Gemcitabine plus nab-PAclitaxel as switch maiNTEnance versus cONtinuation of modified FOLFIRINOX as first-line chemotherapy in patients with advanced pancreatic cancer: the PANThEON phase III Trial

Prior treatment

• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA > II, unstable angina pectoris, history of myocardial infarction within 3 months before study entry, significant arrhythmia).
• Previous or concurrent systemic (eg cytotoxic or targeted or other experimental drugs) therapy for advanced pancreatic adenocarcinoma. Note: previous (neo)adjuvant or perioperative anti-cancer therapy for non-metastatic, resectable or borderline resectable PDAC, associated with surgery on the primary tumor, is allowed if ≥ 9 months have elapsed from the last dose of therapy and documented disease progression or relapse.
• Major surgery or radiation therapy performed within ≤4 weeks before randomization. Palliative radiotherapy to bone lesions is allowed if performed ≥ 2 weeks prior to start of study treatment. Patients must have recovered from any effect from major surgery.
• Unresolved toxicity ≥ CTCAE grade 2 attributed to any prior therapies (e.g. grade ≥2 peripheral neurotoxicity), excluding anemia or alopecia.
• 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. Participants with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study entry.
• Chronic or current active infectious disease requiring systemic antibiotics or antifungal treatment within 2 weeks prior to enrollment.

Other illness

• Presence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent.
• Any serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial.
• Known allergy or hypersensitivity to study drugs and/or their excipients.
• Any known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years prior to study entry except for curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer.
• Know active uncontrolled hepatitis B or hepatitis C. Patients with a past or resolved HBV infection are eligible. Patients with chronic disease controlled by antiviral therapy or requiring prophylactic treatment are eligible.

Lab values

• Known uncontrolled HIV infection. HIV-positive patients are eligible if their CD4+ cell count amounts to 300 cells per μL or more; HIV viral load must be undetectable per standard of care assay, and they must be compliant with antiretroviral treatment.

Other

• Pancreatic neuroendocrine, acinar, squamous/adenosquamous, or islet tumors.
• Pregnant or breast-feeding patient, or patient planning to become pregnant within 7 months after the end of treatment.

• Patient able and willing to provide written informed consent and to comply with the study protocol.
• Adequate renal function, i.e. serum creatinine ≤ 1.5 x institutional ULN and calculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 50 mL/min.
• Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy).
• 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. See Appendix VI of the full protocol for details.
• Women of childbearing potential must agree to remain abstinent (refrain from sexual intercourse) or use highly effective contraceptive methods, as defined in Appendix V of the full protocol, during the treatment period and for at least 7 months after the last administration of study treatments.
• Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause.
• Men must agree to remain abstinent (refrain from sexual intercourse) or use highly effective contraceptive methods, as defined in Appendix V of the full protocol, during the treatment period and for at least 7 months after the last administration of study treatments.
• Participants must agree not to donate eggs/sperm for future use for the purposes of assisted reproduction during the study and for a period of 7 months after receiving the last dose of study treatment. Female and male participants should consider preservation of eggs/sperm prior to study treatment as anti-cancer treatments may impair fertility.
• Subjects must be ≥18 years.
• Histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic adenocarcinoma eligible for treatment in the first-line setting.
• Presence of measurable or non-measurable disease assessed by CT scan and/or MRI according to RECIST 1.1 (Appendix I of the protocol). Note: any lesion which has been subjected to percutaneous therapies or radiotherapy should not be considered measurable, unless the lesion has clearly progressed since the procedure.
• Availability of archival tumor sample (primary tumor or metastatic site) for biomarker analysis.
• ECOG performance status of 0-1 (if age < 70 years). If age ≥70 years, ECOG PS must be 0.
• Estimated life expectancy > 3 months.
• Adequate baseline hematologic function characterized by the following at screening: a. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L b. platelets count ≥ 100 × 109/L c. hemoglobin ≥ 9 g/dl. Note: prior transfusions for patients with low hemoglobin are allowed.
• Adequate liver function characterized by the following at screening:a. Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL. Note: Subjects with Serum total bilirubin ≥ 1.5 × ULN and conjugated bilirubin ≤ ULN or < 40% of total bilirubin are allowed. b. Serum transaminases (AST and/or ALT) < 3 x ULN (< 5 x ULN in presence of liver metastasis). In participants with elevated AST or ALT, the values must be stable for at least 2 week and with no evidence of biliary obstruction by imaging.