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

Study Overview
=================
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 cemiplimab or docetaxel in patients with advanced or metastasized non-small cell lung cancer (NSCLC) and unresectable NSCLC after chemoradiotherapy (CRT). Furthermore, the trial aims to establish the safety and feasibility of BNT116 in combination with cemiplimab and chemotherapy (carboplatin+paclitaxel) as neo-adjuvant treatment in resectable NSCLC followed by surgery and adjuvant BNT116 + cemiplimab. The trial will comprise several cohorts for dose confirmation in monotherapy as well as in combinations of BNT116 as mentioned above.

Official Title
-----------------
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

Conditions
-----------------
Non-Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Biological: BNT116
* Biological: Cemiplimab
* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: 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 in Cohorts 1 to 4 must present with unresectable Stage III or metastatic Stage IV NSCLC by American Joint Commission on Cancer (AJCC) Cancer Staging Manual, Eighth Edition. 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 in Cohorts 2, 3, and 6 must have an Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1. Patients in Cohort 1, 4, and 5 with an ECOG-PS of 0-2 are eligible. 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 v4.0 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 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. Key Exclusion Criteria: 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 in Cohorts 1 to 4 if they: had radiotherapy or another appropriate therapy for the brain or spinal bone 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A - BNT116 monotherapy<br> | Biological: BNT116<br>* intravenous injection<br>|
| Experimental: Cohort 1B - BNT116 monotherapy<br> | Biological: BNT116<br>* intravenous injection<br>|
| Experimental: Cohort 2 - BNT116 + cemiplimab (PD-1/PD-L1 inhibitor refractory/relapsed patients)<br> | Biological: BNT116<br>* intravenous injection<br>Biological: Cemiplimab<br>* intravenous infusion<br>|
| Experimental: Cohort 3 - BNT116 + docetaxel<br> | Biological: BNT116<br>* intravenous injection<br>Drug: Docetaxel<br>* intravenous infusion<br>|
| Experimental: Cohort 4 - BNT116 + cemiplimab (frail patients)<br> | Biological: BNT116<br>* intravenous injection<br>Biological: Cemiplimab<br>* intravenous infusion<br>|
| Experimental: Cohort 5 - BNT116 + cemiplimab (after concurrent chemoradiotherapy [CRT])<br> | Biological: BNT116<br>* intravenous injection<br>Biological: Cemiplimab<br>* intravenous infusion<br>|
| Experimental: Cohort 6 - BNT116 + cemiplimab + carboplatin + paclitaxel<br>BNT116 + cemiplimab + carboplatin + paclitaxel as neo-adjuvant treatment followed by surgery, thereafter adjuvant treatment with BNT116 + cemiplimab | Biological: BNT116<br>* intravenous injection<br>Biological: Cemiplimab<br>* intravenous infusion<br>Drug: Carboplatin<br>* intravenous infusion<br>Drug: Paclitaxel<br>* intravenous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohorts 1, 2, 3, 4, and 6: Occurrence of dose-limiting toxicities (DLTs) during Cycle 1 |  | assessed during the first cycle (21 days) | 
| Cohorts 1 to 6: Occurrence of treatment-emergent adverse events (TEAEs) reported by relationship, seriousness, and grade according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 |  | up to 27 months | 
| Cohort 6 only: Occurrence of post-surgical adverse events (AEs) related to BNT116 and cemiplimab |  | 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 |  | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohorts 1 to 4: Overall response rate (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 | up to 27 months | 
| Cohorts 1 to 4: Duration of response (DoR) defined as the time from initial response until first objective tumor progression according to RECIST v1.1 |  | up to 27 months | 
| Cohorts 1 to 4: Disease control rate (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 |  | up to 27 months | 
| Cohorts 1 to 4: 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 | 
| Cohorts 1 to 4: Progression-free survival (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 |  | up to 48 months | 
| All cohorts: Overall survival (OS) defined as the time of first trial treatment until death from any cause |  | up to 48 months | 
| Cohort 5 and 6: Event free survival (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. |  | up to 48 months | 
| Cohort 5 and 6: EFS rate at 12 and 24 months defined as the number of patients without an EFS-defining event divided by the number of patients in the efficacy analysis set. |  | up to 24 months | 
| Cohort 6: 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. |  | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cancer Vaccine, Non-Small Cell Lung Cancer