Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced Non-small Cell Lung Cancer

Официальное название

LuCa-MERIT-1: First-in-human, Open Label, Phase I Dose Confirmation Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced Non-small Cell Lung Cancer

Обзор

This first-in-human (FIH) study 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, osimertinib, anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), rearranged during transfection (RET) TKIs, BNT316 (an anti-cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\] antibody), an anti-B7-H3 antibody conjugated to a topoisomerase I inhibitor, an anti-human epidermal growth factor receptor 3 (HER3) antibody conjugated to a topoisomerase I inhibitor or a bispecific antibody for programmed death ligand 1 (PD-L1) and vascular endothelial growth factor A (VEGF-A) in participants with non-small cell lung cancer (NSCLC). The study will comprise several cohorts for dose confirmation in monotherapy as well as in combinations of BNT116 as mentioned above. The study will enroll participants with NSCLC in advanced or metastatic stage in Cohorts 1 to 4 and Cohorts 7 to 10, unresectable NSCLC Stage III in Cohorts 5 and 11, resectable NSCLC of Stage II and III in Cohort 6, advanced/metastatic epidermal growth factor receptor (EGFR)-mutant NSCLC in Cohort EGFR, and advanced/metastatic ALK rearranged or RET rearranged NSCLC in Cohort ALK/RET. Cohort EGFR and Cohort ALK/RET will enroll only at selected sites in the US.

Подробное описание

The maximum duration of treatment for each individual participant in this study is:

* Cohorts 1 to 4, Cohorts 7 to 10, Cohort EGFR, and Cohort ALK/RET: 24 months. * Cohorts 5 and 11: 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.

Вмешательства

• Биопрепарат BNT116
  Intravenous injection
• Биопрепарат Cemiplimab
  Intravenous infusion
• Препарат Docetaxel
  Intravenous infusion
• Препарат Carboplatin
  Intravenous infusion
• Препарат Paclitaxel
  Intravenous infusion
• Биопрепарат BNT316
  Intravenous infusion
• Биопрепарат anti-B7-H3 antibody conjugated to topoisomerase I inhibitor
  Intravenous infusion
• Биопрепарат anti-HER3 antibody conjugated to topoisomerase I inhibitor
  Intravenous infusion
• Биопрепарат Bispecific antibody for PD-L1 and VEGF-A
  Intravenous infusion
• Биопрепарат Osimertinib
  Oral

Первичные конечные точки

• Cohorts 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, EGFR and ALK/RET: Occurrence of Dose-Limiting Toxicities (DLTs) During the DLT Observation Period [Срок оценки: From first dose of IMP up to 21 days]
• Cohorts 1 to 11, EGFR and ALK/RET: Occurrence of Treatment-Emergent Adverse Events (TEAEs) Reported by Relationship, Seriousness, and Grade [Срок оценки: up to 27 months]
• Cohort 6 only: Occurrence of Post-Surgical Adverse Events (AEs) Related to BNT116 and Cemiplimab [Срок оценки: up to 27 months]
• Cohort 6 only: Occurrence of Treatment-Related Delays to Surgery More Than 9 weeks Post the Last Dose of Neo-Adjuvant Treatment [Срок оценки: up to 6 months]

Вторичные конечные точки (12)

• Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Overall Response Rate (ORR) [Срок оценки: up to 27 months]
• Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Duration of Response (DoR) [Срок оценки: up to 27 months]
• Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Disease Control Rate (DCR) [Срок оценки: up to 27 months]
• Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Duration of Disease Control [Срок оценки: up to 27 months]
• Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Progression-Free Survival (PFS) [Срок оценки: up to 48 months]
• Cohorts EGFR (osimertinib): PFS [Срок оценки: up to 48 months]
• Cohort ALK/RET (ALK TKI or RET TKI): PFS [Срок оценки: up to 48 months]
• Cohorts EGFR and ALK/RET: (BNT116): PFS per molecular NSCLC subtype [Срок оценки: up to 48 months]
• Cohorts 1-11: Overall Survival (OS) [Срок оценки: up to 48 months]
• Cohorts 5, 6 and 11: Event Free Survival (EFS) [Срок оценки: up to 48 months]
• Cohort 6: Rate of Pathologic Responses [Срок оценки: At time of surgery (approximately after 3 months treatment)]
• Cohorts 5, 6 and 11: EFS Rate at 12 and 24 months [Срок оценки: up to 24 months]

Критерии участия

Критерии включения

• Participants must have histologically confirmed NSCLC and measurable disease by RECIST v1.1. Note: Participants in Cohorts 1, 5 and 11 as well as in Cohorts EGFR and ALK/RET do not have to present with measurable disease.

• Participants must present with unresectable Stage III or metastatic Stage IV NSCLC by American Joint Commission on Cancer (AJCC) Cancer Staging Manual, Eighth Edition.

EXCEPT

• Participants in Cohorts 5 and 11 must present with unresectable Stage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition before receiving pre-study chemoradiotherapy.
• Participants in Cohort 6 with the initial diagnosis of resectable Stage II and Stage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition.
• Participants in Cohorts 2, 4, 5, 6, 10 and 11 must be able to tolerate (additional) anti-PD-1 therapy (i.e., did not permanently discontinue anti-programmed death protein 1 \[PD-1\] / PD-L1\] therapy due to toxicity).
• Participants must have an Eastern Cooperative Oncology Group performance status (ECOG-PS) less than or equal to (<=) 1, except for participants in Cohorts 1, 4, 5, 10 and 11 who are eligible with an ECOG-PS of 0-2.

Cohort-specific inclusion criteria:

Cohort 1:

• Participants' 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 participant is not candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor and/or another line of systemic therapy). Note: Participants newly enrolled in Cohort 1B under protocol v 5.0 and subsequent versions of the protocol must consent to mandatory blood sampling for peripheral blood mononuclear cells (PBMCs).
• Participants who are to start cemiplimab at Cycle 3 must present with PD-L1 expression of tumor proportion score (TPS) greater than or equal to (>=) 1% in tumor cells (as determined locally).

Cohort 2:

• Participants must present with PD-L1 expression of TPS >= 50% in tumor cells (as determined locally prior to inclusion in this study).
• Participants 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 study.

Cohort 3:

• Participants' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a participant is not candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).
• Participants must present with progressive disease.

Cohort 4:

• Participants 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:

• Participants' NSCLC must have been considered unresectable due to participant's condition and/or tumor-related factors and the participants must have undergone chemoradiotherapy before entering the study.

Cohort 6:

• Participants' NSCLC must be considered technically and medically resectable.
• Participants must be considered eligible for neo-adjuvant treatment.

Cohort 7:

• Participants' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a participant is not a candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor). Note 1: Participants 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), VEGF or VEGF receptor (VEGFR) inhibitor as monotherapy or part of a combination therapy. Note 2: If the participants' prior therapies included a CTLA-4 inhibitor, the participant must be able to tolerate (additional) treatment with the CTLA-4 inhibitor.
• Participants must present with progressive disease at study enrollment.
• Participants must consent to mandatory blood sampling for PBMCs.

Cohorts 8 \& 9:

• Participants' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a participant is not a candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).
• Participants must present with progressive disease at study enrollment.

Cohort 10:

• Participants who are not candidates for chemotherapy as first-line treatment for the advanced or metastasized stage of NSCLC may be enrolled.

Cohort 11:

• Participants' NSCLC must have been considered unresectable due to participants condition and/or tumor related factors and the participants must have undergone chemoradiotherapy before entering the study.

Cohort EGFR (will enroll only at selected sites in the US):

• Participants' NSCLC must have classical EGFR mutations, i.e., ex19Del or L858R.
• Participants must have ongoing treatment with osimertinib.

Cohort ALK/RET (will enroll only at selected sites in the US):

• Participants' NSCLC must have ALK rearrangement or RET rearrangement.
• Participants must have ongoing treatment with a standard of care ALK TKI or RET TKI.

Критерии исключения

• Ongoing active systemic treatment against NSCLC.
• Presence of a driver mutation for which approved target therapies are available except if the participant is not a candidate for the respective targeted therapy. EXCEPT participants in Cohort EGFR and Cohort ALK/RET.
• 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: Participants 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. Participants with leptomeningeal disease are excluded. Participants with known brain or spinal metastases may be eligible for all Cohorts, except for Cohorts 5, 6 and 11, 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 days before the first dose of study treatment. Note: Spinal bone metastases (that is, 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); participants 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 participants in Cohorts 5 and 11 needs to be tapered to <= 5 mg/day prednisolone equivalent at latest on the day before the study treatment starts.
• Other clinically relevant systemic immune suppression within the last 3 months before study enrollment.
• Known history of seropositivity for human immunodeficiency virus (HIV) with cluster of differentiation 4 (CD4)+ T-cell (CD4+) counts less than (<) 350 cells/microlitre (mcL) 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 without additional oxygen).

NOTE: Other protocol defined Inclusion/Exclusion criteria apply to all or some participants depending on the cohort.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Turkey (Türkiye) · 9 центров

• Adana City Training and Research Hospital — Adana
• Haceteppe Hospital — Ankara
• Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital — Ankara
• Ankara City Hospital — Ankara
• Koc University Hospital — Istanbul
• University Medical Faculty Oncology Institute — Istanbul
• Yeditepe University — Istanbul
• Ege University School of Medicine Tulay Aktas Oncology Hospital — Izmir
• … и ещё 1 центр

Испания · 8 центров

• Institut Catala d'Oncologia Badalona, Hospital Germans Trias I Pujol — Badalona
• Hospital Universitario Vall d'Hebron — Barcelona
• MD Anderson Cancer Center — Madrid
• Hospital Universitario Fundacion Jimenez Diaz — Madrid
• START Madrid - CIOCC. Grupo Hospital de Madrid (HM) - Centro Integral Oncologico Clara Cam — Madrid
• Complejo Hospitalario Universitario de Santiago de Compostela (CHUS) - Hospital Clinico Un — Santiago de Compostela
• Hospital Universitario Virgen Macarena — Seville
• Hospital Universitario y Politecnico La Fe — Valencia

США · 6 центров

• University of Kentucky Chandler Medical Center — Lexington
• Norton Cancer Institute — Louisville
• Johns Hopkins Sidney Kimmel Comprehensive Cancer Center — Baltimore
• Ohio State University — Columbus
• MD Anderson Cancer Center — Houston
• NEXT Virginia — Fairfax

Великобритания · 6 центров

• Cambridge University Hospitals NHS Foundation Trust — Cambridge
• Velindre NHS Trust — Cardiff
• The Clatterbridge Cancer Centre NHS Foundation Trust — Liverpool
• Guy's and St Thomas NHS Foundation Trust — London
• University College London Hospitals NHS Foundation Trust — London
• The Newcastle Upon Tyne Hospitals NHS Foundation Trust — Newcastle upon Tyne

Австралия · 4 центра

• Scientia Clinical Research — Randwick
• Royal North Shore Hospital — Sydney
• Cancer Research SA — Adelaide
• Monash Health — Clayton

Германия · 4 центра

• Universitätsklinikum Köln — Cologne
• Krankenhaus Nordwest GmbH - Institut Fuer Klinisch-Onkologische Forschung (IKF) — Frankfurt
• University Medical Center Hamburg-Eppendorf — Hamburg
• Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz KoeR — Mainz

Венгрия · 4 центра

• ICON-PRA Budapest, Fázis 1 Vizsgálóhely — Budapest
• Semmelweis Egyetem ÁOK Belgyógyászati és Onkológiai Klinika — Budapest
• National Institute of Oncology — Budapest
• Clinexpert Ltd — Gyöngyös

Польша · 4 центра

• Uniwersyteckie Centrum Kliniczne — Gdansk
• Warminsko Mazurskie Centrum Chorob Pluc w Olsztynie — Olsztyn
• NZOZ Medpolonia Sp. Z o.o — Poznan
• Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy — Warsaw

Идентификаторы

NCT: NCT05142189 · BNT116-01 · 2021-004739-94 · 2023-509283-14-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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