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
Overview
- Phase
- Phase 1
- Intervention
- BNT321 0.5 mg/kg
- Conditions
- Pancreatic Cancer
- Sponsor
- BioNTech SE
- Enrollment
- 1
- Locations
- 2
- Primary Endpoint
- Phase 1 - The Number and Percentage of Participants With at Least One Dose of Investigational Medicinal Product (IMP) Reporting Treatment Emergent Adverse Events (TEAEs)
- Status
- Terminated
- Last Updated
- 6 months ago
Overview
Brief Summary
This study was designed as a Phase 1/randomized Phase 2 open-label study of modified(m) FOLFIRINOX ± BNT321 for adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC) patients post R0 or R1 resection.
The Phase 1, dose escalation part of this study was planned to be a limited evaluation of two planned BNT321 dose levels (DLs) in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks). Following completion of the dose escalation Phase 1 and identification of the recommended Phase 2 dose (RP2D), the study was designed as a 2-arm, randomized Phase 2 of mFOLFIRINOX ± BNT321 to evaluate the efficacy of mFOLFIRINOX + BNT321 versus mFOLFIRINOX alone as adjuvant therapy in PDAC patients post R0 or R1 resection. Treatment cycles were every 2 weeks (14 days).
Detailed Description
The Phase 1 part of the study was planned to be a limited dose finding evaluation, whereby a minimal number of BNT321 DLs were planned to be tested for safety and tolerability in combination with mFOLFIRINOX chemotherapy. Dose escalation was planned to be conducted using a 3+3 design, with up to six additional participants treated at the Phase 1 defined combination maximum tolerated dose (MTD). Two BNT321 DLs were initially planned, 0.5 mg/kg and a second DL 2. Following evaluation of safety profile for DL 2, additional BNT321 DLs could have been evaluated following safety data review, discussion, and approval by the safety review committee (SRC), and health authority review and approval. Approximately 20 participants were planned to be enrolled into the Phase 1 part. Following completion of the dose escalation Phase 1 and identification of the RP2D, the study was planned to proceed to a randomized Phase 2 part. For this part, an independent data monitoring committee was planned to be be established prior to the inclusion of the first participant in this phase. The randomized Phase 2 was designed to enroll up to 300 participants to enable a robust statistical evaluation of the study's Phase 2 primary endpoint, i.e., median disease-free survival (mDFS). Additional evaluations for Phase 2 were planned to 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. The study was terminated early by the sponsor due to strategic reprioritization and not due to safety concerns. At the time of the termination, only one dose level (i.e., 0.5 mg/kg) of BNT321 was tested.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Has signed an informed consent form (ICF) before initiation of any study-specific procedures
- •Was \>18 years or age deemed to be an adult per local authorities inclusive, at the time of giving written informed consent
- •Were willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions, and other requirements of the study (per investigator assessment, must been capable of understanding and following study-related instructions)
- •Had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- •Had 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 was required
- •Had 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 study medication (i.e., C1D1)
- •Full recovery from surgery and able to receive chemotherapy
- •Had acceptable laboratory parameters
- •Was willing to allow collection of pharmacokinetic samples
Exclusion Criteria
- •Participants were pregnant or breastfeeding or planning pregnancy or to father children during the study or within 60 days after last IMP treatment
- •A medical, psychological, or social condition which, in the opinion of the investigator, could have compromised their wellbeing if they participated in the study, or that could have prevented, limited, or confounded the protocol specified assessments or procedures, or that could have impacted adherence to protocol-described requirements
- •Had major surgery within 3 weeks of first dose of the study treatment, where participation in the study could have compromised the participant's wellbeing in the opinion of the investigator
- •Had abnormal electrocardiograms (ECGs) that were 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)
- •Had a history of anaphylactic reaction to human, or humanized, antibody
- •Have had 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
Arms & Interventions
Phase 1 - BNT321 0.5 mg/kg + mFOLFIRINOX
BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks)
Intervention: BNT321 0.5 mg/kg
Phase 1 - BNT321 0.5 mg/kg + mFOLFIRINOX
BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks)
Intervention: mFOLFIRINOX
Phase 1 - BNT321 DL 2 + mFOLFIRINOX
BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks)
Intervention: BNT321 DL 2
Phase 1 - BNT321 DL 2 + mFOLFIRINOX
BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks)
Intervention: mFOLFIRINOX
Phase 2 - BNT321 RP2D + mFOLFIRINOX
BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks)
Intervention: mFOLFIRINOX
Phase 2 - BNT321 RP2D + mFOLFIRINOX
BNT321 in combination with mFOLFIRINOX chemotherapy (24 weeks) followed by BNT321 monotherapy (24 weeks)
Intervention: BNT321 RP2D
Phase 2 - mFOLFIRINOX
mFOLFIRINOX chemotherapy (24 weeks) as monotherapy
Intervention: mFOLFIRINOX
Outcomes
Primary Outcomes
Phase 1 - The Number and Percentage of Participants With at Least One Dose of Investigational Medicinal Product (IMP) Reporting Treatment Emergent Adverse Events (TEAEs)
Time Frame: from the start of study drug treatment until the end of study (i.e., 164 days)
TEAEs graded per Common Toxicity Criteria for Adverse Events version 5.0 (CTCAE v5.0), including Grade ≥3, serious, fatal TEAE by relationship.
Phase 1 - The Number and Percentage of Participants With at Least One Dose of IMP Reporting Occurrence of Dose Limiting Toxicities (DLTs)
Time Frame: up to 28 days after first dose of BNT321
For all Phase I cohorts the DLT assessment period was planned to encompass the treatment cycles of the first two consecutive BNT321 doses, i.e., 28 days within treatment Cycles 2 and 3. To be considered a DLT, an AE must have met the following three criteria: * Occurred during the DLT assessment period of BNT321. * Was considered BNT321-related (i.e., definitely related or possibly related). * Occurred in the presence of adequate supportive care (e.g., Grade 3 vomiting despite use of an appropriate anti-emetic regimen). In addition, to be considered a DLT, an AE must have met at least one of the additional criteria using CTCAE v5.0 as specified in the protocol.
Phase 2 - Disease-free Survival (DFS)
Time Frame: up to 60 months
DFS was 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.
Secondary Outcomes
- Phase 1 and 2 - OS(up to 60 months)
- Phase 1 and 2 - Relapsed Free Survival (RFS)(up to 60 months)
- Phase 1 and 2 - PK Assessments: Mean Area Under the Curve (AUC) Values Derived From Serum Concentration of IMP(up to 48 weeks)
- Phase 1 and 2 - PK Assessments: Mean Observed Maximum Concentration (Cmax) Derived From Serum Concentration of IMP(up to 48 weeks)
- Phase 1 and 2 - PK Assessments: Median Time to Reach Cmax (Tmax) Derived From Serum Concentration of IMP(up to 48 weeks)
- Phase 1 and 2 - Percentage of Participants With Detectable Anti-drug Antibody (ADA)(up to 48 weeks)
- Phase 1 and 2 - Percentage of Participants With Detectable and Durable ADCC and/or CDC Activity(up to 48 weeks)
- Phase 1 and 2 - Change From Baseline for Participant-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)(up to 60 months)
- Phase 1 and 2 - Change From Baseline for Participant-reported HRQoL Using EORTC Quality of Life Questionnaire for Pancreatic Cancer (QLQ-Pan26) Questionnaires(up to 60 months)
- Phase 1 and 2 - Change From Baseline 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(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(up to 12 months)
- Phase 2 - Occurrence of Abnormal Laboratory Parameters(up to 48 weeks)