This randomized, multi-site, three-part study will test a new treatment called BNT314, which is designed to help the body's immune system fight cancer in combination with another new treatment (BNT327, which is an immune checkpoint inhibitor) and chemotherapy in participants with metastatic colorectal cancer (mCRC). This study will enroll participants with microsatellite stable or mismatch repair proficient (MSS/pMMR) mCRC who did not respond well to their first schema of chemotherapy. In one part of the study (i.e., Part B) mCRC participants will be enrolled, who have not received any systemic therapy before for their cancer.
The main study goals are as follows: * Part A (Phase 1, safety run-in, dose escalation): To see if BNT314 in combination with BNT327 is safe for participants and to investigate if the administration of treatment that can be given safely, without causing severe side effects in participants. * Part B (Phase 1, dose optimization): To see if BNT314 in combination with BNT327 and standard of care (SoC) chemotherapy is safe for participants and to find out the right dose of BNT314 that can be used in Part C. * Part C (Phase 2, randomization against SoC): To see whether BNT314 and BNT327, given in combination with the usual SoC chemotherapy treatment, can shrink tumors or slow down their growth. The study consists of a screening period, a treatment period, a safety follow-up period, and a long-term survival follow-up period. The sponsor plans to proactively assess participant safety on a regular basis for the duration of the study according to a predefined internal review committee. In addition, an independent data monitoring committee will be developed to provide medical oversight over Part C of the study. Participants in the study will continue to receive treatment until their disease worsens, they can no longer tolerate the treatment, or the study ends. They are expected to be on treatment for about of 6-10 months on average. After that, they will be monitored for their survival and any potential long-term side effects even after they stop participating in the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
482
Intravenous (IV) infusion
IV infusion
IV infusion / IV bolus
IV infusion / IV bolus / oral
IV infusion
START Midwest
Grand Rapids, Michigan, United States
RECRUITINGCleveland Clinic Taussig Cancer Institute Case Comprehensive Cancer Center
Cleveland, Ohio, United States
RECRUITINGThe University of Texas MD Anderson Cancer Center
Houston, Texas, United States
RECRUITINGHospital HM Nou Delfos
Barcelona, Spain
RECRUITINGCentro Integral Oncologico Clara Campal
Madrid, Spain
RECRUITINGGuy's & St Thomas' NHS Foundation Trust, Guy's Hospital
London, United Kingdom
RECRUITINGThe Royal Marsden NHS
Sutton, United Kingdom
RECRUITINGPhase I - Part A: Occurrence of dose limiting toxicities (DLTs) during the DLT observation period
Time frame: Up to 28 days after Day 1, Cycle 1
Phase I - Part A: Occurrence of treatment emergent adverse events (TEAEs) and treatment related adverse events (TRAEs)
Assessed according to Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) including Grade ≥3, serious, fatal TEAEs by relationship
Time frame: From initiation of the first dose of BNT314 + BNT327 until 90 days after last dose of investigational medicinal product (IMP)
Phase I - Part A: Occurrence of dose interruption or discontinuation of study treatment due to TEAEs
Time frame: From initiation of the first dose of BNT314 + BNT327 until 90 days after last dose of IMP
Phase I - Part B: Occurrence DLTs during the DLT observation period for the first five participants in each dose cohort
Time frame: Up to 42 days after Day 1, Cycle 1
Phase I - Part B: Occurrence of TEAEs and TRAEs
Assessed according to CTCAE v5.0 including Grade ≥3, serious, fatal TEAEs by relationship
Time frame: From initiation of the first dose of BNT314 + BNT327 + SoC chemotherapy until 90 days after last dose of IMP
Phase I - Part B: Occurrence of dose interruption or discontinuation of study treatment due to TEAEs
Time frame: From initiation of the first dose of BNT314 + BNT327 + SoC chemotherapy until 90 days after last dose of IMP
Phase I - Part B: Objective response rate (ORR)
Defined as the percentage of participants in whom a complete response (CR) or confirmed partial response (PR) (assessed by the blinded independent central review \[BICR\] per Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v1.1\]) is observed as best overall response.
Time frame: From the time of initiation of the first dose of IMP to end of study, up to 57 months
Phase II - Part C: Progression free survival
Defined as the time from randomization to first documented tumor progression (progressive disease assessed by BICR per RECIST v1.1), or death from any cause, whichever occurs first.
Time frame: From the time of initiation of the first dose of IMP to end of study, up to 57 months
Phase II - Part C: ORR
Defined as the percentage of participants in whom a confirmed CR or PR (assessed by BICR per RECIST v1.1) is observed as best overall response
Time frame: From the time of initiation of the first dose of IMP to end of study, up to 57 months
Phase I - Part A: ORR
Defined as the percentage of participants in whom a confirmed CR or PR (assessed by BICR per RECIST v1.1) is observed as best overall response
Time frame: From the time of initiation of the first dose of IMP to end of study, up to 57 months
All parts: Duration of response
Defined as the time from first objective response (CR or PR assessed by BICR per RECIST v1.1) to first occurrence of objective tumor progression (progressive disease assessed by BICR per RECIST v1.1) or death from any cause, whichever occurs first.
Time frame: From the time of initiation of the first dose of IMP to end of study, up to 57 months
Phase I - Part A and Part B: Disease control rate
Defined as the percentage of participants with confirmed CR or PR or stable disease (per RECIST v1.1, assessed at least 6 weeks after the first IMP dose) observed as best ORR per BICR.
Time frame: From the time of initiation of the first dose of IMP to end of study, up to 57 months
Phase I - Part A and Part B: Geometric mean of pharmacokinetic parameter maximum concentration of BNT314 and BNT327 in serum
Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part A and Part B: Geometric mean of pharmacokinetic parameter time taken to reach maximum concentration of BNT314 and BNT327 in serum
Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part A and Part B: Geometric mean of pharmacokinetic parameter half life of BNT314 and BNT327 in serum
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Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part A: Geometric mean of pharmacokinetic parameter volume of distribution of BNT314 and BNT327 in serum
Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part A: Geometric mean of pharmacokinetic parameter area under the curve of BNT314 and BNT327 in serum
Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part A and Part B: Geometric mean of pharmacokinetic parameter clearance of BNT314 and BNT327 in serum
Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part B: Geometric mean of pharmacokinetic parameter steady state volume of distribution of BNT314 and BNT327 in serum
Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part B: Geometric mean of pharmacokinetic parameter total drug exposure across time of BNT314 and BNT327 in serum
Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part B: Geometric mean of pharmacokinetic parameter area under the concentration-time curve from pre-dose to last quantifiable time point prior to the next dose of BNT314 and BNT327 in serum
Per dose level. If data permits.
Time frame: From predose to 42 days after first dose of IMP
Phase I - Part A and Part B: ADA prevalence
Percentage of participants who are ADA positive (either baseline or post-baseline). By dose level. If data permits.
Time frame: Up to 90 days post last dose of IMP
Phase I - Part A and Part B: Anti-drug antibody (ADA) incidence
Percentage of participants having treatment-emergent ADA. By dose level. If data permits.
Time frame: Up to 90 days post last dose of IMP
Phase II - Part C: Overall survival
Defined as the time from randomization to death from any cause
Time frame: From the time of initiation of the first dose of IMP to end of study, up to 57 months
Phase II - Part C: Occurrence of TEAEs and TRAEs
Assessed according to CTCAE v5.0 including Grade ≥3, serious, fatal TEAEs by relationship
Time frame: From initiation of the first dose of BNT314 + BNT327 until 90 days after last dose of IMP
Phase II - Part C: Occurrence of dose interruption or discontinuation of study treatment due to TEAEs
Time frame: From initiation of the first dose of BNT314 + BNT327 until 90 days after last dose of IMP