Timing of Start of systemIc Treatment for Asymptomatic Metastasized Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
Since patients with metastatic pancreatic cancer have a limited life expectancy, it is important to determine the timing of when to start chemotherapy in order to optimize the benefits of chemotherapy relative to the side effects. Therefore, two treatment strategies can be considered: chemotherapy started immediately at diagnosis, or delayed until disease-related symptoms occur.

Official Title
-----------------
TIming of Start of systemIc Treatment for Asymptomatic MEtastasized PANcreatic Cancer (TIMEPAN): a Randomized Controlled Multicenter Trial

Conditions
-----------------
Metastatic Pancreas Cancer

Intervention / Treatment
-----------------
* Drug: Folfirinox


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed, written Institutional Review Board/Ethics Committee-approved Informed Consent Form (ICF). Patients with histologically/cytological confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma. Measurable disease on computed tomography (CT) scan per RECIST version 1.1 criteria. Eastern Cooperative Oncology Group Performance Status of 0-1 Life expectancy ≥ 3 months. Age ≥ 18 years. A negative urine or serum pregnancy test within 7 days before Day 1 (first dose of study medication) if female subject is of childbearing potential. Screening clinical laboratory values as follows: Absolute neutrophil count > 1.5 x 109 /L Total bilirubin ≤ 1.5 times upper limit of normal (ULN). Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 times ULN, (if liver metastases are present, then ≤ 5 times ULN is allowed). Serum creatinine < 1.5 x ULN or creatinine clearance >50 mL/min/1.73 m2 Prothrombin time/international normalized ratio within normal limits (± 15%) or within therapeutic range if subject takes warfarin. Partial thromboplastin time (PTT) within normal limits (± 15%). Platelet count > 100,000 x 109 /L No symptoms related to advanced disease, specified as: no pain requiring regular narcotic analgesics; no weight loss over 5 kg (unless related to surgery or other illness); no persistent nausea requiring medication; no obstructive bowel symptoms; no persistent fever related to metastatic cancer; no other symptom which in the opinion of the clinician was due to progressive metastatic cancer. No prior chemotherapy for metastatic disease (patients might have received adjuvant treatment more than 6 months before the development of metastatic disease, or neoadjuvant treatment before surgery for resectable disease) Exclusion Criteria: Known central nervous system involvement or brain metastases. New York Heart Association Class III or IV cardiac disease or myocardial infarction within the past 12 months Any other disease, active, uncontrolled bacterial, viral or fungal infection requiring systemic therapy, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or that may render the subject at high risk for treatment complications. Inability to comply with study and follow-up procedures as judged by the Investigator. Women currently pregnant or breastfeeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Immediate treatment<br>The treatment schedule will be direct (start within 3 weeks of bate of diagnosis) FOLFIRINOX or nab paclitaxel in combination with gemcitabine per investigator's choice. Dosage and frequency of administration will be according to local protocol. | Drug: Folfirinox<br>* In both arms the intervention will be FOLRINIOX or nab paclitaxel in combination with gemcitabine per investigator's choice<br>|
| Active Comparator: Delayed treatment<br>The treatment schedule will be delayed treatment (based on symptoms) with FOLFIRINOX or nab paclitaxel in combination with gemcitabine per investigator's choice. Dosage and frequency of administration will be according to local protocol. Chemotherapy will start as soon as one of the following criteria is met: Decline in performance status to ECOG < 1 or Karnofsky < 80% Weight loss more than 5% of the total body weight from the time of study entry Persistent nausea requiring medication Pain requiring regular narcotic analgesics Development of clinically significant third-space fluid collections Liver function deterioration in the presence of progressive liver metastases | Drug: Folfirinox<br>* In both arms the intervention will be FOLRINIOX or nab paclitaxel in combination with gemcitabine per investigator's choice<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality adjusted overall survival | Measured in utility-per-month, using the survival in months and the monthly reported quality of life by the EQ-5D-5L questionaire. | From date of randomization until the date of death, assessed up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to disease progression | Restricted mean progression free survival (RM-PFS): are under the Kaplan-Meier PFS curve between randomization and follow-up of the study (estimated 12 months) | 12 months | 
| Quality adjusted progression free survival (PFS) |  | From date of randomization until the date of death, assessed up to 12 months | 
| Duration of time without symptoms of disease progression or toxicities (TWiST) |  | From date of randomization until the date of death, assessed up to 12 months | 
| Overall survival | (In months) | From date of randomization until the date of death, assessed up to 12 months | 
| Number of patients with adverse events | According to NCI CTC version 5.0 | From date of randomization until the date of death, assessed up to 12 months |