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

Study Overview
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Brief Summary
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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).

Detailed Description
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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). Following completion of the dose escalation Phase I and identification of the RP2D, the trial will proceed to a randomized Phase II part. 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.

Official Title
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A Phase I/Randomized Phase II, Open-label Multicenter Trial to Evaluate the Safety, Tolerability, and Efficacy of mFOLFIRINOX With or Without BNT321 as Adjuvant Therapy Following Curative Resection in Patients With Pancreatic Adenocarcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: BNT321 Dose Level 1
* Drug: BNT321 Dose Level 2
* Drug: mFOLFIRINOX
* Drug: BNT321 RP2D


Participation Criteria
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Eligibility Criteria
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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 90 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 90 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 >480 msec (US National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE v5.0] Grade 2) 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) Pre-existing neuropathy Known homozygous for UGT1A1*28 mutation Inflammatory disease of the colon or rectum, or occlusion or sub-occlusion of the intestine or severe post-operative uncontrolled diarrhea Known complete dihydropyrimidine dehydrogenase (DPD) deficiency

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - BNT321 Dose Level 1 + mFOLFIRINOX<br>BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks) | Drug: BNT321 Dose Level 1<br>* Intravenous infusion<br>Drug: mFOLFIRINOX<br>* Intravenous infusion<br>|
| Experimental: Phase 1- BNT321 Dose Level 2 + mFOLFIRINOX<br>BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks) | Drug: BNT321 Dose Level 2<br>* Intravenous infusion<br>Drug: mFOLFIRINOX<br>* Intravenous infusion<br>|
| Experimental: Phase 2 - BNT321 RP2D + mFOLFIRINOX<br>BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks) | Drug: mFOLFIRINOX<br>* Intravenous infusion<br>Drug: BNT321 RP2D<br>* Intravenous infusion<br>|
| Active Comparator: Phase 2 - mFOLFIRINOX<br>mFOLFIRINOX chemotherapy (24 weeks) as monotherapy | Drug: mFOLFIRINOX<br>* Intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 - The proportion (%) of patients with at least one dose of investigational medicinal product (IMP) reporting treatment emergent adverse events (TEAEs) | TEAEs including Grade ≥3, serious, fatal TEAE by relationship. | up to 12 months | 
| Phase 1 - The proportion (%) of patients with at least one dose of IMP reporting occurrence of dose limiting toxicities (DLTs) |  | up to 42 days after first dose of BNT321 | 
| Phase 2 - Disease-free survival (DFS) | DFS is defined as the time from randomization to occurrence of any of the following events, whichever occurs first: Locoregional recurrence or distant metastases as determined by an independent central radiology assessment. Occurrence of second primary (same or other) cancer as determined by an independent central radiology assessment. Death from any cause. | up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and 2 - OS | OS is defined as the time from first dose of trial treatment to death from any cause. | up to 60 months | 
| Phase 1 and 2 - Relapsed free survival (RFS) | RFS is defined as the time from randomization to occurrence of any of the following events, whichever occurs first: Locoregional recurrence or distant metastasis as determined by the investigator. Death from any cause. | up to 60 months | 
| Phase 1 and 2 - PK assessments: Mean Area under the curve (AUC) values derived from serum concentration of IMP | Mean AUC from patients who are dosed with at least one dose of IMP and who have evaluable PK data in Cycles 2 and 3 followed by sparse sampling through end of trial (EOT). | up to 48 weeks | 
| Phase 1 and 2 - PK assessments: Mean observed maximum concentration (Cmax) derived from serum concentration of IMP | Mean Cmax from patients who are dosed with at least one dose of IMP and who have evaluable PK data in Cycles 2 and 3 followed by sparse sampling through EOT. | up to 48 weeks | 
| Phase 1 and 2 - PK assessments: Median time to reach Cmax (tmax) derived from serum concentration of IMP | Median tmax from patients who are dosed with at least one dose of IMP and who have evaluable PK data in Cycles 2 and 3 followed by sparse sampling through EOT. | up to 48 weeks | 
| Phase 1 and 2 - Percentage of patients with detectable anti-drug antibody (ADA) | Percentage of patients who are dosed with at least one dose of IMP and with detectable ADA formation in Cycles 1 and 3, followed by sparse sampling through EOT | up to 48 weeks | 
| Phase 1 and 2 - Percentage of patients with detectable and durable ADCC and/or CDC activity | Percentage of patients who are dosed with at least one dose of IMP with detectable and durable (measurable throughout time on trial) ADCC and/or CDC activity in Cycles 2 and 4, followed by sparse sampling through EOT | up to 48 weeks | 
| Phase 1 and 2 - Change from baseline for patient-reported health-related quality of life (HRQoL) using the European organisation for research and treatment of cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) | Change from baseline at end of Cycle 12 for patient-reported HRQoL using EORTC QLQ-C30 | up to 60 months | 
| Phase 1 and 2 - Change from baseline for patient-reported HRQoL using EORTC Quality of Life Questionnaire for pancreatic cancer (QLQ-Pan26) questionnaires | Change from baseline at end of Cycle 12 for patient-reported HRQoL using EORTC QLQ-Pan26 questionnaires | up to 60 months | 
| Phase 1 and 2 - Change from baseline in combined item scores from EORTC QLQ-C30 | Change from baseline at end of Cycle 12 in combined item scores from EORTC QLQ-C30 | up to 60 months | 
| Phase 1 and 2 - Change from baseline in combined item scores from EORTC QLQ-Pan26 | Change from baseline at end of Cycle 12 in combined item scores from EORTC QLQ-Pan26. | up to 60 months | 
| Phase 2 - Occurrence of TEAEs including Grade ≥3, serious, fatal TEAE by relationship |  | up to 12 months | 
| Phase 2 - Occurrence of dose reduction and discontinuation of IMP due to TEAE | Occurrence within a patient. | up to 12 months | 
| Phase 2 - Occurrence of abnormal laboratory parameters | Occurrence within a patient. | up to 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CA19-9 Positive Malignancies, Pancreatic Cancer and other CA19-9 expressing malignancies, Pancreatic Ductal Adenocarcinoma (PDAC), Sialyl Lewis A (sLea)