Inhaled mRNA Tumor-associated Antigen Dry Powder Vaccine in Advanced Lung Cancer and Lung Metastasis of Solid Tumors.

BMD006 is an inhaled mRNA tumor-associated antigen dry powder vaccine targeting lung cancer and solid tumors with lung metastasis, classified as an off-the-shelf anti-tumor product. The product contains two clinically validated TAA antigen combinations: for patients with solid tumors that have lung metastasis, the mRNA vaccine consists of four mRNA sequences encoding melanoma-associated tumor antigens ; for patients with primary lung cancer, the mRNA vaccine consists of six mRNA sequences encoding tumor-associated antigens of primary lung cancer .

This study is a single-center, open-label, dose-escalation trial designed to evaluate the safety, tolerability, preliminary efficacy, PK, and PD of BMD006 in patients with advanced lung cancer or advanced solid tumors with lung metastasis who have failed standard treatments or have no standard treatment options. Additionally, the study will further explore the effect of BMD006 in combination with PD-1 treatment.

BMD006 is an inhaled mRNA tumor-associated antigen dry powder vaccine targeting lung cancer and solid tumors with lung metastasis, classified as an off-the-shelf anti-tumor product. The product contains two clinically validated TAA antigen combinations: for patients with solid tumors that have lung metastasis, the mRNA vaccine consists of four mRNA sequences encoding melanoma-associated tumor antigens ; for patients with primary lung cancer, the mRNA vaccine consists of six mRNA sequences encoding tumor-associated antigens of primary lung cancer .

This study is a single-center, open-label, dose-escalation trial designed to evaluate the safety, tolerability, preliminary efficacy, PK, and PD of BMD006 in patients with advanced lung cancer or advanced solid tumors with lung metastasis who have failed standard treatments or have no standard treatment options. Additionally, the study will further explore the effect of BMD006 in combination with PD-1 treatment.

In Part 1, the trial plans to enroll approximately 16-31 patients and perform dose escalation in 6 dose groups, including BMD006 50 μ g, 100 μ g, 200 μ g, 400 μ g, 800 μ g, and 1200 μ g.After receiving the first treatment with BMD006 on D1, the patient completed a single treatment DLT observation (14 days) and was evaluated by the researchers to be safe and tolerable.They will enter multiple treatment DLT observation (14 days) and receive BMD006 treatment on D15 and D22, respectively. On D28, the patient will continue to receive QW treatment at the current dose level for 6 times, and then switch to Q3W treatment from the 11th week until 52 weeks after the first treatment or until the termination criteria are met (defined as: disease progression, intolerable toxicity, withdrawal of informed consent, loss to follow-up, death, or end of the study, whichever occurs first). At the same time as the patient enters the treatment period, the next dose group of patients will be initiated for single treatment and observation.

Considering the high safety of starting dose selection (1/20 of the human safety dose inferred from preclinical research data), the 50 μ g group will adopt the method of accelerated titration, and one patient is planned to be enrolled.

During the process of accelerated titration, if there are ≥ 2 levels of adverse events (TRAE) related to investigational product after treatment during the observation period of DLT, two more patients will be added at the current dose level, and the "3+3" mode will be changed from then on.

During the dose escalation process, the investigator can decide whether to add additional dose levels based on the patient's safety evaluation results, as well as PK, PD, biomarker, and other test results (if available), to better explore the risks and benefits of the patient's exposure to the investigational product.

After treatment, safety follow-up and long-term follow-up will be carried out for each patient according to the time specified in the protocol. All patients will receive remote follow-up (by phone, etc.) to assess the overall survival until 2 years after the first treatment or the end point of long-term follow-up (defined as withdrawal of informed consent, withdrawal from the study, loss to follow-up, death or the end of the study, whichever occurs first).

During the study, sample collection and safety assessment of PK, PD and biomarkers will be conducted at the corresponding visit points. Tumor evaluation was performed by the investigator according to RECIST v1.1. Imaging examination was performed every 6 weeks 6 months after the first treatment, and every 9 weeks 6 months later until 2 years after the first treatment or the end point of long-term follow-up.

When the dose escalation of Part 1 is completed and the MTD level ( RP2D of this study) is determined, the dose escalation exploration of BMD006 combined with PD-1 antibody will be carried out.

The dose of BMD006 is explored starting from the previous dose of RP2D, and the next dose was explored to RP2D. According to the "3+3" model, 3-6 patients were enrolled in each dose. The patient will receive BMD006 combined with PD-1 antibody treatment on D1, and BMD006 treatment on D8 and D15. The DLT observation period is 21 days. D21 is safe and tolerable according to the investigator's assessment. The patient will continue to be treated according to QW regimen for 6 times at the current dose level, and then change to q3w treatment from the 10th week until 52 weeks after the first treatment or reaching the standard of termination. During the study, patients will receive fixed dose treatment with PD-1 antibody until 52 weeks after the first treatment or reaching the standard of termination of treatment. When the patient enters the treatment period, the treatment and observation of patients in the next dose group will be started.

Eligibility Criteria:
Inclusion Criteria:

* Able to understand and comply with the requirements of the study protocol, voluntarily participate in the trial, and sign a written informed consent form (ICF).
* Must be between the ages of 18 and 75 (inclusive) at the time of signing the ICF, and both male and female participants are eligible.
* Histologically or cytologically confirmed as advanced lung cancer (driver gene negative) or advanced solid tumors with lung metastasis, and having failed prior standard treatments or having no standard treatment options.
* Agree to provide fresh tumor tissue samples or archived tumor tissue samples within the past two years.
* Tumor tissue samples detected by immunohistochemistry (IHC) method, showing expression of at least one of the nine tumor-associated antigens (TAA), including NY-ESO-1, MAGE-A3, TPTE, Tyrosinase (1-477aa), KK-LC-1, MAGE-A4, CLDN6, PRAME, or MAGE-C1.
* Presence of at least one measurable lesion as defined by RECIST V1.1
* Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1
* Organ function must be adequate at screening (no need for blood transfusion, hematopoietic growth factors, human albumin, or medications for correction within 14 days prior to first treatment), specifically defined as: a) Hematology: Absolute neutrophil count ≥1.5×10\^9/L; platelet count ≥90×10\^9/L; hemoglobin ≥90 g/L (9 g/dL). b) Liver Function: Serum total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); for patients with liver metastasis or a history/suspected history of Gilbert's syndrome (persistent or recurrent hyperbilirubinemia, primarily unconjugated bilirubin, with no evidence of hemolysis or liver pathology), TBIL ≤3×ULN; for patients without liver metastasis, alanine aminotransferase (ALT) and aspartate aminotransferase (AST); for patients with liver metastasis, ALT or AST ≤5×ULN. c) Renal Function: Creatinine (Cr) ≤1.5×ULN or creatinine clearance (CLcr) ≥60 mL/min (calculated using the Cockcroft-Gault formula, see Attachment 3); urine dipstick test result showing urinary protein \<2+; for patients with baseline urine dipstick showing protein ≥2+, a 24-hour urine collection should be conducted, and the protein content in the 24-hour urine should be \<1 g. d) Cardiac Function: Echocardiography showing left ventricular ejection fraction (LVEF) \>50%. e) Pulmonary Function: Shortness of breath ≤Grade 1 as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), and outdoor ambient air oxygen saturation (SpO₂) ≥92%.
* Expected life expectancy ≥12 weeks.
* Female patients of childbearing potential and male patients (and their female partners) must use highly effective contraception from the screening period until at least 6 months after the last dose of the study drug. Patients must not plan to conceive, donate sperm, or donate eggs during this period

Exclusion Criteria:

* Patients with lung cancer who have concurrent other types of malignant tumors or are diagnosed with multiple primary malignancies, except for the following: completely resected basal cell carcinoma and squamous cell carcinoma of the skin, completely resected any type of carcinoma in situ.
* Symptomatic central nervous system metastasis; for patients with asymptomatic brain metastasis or those whose symptoms have been stable for ≥2 weeks after treatment of brain metastasis, they may participate in this study if they meet all the following criteria: measurable lesions in the lungs; cessation of steroid treatment 14 days prior to the first trial product dose.
* Patients with chronic obstructive pulmonary disease (COPD), asthma, or allergies to pollen or dust.
* Patients suspected of having active or latent tuberculosis infection, based on interferon-γ release assay results, clinical symptoms, and/or chest imaging findings (patients with evidence of adequately treated prior active tuberculosis infection may be enrolled after assessment by the investigator; for latent tuberculosis, patients must have completed at least 4 weeks of anti-tuberculosis treatment, with no liver function impairment \[ALT ≤3×ULN, AST ≤3×ULN\], and after the investigator assesses that the risk is manageable, they may be considered for continued screening or enrollment).
* History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis or organizing pneumonia), or active, non-infectious pneumonia requiring immunosuppressive treatment such as corticosteroids.
* Patients with active autoimmune diseases requiring therapeutic intervention.
* History of serious bleeding disorders; or those with coagulation dysfunction (as indicated by laboratory tests or medical history) who are deemed by the investigator to be unsuitable for the trial treatment.
* History or current diagnosis of cardiovascular disease, including any of the following: a) Recent myocardial infarction or coronary artery bypass grafting (CABG) within the past 6 months; b) Uncontrolled congestive heart failure; c) Unstable angina (within the past 6 months); d) Clinically significant (symptomatic) arrhythmias (e.g., sustained ventricular tachycardia, clinically significant second- or third-degree atrioventricular block without a pacemaker).
* Clinically uncontrolled third-space fluid accumulation (e.g., pleural effusion/pericardial effusion; patients with effusions that do not require drainage or those whose effusions have not increased significantly after stopping drainage for 3 days may be included).
* Severe infection requiring intravenous antibiotic treatment or hospitalization at screening, or any uncontrolled active infection within 4 weeks prior to the first dose of the trial product.
* History of severe allergic reactions, or known allergy to any active or inactive component of BMD006 or PD-1 inhibitors.
* Any other metabolic, hematological, renal, hepatic, pulmonary, neurological, endocrine, cardiac, or gastrointestinal disease that, in the investigator's opinion, may present unacceptable risks to the patient during treatment.
* Presence of unresolved toxicity from prior anti-tumor treatments before the first dose of the study product, which has not recovered to Grade 0 or 1 (excluding alopecia) (severity assessed according to NCI CTCAE v5.0).
* Positive test results for hepatitis B at screening \[defined as: ① Hepatitis B surface antigen (HBsAg) positive; ② HBsAg negative but hepatitis B core antibody (HbcAb) positive (further testing through hepatitis B virus deoxyribonucleic acid \[HBV DNA\] is required, and patients with HBV DNA levels exceeding the normal limit for the test method must be excluded)\], positive hepatitis C antibody (HCV Ab) \[further testing through hepatitis C virus ribonucleic acid (HCV RNA) is required, and patients with HCV RNA levels exceeding the normal limit for the test method must be excluded\], or positive human immunodeficiency virus antibody (HIV Ab).
* Underwent major surgery within 4 weeks prior to the first dose of the trial product (cranial, thoracic, or abdominal surgery) or has an unresolved wound, ulcer, or fracture. Note: Thoracoscopic surgery and mediastinoscopy will not be considered major surgery. Patients who are ≥2 weeks post-surgery or who are deemed eligible by the investigator may be included in the study.
* Previously received similar products or treatments, including mRNA vaccines targeting NY-ESO-1, MAGE-A3, TPTE, Tyrosinase (1-477aa), KK-LC-1, MAGE-A4, CLDN6, PRAME, MAGE-C1, peptide vaccines, cell therapies, etc.
* Received other anti-tumor treatments (radiotherapy, chemotherapy, endocrine therapy, targeted therapy, immunotherapy, etc.) within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose of the trial product.
* Received systemic immunosuppressive agents (e.g., systemic corticosteroids) within 3 months prior to the first dose of the trial product.
* Received or planned to receive live or attenuated live vaccines within 3 months prior to the first dose of the trial product or during the study.
* Pregnant or breastfeeding women.
* Participated in any clinical drug trial (defined as being randomized and receiving trial product treatment) within 3 months or 5 half-lives (whichever is longer) prior to screening.
* Any other condition deemed by the investigator to make the patient unsuitable for participation in the trial.