Phase II Study of Becotatug Vedotin Plus Pucotenlimab for Advanced Refractory Solid Tumors With EGFR-Positive

ELEVATE Study: A Phase II Single-Arm Open-Label Single-Center Exploratory Trial of Becotatug Vedotin (MRG003) Plus Pucotenlimab (HX008) in Advanced Refractory Solid Tumors With EGFR-Positive

This phase II trial evaluates the combination of Becotatug Vedotin (MRG003), an EGFR-targeting ADC, and Pucotenlimab (HX008), a PD-1 inhibitor, in patients with high EGFR expressing advanced refractory solid tumors. The study is designed to assess clinical efficacy and safety, building on a strong synergistic rationale and promising early-phase data.

Given the substantial unmet medical need for effective treatment options in patients with advanced refractory solid tumors, and grounded in the synergistic rationale of combining EGFR-targeted therapy with immune checkpoint modulation, the encouraging efficacy and manageable safety profiles observed in early phase studies of Becotatug Vedotin (MRG003) andPucotenlimab (HX008) provide a strong rationale for further investigation. Accordingly, a methodologically rigorous phase II clinical trial is warranted to objectively evaluate the clinical efficacy and safety of this dual regimen specifically in patients with high EGFR expressing advanced refractory solid tumors.

Inclusion Criteria:

1. Age≥18 years at the time of signing the informed consent form (ICF).

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 7 days prior to the first dose. ECOG 2 is allowable if it is solely attributable to tumor progression, as judged by the investigator.

3. Life expectancy≥ 12 weeks.

4. Histologically or cytologically confirmed locally advanced or metastatic solid tumors that have failed standard therapy (progressive disease or intolerance to prior treatment), or for whom standard therapy is currently not applicable or unavailable. There is no limit on the number of prior lines of therapy.

5. Documentation of EGFR expression status is required for enrollment. If not available, the subject must provide adequate fresh or archival tumor tissue samples for EGFR testing. If adequate tumor specimens cannot be provided, a repeat biopsy may be performed if deemed feasible and safe by the investigator and after obtaining the subject's consent; however, repeat biopsy is not mandatory. In cases where repeat biopsy is not feasible or the subject refuses, eligibility must be jointly confirmed by the investigator and the sponsor.

6. EGFR expression positive (2+ or 3+) as determined by immunohistochemistry (IHC).

7. At least one measurable lesion per RECIST version 1.1.

8. Adequate organ function, as defined by the following criteria (no blood components, cell growth factors, leukopoiesis agents, thrombopoiesis agents, or anemia-correcting drugs are allowed within 14 days prior to the first dose):

   A. White blood cell count (WBC) ≥ 3.0 x 10^9/L; absolute neutrophil count (ANC) ≥ 2.0 x 10^9/L.

   B. Hemoglobin (HB) ≥90 g/L. C. Platelet count ≥ 100x10^9/L. D. Serum albumin ≥ 2.8 g/dL. E. Total bilirubin ≤1.5 x upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN.

   F. Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 60 mL/min. G. Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 x ULN (subjects receiving stable doses of anticoagulants, such as low-molecular-weight heparin or warfarin, with INR within the expected therapeutic range for the anticoagulant, are eligible for screening).

9. No contraindications to chemotherapy, targeted therapy, or immunotherapy.

10. No history of immune-related diseases.

11. No uncontrolled pneumonia or pulmonary infection.

12. Females of childbearing potential must agree to use effective contraception during the trial; a serum or urine pregnancy test must be negative within 72 hours before the start of chemotherapy.

13. Subjects must be compliant, able to undergo treatment and follow-up, and willing to comply with the study requirements as specified in the protocol.

14. For male subjects with partners of childbearing potential, effective medical contraception must be used from the signing of the ICF until 6 months after the last dose.

15. Subjects must voluntarily sign the ICF and be able to comply with the protocol-specified visits and procedures.

Exclusion Criteria:

1. Presence of uncontrolled serious medical conditions, including severe cardiac disease, cerebrovascular disease, uncontrolled diabetes, uncontrolled hypertension, uncontrolled infection, active peptic ulcer, etc.

2. History of allergy or hypersensitivity to any component of monoclonal antibody-based agents, or known allergic constitution.

3. Uncontrolled cardiac symptoms or diseases, such as:

   • New York Heart Association (NYHA) Class ≥ II heart failure, or left ventricular ejection fraction (LVEF) < 50% on echocardiography;
   • Unstable angina;
   • Myocardial infarction within 1 year;
   • Clinically significant supraventricular or ventricular arrhythmias requiring intervention (including QTc interval≥470 ms).

4. Severe infection (CTC AE > Grade 2) within 4 weeks before the first dose, such as severe pneumonia requiring hospitalization, bacteremia, infectious complications, etc.; evidence of active pulmonary inflammation on baseline chest imaging; signs or symptoms of infection or need for oral or intravenous antibiotics (excluding prophylactic antibiotics) within 2 weeks before the first dose.

5. Unexplained fever > 38.5 ℃ during screening or before the first dose (subjects with tumor fever, as judged by the investigator, may be enrolled).

6. Active autoimmune disease or history of autoimmune disease (e.g., interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these). Exceptions include: autoimmune-mediated hypothyroidism treated with stable doses of thyroid-replacement hormones; type 1 diabetes mellitus controlled with stable insulin; vitiligo; or childhood asthma/allergy that has resolved and requires no intervention in adulthood.

7. History of immunodeficiency, including HIV-positive status, other acquired or congenital immunodeficiency diseases, or history of organ transplantation or allogeneic bone marrow transplantation.

8. Untreated chronic hepatitis B, or hepatitis B virus (HBV) DNA > 500 IU/mL, or active hepatitis C virus (HCV) infection. Subjects with inactive hepatitis B surface antigen (HBsAg) carriers, treated and stabilized hepatitis B (HBV DNA < 500 IU/mL), or cured hepatitis C may be enrolled.

9. History of interstitial lung disease (excluding radiation pneumonitis that has not been treated with corticosteroids) or non-infectious pneumonitis.

10. Active pulmonary tuberculosis infection by history or CT findings, or history of active tuberculosis within 1 year before enrollment, or history of active tuberculosis more than 1 year ago without adequate treatment.

11. Prior receipt of any of the following treatments:

    A. Any investigational drug within 4 weeks before the first dose. B. Last dose of anticancer therapy (including chemotherapy, radiotherapy, targeted therapy, etc.) ≤ 4 weeks before the first dose.

    C. Systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive agents within 2 weeks before the first dose, except for local inflammation prophylaxis, anti-allergy, or anti-emetic use. Inhaled or topical corticosteroids, and adrenal hormone replacement doses > 10 mg/day prednisone equivalent, are permitted in the absence of active autoimmune disease.

    D. Prior anti-cancer vaccine, or live vaccine within 4 weeks before the first dose.

    E. Major surgery or severe trauma within 4 weeks before the first dose. F. Concurrent enrollment in another clinical study.

12. Dementia, altered mental status, or any psychiatric condition that would interfere with understanding or providing informed consent or completing questionnaires.

13. History of allergy or hypersensitivity to any component of the study treatments.

14. Known history of allogeneic organ or allogeneic hematopoietic stem cell transplantation.

15. Active hepatitis B (HBsAg positive, requiring HBV-DNA testing; HBV-DNA≥500 IU/mL or above the lower limit of detection, whichever is higher) or active hepatitis C (HCV antibody positive with HCV-RNA above the lower limit of detection). Note: Subjects who are HBsAg positive are required to receive anti-HBV therapy during the study treatment period.

16. Positive HIV test or history of acquired immunodeficiency syndrome (AIDS); known active syphilis infection.

17. Major surgery within 4 weeks before the first dose, or anticipated to require major surgery during the study period.

18. Rapid deterioration of clinical condition during the screening period (e.g., significant changes in performance status).

19. Local or systemic disease not caused by malignancy, or disease/symptoms secondary to the tumor, that would pose a higher medical risk or introduce uncertainty in survival assessment, such as leukemoid reaction, cachexia, etc.

20. Any condition that, in the investigator's opinion, would interfere with evaluation of the study drug, compromise subject safety, or confound interpretation of study results, or any other condition rendering the subject unsuitable for participation.