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.
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
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
Single group
Low Dose OXIRI (LD-OXIRI)
DrugThe 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.
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.
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).
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National Cancer Centre, Singapore
Lead sponsor
National Medical Research Council (NMRC), Singapore
Collaborator
