Clinical trial NCT02368860: OXIRI [Oxaliplatin (O), Xeloda (X) and Irinotecan (I)] in Pancreatic Adenocarcinoma
Official title: Phase I Trial of OXIRI [Oxaliplatin (O), Xeloda (X) and Irinotecan (I)] Treatment in Patients With Advanced and/or Metastatic Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pancreatic Cancer
Lead sponsor: National Cancer Centre, Singapore
Sponsor class: OTHER
Collaborators: name: National Medical Research Council (NMRC), Singapore
First posted: 2015-02-23
Enrollment: 33
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: from first dose to 30 days after last dose
Secondary outcomes:
measure: 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
timeFrame: 2 years
measure: Recommended Phase II dose (RP2D) of the OXIRI regimen which is the MTD
timeFrame: 2 years
measure: Pharmacokinetics analysis of capecitabine
timeFrame: cycle 1 day 1
measure: Pharmacokinetics analysis of Irinotecan
timeFrame: cycle 1 day 1
measure: Efficacy of OXIRI as measured by response evaluation criteria in solid tumours (RECIST) version 1.1
timeFrame: 3 years
Other outcomes:
measure: Circulating tumour cells (CTCs) analysis
timeFrame: at pre-treatment, Day 1 of each cycle and during response evaluation by imaging
Locations:
city: Singapore
country: Singapore
facility: National Cancer Centre
Study officials:
affiliation: National Cancer Centre, Singapore
name: Matthew CH Ng, Dr
role: PRINCIPAL_INVESTIGATOR
References: