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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- BioNTech SE
- 入组人数
- 320
- 试验地点
- 86
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must have histologically confirmed NSCLC and measurable disease by RECIST v1.
- •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.
- •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-
- •Cohort-specific inclusion criteria:
- •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).
- •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.
- •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.
- •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).
- •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.
- •Participants' NSCLC must be considered technically and medically resectable.
- •Participants must be considered eligible for neo-adjuvant treatment.
- •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.
- •Participants who are not candidates for chemotherapy as first-line treatment for the advanced or metastasized stage of NSCLC may be enrolled.
- •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.
排除标准
- •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.
研究组 & 干预措施
Cohort ALK/RET: BNT116 + ALK TKI or RET TKI
Dose confirmation for BNT116 in combination with either ongoing ALK-inhibitor or ongoing RET-inhibitor therapy. Treatment with ALK TKI or RET TKI is standard of care.
Cohort will enroll only at selected sites in the US.
干预措施: ALK-inhibitor or RET-inhibitor (Biological)
Cohort 8: BNT116 + 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
干预措施: anti-B7-H3 antibody conjugated to topoisomerase I inhibitor (Biological)
Cohort 9: BNT116 + Anti-HER3 Antibody Conjugated to Topoisomerase I Inhibitor
Dose confirmation 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
干预措施: anti-HER3 antibody conjugated to topoisomerase I inhibitor (Biological)
Cohort 6 - BNT116 + Cemiplimab + Carboplatin + Paclitaxel
BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab
干预措施: Cemiplimab (Biological)
Cohort 6 - BNT116 + Cemiplimab + Carboplatin + Paclitaxel
BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab
干预措施: Carboplatin (Drug)
Cohort 10: BNT116 + Bispecific Antibody for PD-L1 and VEGF-A (Frail Participants)
Dose confirmation for BNT116 in combination with a bispecific antibody for programmed death ligand 1 (PD-L1) and vascular endothelial growth factor A (VEGF-A) will be established.
干预措施: BNT116 (Biological)
Cohort 4 - BNT116 + Cemiplimab (Frail Participants)
干预措施: Cemiplimab (Biological)
Cohort 5 - BNT116 + Cemiplimab (After Concurrent Chemoradiotherapy [CRT])
干预措施: BNT116 (Biological)
Cohort 2 - BNT116 + Cemiplimab (PD-1/PD-L1 Inhibitor Refractory/Relapsed Participants)
干预措施: Cemiplimab (Biological)
Cohort 1A - BNT116 Monotherapy
干预措施: BNT116 (Biological)
Cohort 3 - BNT116 + Docetaxel
干预措施: BNT116 (Biological)
Cohort ALK/RET: BNT116 + ALK TKI or RET TKI
Dose confirmation for BNT116 in combination with either ongoing ALK-inhibitor or ongoing RET-inhibitor therapy. Treatment with ALK TKI or RET TKI is standard of care.
Cohort will enroll only at selected sites in the US.
干预措施: BNT116 (Biological)
Cohort 6 - BNT116 + Cemiplimab + Carboplatin + Paclitaxel
BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab
干预措施: BNT116 (Biological)
Cohort 10: BNT116 + Bispecific Antibody for PD-L1 and VEGF-A (Frail Participants)
Dose confirmation for BNT116 in combination with a bispecific antibody for programmed death ligand 1 (PD-L1) and vascular endothelial growth factor A (VEGF-A) will be established.
干预措施: Bispecific antibody for PD-L1 and VEGF-A (Biological)
Cohort 11: BNT116 + Bispecific Antibody for PD-L1 and VEGF-A (After Concurrent CRT)
Dose confirmation for BNT116 in combination with a bispecific antibody for PD-L1 and VEGF-A will be established in participants after concurrent CRT.
干预措施: Bispecific antibody for PD-L1 and VEGF-A (Biological)
Cohort EGFR : BNT116 + osimertinib
Dose confirmation for BNT116 in combination with ongoing osimertinib therapy. Treatment with osimertinib is standard of care.
Cohort will enroll only at selected sites in the US.
干预措施: Osimertinib (Biological)
Cohort 6 - BNT116 + Cemiplimab + Carboplatin + Paclitaxel
BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab
干预措施: Paclitaxel (Drug)
Cohort 1B - BNT116 Monotherapy
干预措施: BNT116 (Biological)
Cohort 2 - BNT116 + Cemiplimab (PD-1/PD-L1 Inhibitor Refractory/Relapsed Participants)
干预措施: BNT116 (Biological)
Cohort 3 - BNT116 + Docetaxel
干预措施: Docetaxel (Drug)
Cohort 4 - BNT116 + Cemiplimab (Frail Participants)
干预措施: BNT116 (Biological)
Cohort 5 - BNT116 + Cemiplimab (After Concurrent Chemoradiotherapy [CRT])
干预措施: Cemiplimab (Biological)
Cohort 7 - BNT116 + BNT316
Dose finding for the combination of BNT116 with BNT316 (CTLA4 antibody) with dose escalation of BNT316
干预措施: BNT116 (Biological)
Cohort 7 - BNT116 + BNT316
Dose finding for the combination of BNT116 with BNT316 (CTLA4 antibody) with dose escalation of BNT316
干预措施: BNT316 (Biological)
Cohort 8: BNT116 + 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
干预措施: BNT116 (Biological)
Cohort 9: BNT116 + Anti-HER3 Antibody Conjugated to Topoisomerase I Inhibitor
Dose confirmation 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
干预措施: BNT116 (Biological)
Cohort 11: BNT116 + Bispecific Antibody for PD-L1 and VEGF-A (After Concurrent CRT)
Dose confirmation for BNT116 in combination with a bispecific antibody for PD-L1 and VEGF-A will be established in participants after concurrent CRT.
干预措施: BNT116 (Biological)
Cohort EGFR : BNT116 + osimertinib
Dose confirmation for BNT116 in combination with ongoing osimertinib therapy. Treatment with osimertinib is standard of care.
Cohort will enroll only at selected sites in the US.
干预措施: BNT116 (Biological)
结局指标
主要结局
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
时间窗: From first dose of IMP up to 21 days
Cohort EGFR and Cohort ALK/RET will enroll only at selected sites in the US.
Cohorts 1 to 11, EGFR and ALK/RET: Occurrence of Treatment-Emergent Adverse Events (TEAEs) Reported by Relationship, Seriousness, and Grade
时间窗: up to 27 months
According to National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0). Cohort EGFR and Cohort ALK/RET will enroll only at selected sites in the US.
Cohort 6 only: Occurrence of Post-Surgical Adverse Events (AEs) Related to BNT116 and Cemiplimab
时间窗: 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
时间窗: up to 6 months
Cohorts 1, 2, 3, 4, 6, 7, 8, 9, 10 and 11: Occurrence of Dose-Limiting Toxicities (DLTs) During the DLT Observation Period
时间窗: From first dose of IMP up to 21 days
Cohorts 1 to 11: Occurrence of Treatment-Emergent Adverse Events (TEAEs) Reported by Relationship, Seriousness, and Grade
时间窗: up to 27 months
According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
次要结局
- Cohorts EGFR (osimertinib): PFS(up to 48 months)
- Cohort ALK/RET (ALK TKI or RET TKI): PFS(up to 48 months)
- Cohorts EGFR and ALK/RET: (BNT116): PFS per molecular NSCLC subtype(up to 48 months)
- Cohorts 1-11: Overall Survival (OS)(up to 48 months)
- Cohorts 5, 6 and 11: Event Free Survival (EFS)(up to 48 months)
- Cohorts 5, 6 and 11: EFS Rate at 12 and 24 months(up to 24 months)
- Cohort 6: ORR at the End of Neo-Adjuvant Treatment (Using RECIST v1.1)(up to 3 months)
- Cohort 6: Rate of Progressive Disease at the End of Neo-Adjuvant Treatment (Using RECIST v1.1)(up to 3 months)
- Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Disease Control Rate (DCR)(up to 27 months)
- Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Overall Response Rate (ORR)(up to 27 months)
- Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Duration of Response (DoR)(up to 27 months)
- Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Duration of Disease Control(up to 27 months)
- Cohorts 1, 2, 3, 4, 7, 8, 9, and 10: Progression-Free Survival (PFS)(up to 48 months)
- All cohorts: Overall Survival (OS)(up to 48 months)
- Cohort 5, 6 and 11: Event Free Survival (EFS)(up to 48 months)
- Cohort 5, 6 and 11: EFS Rate at 12 and 24 months(up to 24 months)
- Cohort 6: Rate of Pathologic Responses(At time of surgery (approximately after 3 months treatment))
- Cohort 6: ORR at the End of Neo-Adjuvant Treatment (Using RECIST v1.1)(Up to 3 months)
- Cohort 6: Rate of Progressive Disease at the End of Neo-Adjuvant Treatment (Using RECIST v1.1)(Up to 3 months)