Rare Tumor Focused Platform Study of Innovative Therapies and Technologies (PLATFORM2)

This is an open-label, non-randomized, multi-arm, single-center Phase I/II platform study (PLATFORM2). Based on the definition of rare tumors in China (incidence < 2.5/100,000 or specific list), eligible patients will undergo multi-omics screening. Based on the molecular profiling results (gene variations or protein expression), patients will be assigned to corresponding treatment arms (Sub-studies). Therapies include small molecules, protein drugs, Cell and Gene Therapy (CGT) products, and therapeutic vaccines. The study employs a Clopper-Pearson Two-Stage Minimax design for each arm.

Inclusion criteria

• Subjects must meet all of the following inclusion criteria:
• Male or female subjects aged ≥16 years at the time of signing the informed consent form.
• Histologically or cytologically confirmed malignancy.
• ECOG performance status of 0-2 and an expected survival of more than 12 weeks.
• Presence of measurable or evaluable disease for efficacy assessment, as determined by the investigator according to the individualized criteria defined in each sub-protocol.
• Provision of fresh tumor biopsy tissue is recommended, obtained within 12 weeks prior to the first administration of study treatment, consisting of three core needle biopsy specimens. The biopsy tissue must not have been exposed to any antitumor therapy, systemic anti-infective treatment, or vaccination after collection. Peripheral blood samples are also recommended for molecular profiling and enrollment screening.
• Provision of archival formalin-fixed paraffin-embedded (FFPE) tumor tissue from the primary lesion or a metastatic lesion (excluding bone metastases and lesions previously treated with radiotherapy) obtained within the past 2 years is recommended. The required material includes 15-20 unstained slides (4-6 μm thickness), of which 5 slides should be adhesive-coated and baked. If the above requirements cannot be met, enrollment eligibility may be determined at the investigator's discretion.
• If pleural or peritoneal effusion is present, samples must be collected for pathological cytological examination, and provision of at least 50 mL of effusion fluid is recommended, if available.
• If a primary tumor biopsy specimen has been provided, and a metastatic lesion is amenable to biopsy (as judged by the investigator), tissue from the metastatic lesion should be collected for pathological examination, and fresh tissue specimens are recommended.
• Upon disease progression, if conditions permit (as judged by the investigator), collection of fresh tumor tissue from the same biopsy site at enrollment and/or from previously sampled metastatic lesions is recommended.
• Toxicities from prior therapies must have resolved to ≤ Grade 1 or returned to baseline, according to NCI-CTCAE version 5.0, except for alopecia.
• A negative pregnancy test is required for women of childbearing potential. Women not of childbearing potential are defined as those who are postmenopausal for at least 1 year, or who have undergone surgical sterilization or hysterectomy.
• All enrolled subjects, regardless of sex, must agree to use effective contraception throughout the treatment period and for 8 weeks after the last dose of study treatment.
• Subjects must voluntarily participate, provide written informed consent, comply with the study treatment and visit schedule, and be able to cooperate with safety and efficacy assessments.

Exclusion criteria

Subjects meeting any of the following exclusion criteria will not be eligible for participation in this study:

• Prior treatment with any antitumor novel drug or technology of the same class as that investigated in the relevant sub-protocol of this study.
• Known hypersensitivity or allergy to any active component or excipient of the investigational antitumor novel drug or technology.
• Presence of any type of interstitial lung disease or a history of radiation pneumonitis.
• Failure to meet the inclusion or exclusion criteria specified in the applicable sub-protocol.
• Major surgery performed within 4 weeks prior to the first administration of study treatment, or surgical wounds that have not fully healed.
• History of hypersensitivity reactions to drugs whose chemical structures are similar to the active or inactive components of the investigational antitumor novel drug or technology, or to agents of the same class.
• Active infection requiring systemic therapy (e.g., antibiotics), or the presence of any of the following conditions:

• Positive human immunodeficiency virus (HIV) test or a known history of acquired immunodeficiency syndrome (AIDS);
• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, defined as HBsAg positivity with HBV DNA levels above the upper limit of normal (ULN), or HCV antibody positivity;
• Active tuberculosis, defined as a history of exposure or a positive tuberculosis test accompanied by clinical symptoms and/or radiographic findings.
• Evidence of severe or uncontrolled systemic disease, as determined by the investigator, including but not limited to severe psychiatric or neurological disorders (such as epilepsy or dementia), unstable or uncompensated respiratory, cardiovascular, hepatic, or renal disease, or uncontrolled hypertension (defined as blood pressure remaining at or above CTCAE Grade 3 despite medical treatment).
• Myocardial infarction, coronary artery bypass grafting, peripheral artery bypass grafting, or cerebrovascular accident occurring within 3 months prior to enrollment.
• History of any organ transplantation, including allogeneic hematopoietic stem cell transplantation, except for transplants not requiring immunosuppressive therapy (e.g., corneal transplantation or hair transplantation).
• Presence of cardiovascular disease or conditions including any of the following:

• Congestive heart failure requiring treatment, or New York Heart Association (NYHA) Class III or IV heart failure;
• Ventricular arrhythmias requiring antiarrhythmic therapy, or uncontrolled or unstable arrhythmias;
• Severe conduction abnormalities, such as second- or third-degree atrioventricular block;
• Angina pectoris requiring treatment;
• Prolonged QT interval on 12-lead electrocardiogram, defined as QTc ≥450 ms for males or ≥470 ms for females;
• History of congenital long QT syndrome, congenital short QT syndrome, torsades de pointes, or pre-excitation syndrome;
• Left ventricular ejection fraction (LVEF) <50%, as determined by echocardiography or MUGA scan;
• Myocardial infarction diagnosed within the past 6 months.
• Inadequate bone marrow reserve or organ function, as evidenced by any of the following laboratory findings:

• Absolute neutrophil count <1.0 × 10⁹/L;
• Platelet count <80 × 10⁹/L (patients dependent on platelet transfusion are excluded);
• Hemoglobin <90 g/L;
• In the absence of liver metastases, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN; in the presence of liver metastases, ALT or AST >5 × ULN (as determined by the investigator per sub-protocol);
• In the absence of liver metastases, total bilirubin >1.5 × ULN; in patients with Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases, total bilirubin >3 × ULN (as determined by the investigator per sub-protocol);
• Serum creatinine >1.5 × ULN with concomitant creatinine clearance <50 mL/min (measured or calculated using the Cockcroft-Gault formula); creatinine clearance assessment is required only when serum creatinine exceeds 1.5 × ULN;
• Coagulation abnormalities, defined as INR, PT, or APTT >1.5 × ULN in patients not receiving anticoagulant therapy; eligibility of patients receiving anticoagulants will be determined by the investigator;
• Elevated creatine kinase (CK) or CK-MB above the normal range (as determined by the investigator per sub-protocol).
• Pregnant or breastfeeding women.
• Any other condition that, in the opinion of the investigator, may pose a potential risk or render the subject unsuitable for participation in this study.