PRaG-1 Plus PRaG Therapy in Advanced Solid Tumors: A Prospective Clinical Trial (PRaG 10.0)

• This clinical study utilizes PRaG-1 Cordycepin Tablets (oral administration) to modulate immune cell and cytokine profiles. Lymphocyte subset analysis is performed before and after treatment to quantify immune function changes.
• Treatment phases:

Cordycepin: PRaG-1 Cordycepin Tablets (manufactured by Life Origin Biotechnology Co., Ltd., affiliated with the National Bioengineering Engineering Technology Center, Nanjing Tech University) contain 200 mg cordycepin per tablet and hold National Food Production License No. SC11332019200201.

Loading dose: Initiated 1 week prior to radiotherapy, administered as 2 tablets once daily after meals with water for 7 consecutive days.

Maintenance dose: Following loading dose completion, 1 tablet once daily after meals with water is continued starting with radiotherapy for 2 weeks per cycle (every 3 weeks). Efficacy is assessed at each cycle.

Biospecimen collection: 5 mL blood and 2 g tumor biopsy tissue are obtained before and after the first two treatment cycles for immune function analysis (including bulk RNA sequencing, single-cell sequencing, TCR sequencing, proteomic analysis, metabolomic analysis, gut microbiome analysis, and urinary extracellular vesicle analysis).

Treatment discontinuation criteria: Confirmed disease progression, intolerable toxicity, withdrawal of informed consent, death, or other protocol-specified criteria.

Radiotherapy: Begins on Day 1 of the treatment cycle; 5-12 Gy total dose delivered in 2-3 fractions per lesion, once daily.

GM-CSF: 200 μg subcutaneously daily starting on radiotherapy day, continued for 7 days.

Immunotherapy: PD-1/PD-L1 inhibitors initiated within one week post-radiotherapy.

• Maintenance phases:

Stage A: ≥2 cycles of cordycepin combined with radiotherapy, PD-1/PD-L1 inhibitors, and GM-CSF.

Stage B: Maintenance therapy with PD-1/PD-L1 inhibitors, GM-CSF, and cordycepin for ≥6 months.

Stage C: Continued PD-1/PD-L1 inhibitor monotherapy until disease progression or unacceptable toxicity.

Inclusion criteria

• Age ≥ 18 years.
• Histologically confirmed treatment-naïve or relapsed/metastatic advanced solid malignancies with no standard treatment option per current clinical guidelines or intolerance to standard therapy; measurable metastatic lesions ≥1 cm (by RECIST criteria); absolute lymphocyte count (ALC) below lower limit of normal (LLN).
• No history of congestive heart failure, unstable angina, or unstable cardiac arrhythmias within the past 6 months.
• ECOG performance status 0-3; estimated life expectancy ≥3 months.
• No history of significant hematologic, cardiac, pulmonary, hepatic, or renal dysfunction.
• Baseline AST ≤3×ULN and ALT ≤3×ULN (≤5×ULN for hepatocellular carcinoma or liver metastases); creatinine ≤3×ULN.
• Capacity to comprehend study procedures and voluntarily provide written informed consent.

Exclusion criteria

• History of other malignancies within the past 5 years, except for adequately treated non-melanoma skin cancer or cervical carcinoma in situ.
• Uncontrolled epilepsy, central nervous system disorders, or psychiatric disorders that, in the investigator's judgment, may interfere with informed consent or treatment adherence.
• Clinically significant active cardiac disease, including symptomatic coronary artery disease, NYHA Class II or higher congestive heart failure, severe arrhythmias requiring pharmacological intervention, or myocardial infarction within the past 12 months.
• History of solid organ transplant requiring ongoing immunosuppressive therapy.
• Known significant active infection, or significant hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction, or other serious uncontrolled comorbidities as determined by the investigator.
• Allergy to any component of the study drug(s).
• History of immunodeficiency, including HIV infection, acquired or congenital immunodeficiency disorders, solid organ transplant, or chronic immunosuppressive therapy for immune-related conditions.
• Active or latent tuberculosis infection confirmed by positive T-SPOT.TB test or chest X-ray findings suggestive of tuberculosis.
• Any other condition that, in the investigator's clinical judgment, may compromise study participation or safety.