PANTHEON

Pancreatic cancer is a deadly neoplasm with more than 95% of patients affected dying of their disease. Chemotherapy represents the standard of care for both unresectable locally advanced and metastatic PDAC, with Gemcitabine + Nab-Paclitaxel and mFOLFIRINOX being standard of care for first line treatment since 2013. First-line treatment is generally continued until the progression of the disease, although this is associated with a gradual rise in toxicity over time and the development of mechanisms by which the tumor resists therapy and reduces its effectiveness. Therefore, the early administration of a active, non-cross resistant treatment after first-line therapy, before disease progression, might prolong the benefit of first-line treatment and could delay clinical deterioration, rescuing all those subjects that become ineligible for a second-line therapy.

Key Inclusion criteria

1. Subjects must be ≥18 years.
2. Histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic adenocarcinoma eligible for treatment in the first-line setting.
3. ECOG PS 0/1, If age ≥70 years, ECOG PS must be 0
4. Adequate organ function as per protocol
5. Estimated life expectancy > 3 months.
6. Presence of measurable or non-measurable disease assessed by CT scan and/or MRI according to RECIST 1.1
7. Availability of archival tumor sample (primary tumor or metastatic site) for biomarker analysis.
8. No presence of complete dihydropyrimidine dehydrogenase (DPYD) enzyme deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT) with DPYD gene testing mandatory at screening as per national guidelines. UDP-glucuronosyltransferase 1A1 (UGT1A1) testing is not mandatory. However, if UGT test is routinely performed in the participating centers, enrolment of patients carriers of variants of DPYD and homozygous variant UGT1A1 [7/7] has to be discussed with the Sponsor.

Key Inclusion criteria (after induction)

1. Patient must have received a minimum of 4 mFOLFIRINOX administrations during the induction phase.
2. Complete/partial response or stable disease (CR/PR/SD) or without evidence of progressive disease (PD) in case of non-measurable disease after 3 months (i.e. up to 14 weeks, corresponding to ~6 cycles) of mFOLFIRINOX induction chemotherapy.

Key Exclusion criteria

1. Pancreatic neuroendocrine, acinar, squamous/adenosquamous, or islet tumors.
2. Previous or concurrent systemic (e.g. cytotoxic or targeted or other experimental drugs) therapy for advanced pancreatic adenocarcinoma
3. Major surgery or radiation therapy performed within <4 weeks before randomization.
4. Known allergy or hypersensitivity to study drugs and/or their excipients.
5. Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that requires directed therapy (such as radiotherapy or surgery) or increasing doses of corticosteroids 2 weeks prior to study entry.
6. Any known additional malignancy that is progressing or requires active treatment
7. Any serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial.

PANTHEON is a no-profit, multicentre, randomized phase III trial aimed at improving clinical practice by investigating whether switching first-line treatment to Gem-NabP after a mFOLFIRINOX-based 3 months induction may improve patients’ OS and tolerability as compared with mFOLFIRINOX continuation.

Primary endpoint: Overall Survival (OS)

Key secondary endpoints:
Progression Free Survival (PFS), Time to treatment failure (TTF), Overall response rate (ORR), Quality of life (QoL) and Toxicity