A Phase I/II, Randomized, Multi-site Trial to Investigate the Efficacy and Safety of BNT314 in Combination With Pumitamig and Chemotherapy in Participants With Metastatic Colorectal Cancer

Study Identifier:
BNT314-02
CT.gov Identifier:
NCT07079631
EudraCT Identifier:
202552176836
EU Trial (CTIS) Number:
2025-521768-36-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

This randomized, multi-site, three-part study will test a new treatment called BNT314, which is designed to help the body's own defense to fight cancer in combination with another new treatment (pumitamig, which is a cancer immunotherapy drug also known as BNT327 and PM8002) and chemotherapy in participants with metastatic colorectal cancer (mCRC).

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Bowel (Colorectal)
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18+ years
Study Drug
Drug: Experimental: Phase 1 (Part A): BNT314 (escalating dose levels) + BNT327
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Drug: Drug: BNT327
Drug: Experimental: Phase 1 (Part B): BNT314 + BNT327 + SoC chemotherapy 1
Drug: One selected dose level of BNT327.
Drug: Biological: BNT314
Drug: Drug: SoC chemotherapy treatment 1
Drug: Experimental: Phase 1 (Part B): BNT314 + BNT327 + SoC chemotherapy 2
Drug: Drug: SoC chemotherapy treatment 2
Drug: Experimental: Phase 2 (Part C): BNT314 + BNT327 + SoC chemotherapy 1
Drug: Active Comparator: Phase 2 (Part C): Bevacizumab + SoC chemotherapy 1
Drug: Drug: Bevacizumab
Drug: Experimental: Phase 2 (Part C): BNT327 + SoC chemotherapy 1
Drug: 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.
Drug: 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.
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • Have unresectable histologically confirmed adenocarcinoma of the colon or rectum.Have confirmed non-microsatellite instability-high (non-MSI-H)/pMMR mCRC per Food and Drug Administration (FDA)/European Commission (EC) approved test or based on local testing.Have measurable disease defined by RECIST v1.1.Must provide a tumor tissue sample (formalin-fixed, paraffin-embedded or tissue slides) collected before C1D1 for enrollment. A newly obtained tumor sample is preferred. If it is not feasible to obtain a recent tumor sample, participants can provide archival tumor tissue (less than 2 years prior treatment).Have Eastern Cooperative Oncology Group Performance Status of 0 or 1.Have a life expectancy of ≥12 weeks.Have an adequate organ and bone marrow function within ≤7 days of Day 1 as defined in the protocol.Have had an adequate previous treatment washout period before randomization/enrollment as defined in the protocol.Inclusion criteria applicable to only protocol-specific cohorts:
  • Have histologically confirmed metastatic colorectal cancer and radiographically documented disease progression after ≥2 prior lines of systemic therapy for metastatic disease as defined in the protocol.Have progressed following first-line chemotherapy as specified in the protocol.Have not received prior systemic therapy for MSS/pMMR mCRC. Participants who received chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease in the neoadjuvant or adjuvant setting are eligible for the study if therapy was completed at least 6 months prior to initiation of study treatment.Other cohort-specific inclusion criteria apply.
  • Participants are only eligible for enrollment in this trial if all of the following criteria apply at screening:
  • 1.Have unresectable histologically confirmed adenocarcinoma of the colon or rectum.
  • 2.Have confirmed non-MSI-H/pMMR mCRC (per FDA/CE approved test or based on local testing).
  • 3.Have known RAS status.
  • 4.Have given informed consent by signing and dating an ICF in accordance with ICH GCP and local legislation before the initiation of any trial-specific procedures.
  • 5.Are willing and able to comply with scheduled visits, treatment schedule, theplanned trial assessments (including participant completed diaries), lifestyle restrictions, and other requirements of the trial. This includes that they are able to understand and follow trial-related instructions.
  • 6.Aged >=18 years at the time of giving informed consent.
  • 7.Have measurable disease defined by RECIST 1.1.
  • 8.Must provide a tumor tissue sample (formalin-fixed, paraffin-embedded or tissue slides) collected before C1D1 for enrollment. A newly obtained tumor sample is preferred. If it is not feasible to obtain a recent tumor sample, participants can provide archival tumor tissue (less than 2 years prior treatment). Details are provided in the Laboratory Manual.
  • 9.Have ECOG PS of 0 or 1.
  • 10.Have a life expectancy of >=12 weeks.
  • 11.Have an adequate organ and bone marrow function within <=7 days of Day 1.
  • 12.Have had an adequate treatment washout period before randomization/enrollment.
  • 13.Have no clinical signs and symptoms of pancreatitis and serum amylase and lipase <=1.5 x ULN at screening. Participants with values between ULN and <=1.5 x ULN require the approval of the trial Medical Monitor.
  • 14.Agree not to enroll in another trial of an IMP, starting from the time of giving informed consent and continuously until the last planned visit in this trial.
  • 15. For POCBP: Have a negative blood-based B-hCG pregnancy test at screening. Participants who are post-menopausal (defined as 12 months with no menses without an alternative medical cause) or permanently sterilized (i.e., have had a hysterectomy, bilateral salpingectomy and bilateral oophorectomy, as verified by medical records) will not be considered POCBP and therefore are not required to undergo pregnancy testing.
  • 16. For POCBP: Agree to practice a highly effective form of contraception and to require their potentially fertile male partners to use condoms starting at the time of giving informed consent and continuously 6 months after receiving the last dose of IMP.
  • 17. For POCBP: Agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting at the time of giving informed consent and continuously until 6 months after receiving the last dose of IMP.
  • 18. Are male who are sterile or if they are potentially fertile (i.e., are not surgically [e.g., have had a vasectomy] or congenitally sterile) and sexually active with a partner of childbearing potential, who agree to use condoms and to ask their female sexual partners to practice a highly effective form of contraception during the trial, starting at the time of giving informed consent and continuously until 6 months after receiving the last dose of IMP.
  • 19. Are potentially fertile male who are willing to refrain from sperm donation, starting at the time of giving informed consent and continuously until 6 months after receiving the last dose of IMP.
  • 20. Participants must present with progressive disease at trial enrollment.
  • Have histologically confirmed metastatic colorectal cancer and radiographically documented disease progression after >=2 prior lines of systemic therapy for metastatic disease, which must include at least TWO of the following treatment categories, as appropriate for the tumor's molecular profile:
  • --Chemotherapy backbone:
  • -Fluoropyrimidines
  • -Oxaliplatin
  • -Irinotecan
  • --Targeted therapy in RAS wild-type tumors:
  • -Cetuximab or panitumumab
  • --Targeted therapy in BRAF V600E-
  • mutated, RAS wild-type tumors:
  • -Encorafenib in combination with cetuximab or panitumumab
Exclusion criteria
  • Confirmed MSI-H/deficient mismatch repair mCRC (per FDA/CE approved test or based on local testing).Prior treatment with epithelial cell-adhesion molecule or 4-1BB targeted or immunotherapy.Prior treatment with immune checkpoint inhibitors or programmed death-ligand 1 (PD[L]-1)/vascular endothelial growth factor bispecific antibody.Is a candidate to locoregional treatment (including surgical resection, stereotactic radiation therapy or tumor ablation) with potential to induce complete or near complete response and prolonged tumor control (sometimes described as "radical" intent), per investigator's assessment.Have uncontrolled or significant cardiovascular disease as specified in the protocol.Have left ventricular ejection fraction <50% by echocardiogram or multigated acquisition within 28 days before randomization/enrollment.Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment.Have clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. Participants with untreated, asymptomatic brain metastases for whom local therapy is not indicated per SoC may be eligible if neurologically stable and (if deemed necessary by the investigator). Except for brain metastases history, any participants at imminent risk for spinal cord compression or leptomeningeal disease are not eligible.Have unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline toxicities that have resolved with sequelae (e.g., tracheostomy, chronic use of feeding tube, replacement hormones) are allowed, if not associated with increased risk of complications per investigator's assessment.Participants in Part B or C who fulfill one of the conditions:Prior treatment with anticancer therapies (as defined in the protocol) with unusual toxicity, orKnown dihydropyrimidine dehydrogenase (DPD) deficiency, testing performed according to the local guidelines. If not tested, lack of DPD activity must be tested for the participants who have not received anticancer therapies (as defined in the protocol) in the prior lines of treatment; testing should be performed according to the local guidelines.Have a history of another primary malignancy within 2 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated (adjuvant hormone therapy for malignancies at low risk of relapse is allowed) or have a known additional malignancy that is progressing or requires treatment.Have a history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP.Have 24-h urine protein excretion ≥1 g. If qualitative urine protein is ≤1+, a 24-h urine protein quantitative test is not required.Have active autoimmune disease or a history of autoimmune disease (myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, vasculitis, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis) with a risk of exacerbation following PD-L1 inhibition or have an immune deficiency (allogeneic hematopoietic stem cell transplantation or organ transplantation). Participants with protocol-specified conditions may be eligible.Have serious non-healing wounds, ulcers, or bone fractures. This includes history of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess or esophageal and gastric varices, acute gastrointestinal bleeding for which an interval of 6 months must pass before enrollment into this study. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.Have evidence of major coagulation disorders or other significant risks of hemorrhage as specified in the protocol.NOTE: Other protocol defined Inclusion/Exclusion criteria apply.
  • Participants are not eligible for enrollment in this trial if any of the following criteria apply at screening:
  • 1. Confirmed MSI-H/dMMR mCRC.
  • 2. Have 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.
  • 3. Prior treatment with EpCAM or 4-1BB targeted or immunotherapy.
  • 4. Prior treatment with immune checkpoint inhibitors or PD(L)-1/VEGF bispecific
  • antibody.
  • 5. Is a candidate to locoregional treatment (including surgical resection, stereotactic radiation therapy or tumor ablation) with potential to induce complete or near complete response and prolonged tumor control (sometimes described as radical\" intent), per investigator's assessment.
  • 6. Have an uncontrolled concomitant or intercurrent illness, that in the opinion of the investigator, contra-indicates trial participation, limits compliance with trial procedures or substantially increases the risk of incurring AEs, including:
  • a. Bleeding diathesis or active hemorrhage,
  • b. Active infection,
  • c. Child-Pugh class B or C cirrhosis,
  • d. Pulmonary disease with significant impact in lung function, including a history of (non-infectious) interstitial lung disease/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
  • e. Oncologic emergencies or complications (e.g. malignant hypercalcemia, superior vena cava syndrome, carcinoid syndrome that is unstable and with available alternative therapies),
  • f. Psychiatric or abuse condition.
  • g. History of acute or chronic pancreatitis of any etiology within 6 weeks prior to the start of trial treatment.
  • 7. Have uncontrolled or significant cardiovascular disease.
  • 8. Have left ventricular ejection fraction (LVEF) <50% by ECHO or MUGA within 28 days before randomization/enrollment.
  • 9. Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment.
  • 10. Have clinically active central nervous system metastases.
  • 11. Participants who have a known history or a positive test at screening of any of the following:
  • a. Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome, with the following exceptions:
  • - Participants with CD4+ T-cell counts >=350 cells/mL per local laboratory.
  • - Participants who have not had an opportunistic infection within the past 12 months should generally be eligible for the trial.
  • b. Hepatitis B infection, as defined by the presence of HBsAg or HBV DNA positivity. Testing of HBV DNA is mandatory if HBC antibody is positive.
  • c. Have an active Hepatitis C virus infection; individuals who have completed curative antiviral treatment with Hepatitis C virus viral load below the limit of quantification are allowed.
  • 12. Have unresolved toxicities from previous anticancer therapy.
  • 13. Are pregnant or breastfeeding or are planning pregnancy or cannot discontinue breastfeeding for the duration of the trial at least 9 months following the last dose of oxaliplatin or 6 months after receiving last dose of BNT314 and pumitamig if continued for >=3 months after the last dose of oxaliplatin.
  • 14. Have a history of allergies, hypersensitivities, or intolerance to the trial treatments including any excipients thereof.
  • 15. Participants in Part B or C who fulfill one of the conditions:
  • - Prior treatment with 5-FU, capecitabine or S1 with unusual toxicity, or
  • - Known DPD deficiency, testing performed according to the local guidelines
  • - if not tested, lack of DPD activity must be tested for the participants who have not received 5-FU, Capecitabine or S1 in the prior lines of treatment; testing should be performed according to the local guidelines.
  • 16. Have a history of another primary malignancy within 2 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated (adjuvant hormone therapy for malignancies at low risk of relapse is allowed) or have a known additional malignancy that is progressing or requires treatment.
  • 17. Use of any IMP within 28 days or five half-lives if known (whichever is longer) before administration of first dose of trial treatment or ongoing participation in the active treatment phase of another interventional clinical trial or prior randomization or treatment in a previous trial with the same IMPs as the current trial, regardless of treatment assignment.
  • 18. Have a medical, psychological, or social condition or substance abuse 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.
  • 19. Are enrolled in another investigational trial or are subject to exclusion periods from another investigational trial.
  • 20. Are vulnerable individuals as per ICH E6 definition, i.e., are individuals whose willingness to volunteer 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. This includes all sponsor, trial site, or third party (e.g., CRO, vendor) personnel directly involved in the conduct of the trial and their family members or dependents, as well as all trial site personnel otherwise supervised by the investigator.
  • 21. Have a history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP.
  • 22. Have 24-h urine protein excretion >=1 g. If qualitative urine protein is <=1+, a 24-h urine protein quantitative test is not required.
  • 23. Have a history of Grade >=3 irAEs that led to treatment discontinuation of a prior checkpoint inhibitor.
  • 24. Have active autoimmune disease or a history of autoimmune disease (myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, vasculitis, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis) with a risk of exacerbation following PD-L1 inhibition or have an immune deficiency (allogeneic hematopoietic stem cell transplantation or organ transplantation).
  • 25. Have serious non-healing wounds, ulcers, or bone fractures. This includes history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess or esophageal and gastric varices, acute gastrointestinal bleeding for which an interval of 6 months must pass before enrollment into this trial. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.
  • 26. Have evidence of major coagulation disorders or other significant risks of hemorrhage.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Barcelona
Barcelona, Spain, 08023
Investigator
Tatiana Hernandez Guerrero
Status
Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)
Location
START Midwest
Grand Rapids, MI, United States, 49546
Investigator
Sreenivasa Chandana
Status
Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Irene Moreno
Status
Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)