OXIRI [Oxaliplatin (O), Xeloda (X) and Irinotecan (I)] in Pancreatic Adenocarcinoma (OXIRI)

Phase I Trial of OXIRI [Oxaliplatin (O), Xeloda (X) and Irinotecan (I)] Treatment in Patients With Advanced and/or Metastatic Pancreatic Adenocarcinoma

This is an exploratory Phase I study is to assess the safety and tolerability of the OXIRI regimen [oxaliplatin (O), xeloda (X) and irinotecan (I)] and to evaluate for preliminary evidence of efficacy, in patients with advanced and/or metastatic pancreatic adenocarcinoma. The investigators hypothesize that 2 of 3 weekly doses of oxaliplatin and genotype directed-dosing of irinotecan in combination with chronomodulated capecitabine (xeloda) administered continuously will be more tolerable than the FOLFIRINOX regimen (folinic acid, fluorouracil, irinotecan and oxaliplatin) while maintaining anti-tumour activity.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: oxaliplatin, irinotecan, capecitabine

Detailed Description

This study comprises a dose escalation phase using 3+3 design to determine the safety, tolerability and pharmacokinetics of the OXIRI regimen and an expansion phase to further evaluate the MTD and to determine early signs of efficacy.

Eligible patients will receive a novel chemotherapeutic regimen (OXIRI regimen) with xeloda being administered in a chronomodulated fashion and the dose of irinotecan being guided by the UGT1A1*28 and UGT1A1*6 genotype status of the patient.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients between 21 to 75 years of age
2. A histopathologically or cytological confirmed diagnosis of locally advanced and/or metastatic PDAC that is unresectable
3. Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) ver 1.1 criteria
4. Life expectancy of at least 12 weeks
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
6. Adequate hematologic function (neutrophils count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L)
7. Adequate hepatic function (total bilirubin ≤ 1.5 x the upper limits of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
8. Adequate renal function (calculated creatinine clearance > 50 mL/min)
9. Able to give informed consent
10. Toxicity related to previous radiotherapy or chemotherapy resolved to ≤ Grade 1

Exclusion Criteria:

1. History of prior malignancy except non-melanoma skin cancer within the last 5yrs
2. Uncontrolled central nervous system (CNS) metastases or carcinomatous meningitis
3. Uncontrolled concomitant medical illnesses (e.g. hypertension, myocardial infarct, heart failure, ventricular arrhythmia, diabetes, severe infection)
4. Major surgery within four weeks prior to study treatment
5. Patients on chronic immunosuppressive therapy
6. Pregnant or breast-feeding female patients
7. On anticoagulant therapy with vitamin K antagonists.

8. Dose-escalation cohort:

   • Patients homozygous for uridine diphosphate glucuronosyltransferase (UGT)1A1*6/*6 or UGT1A1*28/*28
   • Previous oxaliplatin or irinotecan chemotherapy

   • Treatment with any of the following anti-cancer therapies prior to the first dose of OXIRI within the stated timeframes

     • Cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment. Exception for weekly chemotherapy regimens, where a minimum of 2 week washout from the last dose is required.
     • Biological therapy (e.g., antibodies) within a period of time that is ≤ 5 t1/2 or ≤ 4 weeks, whichever is shorter, prior to starting study drug
     • Continuous or intermittent small molecule therapeutics within a period of time that is ≤ 5 t1/2 or ≤ 4 weeks (whichever is shorter) prior to starting study drug
     • Any other investigational agents within a period of time that is ≤ 5 t1/2 or less than the cycle length used for that treatment or ≤ 4 weeks (whichever is shortest) prior to starting study drug
     • Wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug

9. Dose-expansion cohort:

   • Previous chemotherapy or radiotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OXIRI; OXIRI regimen: oxaliplatin, irinotecan, capecitabine	Drug: oxaliplatin, irinotecan, capecitabine; fixed doses of intravenous oxaliplatin 50 mg/m2, and intravenous irinotecan administered on days 1 and 8 in a 21 day-cycle while xeloda will be administered daily at around midnight from day 1 to day 14; Other Names: Eloxatin, Camptosar, CPT-11, Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of the OXIRI regimen as measured by the frequency of significant adverse events incurred by the participants, using CTCAE ver. 4 grading system	The safety and tolerability of the regimen will be assessed when the patient is on treatment and till 30 days after treatment.	from first dose to 30 days after last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) of capecitabine when administered in a continuous chronomodulated fashion with genotype-directed dosing of irinotecan and metronomic dosing of oxaliplatin, using a conventional 3+3 design		2 years
Recommended Phase II dose (RP2D) of the OXIRI regimen which is the MTD		2 years
Pharmacokinetics analysis of capecitabine	Plasma level of capecitabine, its intermediary metabolites (5'-deoxy-5-fluorocytidine [DFCR] and 5'- deoxy-5- fluorouridine [DFUR]) and 5FU will be measured at multiple time points on C1D1	cycle 1 day 1
Pharmacokinetics analysis of Irinotecan	Plasma level of Irinotecan, SN-38 (active metabolite of irinotecan) and SN-38G will be measured at multiple time points on C1D1	cycle 1 day 1
Efficacy of OXIRI as measured by response evaluation criteria in solid tumours (RECIST) version 1.1		3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating tumour cells (CTCs) analysis	CTC characterization, and the changes of CTCs number and their relationship to changes in serum CA19-9 levels, tumour response on imaging etc. will be analysed.	at pre-treatment, Day 1 of each cycle and during response evaluation by imaging

Collaborators and Investigators

• Sponsor: National Cancer Centre, Singapore
• Collaborators: National Medical Research Council (NMRC), Singapore
• Investigators: Principal Investigator: Matthew CH Ng, Dr, National Cancer Centre, Singapore

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2013
• Primary Completion (Actual): May 21, 2020
• Study Completion (Actual): May 21, 2020

Study Registration Dates

• First Submitted: January 29, 2015
• First Submitted That Met QC Criteria: February 15, 2015
• First Posted (Estimate): February 23, 2015

Study Record Updates

• Last Update Posted (Actual): June 1, 2021
• Last Update Submitted That Met QC Criteria: May 28, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Capecitabine; Oxaliplatin; Irinotecan
• Other Study ID Numbers: NCC-13-01