IRB Study Number 25-588
Status Recruiting
Phases Phase 1, Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary objective
Phase I – Safety run-in (Part A)
To determine the safety profile, and tolerability of BNT314 + BNT327 for each dose level in participants with 2L+ MSS/pMMR mCRC.
Phase I – Dose optimization (Part B)
To determine the safety profile, and tolerability of BNT314 + BNT327 + FOLFIRI in participants with 2L MSS/pMMR mCRC per dose level.
To determine the safety profile, and tolerability of BNT314 + BNT327 + mFOLFOX6/CAPEOX in participants with 1L MSS/pMMR mCRC per dose level.
To evaluate the efficacy of BNT314 + BNT327 + FOLFIRI with 2L MSS/pMMR mCRC per dose level in terms of ORR.
To evaluate the efficacy of BNT314 + BNT327 + mFOLFOX6/CAPEOX with 1L MSS/pMMR mCRC per dose level in terms of ORR.
Pivotal Phase II (Part C)
To compare the efficacy of BNT314 + BNT327 + FOLFIRI to bevacizumab + FOLFIRI in terms of HR for PFS as assessed by BICR in the ITT Set.
The intercurrent event of initiation of subsequent anticancer therapy will follow a hypothetical strategy.
Secondary objectives
Pivotal Phase II (Part C)
To compare the efficacy of BNT314 + BNT327 + FOLFIRI to bevacizumab + FOLFIRI in terms of ORR difference as assessed by BICR in the ITT Set.
The intercurrent event of initiation of subsequent anticancer therapy will follow a composite strategy.
Phase I – Safety run-in (Part A)
To determine the anti-tumor activity of BNT314 + BNT327 in participants with 2L+ MSS/pMMR mCRC per dose level in terms of ORR, DOR, and DCR.
To characterize the PK of BNT314 and BNT327 in participants with 2L+ MSS/pMMR mCRC per dose level.
To compare the safety profile of FOLFIRI plus BNT327 ± BNT314 to bevacizumab + FOLFIRI in the Safety Set.
Inclusion Criteria
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, the planned 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 (see Section 8.5.1 for details).
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 (see Section 8.3.3 for details).
10 Have a life expectancy of ≥12 weeks.
11 Have an adequate organ and bone marrow function within ≤7 days of Day 1. For all parameters listed below, the most recent results available must be used to meet the inclusion criteria: (See protocol)
12 Have had an adequate treatment washout period before randomization/enrollment, defined as in the table below: (See protocol)
13 Have no clinical signs and symptoms of pancreatitis and serum amylase and lipase ≤1.5 × ULN at screening. Participants with values between ULN and ≤1.5 × ULN require the approval of the trial Medical Monitor.
14 Agree not to enroll in another trial of an IMP, starting at the time of giving informed consent and continuously until the last planned visit in this trial.
15 Are POCBP who have a negative blood-based beta-hCG pregnancy test at screening. Women who are post-menopausal (defined as 12 months with no menses without an alternative medical cause) or permanently sterilized (verified by medical records) will not be considered POCBP and therefore are not required to undergo pregnancy testing.
16 Are POCBP who 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. For guidance on highly effective forms of contraception, see Section 13.3.2.
17 Are POCBP who 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.
For guidance on highly effective forms of contraception, see Section 13.3.2.
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.
Cohort-specific inclusion criteria
Additional inclusion criteria for Part A Safety run-in:
20 Have received at least two previous lines of therapy for metastatic disease. Participants must present with progressive disease at trial enrollment.
Additional inclusion criteria for Part B Dose optimization
Cohorts B1 and B2 (2L):
21 Have progressed following first-line chemotherapy with fluoropyrimidine (5-FU/l-LV, capecitabine, or S-1) plus oxaliplatin combined with or without bevacizumab, or cetuximab, or panitumumab, or encorafenib for participants with RAS wildtype tumors.
Cohorts B3 and B4 (1L):
22 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 trial if therapy was completed at least 6 months prior to initiation of trial treatment. Participants with Stage IV and oligometastatic disease who underwent resection or tumor ablation therapy can be included. Oligometastatic disease refers to a state in which a patient has a controlled primary tumor (which may have been removed), along with a small number of cancerous growths (1-5, occasionally more if complete eradication is possible) in one or two areas that can be safely treated with local treatments.
23 Are POCBP who agree to practice a highly effective form of contraception of at least 9 months following the last dose of oxaliplatin or 6 months after receiving the last dose of IMP if IMP treatment was continued for ≥3 months after the last dose of oxaliplatin.
Additional inclusion criteria for Part C (Phase II):
24 Have progressed following first-line chemotherapy with fluoropyrimidine (5-FU/l-LV, capecitabine, or S-1) plus oxaliplatin combined with bevacizumab, or cetuximab, or panitumumab for participants with RAS wildtype tumors.
Exclusion Criteria
1 Confirmed MSI-H/dMMR mCRC (per FDA/CE approved test or based on local testing).
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 including any of the following:
a. Medical history of unstable angina, acute coronary syndrome, cerebral vascular accident or other Grade ≥3 cardiovascular events, within 6 months before randomization/enrollment or symptomatic chronic heart failure (New York Heart Association Class II to IV). Participants with troponin levels above ULN at screening and without any myocardial infarction related symptoms should have a cardiologic consultation before randomization/enrollment to rule out myocardial infarction.
b. Central or symptomatic peripheral pulmonary embolism within 3 months prior to randomization/enrollment. Participants with deep venous thrombosis and incidentally diagnosed peripheral pulmonary embolism are eligible if on a stable antithrombotic regimen.
c. Uncontrolled hypertension (defined as systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg) while on antihypertensive medicine.
d. Uncontrolled and/or clinically important cardiac arrhythmias.
e. Corrected QTcF prolongation to >470 ms based on single 12-lead ECG at screening.
8 Have left ventricular ejection fraction (LVEF) <50% by ECHO 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, 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 trial if they have recovered from the acute toxic effect of radiotherapy. Participants with untreated, asymptomatic brain metastasis for whom local therapy is not indicated per SoC may be eligible if neurologically stable and (if deemed necessary by the investigator) after discussion with the sponsor’s medical monitor. Participants at imminent risk for spinal cord compression or leptomeningeal disease are not eligible.
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, 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.
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 BNT327 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 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 the following conditions are eligible for the trial:
a. A history of autoimmune-related hypothyroidism and on thyroid replacement hormone.
b. Controlled Type 1 diabetes mellitus and on a stable insulin regimen.
c. Asthma that requires intermittent use of bronchodilators at no significant risk of clinically important exacerbation.
d. Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only provided all of following are true:
• Rash covers <10% of body surface area.
• Disease is well controlled at baseline and requires only low-potency topical corticosteroids.
• No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.
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 such as:
a. History of intracranial or intraspinal hemorrhage.
b. Imaging findings during the screening period that show that the tumor lesions invade major airways (such as trachea) or major large blood vessels (such as aorta and superior vena cava) or vital organs (such as the heart, pericardium, and esophagus) or central tumor with cavities or necrosis and, in the opinion of the investigator, there is a risk of bleeding.
c. Vascular diseases (such as aortic aneurysm with a risk of rupture) that require hospitalization.
d. Acute gastrointestinal bleeding within 6 months before the first dose.
e. Clinically significant hemoptysis or tumor hemorrhage within 1 month prior to the first dose of IMP including but not limited to:
• Hemoptysis, defined as coughing up more than one teaspoon of blood or small blood clots (those with blood in the sputum are allowed to be enrolled).
f. Continuous or therapeutic anticoagulation or antiplatelet therapy:
• Continuous antiplatelet or anticoagulant therapy (except for preventive use of anticoagulants, such as the use of anticoagulants to maintain venous patency) within 14 days before the first dose.
• Ongoing treatment with therapeutic anticoagulation (other than low molecular weight heparin) or antiplatelet treatment. However, prophylactic anticoagulant or antiplatelet medication such as low dose (≤100 mg/day) aspirin is allowed.
