by RECIST 1.1 criteria Life expectancy of at least 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Adequate hematologic function (granulocyte count ≥ 1.5 × 10**9/L, platelet count ≥ 100 × 10**9/L), Adequate hepatic function (total bilirubin ≤ 1.5 x the upper limits of normal [ULN], AST and ALT, ALP ≤ 3 x ULN or < 5 x ULN in case of hepatic involvement), Adequate renal function (creatinine clearance > 50 mL/min) will be eligible for inclusion into the study. Able to provide written and informed consent Exclusion Criteria: Any patient meeting any of the exclusion criteria at baseline will be excluded from participation. History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free after definitive primary treatment for at least 5 years. Untreated CNS metastases or leptomeningeal disease. Patients with brain metastases that have been treated, and are asymptomatic, and have been stable for 3 or more months after treatment are allowed. A baseline CT or MRI brain is only required if there is clinical suspicion of CNS involvement. Concurrent illness, including severe infection, that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol Treatment with palliative chemotherapy or radiotherapy within 4 weeks prior to enrolment into the study Major surgery within two weeks prior to enrolment into the study Patients on chronic immunosuppressive therapy Pregnancy, lactation or inadequate contraception. Women of childbearing potential must have a negative pregnancy test within 3 days of enrolment and agree to use a reliable means of contraception. Men must have been surgically sterilised or agree to use a barrier method of contraception Patients on anticoagulant therapy with vitamin K antagonists.

Sites / Locations

  • National Cancer Centre, Singapore

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Low Dose OXIRI (LD-OXIRI)

Arm Description

Low Dose OXIRI (LD-OXIRI) regimen comprises Metronomic Oxaliplatin (O) and Metronomic Capecitabine (xeloda; X) in combination with UGT1A1-directed dosing of Irinotecan (IRI).

Outcomes

Primary Outcome Measures

Overall Response Rate (ORR).
The proportion of patients who have a partial or complete response as specified in RECIST 1.1.
Clinical Benefit Rate (CBR).
The percentage of advanced cancer patients who achieve complete response, partial response, or at least six months of stable disease as specified in RECIST 1.1.
The Grade 3-5 Toxicity Rate.
The proportion of patients who have adverse event(s) with Grade 3-5 toxicity as defined in CTCAE 5.0.

Secondary Outcome Measures

Maximum plasma concentration [(Cmax)] of low dose Capecitabine and its intermediary metabolites (5'-deoxy-5-fluorocytidine [DFCR] and 5'- deoxy-5-fluorouridine [DFUR]) and 5FU.
Maximum plasma concentration [(Cmax)] of low dose capecitabine and its intermediary metabolites (5'-deoxy-5-fluorocytidine [DFCR] and 5'- deoxy-5-fluorouridine [DFUR]) and 5FU at Cycle 1 Day 1.
Trough concentration of low dose capecitabine and its intermediary metabolites and 5FU.
Trough concentration of low dose capecitabine and its intermediary metabolites (5'-deoxy-5-fluorocytidine [DFCR] and 5'- deoxy-5-fluorouridine [DFUR]) and 5FU.
Immunophenotyping from extracted peripheral blood mononuclear cells (PBMCs) - measurement of cytokine and chemokine concentrations in picograms per milliliters using multiplex flow cytometry.
Immunophenotyping from extracted peripheral blood mononuclear cells (PBMCs) - measurement of cytokine and chemokine concentrations in picograms per milliliters using multiplex flow cytometry at these time-points: at predose, end of oxaliplatin infusion, end of irinotecan infusion on Cycle 1 Day 1 (each cycle is 21 days); at predose of Cycle 2 Day 1 and at disease progression (up to three years).
Genomic analysis of circulating tumour DNA (ctDNA).
Genomic analysis of circulating tumour DNA (ctDNA) from whole blood at these time-points: at predose of every two cycles (Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, etc - each cycle is 21 days) and at disease progression (up to three years).
Identification of exosomal proteins secreted by extracellular vesicles from plasma.
Identification of exosomal proteins secreted by extracellular vesicles from plasma using mass spectrometry, at the following time-points: at predose, end of oxaliplatin infusion, end of irinotecan infusion on Cycle 1 Day 1 (each cycle is 21 days); at predose of Cycle 2 Day 1 and at disease progression (up to three years).
Progression-free survival (PFS).
Time from first dose of treatment to disease progression or death, whichever comes first.
Overall survival (OS).
Time from first dose to death.

Full Information

First Posted
April 24, 2023
Last Updated
June 29, 2023
Sponsor
National Cancer Centre, Singapore
Collaborators
National Medical Research Council (NMRC), Singapore
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1. Study Identification

Unique Protocol Identification Number
NCT05929885
Brief Title
Metronomic Capecitabine, Oxaliplatin and UGT1A1 Genotype-directed Irinotecan in Metastatic Pancreatic Cancer Patients
Official Title
A Phase II Study of Metronomic Capecitabine, Oxaliplatin and UGT1A1 Genotype-directed Irinotecan in Metastatic Pancreatic Cancer Patients.
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
July 2023 (Anticipated)
Primary Completion Date
February 28, 2026 (Anticipated)
Study Completion Date
February 28, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Centre, Singapore
Collaborators
National Medical Research Council (NMRC), Singapore

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a single-centre, non-randomized, open label phase II trial to be conducted at the National Cancer Centre, Singapore (NCCS). Patients diagnosed with metastatic PDAC will be eligible to enrol. The investigators hypothesize the anticancer activity of low dose OXIRI (LD-OXIRI) regimen comprising of metronomic oxaliplatin (O) and metronomic capecitabine (xeloda; X) in combination with UGT1A1-directed dosing of irinotecan (IRI) to be a tolerable regimen in patients with advanced PDAC and will lead to a favourable response rate. Patients will be prospectively enrolled in two stages - In stage 1, patients will be recruited and evaluated for response and toxicity. In stage 2, more patients will be recruited for further evaluation of response and toxicity.
Detailed Description
Eligible patients will be recruited from the National Cancer Centre, Singapore (NCCS). Patients will be referred for assessment by the primary physician to a study investigator for screening. Informed written consent for entry into the trial will be obtained from the patient by a delegated investigator. All patients eligible for study entry will receive the LD-OXIRI regimen at the National Cancer Centre, Singapore. All concomitant medication taken during the study must be recorded. If a drug is administered prophylactically, this must be noted. The patients will not receive any other investigational drugs while on this study. There will be a screening period of 28 days, a treatment period till disease progression or unacceptable toxicity, and a post-treatment follow up period of up to 24 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Pancreatic Cancer
Keywords
Low Dose OXIRI (LDOXIRI), Pancreatic Cancer, Irinotecan, Oxaliplatin, Capecitabine, Pharmacokinetics, Metronomic Chemotherapy, UGT1A1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
43 patients will be enrolled in two stages - In stage 1, a total of 19 patients will be recruited and evaluated for response and toxicity. In stage 2, another 24 patients will be recruited for further evaluation of response and toxicity. Up to 7 patients will be recruited to account for any drop outs (i.e. up to total of 50 patients).
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Low Dose OXIRI (LD-OXIRI)
Arm Type
Experimental
Arm Description
Low Dose OXIRI (LD-OXIRI) regimen comprises Metronomic Oxaliplatin (O) and Metronomic Capecitabine (xeloda; X) in combination with UGT1A1-directed dosing of Irinotecan (IRI).
Intervention Type
Drug
Intervention Name(s)
Low Dose OXIRI (LD-OXIRI)
Intervention Description
The LD-OXIRI regimen will be administered in the following sequence: metronomic capecitabine (Xeloda; X) 650mg/m2 will administered twice a day on a daily a continuous basis; intravenous metronomic oxaliplatin (O) 50 mg/m2 will be infused over 120 minutes on days 1 and 8 of a 21 day-cycle; followed by intravenous irinotecan (I) will be infused over 90 minutes on days 1 and 8 of a 21 day-cycle. The dose of irinotecan will be based on the particular patient's UGT1A1*6 and UGT1A1*28 genotype status.
Primary Outcome Measure Information:
Title
Overall Response Rate (ORR).
Description
The proportion of patients who have a partial or complete response as specified in RECIST 1.1.
Time Frame
Up to 3 years.
Title
Clinical Benefit Rate (CBR).
Description
The percentage of advanced cancer patients who achieve complete response, partial response, or at least six months of stable disease as specified in RECIST 1.1.
Time Frame
Up to 3 years.
Title
The Grade 3-5 Toxicity Rate.
Description
The proportion of patients who have adverse event(s) with Grade 3-5 toxicity as defined in CTCAE 5.0.
Time Frame
Up to 3 years.
Secondary Outcome Measure Information:
Title
Maximum plasma concentration [(Cmax)] of low dose Capecitabine and its intermediary metabolites (5'-deoxy-5-fluorocytidine [DFCR] and 5'- deoxy-5-fluorouridine [DFUR]) and 5FU.
Description
Maximum plasma concentration [(Cmax)] of low dose capecitabine and its intermediary metabolites (5'-deoxy-5-fluorocytidine [DFCR] and 5'- deoxy-5-fluorouridine [DFUR]) and 5FU at Cycle 1 Day 1.
Time Frame
At predose, 1 hr, end of irinotecan infusion on Cycle 1 Day 1 (each cycle is 21 days)
Title
Trough concentration of low dose capecitabine and its intermediary metabolites and 5FU.
Description
Trough concentration of low dose capecitabine and its intermediary metabolites (5'-deoxy-5-fluorocytidine [DFCR] and 5'- deoxy-5-fluorouridine [DFUR]) and 5FU.
Time Frame
At predose of Cycle 2 Day 1 and Cycle 3 Day 1 (each cycle is 21 days)
Title
Immunophenotyping from extracted peripheral blood mononuclear cells (PBMCs) - measurement of cytokine and chemokine concentrations in picograms per milliliters using multiplex flow cytometry.
Description
Immunophenotyping from extracted peripheral blood mononuclear cells (PBMCs) - measurement of cytokine and chemokine concentrations in picograms per milliliters using multiplex flow cytometry at these time-points: at predose, end of oxaliplatin infusion, end of irinotecan infusion on Cycle 1 Day 1 (each cycle is 21 days); at predose of Cycle 2 Day 1 and at disease progression (up to three years).
Time Frame
Up to 3 years.
Title
Genomic analysis of circulating tumour DNA (ctDNA).
Description
Genomic analysis of circulating tumour DNA (ctDNA) from whole blood at these time-points: at predose of every two cycles (Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, etc - each cycle is 21 days) and at disease progression (up to three years).
Time Frame
Up to 3 years.
Title
Identification of exosomal proteins secreted by extracellular vesicles from plasma.
Description
Identification of exosomal proteins secreted by extracellular vesicles from plasma using mass spectrometry, at the following time-points: at predose, end of oxaliplatin infusion, end of irinotecan infusion on Cycle 1 Day 1 (each cycle is 21 days); at predose of Cycle 2 Day 1 and at disease progression (up to three years).
Time Frame
Up to 3 years.
Title
Progression-free survival (PFS).
Description
Time from first dose of treatment to disease progression or death, whichever comes first.
Time Frame
Up to 3 years.
Title
Overall survival (OS).
Description
Time from first dose to death.
Time Frame
Up to 3 years.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The patient must meet all of the inclusion criteria to participate in the study. Aged above 21 Histopathological diagnosis of pancreatic cancer Advanced disease not amenable to curative resection (locally advanced or metastatic disease) Measureable disease by RECIST 1.1 criteria Life expectancy of at least 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Adequate hematologic function (granulocyte count ≥ 1.5 × 10**9/L, platelet count ≥ 100 × 10**9/L), Adequate hepatic function (total bilirubin ≤ 1.5 x the upper limits of normal [ULN], AST and ALT, ALP ≤ 3 x ULN or < 5 x ULN in case of hepatic involvement), Adequate renal function (creatinine clearance > 50 mL/min) will be eligible for inclusion into the study. Able to provide written and informed consent Exclusion Criteria: Any patient meeting any of the exclusion criteria at baseline will be excluded from participation. History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free after definitive primary treatment for at least 5 years. Untreated CNS metastases or leptomeningeal disease. Patients with brain metastases that have been treated, and are asymptomatic, and have been stable for 3 or more months after treatment are allowed. A baseline CT or MRI brain is only required if there is clinical suspicion of CNS involvement. Concurrent illness, including severe infection, that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol Treatment with palliative chemotherapy or radiotherapy within 4 weeks prior to enrolment into the study Major surgery within two weeks prior to enrolment into the study Patients on chronic immunosuppressive therapy Pregnancy, lactation or inadequate contraception. Women of childbearing potential must have a negative pregnancy test within 3 days of enrolment and agree to use a reliable means of contraception. Men must have been surgically sterilised or agree to use a barrier method of contraception Patients on anticoagulant therapy with vitamin K antagonists.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dr Joycelyn LEE, MBBS, MRCP (UK), M Med
Phone
+65 64368000
Email
joycelyn.lee.j.x@singhealth.com.sg
First Name & Middle Initial & Last Name or Official Title & Degree
Hui Shan CHONG
Phone
+65 64368000
Email
chong.hui.shan@singhealth.com.sg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dr Joycelyn LEE, MBBS, MRCP (UK), M Med
Organizational Affiliation
National Cancer Centre, Singapore
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Cancer Centre, Singapore
City
Singapore
ZIP/Postal Code
168583
Country
Singapore
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr Joycelyn LEE, MBBS, MRCP, M Med

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Metronomic Capecitabine, Oxaliplatin and UGT1A1 Genotype-directed Irinotecan in Metastatic Pancreatic Cancer Patients

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