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

Phase 1

Completed

• Conditions: Pancreatic Cancer
• Interventions: Drug: oxaliplatin, irinotecan, capecitabine

• Registration Number: NCT02368860
• Lead Sponsor: National Cancer Centre, Singapore

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.

Study Timeline

• Study Start: 2013-09-17
• Study First Submitted: 2015-01-29
• Study First Submitted QC: 2015-02-15
• Study First Posted: 2015-02-23
• Primary Completion: 2020-05-21
• Study Completion: 2020-05-21
• Status Verified: 2021-05
• Last Update Submitted: 2021-05-28
• Last Update Posted: 2021-06-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 33

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
OXIRI	oxaliplatin, irinotecan, capecitabine	OXIRI regimen: oxaliplatin, irinotecan, capecitabine

Primary Outcome Measures

Name	Time	Method
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	from first dose to 30 days after last dose	The safety and tolerability of the regimen will be assessed when the patient is on treatment and till 30 days after treatment.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics analysis of capecitabine	cycle 1 day 1	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
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
Efficacy of OXIRI as measured by response evaluation criteria in solid tumours (RECIST) version 1.1	3 years
Recommended Phase II dose (RP2D) of the OXIRI regimen which is the MTD	2 years
Pharmacokinetics analysis of Irinotecan	cycle 1 day 1	Plasma level of Irinotecan, SN-38 (active metabolite of irinotecan) and SN-38G will be measured at multiple time points on C1D1

Trial Locations

Locations (1)

National Cancer Centre; 🇸🇬 Singapore, Singapore