Clinical Study of the Therapeutic Effectiveness of In-silico-Designed, Machine Learning Inspired, and Quantum-molecularly Coupled Personalized Neoantigenic Vaccines Microlyvaq™ in Patients With Advanced Non-small Cell Lung Cancer

NCT07285434 | Enrolling By Invitation Early Phase 1 DMC

• 1 other identifier: Biogenea2
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Microlyvaq™ is a first-line, non-randomized, two-arm clinical trial in advanced non-small cell lung cancer (NSCLC). In both arms, patients receive a personalized multi-epitope vaccine (Microlyvaq™) on top of standard-of-care chemo-immunotherapy, with treatment tailored by histology: Arm 1 - Squamous NSCLC: Microlyvaq™ + carboplatin AUC 5 + paclitaxel 175 mg/m² + pembrolizumab Arm 2 - Non-squamous NSCLC: Microlyvaq™ + carboplatin AUC 5 + pemetrexed 500 mg/m² + pembrolizumab Because this is a non-randomized study, patients are assigned to arms based on tumor histology (squamous vs non-squamous), not by random allocation. The core problem it addresses is that even with pembrolizumab plus histology-appropriate chemotherapy, many patients either never respond or respond briefly and then progress. Tumors evade by exhausting T cells, excluding them from the tumor bed, evolving antigen loss, and maintaining suppressive myeloid and stromal niches. Microlyvaq™ is designed to overcome these resistance modes by actively installing new, durable, polyfunctional anti-tumor immunity rather than relying only on pre-existing T cells. Here's how it works. Each patient's tumor is sequenced (whole exome and RNA-seq) to identify both well-known lung cancer-associated antigens (e.g. NY-ESO-1, SOX2, p53, MAGE-A4, BRAF, BMI1, FXR1, HuD, HuC, CAGE) and private neoantigens created by that tumor's specific mutations, fusions, and splice variants. From this large antigen pool, machine learning models score each candidate epitope for that specific patient. The models consider predicted HLA class I and II presentation, how efficiently the antigen will actually be processed and displayed, whether it's expressed in tumor but not healthy tissue, how essential it is to most malignant cells (to avoid easy escape), and whether it is likely to drive functional, non-exhausted T-cell responses. This is not a generic ranking; it is individualized per patient. The most promising epitopes then undergo a quantum molecular coupling evaluation. Instead of simply asking whether a peptide binds a given HLA, Microlyvaq™ modeling simulates the peptide-MHC complex as a physical system and approximates solutions to Ĥψ = Eψ to estimate whether the peptide will form a stable, low-energy, presentation-competent conformation that a realistic T-cell receptor can dock to without high energetic penalty. Epitopes that look good in simple binding screens but are predicted to be unstable, transient, or geometrically inaccessible to TCRs are excluded. The remaining epitope set is engineered to: (1) recruit potent CD8⁺ cytotoxic T cells that can kill tumor cells, and (2) recruit CD4⁺ Th1 helper T cells that produce IFN-γ, TNF-α, and IL-2 to sustain and support those killers. The vaccine is therefore intentionally multi-epitope, Th1-biased, and patient-specific. Each personalized Microlyvaq™ lot is manufactured under GMP and given as a prime-boost series in sync with pembrolizumab and the appropriate chemotherapy backbone for the patient's histologic arm (carboplatin/paclitaxel for squamous; carboplatin/pemetrexed for non-squamous). Timing is deliberate: chemotherapy induces immunogenic tumor cell death and antigen release and transiently "opens up" the tumor microenvironment, while pembrolizumab lifts PD-1-mediated brakes on emerging T cells. Microlyvaq™ is dosed into that vulnerable window to expand vaccine-encoded clones just as new antigen is exposed and suppression is partially relieved. The goal is to generate rapid tumor shrinkage, then sustained immune pressure on residual disease, plus epitope spreading - where the immune system begins to recognize additional tumor targets beyond those in the vaccine, making escape more difficult. The trial itself is structured as a seamless, adaptive, non-randomized Phase I/IIa study, with two predefined histology-based arms (squamous vs non-squamous) rather than randomized treatment allocations. The primary early endpoint is objective response rate (RECIST v1.1). Key secondary endpoints include progression-free survival, duration of response, and overall survival. In addition, the study incorporates real-time translational signals as decision points, including:

1. 1.polyfunctional Th1 and CD8⁺ responses to vaccine epitopes by ELISpot/ICS,
2. 2.durable expansion and persistence of vaccine-linked TCR clonotypes in blood and, when feasible, in tumor,
3. 3.rapid decline in circulating tumor DNA as an early molecular marker of tumor clearance,
4. 4.improved tumor infiltration by CD8⁺ and Th1 cells, and
5. 5.remodeling of the tumor microenvironment away from suppressive myeloid states. If a given histology arm shows strong clinical responses plus these immune/molecular signals, that arm can seamlessly expand into survival-powered confirmation. If it does not, predefined futility rules allow that arm to stop, all within this non-randomized, adaptive framework.

Conditions

NSCLC (Non-small Cell Lung Cancer); Squamous Lung Cancer With FGFR1 Amplification; Non-Squamous Non Small Cell Lung Cancer

Keywords

Microlyvaq™; Neoantigen vaccine; Quantum molecular coupling; AI/ML-driven personalization; Th1 polyfunctional T-cell response; Pembrolizumab combination; Circulating tumor DNA (ctDNA) monitoring

Outcome Measures

Primary Outcomes (2)

• Overall Survival (OS): AI epitope ranking, quantum energetics, TCR repertoire engineering, ctDNA collapse, spatial immune remodeling - is in service of extending OS safely. Subjects alive at cut-off are censored at last known alive.

  Overall survival is the time from first dose of study treatment to death from any cause. Survival will be summarized with Kaplan-Meier curves; between-arm comparisons will use a stratified Cox model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). If non-proportional hazards are detected, restricted mean survival time (RMST) will be used. Stratification factors may include PD-L1 proportion score (TPS), smoking status, actionable driver status (EGFR/ALK/ROS1/ERBB2/KRAS-G12C), and geographic region. Subsequent anti-cancer therapy after progression will not reset survival time (treatment-policy strategy). Patients lost to follow-up will be censored at the last date known alive. Overall survival will be evaluated in two non-randomized histology cohorts: Arm 1 (squamous NSCLC): Microlyvaq™ + carboplatin + paclitaxel + pembrolizumab; Arm 2 (non-squamous NSCLC): Microlyvaq™ + carboplatin + pemetrexed + pembrolizumab (with folate/B12 and steroid support).

  Survival status assessed approximately every 12 weeks during long-term follow-up, through study completion, up to approximately 36 months.

• Objective Response Rate (ORR; Confirmed CR+PR): The Microlyvaq™ vaccine is delivered into a "window of susceptibility": right when chemotherapy has induced immunogenic cell death and pembrolizumab has lifted PD-1 brakes on on exhausted T cells.

  * ORR (%) with 95% CI in the Full Analysis Set (all randomized with measurable disease at baseline). * Between-arm comparison via stratified CMH or logistic regression adjusting for prespecified strata. * Missing confirmatory scan defaults to "non-responder" in the primary analysis to avoid false inflation. In Microlyvaq™, ORR is not just "does tumor shrink." It's "does our AI / ML / quantum-informed control signal actually force the tumor-immune system into the kill state we predicted, on schedule."• Each Microlyvaq™ lot is not a fixed commercial SKU. It's a computationally composed payload of \~17-25 epitopes, each picked for that exact patient by AI/ML plus quantum energy modeling to maximize productive peptide-HLA display, stable TCR engagement geometry, and resistance to tumor immune escape. In Microlyvaq™, ORR is not just "does tumor shrink." It's "does our AI / ML / quantum-informed signal actually force the tumor-immune system into the kill state we predicted, on schedule"

  Confirmation window: Response must be confirmed 8 weeks after first CR/PR call, so typically ~Week 14 for first responders.Update cadence: Every imaging timepoint: 6 weeks through Week 24, then 12 weeks thereafter.

Secondary Outcomes (6)

• Progression-Free Survival (PFS): Time from randomization to first of either: 1. RECIST v1.1 progression (investigator), or 2. Death from any cause. Sensitivity analysis uses blinded ERC progression calls.

  Time Frame: From baseline (scan within 28 days before Day 1) through study completion, with tumor assessments every 6 weeks through Week 24, then every 12 weeks thereafter (up to approximately 24 months).

• Duration of Response (DoR) for confirmed responders (CR/PR)

  From end of on-treatment follow-up, survival status assessed approximately every 12 weeks through study completion, up to approximately 36 months.

• Disease Control Rate (DCR): CR + PR + durable stable disease (SD ≥6 weeks at the first scheduled post-baseline scan).

  From the first post-baseline tumor assessment (approximately Week 6) through confirmation of disease control, with tumor assessments every 6 weeks through Week 24, then every 12 weeks thereafter through study completion (up to approximately 24

• Time to Response (TTR):Among responders, time from randomization to first confirmed CR/PR.

  First evaluable: First scan with CR/PR (~Week 6).Confirmation anchor: Responses are only counted once confirmed 4-8 weeks later (so confirmed TTR for early responders ~Week 10-14).

• Incidence of Treatment-Emergent Adverse Events (TEAEs)

  From first dose of any study drug through 30 days after the last dose of any study drug (up to approximately 12 months, depending on treatment duration).

Other Outcomes (6)

• Incidence of Procedure-Related Serious Adverse Events (SAEs)

  From baseline (Day 1) through study completion, up to approximately 36 months.

• Change From Baseline in EORTC QLQ-C30 Global Health Status/Quality of Life (QoL) Score

  From baseline (Day 1) through end of study or up to approximately 36 months, with EORTC QLQ-C30 assessments collected at scheduled study visits (approximately every 3 weeks through Week 24, then every 9-12 weeks thereafter).

• Proportion of Patients Achieving ctDNA Major Molecular Response (MMR)

  From baseline (pre-treatment sample) to the first on-treatment ctDNA assessment at approximately Week 6 (with an assessment window extending up to Week 9).

Study Arms (2)

Microlyvaq™ + carboplatin AUC 5, pemetrexed 500 mg/m2, pembrolizumab (Non-Squamous Backbone)

ACTIVE COMPARATOR

Arm A: Microlyvaq™ + Carboplatin + Pemetrexed + Pembrolizumab (Non-Squamous NSCLC) Target population: Adults with advanced/metastatic non-squamous NSCLC (adenocarcinoma, large-cell, or NSCLC-NOS adjudicated non-squamous) in the first-line systemic setting, with no prior systemic therapy for metastatic disease. Regimen: Patients receive a personalized Microlyvaq™ multi-epitope vaccine (AI/ML- and quantum-refined, derived from tumor WES/RNA-seq and high-resolution HLA typing) administered intradermally or subcutaneously (per pharmacy manual), together with carboplatin AUC 5, pemetrexed 500 mg/m², and pembrolizumab at protocol-specified doses and schedule. Microlyvaq™ is given as a prime on Cycle 1 Day 1 (±window), with boosts around Cycle 2 (\~Week 3) and Cycle 3 (\~Week 6), and optional maintenance/booster doses aligned with pembrolizumab (±pemetrexed) maintenance.

Biological: Microlyvaq™ (Personalized Multi-Epitope Immunotherapeutic)

Microlyvaq™ + carboplatin AUC5, paclitaxel 175 mg/m2, pembrolizumab (Squamous-Adapted Backbone)

ACTIVE COMPARATOR

Arm A: Microlyvaq™ + carboplatin AUC5, paclitaxel 175 mg/m2, pembrolizumab (Squamous NSCLC) Target population / stratum: Adults with advanced/metastatic squamous NSCLC in the first-line systemic setting, with no prior systemic therapy for metastatic disease in this line. Regimen: Patients receive personalized Microlyvaq™ (AI/ML-driven epitope discovery, quantum molecular stability screening, Th1-skewed design) plus carboplatin AUC 5, paclitaxel 175 mg/m², and pembrolizumab at protocol-specified doses and schedule. Microlyvaq™ dosing follows the same core prime/boost structure as the non-squamous arm: Prime: Cycle 1 (Day 1 ± window) Boost 1: \~Week 3 (Cycle 2) Boost 2: \~Week 6 (Cycle 3) Optional continued boosters aligned with pembrolizumab maintenance. The same observation, safety, and reactogenicity monitoring rules apply as in the non-squamous arm.

Biological: Microlyvaq™ (Personalized Multi-Epitope Immunotherapeutic)

Interventions

Microlyvaq™ (Personalized Multi-Epitope Immunotherapeutic) BIOLOGICAL

1\. Investigational Intervention 1.1 Microlyvaq™ (Personalized Multi-Epitope Immunotherapeutic) A patient-specific, algorithmically composed, GMP-manufactured multi-epitope immunotherapy. Each subject's Microlyvaq™ lot is built using: Whole exome sequencing (WES), RNA-seq of that subject's tumor, Matched normal DNA (when available), High-resolution HLA typing, AI/ML epitope immunogenicity ranking (tumor specificity, clonality, escape risk, Th1 bias), Quantum molecular coupling / stability modeling of peptide-HLA-TCR energetics. The final product intentionally contains: Class I-restricted epitopes (for CD8⁺ cytotoxic T cells), Class II-restricted epitopes (for CD4⁺ Th1 helper support and durability), All screened for manufacturability, sterility, and safety (GMP, QP release). Formulation / administration Multi-peptide (or peptide-adjuvant co-formulation) given intradermally/subcutaneously (route finalized in pharmacy manual). Co-administered with a Th1-skewing immunostimulator

Microlyvaq™ + carboplatin AUC 5, pemetrexed 500 mg/m2, pembrolizumab (Non-Squamous Backbone); Microlyvaq™ + carboplatin AUC5, paclitaxel 175 mg/m2, pembrolizumab (Squamous-Adapted Backbone)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects are eligible if all of the following are met:
• Age
• ≥18 years at the time of informed consent. Diagnosis / Histology
• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is:
• Non-squamous (e.g. adenocarcinoma, large-cell, NSCLC-NOS adjudicated non-squamous), or Squamous (if/when that stratum is open). Diagnosis must be locally documented and source-verifiable. Stage / Disease Status Stage IIIB / IIIC / IV or recurrent/metastatic NSCLC not amenable to curative surgery or radiotherapy, per AJCC 8th edition staging.
• Disease is considered first-line metastatic/systemic setting:
• No prior systemic therapy for advanced/metastatic disease in this line. Prior adjuvant/neoadjuvant therapy or consolidation chemo-RT is allowed if completed and the subject relapsed outside the protocol-defined disease-free interval (e.g. relapse ≥6-12 months after completion, per final protocol text).
• Measurable Disease At least one measurable lesion per RECIST v1.1 at baseline imaging. Baseline imaging must be within 28 days prior to Day 1 (CT chest/abdomen/pelvis ± contrast, plus brain MRI if clinically indicated).
• ECOG Performance Status ECOG 0 or 1 at screening. Subject must be ambulatory and clinically stable enough to receive combination therapy (pembrolizumab + chemo ± Microlyvaq™).
• Adequate Organ and Marrow Function (Representative thresholds - to be finalized numerically in the protocol SOP, but typically:) Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L. Platelets ≥100 × 10⁹/L. Hemoglobin ≥9.0 g/dL (transfusion allowed per institutional standard prior to enrollment).
• AST and ALT ≤2.5 × upper limit of normal (ULN), or ≤5 × ULN if liver metastases are present.
• Total bilirubin ≤1.5 × ULN (≤3 × ULN if known Gilbert's syndrome). Creatinine clearance / eGFR ≥45 mL/min/1.73 m² (sufficient for pemetrexed/platinum; final numeric cutoff may align to pemetrexed label).
• Coagulation: INR and aPTT compatible with safe biopsy (if biopsy expected) per site policy.
• Oxygenation: No resting hypoxemia prohibitive for safe treatment in investigator judgment.
• Tumor Tissue Availability

You may not qualify if:

• Subjects must not meet any of the following:
• Prior Systemic Therapy in Metastatic Setting Any prior systemic therapy for metastatic / unresectable NSCLC in the current line.
• Known Oncogene-Addicted Disease Requiring Targeted SOC Subjects whose tumors harbor actionable drivers for which an approved targeted therapy is standard first-line care (e.g. EGFR activating mutation, ALK rearrangement, ROS1 rearrangement, certain ERBB2/HER2 drivers, MET exon 14 skipping, RET fusion, NTRK fusion, KRAS G12C where local standard is targeted frontline) may be excluded or enrolled only in specific sub-cohorts if allowed by the statistical design.
• Rationale: It may be unethical to withhold proven first-line targeted agents. The final protocol will define whether these genotypes are (a) excluded, (b) stratified, or (c) routed to a molecularly restricted exploratory cohort.
• Uncontrolled CNS Disease Active, symptomatic brain metastases or leptomeningeal disease requiring immediate local intervention.
• Allowed:
• Previously treated/stable brain metastases are permitted if:
• Clinically stable, Off high-dose steroids (e.g. \>10 mg prednisone equivalent daily) for ≥14 days before Day 1, No new/worsening neurologic symptoms for ≥2 weeks.
• Excluded:
• Ongoing steroid dependency above immunosuppressive thresholds, uncontrolled seizures, mass effect with high intracranial pressure, or unstable neuro deficits judged unsafe.
• Autoimmune / Immune-Mediated Conditions of Concern Active, uncontrolled autoimmune disease that has required systemic immunosuppression \>10 mg/day prednisone-equivalent (or biologic immunosuppressive agent) within 14 days prior to Day 1.
• History of severe (life-threatening) immune-related adverse event (irAE) to prior PD-1/PD-L1/CTLA-4 (e.g. Grade 4 pneumonitis, myocarditis, neurologic irAE that did not fully resolve), unless cleared by Medical Monitor.
• Autoimmune disorders that are mild, stable, and not expected to flare under PD-1 blockade (e.g. controlled hypothyroidism on replacement; vitiligo; stable type 1 diabetes on insulin) may be allowed.
• Significant Active Infection Any uncontrolled active infection requiring IV antibiotics or hospitalization at screening.
• Uncontrolled HBV, HCV, or HIV viremia above protocol thresholds:

Sponsors & Collaborators

• Biogenea Pharmaceuticals Ltd.: lead
• https://interonco.gr/en/: collaborator

Study Sites (1)

Biogenea Pharmaceuticals Ltd

Thessaloniki, Macedonia, 54627, Greece

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: John Grigoriadis, PharmDr (JGrigoriadis), Principal Investigator and Chief Scientific Officer

Model Details: The Microlyvaq™ interventional study model is a non-randomized, seamless adaptive Phase II/III, histology-stratified trial in first-line advanced NSCLC. Patients are not randomized between regimens; instead, they are assigned to one of two predefined treatment arms solely on the basis of tumor histology: Arm 1 - Squamous NSCLC: Microlyvaq™ personalized multi-epitope vaccine administered in combination with carboplatin AUC 5, paclitaxel 175 mg/m², and pembrolizumab. Arm 2 - Non-squamous NSCLC: Microlyvaq™ personalized multi-epitope vaccine administered in combination with carboplatin AUC 5, pemetrexed 500 mg/m², and pembrolizumab. The intervention is not one-size-fits-all: within each non-randomized arm, each patient's Microlyvaq™ lot is uniquely generated using AI/ML-guided selection of neoantigens, followed by quantum molecular stability ("quantum immunogenetics") to prioritize epitopes predicted to be stably presented and highly immunogenic.

Study Record Dates

• First Submitted: November 14, 2025
• First Posted: December 16, 2025
• Study Start: February 2, 2026
• Primary Completion (Estimated): February 2, 2028
• Study Completion (Estimated): February 2, 2030
• Last Updated: December 16, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: The IPD package described above will be prepared after: Database lock for the primary clinical analysis of the relevant cohort/arm, Resolution of all serious safety queries for that analysis set, Acceptance or public presentation/publication of primary efficacy and key safety results. A structured dictionary / codebook (variable definitions, derivations, censoring rules) will accompany the shared IPD so that outside investigators can interpret the fields without needing access to internal SOPs.
• Access Criteria: We will share de-identified, subject-level clinical efficacy, safety, imaging-derived response calls, ctDNA kinetics summaries, T-cell pharmacodynamic summaries (polyfunctionality and clonal expansion/persistence scores), and predefined tumor microenvironment scores. We will not broadly release raw genomic sequences, raw TCR sequences, full unmasked pathology images, or any directly identifying information. Access to more granular molecular data can be requested, but will require enhanced review, additional agreements, and documented safeguards.

Locations

GR (1)