A First-in-human, Dose Escalation and Indication Expansion Study of BNT3212 as Monotherapy or in Combination With BNT327 in Adults With Advanced Solid Tumors

Official title

A Phase I/II, First-in-human, Open-label, Dose Escalation and Indication Expansion Study of the Safety, Tolerability, Pharmacokinetics, Immunogenicity and Preliminary Efficacy of BNT3212 as Monotherapy or in Combination With BNT327 in Adults With Advanced Solid Tumors

Overview

The aim of this first-in-human (FIH) open-label, multi-site study is to evaluate safety, tolerability, pharmacokinetics (PK), immunogenicity and preliminary clinical efficacy of BNT3212, including identification of the recommended dose of BNT3212 for use as monotherapy and with pumitamig (also known as BNT327 or PM8002) as combination therapy, in adults with advanced solid tumors who have exhausted other treatment options.

Detailed description

This study will include four parts:

* Part A (BNT3212 monotherapy - dose escalation) * Part B (BNT3212 monotherapy - dose expansion cohorts) * Part C (BNT3212 + pumitamig combination therapy - dose escalation) * Part D (BNT3212 + pumitamig combination therapy - dose expansion cohorts)

This study will follow a stepwise approach, beginning with a typical dose escalation in advanced solid tumors, followed by dose expansion in a range of indications. This design allows to gradually assess safety, preliminary efficacy, potential recommended Phase 2 dose (RP2D), and indications, while ensuring an acceptable benefit-risk balance along the way. Throughout this process, clinical data, including PK, biomarker, immunogenicity, safety, and efficacy, as well as non-clinical data, will be continuously collected and evaluated to support decision-making and ensure participant safety.

Interventions

• Biological BNT3212
  Intravenous infusion
• Biological Pumitamig
  Intravenous infusion

Primary outcome measures

• Parts A and C - Occurrence of dose limiting toxicities (DLTs) within a participant during the DLT observation period [Time frame: Up to 28 days after first dose of investigational medicinal product (IMP).]
• All parts - Percentage of participants with treatment-emergent adverse events (TEAEs) including Grade ≥3, serious, and fatal TEAEs by relationship [Time frame: From the time of the first dose of IMP until 90 days after the last dose of IMP, approximately up to 31 months.]
• Parts A and C - Percentage of participants with dose interruptions or discontinuations of study treatment due to TEAEs [Time frame: From the time of the first until last dose of IMP, approximately up to 31 months.]
• Parts B and D - Percentage of participants with dose interruptions, reductions or discontinuations of study treatment due to TEAEs [Time frame: From the time of the first until last dose of IMP, approximately up to 31 months.]
• Parts B and D (expansion cohorts) - Objective response rate (ORR) [Time frame: From first dose of IMP until end of study, approximately up to 31 months.]

Secondary outcome measures (10)

• All parts - PK assessment: Maximum concentration (Cmax) derived from serum/plasma concentrations [Time frame: From predose to 28 days after first dose of IMP.]
• All parts - PK assessment: Area under the concentration-time curve (AUC0-t) derived from serum/plasma concentrations [Time frame: From predose to 28 days after first dose of IMP.]
• All parts - PK assessment: Minimum concentration (Ctrough) derived from serum/plasma concentrations [Time frame: From predose until 90 days after the last dose of IMP.]
• All parts - Anti-drug antibody (ADA) prevalence [Time frame: For up to 90 days from the last dose of IMP.]
• All parts - ADA incidence [Time frame: For up to 90 days from the last dose of IMP.]
• All parts - Disease control rate (DCR) [Time frame: From first dose of IMP until end of study, approximately up to 31 months.]
• All parts - Duration of response (DOR) [Time frame: From first dose of IMP until end of study, approximately up to 31 months.]
• All parts - Progression free survival (PFS) [Time frame: From first dose of IMP until end of study, approximately up to 31 months.]
• All parts - Time to response (TTR) [Time frame: From first dose of IMP until end of study, approximately up to 31 months.]
• All parts - Overall survival (OS) [Time frame: From first dose of IMP until end of study, approximately up to 31 months.]

Eligibility criteria

Inclusion criteria

• Participants with histologically or cytologically confirmed locally advanced, recurrent, or metastatic solid tumors that have received prior adequate therapy in accordance with local practice for their tumor type and stage of disease; or for whom the standard therapy is considered inappropriate or intolerable.
• Have at least one measurable lesion based on RECIST v1.1.
• Eastern Cooperative Oncology Group performance status of 0 (fully active, able to carry out all pre-disease activities without restriction) or 1 (unable to perform physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature).
• Predicted life expectancy of ≥3 months.
• Left ventricular ejection fraction ≥50% by either echocardiography or multigated acquisition scan within 28 days prior to first dose of study treatment.
• Adequate liver, renal, hematological, and coagulation function.
• Recovery to Grade 0-1 (or baseline) from adverse reactions related to prior anti cancer therapy except for:

• Asymptomatic laboratory abnormalities such as elevated alkaline phosphatase, hyperuricemia, elevated serum amylase/lipase, and elevated blood glucose.
• Toxicity that the investigator determined to have no safety risk, such as alopecia, Grade 2 peripheral neurotoxicity, hypothyroidism stabilized by hormone replacement therapy, etc.
• The investigator considers discontinuation of protocol-defined anti-cancer therapies and restricted medications with protocol-defined washout periods as medically acceptable.
• For Parts B and D only: Participants must be diagnosed with specific indications.

Exclusion criteria

• Active infection (e.g., bacterial or fungal infections) requiring systemic treatment (e.g., severe pneumonia, bacteremia, sepsis), except oral antibiotics.
• Participants with primary central nervous system (CNS) malignancies.
• Active CNS metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
• Unstable pleural effusion or ascites requiring thoracentesis or paracentesis within 14 days prior to initiation of study treatment.
• Have active, or a history of, pneumonitis requiring treatment with steroids, or has active, or a history of, interstitial lung disease.
• Clinically significant pulmonary complications.
• History of severe cardiovascular disease.
• Have a history of significant hematologic toxicity to prior lines of therapy, as assessed by investigator, e.g., Grade 4 febrile neutropenia or recurrent/persistent Grade 3 to 4 neutropenia.
• Have active or chronic corneal disorders or with any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy.
• Have uncontrolled hypertension while on antihypertensive medicine or poorly controlled diabetes.
• Concurrent malignancy within 5 years prior to study enrollment. Exceptions: basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma in situ after radical resection.
• Unstable thrombotic event (e.g., deep vein thrombosis, arterial thrombosis, pulmonary embolism).
• Have adverse reactions from prior anti-tumor therapy that have not returned to Grade 1 (graded by NCI CTCAE v5.0 criteria) or below (unless the investigator determines that certain AEs pose no safety risk to participants, such as hair loss, Grade 2 peripheral neuropathy or stable hypothyroidism under hormone replacement therapy) are not eligible for the study.
• For Parts C and D only: Prior treatment with PD-1/L1 and VEGF-A antibody combinations (including bispecific antibodies to PD-1/L1 and VEGF-A).
• For Parts C and D only: Have active, or history of, autoimmune disease with risk of exacerbation following PD-L1 inhibition OR an immune deficiency (e.g., allogeneic hematopoietic stem cell transplantation or organ transplantation). Participants with protocol-specified conditions may be eligible.
• For Parts C and D only: Have serious non-healing wounds, ulcer, or bone fracture.
• For Parts C and D only: Have evidence of major coagulation disorders or other significant risks of hemorrhage.
• For Parts C and D only: Have a history of serious Grade 3 or higher immune-related adverse events that led to treatment discontinuation of a prior immunotherapy.
• For Parts C and D only: Have a history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP.
• For Parts C and D only: Have received:

• Anticoagulant therapy for therapeutic purposes (except low molecular weight heparin) within 14 days prior to the first dose of IMP.
• Antiplatelet drugs within 10 days prior to the initiation of study treatment.

NOTE: Other protocol defined Inclusion/Exclusion criteria apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 11 centers

• Beijing Cancer Hospital — Beijing
• Anhui Provincial Hospital — Hefei
• First Affiliated Hospital of Xinxiang Medical University — Henan
• Hunan Province Cancer Hospital — Hunan
• Shandong University-Jinan Central Hospital — Shandong
• Qilu Hospital of Shandong University' — Shandong
• Linyi Tumor Hospital — Shandong
• Shanghai East Hospital — Shanghai
• … and 3 more centers

Australia · 6 centers

• Cancer Research SA — Adelaide
• Monash Medical Centre — Clayton
• Peter MacCallum Cancer Centre — Melbourne
• The Alfred Hospital — Melbourne
• One Clinical Research — Nedlands
• Scientia Clinical Research Limited — Randwick

Identifiers

NCT: NCT07147348 · BNT3212-01 · CTR20253266

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)
• NMPA/CDE CTR20253266 (chinadrugtrials.org.cn platform)

View this study on ClinicalTrials.gov ↗