The Safety and Efficacy of MRG003 With or Without Putrelimab in Recurrent or Metastatic Salivary Gland Cancer: a Single-center, Open-label Cohort Study

The Safety and Efficacy of MRG003 With or Without Putrelimab in Recurrent or Metastatic Salivary Gland Cancer: a Single-center, Open-label Cohort Study

This study is a four-cohort, open-label, single-center Phase II clinical trial aimed at evaluating the efficacy and safety of MRG003 alone or in combination with pertuzumab in patients with recurrent or metastatic adenoid cystic carcinoma (ACC) and other salivary gland cancers (non- ACC SGCs). This study is an exploratory one without a randomized control. After fully informed and signing the informed consent form, eligible subjects will be enrolled in MRG003 treatment [Cohort 1 (ACC) and Cohort 2 (non-ACC SGCs) ] in the order of the study sequence. After the completion of enrollment in Cohort 1, subsequent eligible ACC subjects will be included in the MRG003 plus pertuzumab treatment (Cohort 3), and after the completion of enrollment in Cohort 2, subsequent eligible non-ACC SGC subjects will be included in the MRG003 plus pertuzumab treatment (Cohort 4). Patients in Cohort 1 and Cohort 2 will receive intravenous infusion of MRG003 on the first day of each treatment cycle at a dose of 2.3 mg/kg. Patients in Cohort 3 and Cohort 4 will receive intravenous infusion of pertuzumab on the first day of each treatment cycle at a dose of 3 mg/kg (up to a maximum of 200 mg), followed by MRG003 at a dose of 2.0 mg/kg at least 30 minutes after the completion of pertuzumab infusion. All patients will receive single-agent or combination therapy every three weeks until the end of two years of treatment or the occurrence of a treatment discontinuation event as specified in the protocol. After the treatment, safety follow-up and survival follow-up will be conducted for each subject. For subjects who end treatment due to reasons other than disease progression or death and have not started a new anti-tumor study, tumor imaging assessment will continue as originally planned until disease progression, initiation of new anti-tumor treatment, withdrawal of informed consent, loss to follow-up, or death, whichever occurs first. During the clinical study, we will establish PDX models for mechanism validation. In addition, it is recommended to analyze the following markers for subjects: IHC: ER, PR, AR, HER2, EGFR; FISH: HER2. Genetic testing is recommended based on the economic conditions of the subjects, but it is not mandatory. For subjects with HER2 3+ or HER2 2+ and FISH positive, it is recommended to receive anti-HER2 treatment first. For subjects who have undergone testing, we will collect the test results. For subjects who have not undergone testing, we will conduct relevant tests.

Inclusion Criteria:

1. The subject must provide voluntary informed consent and agree to comply with all protocol requirements.

2. The subject must be at least 18 years of age on the date of informed consent form signing, with no restrictions based on gender.

3. Expected survival duration of at least 12 weeks.

4. Histopathologically confirmed recurrent or metastatic salivary gland cancer that cannot be treated with curative surgery or radiotherapy, including major subtypes such as adenoid cystic carcinoma, mucoepidermoid carcinoma, and adenocarcinoma; and immunohistochemically confirmed EGFR expression or positivity.

5. Patients diagnosed with adenoid cystic carcinoma (ACC) or acinic cell carcinoma must meet one of the following criteria: evidence of radiographic progression within 6 months prior to enrollment, or new or worsening tumor-related symptoms.

6. The subject must be able to provide a tumor tissue specimen-either from the primary or metastatic site-for pathological evaluation. Acceptable specimens include formalin-fixed paraffin-embedded blocks, paraffin-embedded sections, or fresh tissue sections. If archived tissue is unavailable, a new biopsy must be performed.

7. According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the subject must have at least one measurable lesion at baseline, defined as a lesion with a longest diameter ≥10 mm on CT imaging (or a short axis ≥15 mm for lymph nodes). Lesions previously irradiated may be considered target lesions if there is radiological evidence of progression; however, non-irradiated lesions are preferred.

8. The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 within 7 days prior to the first administration of study drug.

9. Organ function must meet the following criteria within 7 days prior to dosing:

   • Hematologic function: Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and hemoglobin ≥90 g/L. Subjects must not have received blood or platelet transfusions within 14 days prior to first dosing, nor growth factor support (e.g., granulocyte colony-stimulating factor or erythropoiesis-stimulating agents) within 7 days prior to first dosing.
   • Hepatic function: For patients without liver metastases, total serum bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN. For patients with liver metastases, TBIL ≤1.5 × ULN, and ALT and AST ≤5 × ULN.
   • Coagulation function: International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN. Stable low-dose anticoagulation (e.g., aspirin 100 mg daily) is permitted.
   • Renal function: Creatinine clearance (CrCl) ≥50 mL/min, calculated using the Cockcroft-Gault formula.

10. Male subjects with reproductive potential and female subjects of childbearing potential must agree to use effective contraception from the time of informed consent through at least 6 months after the final dose of investigational product. Female subjects are considered of childbearing potential if they are premenopausal or within 2 years of menopause. A negative serum pregnancy test is required for all female subjects of childbearing potential within 7 days prior to the first administration of study drug.

Exclusion Criteria:

1. A history of other malignancies within the past five years is exclusionary, except for adequately treated and cured cervical carcinoma in situ, thyroid cancer (excluding medullary or anaplastic types), or basal cell carcinoma of the skin.

2. Prior receipt of any of the following treatments:

   • Administration of an antibody-drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload within 3 months prior to first dose;
   • Exposure to any investigational agent in a clinical trial within 28 days prior to first dose;
   • Receipt of systemic anti-tumor therapy (including chemotherapy, radiotherapy, targeted therapy, or other modalities) within 28 days prior to first dose;
   • Undergone major surgery within 28 days prior to first dose without full recovery, or scheduled to undergo major surgery during the first 12 weeks following initiation of study treatment.

3. Patients with HER2-positive status at baseline who have not received HER2-targeted or combination therapy (including HER2 monoclonal antibody-based combinations, HER2 ADCs, or HER2-targeted small-molecule agents; receipt of any one of these is acceptable for enrollment).

4. Presence of symptomatic central nervous system (CNS) metastases or leptomeningeal disease; or history of CNS metastasis treatment within 3 months prior to first dose.

5. Clinically symptomatic pleural, peritoneal, or pericardial effusion requiring puncture drainage; except for patients with stable disease after symptomatic treatment, as determined by the investigator to be eligible for enrollment.

6. Any severe or uncontrolled systemic illness, as determined by the investigator, including but not limited to poorly controlled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg), inadequately controlled diabetes mellitus, or evidence of active bleeding.

7. Poorly controlled cardiac disease, including heart failure of New York Heart Association (NYHA) class ≥2, unstable angina, myocardial infarction within the past year, or clinically significant supraventricular or ventricular arrhythmia requiring treatment.

8. Active or uncontrolled infection, including:

   • Hepatitis B virus (HBV): HBsAg positive and HBV DNA ≥2,000 IU/mL (with exclusion of drug-induced or other non-viral causes of hepatitis);
   • Hepatitis C virus (HCV): anti-HCV antibody positive and detectable HCV RNA above the assay's lower limit of quantification;
   • Human immunodeficiency virus (HIV) infection;
   • Uncontrolled bacterial, viral (non-HBV/HCV), fungal, rickettsial, or parasitic infections, unless resolved with appropriate treatment prior to first administration of study drug.

9. History of hypersensitivity to Ptoridimab or any excipient in MRG003 (histidine, histidine hydrochloride, sucrose, mannitol, polysorbate 80), or prior grade ≥3 hypersensitivity reaction to monoclonal antibodies or other large protein therapeutics.

10. Known history of primary immunodeficiency or active autoimmune disease requiring immunosuppressive therapy; current or recent (within 2 weeks before enrollment) use of systemic immunosuppressants or corticosteroids at a dose equivalent to ≥10 mg/day prednisone.

    Note: The following are permitted: type 1 diabetes mellitus with stable control; hypothyroidism managed with hormone replacement; vitiligo or psoriasis not requiring systemic therapy; use of topical or inhaled corticosteroids; or short-term (≤7 days) systemic corticosteroid use for non-autoimmune indications such as allergy prophylaxis or acute inflammation.

11. History of or concurrent moderate-to-severe interstitial lung disease, radiation pneumonitis, severe chronic obstructive pulmonary disease, severe pulmonary insufficiency, or symptomatic bronchospasm.

12. Failure to recover from prior anti-cancer therapy-related toxicities to Grade ≤1 according to NCI-CTCAE v5.0, excluding alopecia, any degree of skin hyperpigmentation, or stable Grade 2 hypothyroidism on hormone replacement.

13. Peripheral neuropathy of Grade >1.

14. Any other condition that, in the investigator's judgment, contraindicates participation in the study, including substance abuse (e.g., alcoholism, drug addiction), or inability to comply with study procedures.