Phase I Single-Arm Open-Label Study of GYNORYLAQ™-VLINIVAL™ Quantum-Entangled Personalized Neoantigen Peptide Vaccine (Seq⊗HLA⊗Immune→|ΨT⟩) in High-Risk/Recurrent Endometrial Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Incidence of Treatment-Emergent AEs/SAEs and DLTs (CTCAE v5.0) With GYNORYLAQ™ Plus Oncologist-Selected Drug Regimens
研究概览
简要总结
GYNORYLAQ-VLINIVAL is an Early Phase I, non-randomized, single-arm, open-label clinical trial enrolling 40 patients with high-risk or recurrent endometrial carcinoma. All participants receive GYNORYLAQ-TM, a personalized neoantigenic peptide vaccine generated by the GYNORYLAQ-EC™ quantum-classical engine, in combination with systemic and supportive drug regimens that are individually selected and prescribed by the treating medical oncologist, Dr Emmanouelides Christos, according to contemporary standards of care and the clinical status of each patient. Only the GYNORYLAQ-TM vaccine is considered investigational within this protocol; all concomitant drugs (including antineoplastic agents and supportive care medications) are non-investigational, chosen and adjusted at the discretion of Dr Emmanouelides Christos. The primary objectives are to evaluate the safety/tolerability of GYNORYLAQ-TM in this real-world therapeutic context and the feasibility of quantum-guided, GMP-grade personalized vaccine manufacture. Secondary and exploratory objectives characterize vaccine-induced T-cell immunity and explore correlations between quantum/physics-based scores and clinical/immunologic outcomes.
详细描述
Clinical Background
Endometrial carcinoma is the most common gynecologic malignancy in developed regions. While many early-stage tumours are cured with surgery ± radiotherapy, patients with high-risk, recurrent, or metastatic disease frequently experience relapse after standard therapy and have limited durable options. Particularly poor prognoses are seen in:
Copy-number-high / p53-mutated and serous histologies pMMR tumours with "cold" microenvironments and modest immunotherapy responses MMRd/MSI-H tumours that initially respond to PD-1 blockade but often ultimately progress Across these molecular subtypes, tumours generate patient-specific neoantigens from point mutations, indels, frameshifts in coding microsatellites, fusions, and splice alterations. These mutant peptides can be processed and presented on HLA class I and II molecules, where they may be recognized by T cells as "non-self." This provides a biologically compelling target space for personalized neoantigen vaccination.
However, conventional neoantigen pipelines are largely sequence-based, dependent on binding predictors and heuristic scoring, with limited use of structural information, energetics, or explicit uncertainty quantification. Clinically, many vaccine trials have paired neoantigen constructs with fixed chemotherapy or checkpoint regimens that do not reflect the heterogeneity of real-world oncology practice.
GYNORYLAQ-VLINIVAL is designed to address both issues. It integrates a physics-aware, quantum-classical computational vaccine platform (GYNORYLAQ-EC™) with individualized clinical oncology practice:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following criteria to be eligible:
- •Informed Consent and Legal Capacity 1.
- •Ability to understand the nature of the study and provide written informed consent personally or via a legally authorized representative, in accordance with local regulations.
- •Willingness and ability (participant and/or guardian) to comply with scheduled visits, vaccination procedures, blood draws, imaging, and other study-related assessments.
- •Diagnosis and Histology 2.
- •Histologically confirmed endometrial carcinoma (endometrioid, serous, clear cell, mixed histology, carcinosarcoma, or other specified high-risk subtypes), documented by pathology report.
- •High-risk, recurrent, or metastatic disease, defined by at least one of: FIGO Stage III or IV at initial diagnosis, and/or Recurrent or progressive disease after prior surgery ± radiotherapy ± systemic therapy, not amenable to curative-intent surgery or radiotherapy.
- •Disease Status at Enrollment 3.
- •Radiologically measurable disease per RECIST v1.1, or evaluable disease if allowed by protocol (e.g., measurable by other validated imaging or biomarker criteria).
- •Disease status documented by CT/MRI (or PET/CT, if local standard) within 28 days before the first GYNORYLAQ-TM vaccination.
- •Prior Anti-cancer Therapy 4.
- •Participants may have received prior surgery, radiotherapy, chemotherapy, endocrine therapy, and/or targeted agents, provided all of the following apply:
- •3 weeks since last dose of cytotoxic chemotherapy (≥6 weeks for mitomycin C or nitrosoureas).
- •2 weeks since last dose of endocrine therapy (if applicable).
- •4 weeks (or 5 half-lives, whichever is longer) since last dose of any investigational systemic agent or biologic therapy.
- •2 weeks since completion of palliative radiotherapy to non-CNS sites, with radiotherapy-related toxicities recovered to Grade ≤1 (CTCAE v5.0).
- •Recovery from acute toxicity of prior therapies to Grade ≤1 or baseline (CTCAE v5.0), except for: Alopecia, Stable peripheral neuropathy (≤Grade 2), Other protocol-specified exceptions. 4.
- •Prior immune checkpoint inhibitor therapy (e.g., anti-PD-1/PD-L1) is allowed, provided there is no history of Grade ≥3 immune-related adverse event that mandated permanent discontinuation.
- •Suitability for Systemic Therapy (Clinical Practice Integration) 5.
- •In the opinion of the treating medical oncologist Dr Emmanouelides Christos, the participant is suitable for ongoing systemic anti-cancer and supportive drug treatment (e.g., chemotherapy, endocrine therapy, targeted therapy) consistent with prevailing guidelines and local standards of care.
- •There is no absolute contraindication to all forms of systemic therapy that might reasonably be selected by Dr Emmanouelides Christos.
- •The participant agrees that systemic and supportive drugs will be chosen, initiated, and adjusted by Dr Emmanouelides Christos and recorded as background therapy.
- •Tumour Tissue and Blood Availability 6.
- •Availability of sufficient tumour material for sequencing and neoantigen discovery: Fresh tumour tissue from recent biopsy or surgery (preferred) obtained within approximately the last 6 months, or Adequate archival FFPE tumour tissue (block or unstained slides) deemed sufficient by the central laboratory for DNA/RNA extraction.
- •Availability of matched normal sample (e.g., peripheral blood) for germline reference.
- •Willingness, when clinically safe and feasible, to undergo additional tumour biopsy/biopsies for translational and correlative studies per protocol.
- •Performance Status and Clinical Stability 7.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or
- •Anticipated life expectancy of ≥ 3 months, as judged by the investigator. Adequate Organ and Marrow Function (All labs within 14 days prior to first vaccine dose; repeat as clinically indicated.) 8.
- •Hematologic function Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (without growth factor support within 7 days).
- •Platelets ≥ 100 × 10⁹/L (without transfusion within 7 days). Hemoglobin ≥ 9.0 g/dL (transfusion allowed if stable for ≥1 week). 8.
- •Hepatic function Total bilirubin ≤ 1.5 × upper limit of normal (ULN); In participants with documented Gilbert's syndrome, total bilirubin ≤3 × ULN may be allowed if direct bilirubin ≤1.5 × ULN.
- •AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤5 × ULN in presence of liver metastases).
- •Alkaline phosphatase ≤ 2.5 × ULN (≤5 × ULN in presence of bone or liver metastases).
- •Renal function Serum creatinine ≤ 1.5 × ULN or Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault or institutional standard). 8.
- •Coagulation (if clinically indicated) INR and aPTT within institutional normal limits or medically acceptable for participants on stable anticoagulation.
- •Infection and Virology 9.
- •No uncontrolled active infection requiring IV antibiotics or hospitalization.
- •Hepatitis B (HBV): Participants with resolved infection (HBsAg-, anti-HBc+) and undetectable HBV DNA may be included with monitoring.
- •Participants with chronic HBV (HBsAg+) may be eligible if HBV DNA is adequately suppressed under antiviral therapy and hepatic function meets criteria.
- •Hepatitis C (HCV): Participants with HCV antibody positivity may be included if HCV RNA is negative or controlled on therapy and hepatic function is acceptable.
- •HIV: Participants with HIV infection may be eligible if on a stable antiretroviral regimen with suppressed viral load and CD4 count above a protocol-defined threshold (e.g., ≥200 cells/μL), without uncontrolled opportunistic infections.
- •Reproductive Potential and Contraception 10.
- •Participants who are capable of causing pregnancy or becoming pregnant must have no evidence of ongoing pregnancy at baseline (e.g., negative pregnancy test where applicable and per local regulations) and must agree to use highly effective contraception or remain abstinent from sexual activity that could result in pregnancy for at least 6 months after the last GYNORYLAQ-TM vaccination.
- •Contraception methods may include, but are not limited to: hormonal contraceptives, intrauterine devices, or a combination of barrier methods, as per local guidelines and clinical judgment.
- •Participants who are permanently infertile (e.g., surgical sterilization) or post-reproductive (per local definitions) are not required to use contraception.
排除标准
- •Participants meeting any of the following will be excluded:
- •Tumour and Disease Characteristics 1.
- •Cancers not consistent with endometrial carcinoma as primary site (e.g., primary cervical or ovarian carcinoma) unless clearly documented as metastatic/endometrial in origin.
- •Disease requiring urgent, life-saving intervention that would preclude safe vaccine administration (e.g., impending organ failure requiring immediate surgery or high-dose radiotherapy).
- •Disease burden or rate of progression such that, in the opinion of the investigator and/or Dr Emmanouelides Christos, any delay associated with vaccine manufacturing and initiation of protocol therapy would be unsafe.
- •Prior Therapies and Confounding Investigational Products 2.
- •Prior receipt of neoantigen-specific or tumour vaccine products that target highly overlapping epitope sets in a way that would confound interpretation of GYNORYLAQ-TM-induced responses, unless approved case-by-case.
- •Participation in another interventional clinical trial with therapeutic intent or receipt of an investigational systemic agent within 4 weeks (or 5 half-lives, whichever is longer) before first GYNORYLAQ-TM dose, unless discussed with and approved by the sponsor/investigator.
- •Prior allogeneic hematopoietic stem cell or solid organ transplantation. Autoimmune and Immune-mediated Conditions 3.
- •Active, known, or suspected autoimmune disease requiring systemic immunosuppressive treatment (e.g., ≥10 mg/day prednisone equivalent) within the past 12 months, including but not limited to: Systemic lupus erythematosus Inflammatory bowel disease (Crohn's disease, ulcerative colitis) Multiple sclerosis Severe rheumatoid arthritis, systemic sclerosis, vasculitis Autoimmune hepatitis 3.
- •Acceptable exceptions may include: Controlled autoimmune thyroiditis on stable hormone replacement Vitiligo, type 1 diabetes mellitus, or psoriasis not requiring systemic immunosuppression Other minor or stable autoimmune conditions deemed acceptable by the investigator.
- •Primary or acquired immunodeficiency states (other than controlled HIV as per inclusion criteria) that, in the investigator's judgment, could significantly compromise vaccine-induced immune responses or increase risk.
- •Concomitant Immunosuppressive Therapy 4.
- •Chronic systemic immunosuppressive therapy including: Steroid therapy equivalent to >10 mg/day prednisone for more than 14 consecutive days within 30 days prior to first vaccine dose, or Other immunosuppressive agents (e.g., calcineurin inhibitors, mTOR inhibitors, anti-TNF agents) without a washout period acceptable to the investigator.
- •Short-term steroid use (e.g., antiemetic prophylaxis, contrast premedication, acute reaction management) is permitted as long as it is not chronic.
- •Central Nervous System Disease 5.
- •Untreated or unstable CNS metastases or carcinomatous meningitis. 5.
- •Participants with previously treated CNS metastases may be eligible if all of the following are true: Radiologically stable or responding for ≥4 weeks after completion of CNS-directed therapy, and Neurologically stable, and Off systemic corticosteroids (or on physiologic replacement doses only) for ≥2 weeks prior to first vaccine dose.
- •Cardiovascular, Pulmonary, and Other Serious Comorbidities 6.
- •Clinically significant, uncontrolled cardiovascular disease, including: Myocardial infarction within 6 months, Unstable angina, Significant uncontrolled arrhythmias (excluding controlled atrial fibrillation), Symptomatic congestive heart failure (NYHA Class III-IV), Uncontrolled hypertension (e.g., systolic ≥180 mmHg or diastolic ≥100 mmHg despite treatment).
- •History of venous thromboembolism (DVT/PE) that is not adequately anticoagulated, or acute events within 4 weeks prior to screening that pose high risk in the investigator's judgment.
- •Severe, uncontrolled pulmonary disease, such as advanced COPD, interstitial lung disease with active symptoms, or chronic oxygen dependence that would substantially increase risk.
- •Active Infections 7.
- •Active, uncontrolled bacterial, viral, or fungal infection requiring IV therapy or hospitalization.
- •Confirmed active tuberculosis infection. 7.
- •Uncontrolled chronic HBV, HCV, or HIV infection not meeting the inclusion conditions.
- •Other Malignancies 8.
- •Another active malignancy within the past 3 years, excluding: Curatively treated non-melanoma skin cancers, In situ carcinoma (e.g., cervical, breast, bladder) treated with curative intent, Other malignancies considered by the investigator to have negligible risk of recurrence and unlikely to interfere with study participation or interpretation.
- •Hypersensitivity 9.
- •Known severe hypersensitivity or anaphylaxis to any component of the GYNORYLAQ-TM peptide vaccine or its excipients.
- •History of severe hypersensitivity reactions to multiple injectable biologics that, in the investigator's judgment, substantially increase risk.
- •Vaccination Confounders 10.
- •Receipt of live attenuated vaccines within 4 weeks before the first GYNORYLAQ-TM dose or planned receipt of live vaccines during protocol-defined at-risk periods (e.g., within 4 weeks after last vaccine dose).
- •Receipt of non-live vaccines within 7 days prior to GYNORYLAQ-TM vaccination that, in the investigator's judgment, could substantially confound immunologic readouts (standard seasonal inactivated influenza and COVID-19 vaccines may be allowed per protocol).
- •Pregnancy and Breastfeeding 11.
- •Known ongoing pregnancy at screening or baseline. 11.
- •Breastfeeding participants, if the investigator believes there may be potential risk to the infant and interruption of breastfeeding is not acceptable to the participant.
- •Compliance and Investigator Judgment 12.
- •Any psychiatric, cognitive, social, or substance abuse condition that, in the investigator's opinion, would interfere with study compliance or the ability to follow protocol requirements.
- •Any other serious medical or non-medical condition which, in the opinion of the investigator and/or Dr Emmanouelides Christos, would place the participant at undue risk, compromise data integrity, or make them unsuitable for the trial.
研究组 & 干预措施
GYNORYLAQ-TM Vaccine With Concomitant Oncologist-Selected Drug Therapy
All participants receive:
- GYNORYLAQ-TM personalized neoantigenic peptide vaccine according to the Early Phase I vaccination schedule, and
- Concomitant systemic and supportive drug regimens selected and prescribed by Dr Emmanouelides Christos, based on tumour characteristics, prior treatments, tolerability, and standard-of-care guidelines.
Only GYNORYLAQ-TM is investigational; all concomitant medications are standard practice and non-investigational.
干预措施: • Biological: GYNORYLAQ-TM Personalized Neoantigenic Peptide Vaccine (Biological)
结局指标
主要结局
Incidence of Treatment-Emergent AEs/SAEs and DLTs (CTCAE v5.0) With GYNORYLAQ™ Plus Oncologist-Selected Drug Regimens
时间窗: From first vaccination through 30 days after last vaccination.
Incidence, severity (CTCAE v5.0 grade), type, and attribution of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), and identification of dose-limiting toxicities (DLTs) during the defined DLT window, accounting for concomitant therapies prescribed by Dr. Christos Emmanouelides.
Feasibility of Quantum-Guided Vaccine Manufacturing
时间窗: Up to 16 weeks from tumor tissue acquisition to vaccine release and first vaccination.
Proportion of participants for whom: adequate tumour and matched normal samples are obtained, the GYNORYLAQ-EC™ pipeline completes successfully, a minimum number of peptides (e.g., ≥10) are synthesized and pass QC, and first vaccination occurs within a prespecified time limit (e.g., ≤16 weeks).
Vaccine Immunogenicity (Early Phase I Co-Primary)
时间窗: Baseline to ~Week 24 and at end of treatment.
Proportion of patients with de novo or boosted T-cell responses to ≥1 vaccine peptide (ELISpot/ICS), and quantitative change in vaccine-specific T-cell frequencies, in the context of concomitant oncologist-managed therapy.
次要结局
- Number and proportion of participants with protocol-defined dose-limiting toxicities (DLTs) related to GYNORYLAQ-TM(From first vaccination through the end of the DLT evaluation window (up to 84 days; Cycles 1-3, each cycle is 28 days).)
- Number of distinct GYNORYLAQ vaccine peptides recognized by participant T cells(Baseline; selected on-treatment timepoints; follow-up to ~12 months.)
- Number of participants with persistent vaccine-induced peptide-specific immune responses (≥3-fold increase)(Up to ~12 months after first vaccination.)
- Objective Response Rate (ORR) in participants with measurable disease receiving GYNORYLAQ-TM plus oncologist-selected therapy(Up to ~36 months.)
- Correlation of quantum/physics-based peptide metrics and predicted immunogenicity probabilities with observed immune and clinical outcomes(Baseline through study completion (an average of 3 years).)
- Proportion of participants with successful end-to-end GYNORYLAQ-TM manufacturing and first vaccination within ≤16 weeks(Up to 16 weeks from tumor tissue acquisition to GYNORYLAQ-TM batch release and first vaccination.)