TIming of start of systemIc treatment for asymptomatic MEtastasized
PANcreatic cancer (TIMEPAN): a prospective multicenter patient preference cohort.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadliest forms of
cancer with a 5-year survival of less than 5% for patients with metastatic
disease. Since the introduction of gemcitabine several decades ago, advances in
therapy of metastatic disease have been slow. Numerous phase III studies have
evaluated different gemcitabine-based regimens as first-line treatment, but in
most cases, observed benefits have been small and restricted to patients with a
good performance status. A significant breakthrough for patients with
metastatic disease was achieved with the FOLFIRINOX regimen (5-fluorouracil,
folinic acid, oxaliplatin and irinotecan) and the combination of nab-paclitaxel
and gemcitabine. Both chemotherapy combination schedules demonstrated a
significant survival improvement compared to gemcitabine alone. However,
despite these improvements, the vast majority of patients will have disease
recurrence or progression within 6 months. Moreover, chemotherapy is at the
cost of substantial toxicity.

Not every patient diagnosed with pancreatic cancer has disease-related symptoms
at initial presentation. Metastatic disease could be diagnosed incidentally or
during routine follow-up visits after a previous diagnosis and resection of
resectable pancreatic cancer. If it turns out that patients with asymptomatic
metastatic pancreatic cancer are incurable, the start of palliative systemic
treatment could be at initial presentation, or could be delayed until
disease-related symptoms occur. Whether starting palliative systemic therapy
immediately after diagnosis has survival benefit and weighs up against the
potential side effects is currently under debate, and will be investigated in
this trial.

Rationale
Prolonging life and improving or maintaining quality of life are the main goals
of palliative systemic treatment in patients with metastatic pancreatic cancer.
It has yet to be determined as to when to commence chemotherapy during the
disease course in patients with asymptomatic metastatic disease. Since patients
with metastatic pancreatic cancer have a limited life expectancy, it is
important to determine the timing of start of chemotherapy in order to optimise
the benefits of chemotherapy relative to the side effects. Typically, patients
who start with systemic therapy experience an initial decrease in quality of
life. Especially in patients without symptoms there is little to gain. So, one
could argue to start chemotherapy only in case of symptoms. In this way,
quality of life may improve again if treatment proves effective. On the other
hand, starting chemotherapy immediately after diagnosis could maximize survival
benefit since disease control may be more difficult to achieve once tumor
burden has increased over time.

Primary objective:
To assess the effect of immediate versus delayed start of chemotherapy on
quality adjusted survival in patients with metastatic pancreatic cancer.

Secondary Objectives:
To determine time to disease progression after randomization
To determine the adverse events according to NCI CTC version 5.0

Exploratory Objectives:
To determine change in CA 19.9

This is a prospective multicenter patient preference cohort study to compare
immediate treatment (to begin within 3 weeks of date of diagnosis) or treatment
delayed until development of symptoms in patients with metastatic pancreatic
cancer.

The treatment schedule will be either FOLFIRINOX or nab paclitaxel in
combination with gemcitabine per investigator*s choice, or delayed treatment
with FOLFIRINOX or nab paclitaxel in combination with gemcitabine per
investigator*s choice.

For patients that will start with delayed treatment based on symptoms,
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

The regimen of FOLFIRINOX consists of oxaliplatin at a dose of 85 mg/m2, given
as a 2-hour i.v. infusion, immediately followed by leucovorin at a dose of 400
mg/m2, given as a 2-hour i.v. infusion, with the addition, after 30 minutes, of
irinotecan at a dose of 180 mg/m2, given as a 90-minute i.v. infusion. This
treatment will immediately be followed by fluorouracil at a dose of 400 mg/m2,
administered by i.v. bolus, followed by a continuous i.v. infusion of 2400
mg/m2 over a 46-hour period. This regimen will be repeated every 2 weeks
The combination of nab-paclitaxel and gemcitabine consist of nab paclitaxel at
a dose of 125 mg/m2, given as a 30 minute infusion, followed by gemcitabine at
a dose of 1000 mg/m2, given as a 30 minute infusion. Both chemotherapeutic
agents will be administered on days 1, 8 and 15 of a 4 week cycle.
Tumor response and progression will be assessed using RECIST version 1.1
criteria. Imaging assessments will be conducted by computed tomography [CT]
scans and/or Magnetic Resonance Imaging [MRI]. Tumor assessment will be
performed every 2 months.
Toxicities will be graded by the Investigator using the National Cancer
Institute (NCI) Common CTCAE Version 5.0 (appendix 2).
The end of the study is defined by the final QoL analysis.

- FOLFIRINOX; a combination of oxaliplatin, leucovorin, irinotecan and
fluorouracil every 2 weeks

or

- Gemcitabine + nab paclitaxel weekly for 3 weeks, every 4 weeks

Postponing chemotherapy can have a negative effect on disease control and tumor
burden. In addition to treatment patients have to fill out questionnaires to
gain insight in the quality of life.