A Phase Ib/II Study of BM230 in Combination With PD-1 Inhibitor for HER2-related Advanced Solid Tumors

A Phase Ib/II, Multicenter, Non-Randomized, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of BM230 in Combination With PD-1 Inhibitor in Patients With HER2-Related Advanced Solid Tumors

This study is a multicenter, non-randomized, open-label, Phase Ib/II combination therapy trial. The trial consists of two parts: Part 1 (Phase Ib), dose-escalation of combination therapy, followed by Part 2 (Phase II), tumor-type exploration of combination therapy. This study will evaluate the RP2D, safety, tolerability, and preliminary efficacy of BM230 in combination with PD-1 inhibitor in patients with HER2-related solid tumors (including but not limited to colorectal cancer, esophageal squamous cell carcinoma, urothelial carcinoma, cholangiocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, etc.).

Inclusion Criteria:

common inclusion criteria (Phase Ib and Phase II) (Criteria 1 to 10)

1. Informed of the study before the start of the study and voluntarily sign their name and date on the informed consent form (ICF)

2. Males and Females≥18 years old（at the time consent is obtained）

3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 1

4. Life expectancy of ≥ 3 months

5. Adequate organ and bone marrow function, defined as:

   • Bone marrow function: hemoglobin ≥ 90 g/L (have not received blood transfusion or erythropoietin treatment within 14 days before the first dose); absolute neutrophil count ≥ 1.5×109/L (have not received granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days before the first dose); platelet count ≥ 100×109/L ((have not received platelet transfusion, thrombopoietin, or interleukin-11 treatment within 14 days before the first dose)
   • Coagulation function: activated partial thromboplastin time and international normalized ratio ≤ 1.5 × ULN
   • Liver function (based on the normal range at the study site): TBIL ≤ 1.5 × ULN if no demonstrable liver lesion(s) (primary or metastases), < 4 × ULN for patients with Gilbert syndrome, or ≤ 3 × ULN in the presence of liver lesion(s); ALT and AST ≤ 3 × ULN if no demonstrable liver lesion(s) (primary or metastases), or ≤ 5 × ULN in the presence of liver lesion(s)
   • Renal function (based on the normal range at the study site): creatinine clearance (CrCl) calculated by the Cockcroft-Gault formula ≥ 50 mL/min, or 24-h urine CrCl ≥ 50 mL/min
   • Cardiac function: LVEF ≥ 50%

6. Female patients of childbearing potential must agree to use a highly effective form of contraception and not donate, or retrieve for their own use, ova from the time of screening and throughout the study period, and for at least 6 months after the last dose of study drug; a negative pregnancy test must be obtained within 7 days before the first dose. Male patients must agree to use a highly effective form of contraception and not freeze or donate sperm from the time of screening and throughout the study period, and for at least 6 months after the last dose of study drug

7. Able and willing to comply with protocol visits and procedures

8. Have HER2 expression (IHC 1+, 2+, or 3+) determined by immunohistochemistry, or HER2 amplification (NGS report indicating HER2 amplification), or (for NSCLC) HER2 exon 8, exon 19, or exon 20 mutations. For Australia, only patients with cancer types covered by Australian Medicare for HER2 expression, amplification, or mutation testing, and/or patients with known HER2 expression, amplification, or mutation identified via any other program are to be considered

9. Willing to provide archived or fresh tumor tissue samples. Patients who are unable to provide tumor samples or have insufficient samples may be eligible on a case-by-case basis after discussion with the sponsor

10. Have at least 1 measurable target tumor lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

    Additional inclusion criteria for Phase II (Criteria 11 to 14)

11. Cohort A: Unresectable or metastatic high microsatellite instability (MSI-H) or mismatch repair-deficient (dMMR) advanced solid tumors in adult patients:

    • Patients with advanced colorectal cancer who have experienced disease progression following prior treatment with fluoropyrimidines, oxaliplatin, and irinotecan
    • Patients with other advanced solid tumors who have experienced disease progression after prior treatment and for whom no satisfactory alternative treatment is available

12. Cohort B: Esophageal squamous cell carcinoma:

    • Locally advanced or metastatic esophageal squamous cell carcinoma that has progressed or is intolerant following first-line standard chemotherapy

13. Cohort C: Urothelial carcinoma:

    • Locally advanced or metastatic urothelial carcinoma that has progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy, or after failure of platinum-based chemotherapy

14. Other tumor types:

    • Locally advanced or metastatic advanced solid tumors that have progressed or are intolerant following first-line standard chemotherapy, including cholangiocarcinoma, endometrial carcinoma, cervical cancer, ovarian cancer, etc

Exclusion Criteria:

Patients who meet any of the following criteria will NOT be included in the study:

1. Have received prior treatment with anti-HER2 antibody agents (excluding HER2 ADC agents).

2. Preexisting autoimmune disease (except for patients with vitiligo) needing treatment with systemic immunosuppressive therapy for more than 28 days within the last 3 years, or clinically relevant immuno-deficiency diseases (eg, agammaglobulinemia or congenital

3. Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other curatively treated solid tumors (including but not limited to adequately treated thyroid cancer, carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated with curative surgery)

4. Insufficient washout period of the prior anticancer treatment before the first dose of the investigational product, defined as follows:

   • Anti-neoplastic treatments such as chemotherapy, biological therapy, endocrine therapy and immunotherapy within 3 weeks before the first dose
   • Palliative radiotherapy for tumors within 2 weeks before the first dose
   • Endocrine therapy for tumors within 2 weeks before the first dose
   • Chinese herbal medicine or Chinese patent medicine for tumor indications within 2 weeks before the first dose
   • Other unmarketed investigational drugs or treatments within 4 weeks before the first dose (fluoropyrimidines and small-molecule targeted drugs: within 2 weeks before the first dose or within 5 half-lives of the drug, whichever is shorter)

5. Undergone major surgery (not including diagnostic surgery) within 4 weeks before the first dose or are expected to undergo major surgery during the study

6. Has a history of allogeneic hematopoietic stem cell transplantation or organ transplantation

7. Received systemic corticosteroids (defined as > 10 mg/day of prednisone or equivalent) or other immuno-suppressive therapy within 2 weeks before the first dose. The following are exceptions to this criterion:

   • Intranasal, inhaled, topical steroids, topical corticosteroids or local steroid injections (eg, intra-articular injections)
   • Systemic steroids at physiological doses as replacement therapy (eg, physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency)
   • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)

8. Received any live vaccines within 4 weeks before the first dose or intend to receive live vaccines during the study

9. Have experienced any Grade ≥3 immune-related adverse event (irAE), or a Grade <3 immune-related adverse event that occurred within 6 months prior to enrollment and has not yet resolved.

10. A history of leptomeningeal disease; or presence of unstable central nervous system (CNS) metastases. Stability is defined as having undergone surgical resection and/or radiation therapy for CNS metastases at least 28 days before the first dose, and meeting all of the following criteria after completion of treatment:

    • No neurological symptoms, or symptoms are stable and ≤ Grade 1
    • No progression of treated lesions and no new lesions on contrast-enhanced CT or MRI within 28 days before the first dose
    • No or mild cerebral edema on imaging at screening, without requirement for systemic corticosteroids or anticonvulsants

11. Uncontrolled or clinically significant cardiovascular disease, including but not limited to:

    • History of symptomatic CHF (New York Heart Association [NYHA] class II-IV) or any arterial thromboembolic events (e.g., myocardial infarction, unstable angina, cerebrovascular accident, transient ischaemic attack) within 6 months before the first dose
    • Uncontrolled hypertension, defined as systolic blood pressure (SBP) >160 mmHg and/or diastolic blood pressure (DBP) >100 mmHg despite antihypertensive therapy
    • Serious cardiac arrhythmia requiring treatment
    • The QT interval corrected by the Fridericia formula (QTcF) is prolonged to > 470 ms

12. Active haemorrhage with significant clinical significance

13. Uncontrolled third-space fluid (eg, pleural effusions, ascites, pericardial effusions) that requires repeated drainage

14. Uncontrolled or unstable systemic diseases, including diabetes mellitus, hepatic cirrhosis, interstitial lung disease, and obstructive lung disease, by the investigator's discretion

15. Uncontrolled infection that requires systemic therapy within 1 week before the first dose

16. Active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or syphilis infection. Active HBV is defined as hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg) positive, and HBV DNA level above ULN at the study site; active HCV is defined as positive hepatitis C antibody and HCV RNA level above ULN at the study site; active HIV is defined as positive HIV antibody; active syphilis is defined as positive Treponema pallidum laboratory test. However, patients with well-controlled HIV (as judged by the investigator) may be considered eligible

17. Unresolved toxicities from previous anticancer therapy, defined as toxicities not yet resolved to NCI CTCAE Grade ≤1, baseline, or the level specified in the inclusion/exclusion criteria with the exception of alopecia (any grade), pigmentation (any grade), and peripheral neuropathy (Grade ≤2). Patients with irreversible toxicity (eg, hearing loss) that is reasonably not expected to be aggravated by the study drug can be enrolled after discussion with the sponsor

18. A history of severe hypersensitivity reactions to the drug substances, inactive ingredients in the drug product, or other mAbs

19. Has a history of ≥ Grade 3 hypersensitivity or allergic reaction to IgG4 monoclonal antibodies and/or their excipients, or to the PD-1 inhibitor used in the corresponding cohort and/or its excipients.

20. Women who are breastfeeding or pregnant as confirmed by pregnancy tests performed within 7 days before the first dose

21. Any illness, medical condition, organ system dysfunction, or social situation, including but not limited to mental illness or substance/alcohol abuse, deemed by the investigator to be likely to interfere with a patient's ability to sign informed consent, adversely affect the patient's ability to cooperate and participate in the study, or compromise the interpretation of study results