Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced Non-small Cell Lung Cancer
- Conditions
- Non-Small Cell Lung Cancer
- Interventions
- Biological: anti-B7-H3 antibody conjugated to topoisomerase I inhibitorBiological: anti-HER3 antibody conjugated to topoisomerase I inhibitor
- Registration Number
- NCT05142189
- Lead Sponsor
- BioNTech SE
- Brief Summary
This first-in-human (FIH) trial for BNT116 aims to establish the safety profile and a safe dose for BNT116 monotherapy as well as for BNT116 in combination with approved medicinal products and/or in combination with investigational medicinal products (IMPs) including, but not limited to, cemiplimab, docetaxel, carboplatin, paclitaxel, BNT316 (an anti-cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\] antibody), an anti-B7-H3 antibody conjugated to a topoisomerase I inhibitor, or an anti-human epidermal growth factor receptor 3 (HER3) antibody conjugated to a topoisomerase I inhibitor in patients with non-small cell lung cancer (NSCLC).
The trial will comprise of several cohorts for dose confirmation in monotherapy as well as in combinations of BNT116 as mentioned above.
The trial will enroll patients with NSCLC in advanced or metastatic stage in Cohorts 1 to 4 and Cohorts 7 to 9, unresectable NSCLC Stage III in Cohort 5, and resectable NSCLC of Stage II and III in Cohort 6.
- Detailed Description
The maximum duration of treatment for each individual patient in this trial is:
* Cohorts 1 to 4, and Cohorts 7 to 9: 24 months
* Cohort 5: 18 cycles, i.e., 12 months
* Cohort 6: 4 cycles of neo-adjuvant treatment and 18 cycles of adjuvant treatment, i.e., 12 months of adjuvant treatment
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 220
-
Patients must have histologically confirmed NSCLC and measurable disease by RECIST v1.1. Note: Patients in Cohort 1 and Cohort 5 do not have to present with measurable disease.
-
Patients must present with unresectable Stage III or metastatic Stage IV NSCLC by American Joint Commission on Cancer (AJCC) Cancer Staging Manual, Eighth Edition.
EXCEPT
-
Patients in Cohort 5 must present with unresectable Stage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition before receiving pre-trial chemoradiotherapy.
-
Patients in Cohort 6 with the initial diagnosis of resectable Stage II and Stage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition.
-
-
Patients in Cohorts 2, 4, 5, and 6 must be able to tolerate (additional) anti-PD-1 therapy (i.e., did not permanently discontinue anti-programmed death protein 1 [PD-1] / programmed death ligand 1 [PD-L1] therapy due to toxicity).
-
Patients must have an Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1, except for patients in Cohorts 1, 4, and 5 who are eligible with an ECOG-PS of 0-2.
Cohort-specific inclusion criteria:
Cohort 1:
- Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen as well as one other line of systemic therapy (except if a patient is not candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor and/or another line of systemic therapy). Note: Patients newly enrolled in Cohort 1B under clinical trial protocol v5.0 and subsequent versions of the clinical trial protocol must consent to mandatory blood sampling for peripheral blood mononuclear cells (PBMCs).
- Patients who are to start cemiplimab at Cycle 3 must present with PD-L1 expression of tumor proportion score (TPS) ≥1% in tumor cells (as determined locally).
Cohort 2:
-
Patients must present with PD-L1 expression of tumor proportion score (TPS) ≥50% in tumor cells (as determined locally prior to inclusion in this trial).
-
Patients must present with progressive disease either
- in the advanced or metastasized stage of NSCLC: while on a PD-1/PD-L1 inhibitor therapy or within 6 months of termination of this treatment as first-line treatment. Or
- be refractory to ongoing adjuvant therapy/maintenance treatment after CRT with a PD-1/PD-L1 inhibitor that has been given for at least 3 months in monotherapy (i.e., after an initial combination therapy) before being enrolled into this trial.
Cohort 3:
- Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a patient is not candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).
- Patients must present with progressive disease.
Cohort 4:
- Patients' who are not candidates for chemotherapy as first-line treatment for the advanced or metastasized stage of NSCLC may be enrolled if presenting with PD-L1 expression: TPS ≥1% in tumor cells (as determined locally).
Cohort 5:
- Patients' NSCLC must have been considered unresectable due to patients' condition and/or tumor-related factors and the patients must have undergone chemoradiotherapy before entering the trial.
Cohort 6:
- Patients' NSCLC must be considered technically and medically resectable.
- Patients must be considered eligible for neo-adjuvant treatment.
Cohort 7:
- Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a patient is not a candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor). Note 1: Patients may have received prior therapy targeting CTLA-4, lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain (TIGIT), vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR) inhibitor as monotherapy or part of a combination therapy. Note 2: If the patient's prior therapies included a CTLA-4 inhibitor, the patient must be able to tolerate (additional) treatment with the CTLA-4 inhibitor.
- Patients must present with progressive disease at trial enrollment.
- Patients must consent to mandatory blood sampling for PBMCs.
Cohorts 8 & 9:
- Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a patient is not a candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).
- Patients must present with progressive disease at trial enrollment.
Key
- Ongoing active systemic treatment against NSCLC.
- Presence of a driver mutation for which approved target therapies are available except if the patient is not a candidate for the respective targeted therapy.
- Ongoing or recent evidence (within the last 5 years) of significant autoimmune disease that required treatment with systemic immunosuppressive treatments which may suggest risk for immune-related adverse events. Note: Patients with autoimmune-related hyperthyroidism, autoimmune-related hypothyroidism who are in remission, or on a stable dose of thyroid-replacement hormone, vitiligo, or psoriasis may be included.
- Current evidence of new or growing brain or spinal metastases during screening. Patients with leptomeningeal disease are excluded. Patients with known brain or spinal metastases may be eligible for all Cohorts, except for Cohort 5 and 6, if they:
- had radiotherapy or another appropriate therapy for the brain or spinal metastases, AND
- have no neurological symptoms that can be attributed to the current brain lesions, AND
- have stable brain or spinal disease on the computed tomography (CT) or magnetic resonance imaging (MRI) scan within 4 weeks before signing the informed consent (confirmed by stable lesions on two scans at least 4 weeks apart), AND
- do not require steroid therapy for the treatment of brain or spinal metastases within 14 d before the first dose of trial treatment. Note: Spinal bone metastases (i.e., of the vertebrae) are allowed, unless imminent fracture or cord compression is anticipated.
- Systemic immune suppression:
- Current use of chronic systemic steroid medication (≤5 mg/day prednisolone equivalent is allowed); patients using physiological replacement doses of prednisone for adrenal or pituitary insufficiency are eligible. Note: Steroid medication given for supportive or prophylactic reasons during CRT for patients in Cohort 5 needs to be tapered to ≤5 mg/day prednisolone equivalent at latest on the day before the trial treatment starts.
- Other clinically relevant systemic immune suppression within the last 3 months before trial enrollment.
- Known history of seropositivity for human immunodeficiency virus (HIV) with CD4+ T-cell (CD4+) counts <350 cells/µL and with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections.
- Prior splenectomy.
- History/risk of interstitial lung disease or low baseline lung function (baseline pulse oximetry of less than 92% oxygen saturation [SpO2] without additional oxygen).
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply to all or some patients depending on the cohort.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 6 - BNT116 + cemiplimab + carboplatin + paclitaxel Paclitaxel BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab Cohort 7 - BNT116 + BNT316 BNT116 Dose finding for the combination of BNT116 with BNT316 (CTLA4 antibody) with dose escalation of BNT316 Cohort 7 - BNT116 + BNT316 BNT316 Dose finding for the combination of BNT116 with BNT316 (CTLA4 antibody) with dose escalation of BNT316 Cohort 8: BNT116 + anti-B7-H3 antibody conjugated to topoisomerase I inhibitor BNT116 Dose finding for the combination of BNT116 with an anti-B7-H3 antibody conjugated to a topoisomerase I inhibitor with dose escalation of the anti-B7-H3 antibody conjugated to a topoisomerase I inhibitor Cohort 8: BNT116 + anti-B7-H3 antibody conjugated to topoisomerase I inhibitor anti-B7-H3 antibody conjugated to topoisomerase I inhibitor Dose finding for the combination of BNT116 with an anti-B7-H3 antibody conjugated to a topoisomerase I inhibitor with dose escalation of the anti-B7-H3 antibody conjugated to a topoisomerase I inhibitor Cohort 9: BNT116 + anti-HER3 antibody conjugated to topoisomerase I inhibitor BNT116 Dose finding for the combination of BNT116 with an anti-HER3 antibody conjugated to a topoisomerase I inhibitor with dose escalation of the anti-HER3 antibody conjugated to a topoisomerase I inhibitor Cohort 9: BNT116 + anti-HER3 antibody conjugated to topoisomerase I inhibitor anti-HER3 antibody conjugated to topoisomerase I inhibitor Dose finding for the combination of BNT116 with an anti-HER3 antibody conjugated to a topoisomerase I inhibitor with dose escalation of the anti-HER3 antibody conjugated to a topoisomerase I inhibitor Cohort 1A - BNT116 monotherapy BNT116 - Cohort 1B - BNT116 monotherapy BNT116 - Cohort 2 - BNT116 + cemiplimab (PD-1/PD-L1 inhibitor refractory/relapsed patients) BNT116 - Cohort 2 - BNT116 + cemiplimab (PD-1/PD-L1 inhibitor refractory/relapsed patients) Cemiplimab - Cohort 3 - BNT116 + docetaxel BNT116 - Cohort 3 - BNT116 + docetaxel Docetaxel - Cohort 4 - BNT116 + cemiplimab (frail patients) BNT116 - Cohort 4 - BNT116 + cemiplimab (frail patients) Cemiplimab - Cohort 5 - BNT116 + cemiplimab (after concurrent chemoradiotherapy [CRT]) BNT116 - Cohort 5 - BNT116 + cemiplimab (after concurrent chemoradiotherapy [CRT]) Cemiplimab - Cohort 6 - BNT116 + cemiplimab + carboplatin + paclitaxel BNT116 BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab Cohort 6 - BNT116 + cemiplimab + carboplatin + paclitaxel Cemiplimab BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab Cohort 6 - BNT116 + cemiplimab + carboplatin + paclitaxel Carboplatin BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab
- Primary Outcome Measures
Name Time Method Cohorts 1, 2, 3, 4, 6, 7, 8, and 9: Occurrence of dose-limiting toxicities (DLTs) during the DLT observation period From first dose of IMP up to 21 days Cohorts 1 to 9: Occurrence of treatment-emergent adverse events (TEAEs) reported by relationship, seriousness, and grade up to 27 months According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
Cohort 6 only: Occurrence of treatment-related delays to surgery more than 9 weeks post the last dose of neo-adjuvant treatment up to 6 months Cohort 6 only: Occurrence of post-surgical adverse events (AEs) related to BNT116 and cemiplimab up to 27 months
- Secondary Outcome Measures
Name Time Method Cohorts 1, 2, 3, 4, 7, 8, and 9: Overall response rate (ORR) up to 27 months ORR defined as the number of patients with complete response (CR) or partial response (PR) as best overall response (BOR) according to response evaluation criteria in solid tumors (RECIST) v1.1 divided by the number of patients in the efficacy analysis set.
Cohorts 1, 2, 3, 4, 7, 8, and 9: Duration of response (DoR) up to 27 months DoR defined as the time from initial response until first objective tumor progression according to RECIST v1.1.
Cohorts 1, 2, 3, 4, 7, 8, and 9: Disease control rate (DCR) up to 27 months DCR defined as the number of patients with CR or PR or stable disease (SD) as BOR according to RECIST v1.1 divided by the number of patients in the efficacy analysis set.
Cohorts 1, 2, 3, 4, 7, 8, and 9: Duration of disease control defined as the time from initial detection of stable disease or response until first objective tumor progression according to RECIST v1.1 up to 27 months Duration of disease control defined as the time from initial detection of stable disease or response until first objective tumor progression according to RECIST v1.1.
Cohorts 1, 2, 3, 4, 7, 8, and 9: Progression-free survival (PFS) up to 48 months PFS defined as the time of first trial treatment until the first objective tumor progression according to RECIST v1.1 or death from any cause, whichever occurs first.
All cohorts: Overall survival (OS) up to 48 months OS defined as the time of first trial treatment until death from any cause.
Cohort 5 and 6: Event free survival (EFS) up to 48 months EFS defined as the length of time from first trial treatment to any of the following events: progression of disease, recurrence of disease or death from any cause, whichever occurs first.
Cohort 5 and 6: EFS rate at 12 and 24 months up to 24 months EFS rate defined as the number of patients without an EFS-defining event divided by the number of patients in the efficacy analysis set.
Cohort 6: Rate of pathologic responses At time of surgery (approximately after 3 months treatment) Rate of pathologic responses defined as the number of patients with major or complete pathologic response in the surgical specimen from surgery after neo-adjuvant trial treatment divided by the number of patients in the efficacy analysis set.
Cohort 6: ORR at the end of neo-adjuvant treatment (using RECIST v1.1) Up to 3 months ORR defined as the number of patients with CR or PR as BOR according to response evaluation criteria in solid tumors (RECIST) v1.1 divided by the number of patients in the efficacy analysis set.
Cohort 6: Rate of progressive disease at the end of neo-adjuvant treatment (using RECIST v1.1) Up to 3 months
Trial Locations
- Locations (39)
START Madrid - CIOCC. Grupo Hospital de Madrid (HM) - Centro Integral Oncologico Clara Campal (CIOCC)
🇪🇸Madrid, Spain
Krankenhaus Nordwest GmbH - Institut Fuer Klinisch-Onkologische Forschung (IKF)
🇩🇪Frankfurt, Germany
MD Anderson Cancer Center
🇪🇸Madrid, Spain
Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Complejo Hospitalario Universitario de Santiago de Compostela (CHUS) - Hospital Clinico Universitario (University Clinical Hospital)
🇪🇸Santiago De Compostela, Spain
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain
Hospital Universitario y Politecnico La Fe
🇪🇸Valencia, Spain
Yeditepe University
🇹🇷Istanbul, Turkey
Guy's and St Thomas NHS Foundation Trust
🇬🇧London, United Kingdom
University Medical Center Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Universitätsklinikum Köln
🇩🇪Köln, Germany
Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz KoeR
🇩🇪Mainz, Germany
ICON-PRA Budapest, Fázis 1 Vizsgálóhely
🇭🇺Budapest, Hungary
Semmelweis Egyetem ÁOK Belgyógyászati és Onkológiai Klinika
🇭🇺Budapest, Hungary
National Institute of Oncology
🇭🇺Budapest, Hungary
Clinexpert Ltd
🇭🇺Gyongyos, Hungary
Uniwersyteckie Centrum Kliniczne
🇵🇱Gdańsk, Poland
Adana Sehir Hospital
🇹🇷Adana, Turkey
Haceteppe Hospital
🇹🇷Ankara, Turkey
Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital
🇹🇷Ankara, Turkey
Warminsko Mazurskie Centrum Chorob Pluc w Olsztynie
🇵🇱Olsztyn, Poland
NZOZ Medpolonia Sp. Z o.o
🇵🇱Poznań, Poland
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
🇵🇱Warsaw, Poland
Institut Catala d'Oncologia Badalona, Hospital Germans Trias I Pujol
🇪🇸Badalona, Spain
Ankara City Hospital
🇹🇷Ankara, Turkey
Koc University Hospital
🇹🇷Istanbul, Turkey
University Medical Faculty Oncology Institute
🇹🇷Istanbul, Turkey
Ege University School of Medicine Tulay Aktas Oncology Hospital
🇹🇷Izmir, Turkey
Dokuz Eylul Medical School
🇹🇷İzmir, Turkey
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
Velindre NHS Trust
🇬🇧Cardiff, United Kingdom
The Clatterbridge Cancer Centre NHS Foundation Trust
🇬🇧Liverpool, United Kingdom
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
University of Kentucky Chandler Medical Center
🇺🇸Lexington, Kentucky, United States
Norton Cancer Institute
🇺🇸Louisville, Kentucky, United States
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
NEXT Virginia
🇺🇸Fairfax, Virginia, United States
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
🇬🇧Newcastle Upon Tyne, United Kingdom