Clinical Trial 23655

• Overview

  Study Title:

  A Phase I/II, open-label, adaptive two-part trial to evaluate the safety, efficacy, optimal dose and pharmacokinetics of BNT326 as monotherapy and in combination with cancer immunotherapies in participants with advanced solid tumors

  Summary:

  This study will evaluate the safety, efficacy, optimal dose, and pharmacokinetics (PK) of BNT326 as monotherapy (Part 1) and as combination treatment with immunotherapeutic agents (Part 2) in participants with histologically or cytologically confirmed solid tumors that are advanced (i.e., either metastatic or recurrent tumors with no further definitive treatment possible) and/or have relapsed/progressed after prior therapy.

  Objective:

  Primary, Monotherapy: * To assess the safety profile of BNT326 monotherapy. * To assess the efficacy of BNT326 monotherapy according to RECIST 1.1. Primary Combination: * To assess the safety profile of BNT326 in each combination treatment with immunotherapy (e.g., BNT327). * To assess the efficacy of BNT326 in each combination treatment with immunotherapy (e.g., BNT327) according to RECIST 1.1. Secondary Monotherapy: * To evaluate the efficacy of BNT326 (other than ORR) as monotherapy and in each combination treatment with immunotherapy (e.g., BNT327). * To assess the PK of BNT326 (BNT326 ADC, total anti-HER3 antibody component, and unconjugated payload YL0010014 component) as monotherapy and in each combination treatment with immunotherapy (e.g., BNT327). * To evaluate immunogenicity of BNT326 as monotherapy and in each combination treatment with immunotherapy (e.g., BNT327). Primary, Drug-Drug Interaction Cohort: * Arm 1: To evaluate the effect of itraconazole (a strong inhibitor of CYP3A) on BNT326 and YL0010014 PK in participants with advanced solid malignant tumors. * Arm 2: To evaluate the effect of paroxetine a (strong CYP2D6 inhibitor) on BNT326 and YL0010014 PK in participants advanced solid malignant tumors. Secondary, Drug-Drug Interaction Cohort: * To evaluate the safety of BNT326 with/without itraconazole or paroxetine. * To evaluate the efficacy of BNT326. * To assess the incidence of ADA against BNT326.

• Treatments

  Therapies:

  HER3-targeting antibody-drug conjugate (ADC); Immunotherapy; Recombinant bispecific antibody targeting PD-L1 and VEGF

  Medications:

  BNT326 (); BNT327 ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Aged ≥18 years at the time of giving informed consent.
  • Have histologic or cytologic documented advanced disease, either at relapse or upon diagnosis of metastatic disease. This requirement may be considered met when advanced disease derives from unequivocal progression of a previously biopsied site of disease (e.g., progression of residual tumor after concomitant chemo-radiation for Stage III NSCLC).
  • Have measurable disease defined by RECIST 1.1.
  • All participants must provide a tumor tissue sample (Formalin-fixed paraffin-embedded [FFPE] slides) from archival tissue. The archival tissue can be an FFPE block or freshly cut slides derived from the advanced setting or a new/fresh tumor biopsy.
  • Have ECOG performance status of 0 or 1.
  • Have adequate organ and bone marrow function within 7 days before randomization/enrollment.
  • Cohort 1A: Have histologically or cytologically confirmed diagnosis of unresectable or metastatic cutaneous melanoma not amenable to local therapy. Participants must have previously received a PD-1 or PD-L1 inhibitor, and, for participants with human gene that encodes a protein called B-Raf (BRAF) gene mutant melanoma, a prior treatment regimen that included vemurafenib, dabrafenib, or another BRAF gene inhibitor with or without mitogen-activated protein kinase protein inhibitor, if available and clinically indicated per local standard of care (SoC) and have experienced progression during or after the previous treatment or discontinued from prior therapy due to intolerance.
  • Cohort 1B and 1C: Have advanced (i.e., metastatic or locally recurrent where local therapy with curative intent is not possible) non-squamous or squamous NSCLC.
  • Cohort 1B: Have no actionable genomic alterations, such as EGFR 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. 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. Participants must have received 1 to 3 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 fewer than 2 lines.
  • Cohort 1C: Have documented positive test results for an EGFR-sensitizing mutation (EGFR-sensitizing mutation Exon 21-L858R and 19del). Participants must have received one or two prior lines of systemic therapy for advanced and/or metastatic disease, which must include treatment with an approved EGFR Tyrosine Kinase Inhibitors (TKI), with at least one being a third-generation EGFR TKI. If there is no third-generation EGFR TKI approved as part of SoC by local health authorities in a certain country, failure/progression on any EGFR TKI is acceptable for eligibility. Participants receiving an EGFR TKI at the time of signing informed consent may continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1. Chemotherapy is permitted only if it was administered in combination with an EGFR TKI as part of a single line of therapy and as the initial (first line) treatment for advanced/metastatic disease. Participants must not have received any other systemic therapies (such as chemotherapy, immunotherapy, or targeted agents) for advanced/metastatic disease, unless those treatments were given in combination with an EGFR TKI.
  • Other protocol defined Inclusion/Exclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Have a history of intolerance to treatment with a topoisomerase I inhibitor or intolerance to an ADC that consists of a topoisomerase I inhibitor, including but not limited to topotecan, irinotecan, and deruxtecan (e.g., severe diarrhea).
  • Have an uncontrolled concomitant or intercurrent illness that contra-indicates study participation, limits compliance with study procedures or substantially increases the risk of incurring adverse events, including: Bleeding diathesis or active hemorrhage, Active infection, Child-Pugh class B or C cirrhosis, Pulmonary disease with significant impact in lung function, Oncologic emergencies or complications (e.g., malignant hypercalcemia, superior vena cava syndrome, carcinoid syndrome that is unstable and with available alternative therapies), Psychiatric or abuse condition.
  • Have LVEF > 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 a history of (non-infectious) interstitial lung disease (ILD) /pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Asymptomatic interstitial changes caused by previous radiation therapy, chemotherapy, or other factors such as smoking are acceptable.
  • Are a participant of child-bearing potential who are pregnant or breastfeeding or are planning pregnancy within 225 days (~7.5 months) after receiving last dose of BNT326 and within 6 months after last dose of BNT327, whichever is longer.
  • Are potentially fertile males, who are planning to father children during the study or within 135 days (~4.5 months) after the last dose of BNT326 and within 6 months after last dose of BNT327, whichever is longer.
  • Are subject to exclusion periods from another investigational study.
  • Participants with significant risks of hemorrhage or evidence of major coagulation disorders as specified in the protocol.
  • Cohort 1E: Have histological diagnosis of fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
  • Other protocol defined Inclusion/Exclusion criteria may apply.

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