IRB Study Number 25-748
Status Recruiting
Phases Phase 1, Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives
Monotherapy Part (Part 1)
• To assess the safety profile of BNT326 monotherapy.
• To assess the efficacy of BNT326 monotherapy according to RECIST 1.1.
Combination Therapy Part (Part 2)
• To assess the safety profile of BNT326 in each combination treatment with immunotherapy such as BNT327.
• To assess the efficacy of BNT326 in each combination treatment with immunotherapy such as BNT327 according to RECIST 1.1.
DDI Cohort (Cohort 1F) Primary Objectives
• Arm 1: To evaluate the effect of itraconazole, a strong inhibitor of CYP3A, on BNT326 and YL0010014 pharmacokinetics in participants with advanced solid malignant tumors.
• Arm 2: To evaluate the effect of paroxetine, a strong CYP2D6 inhibitor, on BNT326 and YL0010014 pharmacokinetics in participants with advanced solid malignant tumors.
Secondary Objectives
Monotherapy and Combination Therapy
• To evaluate the efficacy of BNT326, other than ORR, as monotherapy and in each combination treatment with immunotherapy.
• To assess the pharmacokinetics of BNT326, including BNT326 ADC, total anti HER3 antibody component, and unconjugated payload YL0010014, as monotherapy and in each combination treatment with immunotherapy.
• To evaluate immunogenicity of BNT326 as monotherapy and in each combination treatment with immunotherapy.
DDI Cohort (Cohort 1F) Secondary Objectives
• To evaluate the safety of BNT326 with or without itraconazole or paroxetine.
• To evaluate the efficacy of BNT326.
• To assess the incidence of anti drug antibodies against BNT326.
Exploratory Objectives
Monotherapy and Combination Therapy
• To evaluate HER3 and PD L1 protein expression in tumor tissue and its relationship with efficacy.
• To assess the pharmacokinetics of BNT327 after BNT327 administration in combination with BNT326.
• To evaluate immunogenicity of BNT327 after BNT327 administration in combination with BNT326.
• To assess the anti tumor activity of BNT326 in combination with other treatments according to iRECIST as assessed by the investigator.
DDI Cohort (Cohort 1F) Exploratory Objective
• To assess the effect of genetic polymorphism in CYP2D6 on exposure to YL0010014.
Inclusion Criteria
Inclusion Criteria (All Parts & Cohorts)
- General Eligibility
• Must provide written informed consent before any study-specific procedures.
• Must be ≥18 years old at the time of consent.
• Must be willing and able to comply with all trial visits, treatments, assessments, and restrictions.
• Must have histologically or cytologically confirmed:
o Advanced, unresectable, or metastatic solid tumor, OR
o Recurrent disease with no further curative options available.
• Must have measurable disease per RECIST 1.1. - Required Tumor Tissue
• Must provide tumor tissue (FFPE)—archival or fresh biopsy—before Cycle 1 Day 1.
• If archival tissue unavailable (≥2 years old or insufficient), fresh biopsy required unless contraindicated.
• Sponsor Medical Monitor approval required if no tissue can be obtained. - Performance Status
• ECOG Performance Status 0–1. - Adequate Organ & Bone Marrow Function (Within 7 days prior to enrollment)
• Platelets ≥100,000/mm³
• Hemoglobin ≥9.0 g/dL
• ANC ≥1,500/mm³
• eGFR >60 mL/min (per MDRD method)
• AST/ALT ≤2× ULN (≤5× ULN if liver metastases)
• Total bilirubin ≤1.5× ULN (≤2.0× ULN for Gilbert’s or liver mets)
• Albumin ≥3.0 g/dL
• INR/PT/aPTT ≤1.5× ULN unless on stable anticoagulation. - Treatment Washout Requirements
Participants must complete a minimum washout from prior therapies:
• Hormonal therapy: ≥1 week
• Chemo or immunotherapy: ≥3 weeks
• Small molecule targeted therapy: ≥2 weeks or ≥5 half lives
• Antibody therapy: ≥4 weeks
• Chloroquine/hydroxychloroquine: ≥3 months
• Traditional Chinese medicine: ≥3 weeks
• Major surgery: ≥4 weeks
• Radiation: ≥4 weeks (non thoracic); ≥8 weeks (chest)
• Cell therapy: ≥4 weeks - Pregnancy & Contraception Requirements
For people of childbearing potential (POCBP):
• Negative serum β hCG within 7 days before first dose.
• Must use highly effective contraception from consent through:
o 225 days (~7.5 months) after last BNT326 dose
o OR 6 months after last BNT327 dose (if applicable) - • No egg donation during this period.
For fertile men:
• Must use condoms and ensure partner contraception through:
o 135 days (~4.5 months) after last BNT326 dose
o OR 6 months after last BNT327 dose
• No sperm donation during this period.
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(These must be met in addition to the general criteria above.)
Cohort 1A – Cutaneous Melanoma (2L+)
• Unresectable/metastatic melanoma
• Prior PD 1/PD L1 inhibitor required
• Must have had BRAF therapy if BRAF mutated
• Disease progression or intolerance to prior therapy
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Cohort 1B – AGA-Negative NSCLC (2L+)
• No actionable oncogenic alterations (e.g., EGFR, ALK)
• Prior platinum chemo and/or checkpoint inhibitor
• 1–3 prior systemic therapy lines; progression required
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Cohort 1C – EGFR Mutated NSCLC (2L+)
• Documented EGFR sensitizing mutation (Ex19del or L858R)
• Prior EGFR TKI therapy, including ≥1 third generation TKI
• Limited chemo exposure: only allowed if part of 1L EGFR TKI + chemo combination
• Must have progressed on or been intolerant to prior therapy
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Cohort 1D – Rare Melanoma
• Acral, mucosal, or uveal melanoma
• Prior PD 1/PD L1 therapy required
• Uveal melanoma: prior tebentafusp required if HLA A*02:01 positive
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Cohort 1E – Other Advanced Solid Tumors
Includes:
Cholangiocarcinoma, HCC, RCC, endometrial carcinoma, neuroendocrine tumors, PDAC
• 1–3 prior therapy lines
• Disease progression or intolerance
• Complications controlled/stable
PDAC specific:
• 1–2 prior lines
• MSI H/dMMR/TMB high must have prior anti PD L1 therapy (if available)
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Cohort 2A – Melanoma (2L+) for Combination Therapy
Same criteria as Cohort 1A (above).
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Cohort 2B – HER2 Negative Breast Cancer
Includes HR+/HER2− and TNBC
• Recurrent unresectable/metastatic BC
• Prior endocrine therapy + CDK4/6 inhibitor if HR+
• ≤1 prior chemotherapy line (HR+)
• TNBC:
o ≤2 prior therapy lines
o Prior PD 1/PD L1 if CPS ≥10
o Prior PARP or platinum if BRCA1/2 mutated
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DDI Cohort 1F – Drug–Drug Interaction
• Same general inclusion criteria
• Tumors must have clinically relevant HER3 expression
• 1–3 prior therapy lines
• No prohibited CYP3A/CYP2D6 strong inhibitors prior to treatment
Exclusion Criteria
- Medical Conditions & Comorbidities
• Severely impaired hematologic function (e.g., significant cytopenias at baseline).
• Uncontrolled hypertension: systolic >160 mm Hg or diastolic >100 mm Hg despite medication.
• Proteinuria ≥2+, or 24 hour urine protein ≥1 g (for Part 2).
• Acute or uncontrolled infections.
• Severe liver dysfunction (based on LFT abnormalities).
• Corneal disease or pre existing significant ocular conditions.
• Medical history of ILD/pneumonitis, or current suspicion of ILD/pneumonitis.
• Active autoimmune disease with expected relapse, except stable autoimmune thyroid disease or type 1 diabetes.
• History of Grade ≥3 immune related adverse events on prior immunotherapy if these led to treatment discontinuation.
• Coagulopathy or bleeding disorders.
• Clinically significant risk of hemorrhage, including:
o recent hemoptysis
o tumor invading major vessels
o prior intracranial/intraspinal hemorrhage
• Abdominal fistula, perforation, or abscess within 6 months. - Pregnancy, Lactation, and Reproductive Restrictions
• Pregnant or breastfeeding women.
• POCBP unwilling to:
o undergo required pregnancy testing
o use highly effective contraception
o avoid egg donation during the required timeframe
• Fertile men unwilling to use condoms or avoid sperm donation during the required timeframe. - Prior or Concurrent Therapies
• Prior HER3 targeted therapy.
• Intolerance to topoisomerase I inhibitors or prior ADC related severe toxicity.
• Concurrent participation in any other investigational drug trial from consent to last visit.
• Concurrent anticancer therapy, except protocol permitted hormonal therapy or palliative radiation.
• Use of prohibited medications, including:
o strong CYP3A/CYP2D6 inhibitors or inducers
o medications known to prolong QTc (restricted)
o immunosuppressive therapy beyond protocol allowances
o live attenuated vaccines during treatment and 35 days after - Disease Specific Exclusions
• Centrally active or unstable CNS metastases, unless allowed per cohort specifics (not indicated in summary).
• Candidates for radical, curative-intent locoregional therapy (i.e., patients who are appropriately treatable outside a clinical trial). - Safety Related Exclusions
• Unresolved ≥Grade 2 toxicities from prior treatments (except alopecia).
• Significant cardiovascular disease, including:
o unstable angina
o recent myocardial infarction
o clinically significant arrhythmias
o QTc prolongation
o LVEF <50%
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent drainage. - Additional DDI Cohort (1F) Specific Exclusions
For the drug drug interaction cohort:
• Use of strong CYP3A or CYP2D6 inhibitors within 2 weeks (or 5 half lives) before first dose.
• Use of CYP3A/CYP2D6 weak/moderate inhibitors, inducers, or substrates within 2 weeks (or 5 half lives) before first dose through Cycle 4.
