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execution of GBM AGILE can inform future clinical trials in pancreatic cancer, as the two diseases have
similarly low incidence rates and extremely poor survival rates.

SM
Precision Promise (NCT04229004), sponsored by the Pancreatic Cancer Action Network (PanCAN),
opened to recruitment in 2020 at 12 sites and is currently expanding to 30 sites. It is a phase II/III
responsive adaptive clinical trial for patients with metastatic pancreatic adenocarcinoma in the first or
second line of treatment. Like GBM-AGILE and I-SPY 2, the Bayesian adaptive statistical design of
Precision Promise is powered by Berry Consultants. In addition to screening and confirmatory trial stages
to allow for the development of a registration packet, this trial adds a feature of re-randomization to eligible
patients who enrolled in Precision Promise prior to treatment and whose first-line treatment within the trial
is unsuccessful. Precision Promise is designed to continuously evaluate multiple experimental arms (70%)
vs. two control arms (15% gemcitabine+nab-paclitaxel or 15% mFOLFIRINOX) in patients with metastatic
pancreatic adenocarcinoma. The primary endpoint is overall survival. Compared to traditional trial designs,
Precision Promise offers several advantages: multiple investigational treatments can be evaluated in parallel
over time; only ~175 patients per experimental arm are required to initiate a regulatory registration; and
increased learning from every patient during the trial, altogether resulting in both time-saving and a 30%-
50% cost saving. In addition to evaluating the efficacy of investigational treatments, Precision Promise
incorporates innovative supportive care measures like actigraphy to prioritize patients’ quality of life and
includes additional clinical parameters to test within the trial. In effect, Precision Promise has created an
entirely new “learning community” and can substantially accelerate drug development for pancreatic
adenocarcinoma.

Pioneer-Panc (NCT04481204) is a platform trial for randomized phase II investigations in localized
[35]
pancreatic adenocarcinoma that is soon to be underway . Using a Bayesian platform design to evaluate
multiple experimental arms against a control arm, Pioneer-Panc focuses on patients with resectable,
borderline resectable, and locally advanced disease and further divides each stage group based on treatment
history (treatment naïve or previously treated). Within each cohort, adaptive randomization rules are
applied and patients will be randomized to either an experimental arm or the control arm accordingly.
Experimental arms may be added independently to one or more cohorts during the study, and multiple
correlative studies for tissue, blood, and imaging are incorporated.

CONCLUSION AND FUTURE DIRECTIONS
There is considerable momentum in the pancreatic cancer field after a long period during which there were
minimal advances in the standard of care. As Table 1 shows, there were five advances in the standard of care
for pancreatic adenocarcinoma in the 20 years between 1995 and 2015, whereas nine approvals or advances
were recorded in the seven years between 2015 and 2022, albeit for a small number of patients. The field is
galvanized for even greater acceleration of progress over the next decade by the addition of several
innovative trials that gather and focus the expertise of many investigators on the recalcitrant problem of
pancreatic cancer treatment. These studies range from observational studies such as COMPASS that seek to
better understand how the molecular underpinnings of pancreatic adenocarcinoma impact treatment, to
phase I and Ib/II signal-seeking trials such as REVOLUTION and Morpheus with a focus on
immunotherapy development, to the highly flexible Precision-Panc master protocol that allows the addition
of PRIMUS sub-studies for many different sub-populations of pancreatic adenocarcinoma, to the phase II
Pioneer-Panc focused on localized pancreatic adenocarcinoma and the ambitious Precision Promise phase
II/III trial designed to de-risk and accelerate progress for FDA approval for new standards of care for
metastatic pancreatic adenocarcinoma. The field has embraced the Master Protocol concept and banded
[10]
together to rise to the challenge. There is considerable optimism that the next decade of clinical research will