Safety, tolerability, and efficacy of mFOLFIRINOX ±BNT321 as adjuvant therapy following curative resection in patients with pancreatic adenocarcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BioNTech SE

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-02-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BioNTech SE, Mainz, Germany

External identifiers

EU CT number

2023-506014-47-00

ClinicalTrials.gov

NCT06069778

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Dose response, Safety, Pharmacokinetic

For the Phase I part: To assess the safety and identify the recommeded dose for phase II (RP2D) of BNT321 in combination with mFOLFIRINOX as adjuvant therapy in patients with R0 or R1 resected pancreatic ductal adenocarcinoma (PDAC).
For the Phase II part: To assess the efficacy of mFOLFIRINOX + BNT321 versus mFOLFIRINOX alone as adjuvant therapy in PDAC patients post R0 or R1 resection by median disease-free survival (mDFS).

Secondary objectives 7

1. Phase I and II: To further assess the efficacy of mFOLFIRINOX + BNT321 or mFOLFIRINOX as adjuvant therapy in PDAC patients post R0 or R1 resection by overall survival (OS).
2. Phase I and II: To characterize the pharmacokinetics (PK) of BNT321 when coadministered with mFOLFIRINOX.
3. Phase I and II: To characterize immunogenicity of BNT321 when co-administered with mFOLFIRINOX.
4. Phase I and II: To describe the pharmacodynamic (PD) parameters of BNT321 co-administered with mFOLFIRINOX, including Antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
5. Phase I and II: To assess self-reported health-related quality of life (HRQoL) of patients receiving mFOLFIRINOX + BNT321 versus mFOLFIRINOX.
6. For Phase II: To evaluate the safety and tolerability of mFOLFIRINOX with and without BNT321 as adjuvant therapy in patients with R0 or R1 resected pancreatic ductal adenocarcinoma (PDAC).
7. Phase I and II: To further assess the efficacy of mFOLFIRINOX + BNT321 or mFOLFIRINOX as adjuvant therapy in PDAC patients post R0 or R1 resection by RFS and DFS rates.

Conditions and MedDRA coding

Resected (R0 or R1) pancreatic ductal adenocarcinoma

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Has signed the informed consent form (ICF) before initiation of any trial-specific procedures.
2. POCBP who agree to practice a highly effective form of contraception (for guidance on highly effective forms of contraception, see Section 10.5) and to require their male partners to use condoms with a spermicidal agent, starting after signing of the ICF and continuously throughout trial and for a period of 111 days after the last dose of BNT321 and for 9 months after the last oxaliplatin dose. If the highly effective method of contraception is medically contraindicated, then only the use of condoms with a spermicidal agent is acceptable (Section 4.2.3).
3. Full recovery from surgery and able to receive chemotherapy.
4. Has acceptable laboratory parameters including: a) absolute neutrophil count (ANC) ≥1.5x 10E9/L, b) hemoglobin ≥10.0 g/dL, c) platelet count >100,000/mm10E3, d) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0x upper limit of normal range (ULN), e) total bilirubin ≤ULN, f) serum creatinine ≤1.5x ULN or estimated glomerular filtration rate (eGFR) >50 mL/min, g) serum albumin >3.0 g/dL
5. Patient of childbearing potential (POCBP) must have a negative urine beta human chorionic gonadotropin (βhCG) test at screening. Patients that are postmenopausal or permanently sterilized (verified by medical records; for definitions, see Section 10.5) will not be considered POCBP, and therefore are not required to undergo pregnancy testing.
6. Is willing to allow collection of pharmacokinetic samples.
7. POCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting after signing of the ICF and continuously throughout trial and for a period of 3 months after the last dose of BNT321 and for 9 months after the last oxaliplatin dose.
8. Agrees not to enroll in another trial of an investigational medicinal product (IMP), starting after signing of the informed consent form (ICF) and continuously until the last planned visit in this trial.
9. Is >18 years of age or is deemed to be an adult per local authorities at the time of giving written informed consent.
10. Willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions, and other requirements of the trial.
11. Has an ECOG performance status of 0 to 1.
12. Men who are sexually active with a POCBP and have not had a bilateral vasectomy or orchidectomy must agree to use condoms with a spermicidal agent and to require their female partners to practice a highly effective form of contraception during the trial, starting after signing of the ICF and continuously until 111 days after receiving the last dose of BNT321 and for 6 months after the last oxaliplatin dose.
13. Has histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC).
14. Had macroscopically complete resection (R0 or R1 resection) performed between ≥21 and ≤84 days prior to first trial medication (C1D1). Submission of tumor tissue from resection or biopsy is required.
15. Has no radiologic (CT/MRI) evidence of metastatic disease, malignant ascites, or pleural effusion through an assessment obtained within 4 weeks of first trial medication (i.e., C1D1).
16. Men who are willing to refrain from sperm donation, starting after signing of ICF and continuously until 111 days (one sperm cycle) after receiving the last dose of BNT321 and for 6 months after the last oxaliplatin dose.

Exclusion criteria 26

1. Is pregnant or breastfeeding or is planning a pregnancy or to father children during the trial or within 60 days after last treatment with the investigational medicinal product (IMP).
2. Significant cardiovascular risk (past medical history of coronary stenting or myocardial infarction within 6 months, or 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, family history of long QT syndrome).
3. Has pre-existing neuropathy.
4. 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).
5. Homozygous UGT1A1*28 mutation, if testing required by local regulations.
6. Has inflammatory disease of the colon or rectum, or occlusion or sub-occlusion of the intestine or severe post-operative uncontrolled diarrhea.
7. Has used any investigational medicinal product (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.
8. Has a history of seropositivity for human immunodeficiency virus (HIV) with CD4+ T-cell counts <350 cells/μL and a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections.
9. Has 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.
10. 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.
11. 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).
12. Has a history of anaphylactic reactions to human or humanized antibodies.
13. Has serum CA19-9 >180 U/mL within 3 weeks of first treatment with trial medication (C1D1).
14. Incomplete macroscopic tumor removal (R2 resection).
15. Complete dihydropyrimidine dehydrogenase (DPD) deficiency, if testing required by local regulations.
16. Have other known active cancer(s) likely to require treatment in the next 2 years.
17. Had prior radiotherapy or systemic treatment for pancreatic ductal adenocarcinoma (PDAC).
18. Has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic anti-infective therapy that has been administered less than 2 weeks prior to the first dose of BNT321.
19. Is subject to exclusion periods from another investigational trial.
20. Is a vulnerable individual 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.
21. Known hypersensitivity to any of the excipients of the experimental product BNT321.
22. Has a history/positive serology for Hepatitis B requiring active antiviral therapy.
23. Received a live vaccine within 3 weeks prior to the first dose of trial treatment.
24. Patients with a contraindication to receiving mFOLFIRINOX.
25. Patients with active or latent tuberculosis or history of Mycobacterium tuberculosis infection currently or within the last 2 years.
26. Individuals committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. For phase I: The proportion (%) of patients who received at least one dose of investigational medicinal product (IMP) reporting: Incidence and occurrence of treatment-emergent adverse events (TEAEs) including Grade ≥3, serious, fatal TEAE by relationship. Occurrence of DLTs within a cohort during the DLT evaluation period.
2. For phase II: In patients who are randomized into the trial: Disease-free survival (DFS) defined as the time from randomization to occurrence of any of the following: Locoregional recurrence or distant metastasis 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.

Secondary endpoints 7

1. For Phase I and II. In patients who are enrolled/randomized into the trial: Overall survival (OS) defined as the time from first dose of trial treatment to death from any cause.
2. For Phase I and II. In patients who are enrolled/randomized into the trial: 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.
3. For Phase I and II. In patients who are dosed with at least one dose of investigational medicinal product (IMP) and who have evaluable pharmacokinetic (PK) data: PK parameters derived from serum concentration of IMP, including mean AUC, mean Cmax, and median tmax in Cycles 2 and 3 followed by sparse sampling through end of trial (EOT).
4. For Phase I and II. In patients who are dosed with at least one dose of investigational medicinal product (IMP): Percentage of patients with detectable anti-drug antibodies (ADA) formation in Cycles 1 and 3, followed by sparse sampling through end of trial (EOT).
5. For Phase I and II: In all patients who are dosed with at least one dose of investigational medicinal product (IMP): Percentage of patients with detectable and durable antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) in Cycles 2 and 4, followed by sparse sampling through end of trial (EOT).
6. For Phase I and II. In all patients who are dosed with at least one dose of IMP: Change from baseline at end of Cycle 12 for patient-reported health-related quality of life (HRQoL) using EORTC QLQ-C30. Change from baseline at end of Cycle 12 for patient-reported HRQoL using EORTC QLQ-Pan26. Change from baseline at end of Cycle 12 in combined item scores from EORTC QLQ-C30 and EORTC QLQ-Pan26.
7. For Phase II: In patients receiving at least one dose of investigational medicinal product (IMP): Occurrence of treatment-emergent adverse events (TEAEs) within a patient including Grade ≥3, serious, fatal TEAE by relationship. Occurrence of dose reduction and discontinuation of IMP within a patient due to TEAE. Occurrence of abnormal laboratory parameters within a patient.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BioNTech SE

Sponsor organisation

BioNTech SE

Address

An Der Goldgrube 12, Oberstadt Oberstadt

City

Mainz

Postcode

55131

Country

Germany

Scientific contact point

Organisation

BioNTech SE

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

BioNTech SE

Contact name

Clinical Trial Information Desk

Third parties 9

Locations

4 EU/EEA countries · 23 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications