Ignite Creation Date:
2025-12-25 @ 2:21 AM
Ignite Modification Date:
2025-12-26 @ 12:53 AM
Study NCT ID:
NCT07285434
Status:
ENROLLING_BY_INVITATION
Last Update Posted:
2025-12-16
First Post:
2025-11-14
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
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
Sponsor:
Biogenea Pharmaceuticals Ltd.
Organization:
Study Overview
Official Title:
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
Status:
ENROLLING_BY_INVITATION
Status Verified Date:
2025-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Microlyvaq™
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. polyfunctional Th1 and CD8⁺ responses to vaccine epitopes by ELISpot/ICS,
2. durable expansion and persistence of vaccine-linked TCR clonotypes in blood and, when feasible, in tumor,
3. rapid decline in circulating tumor DNA as an early molecular marker of tumor clearance,
4. improved tumor infiltration by CD8⁺ and Th1 cells, and
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.
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. polyfunctional Th1 and CD8⁺ responses to vaccine epitopes by ELISpot/ICS,
2. durable expansion and persistence of vaccine-linked TCR clonotypes in blood and, when feasible, in tumor,
3. rapid decline in circulating tumor DNA as an early molecular marker of tumor clearance,
4. improved tumor infiltration by CD8⁺ and Th1 cells, and
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.
Detailed Description:
This is an early Phase I, non-randomized, open-label, histology-stratified, two-arm interventional study evaluating Microlyvaq™, a personalized multi-epitope peptide vaccine, in combination with first-line pembrolizumab and platinum-based chemotherapy in adults with advanced or metastatic non-small cell lung cancer (NSCLC).
Patients are assigned to treatment arm according to tumor histology only (no randomization):
* 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, with standard folate, vitamin B12, and corticosteroid premedication.
Rationale and Unmet Need Pembrolizumab plus platinum-based chemotherapy is a standard first-line option in metastatic NSCLC and improves survival compared with chemotherapy alone. However, many patients never respond, and responders often experience early progression. Current biomarkers (e.g., PD-L1 expression or tumor mutational burden) do not reliably predict durable benefit. Major causes of failure include incomplete or exhausted tumor-reactive T-cell repertoires, stromal and vascular barriers to T-cell infiltration, immunosuppressive myeloid and cytokine milieus, metabolic constraints in the tumor microenvironment, and antigenic escape under immune pressure. Releasing PD-1-mediated inhibition, even together with chemotherapy-induced antigen release, often does not generate a sustained, diversified, polyfunctional anti-tumor immune response.
Microlyvaq™ is designed to introduce into each patient a de novo, computationally defined set of tumor-directed T-cell specificities that are tailored to the individual tumor mutational and antigenic landscape, aligned with the patient's HLA genotype, and biased toward clonally important, difficult-to-lose lesions to reduce antigen-loss escape. The vaccine is administered in a prime-boost schedule intentionally synchronized with pembrolizumab and the histology-appropriate chemotherapy backbone.
The overarching early Phase I hypothesis is that a personalized multi-epitope vaccine can be safely integrated with standard chemo-immunotherapy, will induce measurable polyfunctional T-cell responses and favorable biomarker changes, and may provide preliminary signals of deeper and more durable clinical responses than would be expected with chemo-immunotherapy alone, thereby justifying later-phase studies.
Microlyvaq™ Platform (Tumor Profiling and Epitope Selection) For each participant, tumor material is analyzed using next-generation sequencing and HLA typing to generate a patient-specific pool of candidate antigens, including private neoantigens (from non-synonymous mutations, indels, fusions or splice variants) and selected tumor-associated antigens that are overexpressed in NSCLC. An AI/machine-learning-based immunogenetic scoring system evaluates each candidate epitope with respect to predicted HLA binding, processing and presentation, tumor specificity, clonality, and likelihood of immune escape. Quantum-inspired structural modeling is then used to further prioritize peptides predicted to form stable peptide-MHC complexes that are accessible to T-cell receptors. From this process, a finite panel of class I and class II peptides is selected to compose the personalized Microlyvaq™ lot for that patient.
The epitope selection algorithm is "context-aware" of the planned chemotherapy backbone (carboplatin/paclitaxel in Arm 1 vs carboplatin/pemetrexed in Arm 2), recognizing that these regimens differentially shape patterns of tumor cell death, vascular and stromal remodeling, and transient changes in lymphoid and myeloid compartments. Panels are therefore optimized with respect to both the patient's tumor biology and the expected treatment-induced immune milieu.
Manufacturing and Administration Microlyvaq™ is manufactured under Good Manufacturing Practice (GMP) conditions. Selected peptides are synthesized, purified, and blended into a multi-epitope peptide formulation, with standard identity, purity, sterility, and endotoxin testing and verification of chain-of-identity and chain-of-custody. Feasibility endpoints include the proportion of enrolled patients in whom a Microlyvaq™ lot can be successfully generated and released within a clinically relevant time window from biopsy to first vaccination, as well as logistical performance across manufacturing, storage, shipping, and on-site handling.
The vaccine is administered by subcutaneous or intradermal injection (final route defined in the protocol) in a prime-boost schedule coordinated with pembrolizumab and chemotherapy (e.g., a prime in Cycle 1 followed by boosts in subsequent cycles and, where appropriate, during pembrolizumab maintenance). Standard premedication and post-dose observation are used to monitor for local and systemic reactions.
Study Objectives and Assessments Because this is an early Phase I non-randomized trial, the primary focus is on safety, tolerability, and feasibility of integrating Microlyvaq™ into standard first-line regimens for squamous and non-squamous NSCLC. Treatment-emergent adverse events, serious adverse events, and immune-related adverse events will be collected and graded using standard criteria. Feasibility measures include adherence to the planned vaccination schedule and the ability to deliver individualized vaccine lots on time.
Key secondary and exploratory objectives include evaluation of vaccine-induced CD4⁺ and CD8⁺ T-cell responses against vaccine-encoded epitopes, T-cell receptor (TCR) repertoire dynamics (clonal expansion and persistence of vaccine-linked clonotypes), circulating tumor DNA (ctDNA) kinetics, and changes in the tumor microenvironment in patients who consent to on-treatment biopsies. Preliminary anti-tumor activity (e.g., overall response rate, duration of response, progression-free survival and overall survival per RECIST v1.1) will be described separately in each arm; the study is not powered for formal inter-arm comparisons.
Patient Population and Treatment Eligible patients are adults with advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC who are candidates for first-line pembrolizumab plus platinum-based chemotherapy according to local standards, have ECOG performance status 0-1, adequate organ function, and sufficient tumor tissue for sequencing and HLA typing. Patients with squamous histology are assigned to Arm 1; those with non-squamous histology (e.g., adenocarcinoma or large-cell) are assigned to Arm 2. Key exclusions include prior PD-1/PD-L1/CTLA-4 blockade in the metastatic setting, uncontrolled CNS metastases, and clinically significant active autoimmune disease. Full eligibility criteria are specified elsewhere in the protocol.
Safety Monitoring and Oversight Patients will undergo regular clinical evaluations, laboratory testing, and radiologic assessments. Dosing of Microlyvaq™, pembrolizumab, and chemotherapy may be withheld, modified, or discontinued according to protocol-defined criteria in the event of toxicity. Immune-related toxicities will be managed in accordance with contemporary guidelines for checkpoint inhibitors, with additional guidance for suspected vaccine-related events. An independent Data Safety Monitoring Board (DSMB) will periodically review accumulating safety, feasibility, and emerging efficacy/biomarker data and may recommend modification, temporary suspension, or early termination of one or both histology-defined arms if warranted.
Sample Size and Design Summary The initial safety cohort will enroll 12 patients who will be evaluable for toxicity. If no Microlyvaq™-related adverse event of \> Grade 2 is observed in more than 3 patients and no Grade 4 Microlyvaq™-related toxicity is observed in any patient, enrollment may expand to a total of 30 patients across both non-randomized arms. Data from this early Phase I study are intended to support the feasibility, safety, and biological activity of Microlyvaq™ and to guide the design of subsequent Phase Ib/II trials in squamous and non-squamous NSCLC.
Patients are assigned to treatment arm according to tumor histology only (no randomization):
* 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, with standard folate, vitamin B12, and corticosteroid premedication.
Rationale and Unmet Need Pembrolizumab plus platinum-based chemotherapy is a standard first-line option in metastatic NSCLC and improves survival compared with chemotherapy alone. However, many patients never respond, and responders often experience early progression. Current biomarkers (e.g., PD-L1 expression or tumor mutational burden) do not reliably predict durable benefit. Major causes of failure include incomplete or exhausted tumor-reactive T-cell repertoires, stromal and vascular barriers to T-cell infiltration, immunosuppressive myeloid and cytokine milieus, metabolic constraints in the tumor microenvironment, and antigenic escape under immune pressure. Releasing PD-1-mediated inhibition, even together with chemotherapy-induced antigen release, often does not generate a sustained, diversified, polyfunctional anti-tumor immune response.
Microlyvaq™ is designed to introduce into each patient a de novo, computationally defined set of tumor-directed T-cell specificities that are tailored to the individual tumor mutational and antigenic landscape, aligned with the patient's HLA genotype, and biased toward clonally important, difficult-to-lose lesions to reduce antigen-loss escape. The vaccine is administered in a prime-boost schedule intentionally synchronized with pembrolizumab and the histology-appropriate chemotherapy backbone.
The overarching early Phase I hypothesis is that a personalized multi-epitope vaccine can be safely integrated with standard chemo-immunotherapy, will induce measurable polyfunctional T-cell responses and favorable biomarker changes, and may provide preliminary signals of deeper and more durable clinical responses than would be expected with chemo-immunotherapy alone, thereby justifying later-phase studies.
Microlyvaq™ Platform (Tumor Profiling and Epitope Selection) For each participant, tumor material is analyzed using next-generation sequencing and HLA typing to generate a patient-specific pool of candidate antigens, including private neoantigens (from non-synonymous mutations, indels, fusions or splice variants) and selected tumor-associated antigens that are overexpressed in NSCLC. An AI/machine-learning-based immunogenetic scoring system evaluates each candidate epitope with respect to predicted HLA binding, processing and presentation, tumor specificity, clonality, and likelihood of immune escape. Quantum-inspired structural modeling is then used to further prioritize peptides predicted to form stable peptide-MHC complexes that are accessible to T-cell receptors. From this process, a finite panel of class I and class II peptides is selected to compose the personalized Microlyvaq™ lot for that patient.
The epitope selection algorithm is "context-aware" of the planned chemotherapy backbone (carboplatin/paclitaxel in Arm 1 vs carboplatin/pemetrexed in Arm 2), recognizing that these regimens differentially shape patterns of tumor cell death, vascular and stromal remodeling, and transient changes in lymphoid and myeloid compartments. Panels are therefore optimized with respect to both the patient's tumor biology and the expected treatment-induced immune milieu.
Manufacturing and Administration Microlyvaq™ is manufactured under Good Manufacturing Practice (GMP) conditions. Selected peptides are synthesized, purified, and blended into a multi-epitope peptide formulation, with standard identity, purity, sterility, and endotoxin testing and verification of chain-of-identity and chain-of-custody. Feasibility endpoints include the proportion of enrolled patients in whom a Microlyvaq™ lot can be successfully generated and released within a clinically relevant time window from biopsy to first vaccination, as well as logistical performance across manufacturing, storage, shipping, and on-site handling.
The vaccine is administered by subcutaneous or intradermal injection (final route defined in the protocol) in a prime-boost schedule coordinated with pembrolizumab and chemotherapy (e.g., a prime in Cycle 1 followed by boosts in subsequent cycles and, where appropriate, during pembrolizumab maintenance). Standard premedication and post-dose observation are used to monitor for local and systemic reactions.
Study Objectives and Assessments Because this is an early Phase I non-randomized trial, the primary focus is on safety, tolerability, and feasibility of integrating Microlyvaq™ into standard first-line regimens for squamous and non-squamous NSCLC. Treatment-emergent adverse events, serious adverse events, and immune-related adverse events will be collected and graded using standard criteria. Feasibility measures include adherence to the planned vaccination schedule and the ability to deliver individualized vaccine lots on time.
Key secondary and exploratory objectives include evaluation of vaccine-induced CD4⁺ and CD8⁺ T-cell responses against vaccine-encoded epitopes, T-cell receptor (TCR) repertoire dynamics (clonal expansion and persistence of vaccine-linked clonotypes), circulating tumor DNA (ctDNA) kinetics, and changes in the tumor microenvironment in patients who consent to on-treatment biopsies. Preliminary anti-tumor activity (e.g., overall response rate, duration of response, progression-free survival and overall survival per RECIST v1.1) will be described separately in each arm; the study is not powered for formal inter-arm comparisons.
Patient Population and Treatment Eligible patients are adults with advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC who are candidates for first-line pembrolizumab plus platinum-based chemotherapy according to local standards, have ECOG performance status 0-1, adequate organ function, and sufficient tumor tissue for sequencing and HLA typing. Patients with squamous histology are assigned to Arm 1; those with non-squamous histology (e.g., adenocarcinoma or large-cell) are assigned to Arm 2. Key exclusions include prior PD-1/PD-L1/CTLA-4 blockade in the metastatic setting, uncontrolled CNS metastases, and clinically significant active autoimmune disease. Full eligibility criteria are specified elsewhere in the protocol.
Safety Monitoring and Oversight Patients will undergo regular clinical evaluations, laboratory testing, and radiologic assessments. Dosing of Microlyvaq™, pembrolizumab, and chemotherapy may be withheld, modified, or discontinued according to protocol-defined criteria in the event of toxicity. Immune-related toxicities will be managed in accordance with contemporary guidelines for checkpoint inhibitors, with additional guidance for suspected vaccine-related events. An independent Data Safety Monitoring Board (DSMB) will periodically review accumulating safety, feasibility, and emerging efficacy/biomarker data and may recommend modification, temporary suspension, or early termination of one or both histology-defined arms if warranted.
Sample Size and Design Summary The initial safety cohort will enroll 12 patients who will be evaluable for toxicity. If no Microlyvaq™-related adverse event of \> Grade 2 is observed in more than 3 patients and no Grade 4 Microlyvaq™-related toxicity is observed in any patient, enrollment may expand to a total of 30 patients across both non-randomized arms. Data from this early Phase I study are intended to support the feasibility, safety, and biological activity of Microlyvaq™ and to guide the design of subsequent Phase Ib/II trials in squamous and non-squamous NSCLC.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: