Safety, Tolerability, and Efficacy of mFOLFIRINOX ± BNT321 as Adjuvant Therapy Following Curative Resection in Patients With Pancreatic Adenocarcinoma

This trial is designed as a Phase I/randomized Phase II open-label trial of modified(m) FOLFIRINOX ± BNT321 for adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC) patients post R0 or R1 resection.

The Phase I, dose escalation part of this trial will be a limited evaluation of two planned BNT321 dose levels in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks). Following determination of the combination recommended Phase II dose (RP2D), the Phase II (randomized treatment) part of this trial will be initiated as an open-label 2-arm evaluation of mFOLFIRINOX ± BNT321 (24 weeks) followed by BNT321 monotherapy (24 weeks) in the combination arm only to complete the adjuvant therapy course. Treatment cycles are every 2 weeks (14 days).

The Phase I part of the trial will be a limited dose finding evaluation, whereby a minimal number of BNT321 dose levels will be tested for safety and tolerability in combination with mFOLFIRINOX chemotherapy. Dose escalation will be conducted using a 3+3 design, with up to six additional patients treated at the Phase I defined combination maximum tolerated dose (MTD). Two BNT321 dose levels are initially planned, Dose Level 1 and Dose Level 2. Following evaluation of safety profile for Dose Level 2, additional BNT321 dose levels may be evaluated following safety data review, discussion, and approval by the safety review committee (SRC), and health authority review and approval. Approximately 20 patients will be enrolled into the Phase I part.

Following completion of the dose escalation Phase I and identification of the RP2D, the trial will proceed to a randomized Phase II part. For this part, an independent data monitoring committee will be established prior to the inclusion of the first patient in this phase.

The Phase II part will be a 2-arm, randomization of mFOLFIRINOX ± BNT321, with up to 300 patients enrolled to enable a robust statistical evaluation of the trial's Phase II primary endpoint, i.e., median disease-free survival (mDFS).

Additional evaluations for Phase II will include determination of combination regimen safety and tolerability, determination of overall survival (OS), pharmacokinetic (PK), and pharmacodynamic (PD) analyses including anti-drug antibody (ADA), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) assessments, cytokine and circulating tumor DNA (ctDNA) assessments.

Eligibility Criteria:
Inclusion Criteria:

* Has signed an informed consent form (ICF) before initiation of any trial-specific procedures
* Is \>18 years or age deemed to be an adult per local authorities inclusive, at the time of giving written informed consent
* Willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions, and other requirements of the trial (per investigator assessment, must be capable of understanding and following trial-related instructions)
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
* Has histologically or cytologically confirmed PDAC
* Had macroscopically complete resection (R0 or R1 resection, Royal College of Pathologists \[RCP\] classification) performed between ≥21 and ≤84 days prior to Cycle 1, Day 1 (C1D1). Submission of formalin-fixed paraffin-embedded tissue (FFPE) tumor tissue from resection or biopsy is required
* Has no radiologic (computed tomography/magnetic resonance imaging) evidence of metastatic disease, malignant ascites, or pleural effusion through an assessment obtained within 4 weeks of first trial medication (i.e., C1D1)
* Full recovery from surgery and able to receive chemotherapy
* Has acceptable laboratory parameters.
* Is willing to allow collection of pharmacokinetic samples
* Agree not to enroll in another trial of an IMP, starting after signing of the ICF and continuously until the last planned visit in this trial
* Patients of childbearing potential (POCBP) must not be pregnant. POCBP, male patients who are sexually active with POCBP, and female partners of male patients should use a highly effective method of contraception continuously throughout the trial and for a period of 111 days after the last dose of BNT321 and for 9 months (POCBP) and 6 months (male patients) after the last oxaliplatin dose
* POCB who agree not to donate eggs (ova, oocytes) starting after signing of the ICF and continuously throughout the trial and for a period of 3 months after the last dose of BNT321 and for 9 months after the last oxaliplatin dose
* Men who are willing to refrain from sperm donation, starting after signing of ICF and continuously throughout the trial until 111 days after receiving the last dose of BNT321 and for 6 months after the last oxaliplatin dose

Exclusion Criteria:

* Patients are pregnant or breastfeeding or planning pregnancy or to father children during the trial or within 60 days after last IMP treatment
* A medical, psychological, or social condition which, in the opinion of the investigator, could compromise their wellbeing if they participate in the trial, or that could prevent, limit, or confound the protocol specified assessments or procedures, or that could impact adherence to protocol-described requirements
* Had major surgery within 3 weeks of first dose of the trial treatment, where participation in the trial could compromise the patient's wellbeing in the opinion of the investigator
* Has abnormal electrocardiograms (ECGs) that are clinically significant, such as Fridericia-corrected QT prolongation \>470 msec (for women) and \>450 msec (for men), (average of three ECGs at least 5 minutes apart)
* Has a history of anaphylactic reaction to human, or humanized, antibody
* Have other known active cancer(s) likely to require treatment in the next 2 years
* Had prior radiotherapy or systemic treatment for PDAC
* Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic antiinfective therapy that has been administered less than 2 weeks prior to the first dose of BNT321
* Known hypersensitivity to any of the excipients of the experimental product BNT321
* Known history of seropositivity for human immunodeficiency virus (HIV) with CD4+ T-cell counts \<350 cells/μL and with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections
* Known history/positive serology for Hepatitis B requiring active antiviral therapy (unless immune due to vaccination or resolved natural infection or unless passive immunization due to immunoglobulin therapy; patients with positive serology must have Hepatitis B virus viral load below the limit of quantification)
* Active Hepatitis C virus infection (patients who have completed curative antiviral treatment with Hepatitis C virus viral load below the limit of quantification are allowed)
* Use of any IMP or device within 21 days before administration of first dose of trial treatment or ongoing participation in the active treatment phase of another interventional clinical trial
* Is subject to exclusion periods from another investigational trial
* Are vulnerable individuals as per ICH E6 definition, i.e., individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.
* Serum CA19-9 \>180 U/mL within 3 weeks of C1D1
* Incomplete macroscopic tumor removal (R2 resection)
* Significant cardiovascular risk (past medical history of coronary stenting or myocardial infarction within 6 months, or New York Heart Association (NYHA) Class III/IV, heart failure, or concurrent unstable angina) or risk factors for QT prolongation (sustained Grade 3 or higher hypokalemia, history of unstable arrhythmia or family history of long QT syndrome)
* Pre-existing neuropathy
* Homozygous UDP glucuronosyltransferase family 1 member A1 (UGT1A1)\*28 mutation, if testing required by local regulations
* Inflammatory disease of the colon or rectum, or occlusion or sub-occlusion of the intestine or severe post-operative uncontrolled diarrhea
* Complete dihydropyrimidine dehydrogenase deficiency, if testing required by local regulations
* Received a live vaccine within 3 weeks prior to the first dose of trial treatment
* Patients with a contraindication to receiving mFOLFIRINOX
* Patients with active or latent tuberculosis or history of Mycobacterium tuberculosis infection currently or within the last 2 years
* Individuals committed to an institution by virtue of an order issued either by the judicial or the administrative authorities