Safety and Preliminary Effectiveness of BNT317, an Investigational Therapy for Advanced Solid Tumors

The study will consist of four parts, Part A, Part B1, Part B2 and Part B3.

Part A will be a dose escalation part to investigate the safety and tolerability of BNT317 in participants with advanced solid tumors and may enroll additional participants with advanced solid tumors to specific dose levels (DLs), based on the emerging safety, PK, and pharmacodynamic data. Part A will evaluate up to six DLs of BNT317 monotherapy.

Part B will include dose optimization and dose expansion components to further investigate the safety and tolerability of BNT317 and to investigate preliminary antitumor activity, i.e.:

• Part B1 will further evaluate BNT317 monotherapy in participants with second-line of therapy or higher (2L+) clear cell renal cell carcinoma (ccRCC). Participants will be randomized 1:1 into two dose groups which will evaluate two DLs (as selected from Part A).
• Part B2 will further evaluate BNT317 when added to standard of care (SoC) treatment in participants with 2L+ human epidermal growth factor receptor 2 (HER2)-negative gastric cancer (GC)/gastroesophageal junction cancer (GEJC). Participants will be randomized 1:1 into two dose groups which will evaluate two DLs (as selected from Part A).
• Part B3 will further evaluate BNT317 when added to SoC treatment in participants with 2L+ actionable genomic alteration (AGA)-negative non-small cell lung cancer (NSCLC) at the higher of the two BNT317 dose groups being investigated in Parts B1 and B2.

Participants may receive investigational medicinal product (IMP) for up to 2 years or until they experience disease progression, unacceptable toxicities, withdrawal of consent, study discontinuation or investigator decision. The total duration of the study for a single participant may be up to 2 years, plus follow-up until the last participant has completed 1 year of survival follow-up (excluding screening).

In Part A (dose escalation), an accelerated titration design for DL1 and a Bayesian Optimal Interval (BOIN) design for dose groups DL2 and above will be used to evaluate dose limiting toxicities (DLTs).

Additional dosing schedules and/or intermediate or higher DLs may be evaluated based on the available safety, antitumor activity, PK, and pharmacodynamic data.

If not specified otherwise, criteria listed below are applicable for all parts.

Key Inclusion Criteria:

• Have histologically or cytologically confirmed advanced tumors, who have failed standard therapy, or for whom no standard treatment option is available, or for whom standard therapy is not appropriate.
• Have at least one measurable lesion based on RECIST v1.1. Lesions treated after prior local treatment (radiotherapy, ablation, interventional procedures, etc.) are generally not considered as target lesions. If the lesion with prior local treatment is the only targeted lesion, evidence-based radiology must be provided to demonstrate disease progression (the single bone metastasis or the single central nervous system [CNS] metastasis should not be considered as a measurable lesion).
• Adequate hematologic and organ function, as defined in the protocol.
• Have had an adequate treatment washout period before randomization/enrollment, as defined in the protocol.
• Part B1 only: Histologically confirmed diagnosis of locally advanced, unresectable (not amenable to curative surgery or radiation therapy) or metastatic clear cell RCC (including those with sarcomatoid features).
• Part B1 2L subgroup only: Had disease progression during or after one line of prior anticancer therapy for recurrent/metastatic disease which must have included immune checkpoint inhibitor and/or tyrosine kinase inhibitor (TKI).
• Part B1 3L+ subgroup only: Had disease progression during or after two or more lines of prior anticancer therapy for recurrent/metastatic disease defined as the following:

a. Prior treatment should also contain one or two of the following treatments:

• One line of immune checkpoint inhibitor.
• At least one line of a TKI.
• Part B2 only: Undergoing SoC treatment or is willing to start SoC treatment for 2L+ HER2-negative GC/GEJC in accordance with the product label and local treatment guidelines.
• Part B2 only: Histologically and/or cytologically documented metastatic adenocarcinoma and squamous carcinoma of GC/GEJC. (Note: Esophageal squamous cell carcinoma is excluded).
• Part B2 2L subgroup only: Had disease progression during or after one prior line of anticancer therapy for recurrent/metastatic disease which must have included a fluoropyrimidine analogue and a platinum agent with or without programmed death (PD)-1/ PD-ligand 1 (PD-L1). The total of cytotoxic containing regimens must be limited to maximum of 1 line for the recurrent/metastatic setting.
• Part B2 3L+ subgroup only: Had disease progression during or after two or more lines of prior anticancer therapy for recurrent/metastatic disease defined as the following:

• Prior treatment must include one line of treatment containing a fluoropyrimidine analogue and a platinum agent, unless the participant is not a candidate in the opinion of the treating physician.
• Prior treatment should also contain one or two of the following treatments:

• One line of a cytotoxic agent per local SoC.
• One line of a non-cytotoxic agent alone or in combination with cytotoxic chemotherapy.
• Treatment with cytotoxic agents at the recurrent/metastatic setting must be limited to a maximum of two lines.
• Part B2 only: Have a helicobacter pylori status result determined and documented prior to trial screening as part of SoC.
• Part B3 only: Undergoing SoC treatment or is willing to start SoC treatment for 2L+ AGA-negative NSCLC in accordance with the product label and local treatment guidelines.
• Part B3 only: Have advanced (i.e., metastatic or locally recurrent where local therapy with curative intent is not possible) non-squamous or squamous NSCLC.
• Part B3 only: Have no actionable genomic alterations, such as Epidermal Growth Factor Receptor mutations, anaplastic lymphoma kinase rearrangements, or other genomic alterations for which targeted molecular therapies are available. For enrolled participants with predominantly squamous histology tumors, molecular testing will not be required in cases where it is not part of the SoC.
• Part B3 only: Have experienced relapse or progression during or after treatment with standard systemic therapy including platinum-based chemotherapy and/or immune checkpoint inhibitor in the advanced/metastatic setting or discontinued from prior therapy due to intolerance.
• Part B3 only: Participants must have received 1 to 3 or more lines of systemic treatment, which can include anti-PD-1/PD-L1 therapy (if PD-L1 positive), chemotherapy, and anti-angiogenic agents. These treatments may be administered concurrently or sequentially. Prior chemotherapy must be limited to 2 lines or less.

Key Exclusion Criteria:

• Have received any of the following therapies or drugs within the noted time intervals prior to study treatment:

• Any prior treatment which inhibits cluster of differentiation 39.
• Vaccination with live attenuated vaccine(s) within 4 weeks prior to the first dose of IMP.
• Any investigational product within 4 weeks or 5 half lives (if the half life of the other investigational product is known), whichever is longer, before the first dose of IMP in this study or ongoing participation in the active treatment phase of another interventional clinical study.
• Systemic cytotoxic chemotherapy, immunotherapy within 3 weeks or five half-lives of the chemotherapy (whichever is shorter) prior to the first dose of IMP.
• Radiation therapy (chest, brain or internal organs) within 4 weeks prior to the first dose of IMP.
• Palliative radiotherapy to metastasis within 2 weeks prior to the first dose of IMP.
• Systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 2 weeks prior to the first dose of IMP. Note: local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens) is allowed.
• Have any of the following CNS metastases:

• Untreated brain metastases that are symptomatic or large (e.g., greater than 2 cm).
• Treated CNS metastases who are not neurologically stable or on steroids or anticonvulsants within 2 weeks before initiating IMP of this study.
• Brain metastases treated with radiotherapy that are not confirmed stable by magnetic resonance imaging or contrast-enhanced computer tomography 4 weeks after radiotherapy.
• Participants with known leptomeningeal metastases.
• Have uncontrolled hypertension or poorly controlled diabetes as specified in the protocol.
• Have a history of allogeneic hematopoietic stem cell transplantation or organ transplantation.
• Have a history of serious Grade ≥3 immune-related adverse events (irAEs) or irAEs that led to discontinuation of a prior immunotherapy. Participants with a history of Grade ≥3 irAEs that did not lead to discontinuation of a prior immunotherapy may be included at the discretion of the investigator. If required by the investigator, after consultation with the sponsor.
• Have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).

NOTE: Other protocol defined Inclusion/Exclusion criteria apply.