Phase 1/2 Study for IPG7236 Combined With Toripalimab in Participants With Advanced Solid Tumors

This is a phase 1/2, multicenter, non-randomized, open-label, dose-escalation and dose-expansion study. Part A (dose escalation) will adopt a standard "3+3" design with two cohorts (IPG7236 500 mg BID + Toripalimab 240 mg Q3W; IPG7236 800 mg BID + Toripalimab 240 mg Q3W) to determine the MTD and/or RP2D. Part B (dose expansion) will enroll approximately 40 CCR8-positive advanced solid tumor patients to further evaluate safety,tolerability and preliminary antitumor activity. The transition from Part A to Part B will be triggered after confirmation of RP2D based on safety, tolerability, PK and preliminary efficacy data.

Inclusion Criteria:

1. Written informed consent must be obtained before any study procedure is performed.

2. Men or women 18 years of age or older.

3. Histologically or cytologically confirmed advanced or recurrent malignant solid tumors that are metastatic or unresectable. (Subjects must submit tumor tissue sections from within the past 5 years for CCR8 expression testing. For subjects without paraffin-embedded tissues, a fine-needle aspiration biopsy may be performed. Subjects who cannot provide tumor tissue sections or undergo biopsy are only eligible for inclusion during the dose escalation phase. During the dose expansion phase, CCR8 positivity must be known or tumor tissue sections must be provided with confirmed CCR8 expression.)

4. Subjects must have failed or been intolerant to standard antitumor therapy, or lack a standard treatment regimen, or be deemed by the investigator as currently unsuitable for standard therapy.

5. According to the RECIST 1.1 criteria, there is at least one measurable lesion.

6. Life expectancy ≥ 3 months.

7. Subjects must be able to swallow the oral investigational drug.

8. The ECOG performance status score is 0 or 1.

9. Sufficient hematologic and organ function, with the following laboratory test values:

   1. Hematology: Absolute Neutrophil Count (ANC) ≥ 1.5×10⁹/L; platelet count ≥ 75×10⁹/L; Hemoglobin ≥ 9 g/dL; lymphocytes ≥ 0.8×10⁹/L;
   2. Renal: Creatinine clearance calculated by the Cockcroft-Gault method ≥ 50 mL/min or serum creatinine ≤ 1.5× upper limit of normal (ULN);
   3. Hepatic: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3×ULN, or ≤ 5×ULN for subjects with liver metastases; total bilirubin ≤ 1.5×ULN, or ≤ 3×ULN for subjects with Gilbert syndrome or genetically equivalent conditions;
   4. Coagulation: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5× upper limit of normal (ULN).

10. Patients must be willing and able to comply with all scheduled visits, treatments, laboratory tests, and other study requirements.

11. Male and female participants of reproductive potential who engage in heterosexual sexual behavior must agree to use reliable contraceptive methods (hormonal, barrier, or abstinence,etc.) for at least 4 months during the trial period and after the last study drug administration (refer to Appendix 13.1 of the protocol)

Exclusion Criteria:

1. Primary malignant tumors of the central nervous system or malignant tumors associated with human immunodeficiency virus (HIV) .

2. Previous use of CCR8-targeted therapy.

3. Received the following treatment within the specified time frame:

   1. Planned major surgery within 4 weeks prior to the first dose administration (excluding minor procedures such as vascular access placement, gastrointestinal/biliary stent placement, or biopsy);
   2. Immunotherapy or biological therapy administered within 28 days prior to the initial administration;
   3. Chemotherapy <21 days prior to the first dose, or mitomycin or nitrosoureas < 42 days prior, or oral fluoropyrimidines < 14 days prior;
   4. Targeted small-molecule therapy or traditional Chinese medicine with antitumor indications administered within 14 days prior to the initial dose;
   5. Hormone therapy or other adjuvant therapies are not permitted if initiated within 14 days prior to the first dose. Exceptions: anti-estrogen therapy, bisphosphonates, RANKL monoclonal antibodies, somatostatin analogs, and leuprorelin are permitted if initiated ≥ 14 days prior to the first dose.
   6. Radiotherapy administered within 28 days prior to the first dose, or palliative radiotherapy within 14 days prior. Exception: Palliative radiotherapy (e.g., for analgesia) may be performed during the study drug administration period, provided that it is not permitted during the DLT observation period, any previously induced adverse events from radiotherapy have been resolved to grade <2, and the radiotherapy was not directed at the target lesion.
   7. Other investigational or treatments administered within 28 days prior to the first dose;
   8. Any previous allogeneic tissue/solid organ transplantation, including allogeneic stem cell transplantation;

4. Previous treatment-related toxicity has not yet resolved to a level of ≤ 1 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v6.0 or to the specified levels in the inclusion/exclusion criteria (except for safety risks deemed by the investigator as not significant, such as alopecia, grade 2 peripheral neuropathy, hypothyroidism or hyperthyroidism, or other endocrine disorders well-controlled by hormone replacement therapy).

5. In combination with other active malignancies (excluding basal cell carcinoma of the skin, cervical carcinoma in situ, or superficial bladder cancer with no evidence of disease after potentially curative treatment; For other patients with previous malignant tumors who have survived without disease for more than 3 years, they are also (acceptable).

6. Immune-related adverse events (irAEs) of grade ≥ 3 or those leading to treatment discontinuation during prior immunotherapy, or grade ≥ 2 immune-mediated myocarditis, or treatment discontinuation due to allergic or infusion-related reactions.

7. Diagnosis of primary or acquired immunodeficiency, or receipt of systemic glucocorticoids or any other form of immunosuppressive therapy within 7 days prior to the first dose. Exceptions: intraocular, intranasal, intra-articular, inhaled, or systemic glucocorticoids (prednisone dose ≤ 10 mg/day or equivalent, or doses used for adrenal replacement therapy), as well as a single dose of immunosuppressive medication for contrast agent allergy prophylaxis (if no active autoimmune disease is present).

8. History of autoimmune disease requiring systemic therapy or active autoimmune diseases (i.e., requiring glucocorticoids or immunosuppressive agents for disease control) within 2 years prior to study initiation are eligible, provided they do not require immunosuppressive therapy for conditions such as type 1 diabetes mellitus, vitiligo, psoriasis,hypothyroidism, or hyperthyroidism.

9. Known severe or life-threatening allergic reactions to humanized monoclonal antibodies (mAbs) or intravenous immunoglobulin (Ig) preparations; known hypersensitivity to any investigational drug, its analogues, or excipients.

10. Untreated brain metastases, meningeal metastases, or spinal cord compression not definitively treated with surgery or radiotherapy. (Patients with brain metastases who have stabilized without symptoms after prior treatment and have not received high-dose steroid therapy are eligible for enrollment.)

11. Uncontrolled or requiring intravenous anti-infective therapy for active bacterial, fungal, or viral infections.

12. Active hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and/or HIV:

    1. Participants must be negative for hepatitis B surface antigen (HBsAg).
    2. For HCV antibody-positive subjects, the HCV RNA quantification must be below the research center's detection limit.
    3. HIV test must be negative at screening;

13. Administration of live or live-attenuated vaccines within 4 weeks prior to the first dose (inactivated vaccines, viral vector vaccines, and mRNA vaccines are permitted; seasonal vaccines should be completed prior to the first dose).

14. The serum pregnancy test is positive within 3 days before the first dose.

15. Lactating female subjects.

16. Pneumonitis, interstitial lung disease, or severe radiation pneumonitis (excluding localized radiation pneumonitis) requiring glucocorticoid therapy.

17. Patients with clinically uncontrollable ascites or pleural effusion are deemed unsuitable for enrollment by the investigator.

18. Symptomatic cardiovascular or cerebrovascular disease; accident/stroke or myocardial infarction (MI), unstable angina, congestive heart failure (NYHA class III or higher), or severe arrhythmias uncontrolled by pharmacotherapy within 6 months prior to enrollment; mean QT interval corrected for heart rate using the Fridericia formula (QTcF) ≥ 470 ms.

19. Any medical or social condition that may expose subjects to higher risks, affect compliance, or obscure the interpretation of safety or other clinical study data