A Study to Evaluate the Efficacy and Safety of MRG003 in Patients With Recurrent Metastatic Nasopharyngeal Carcinoma

The objective of this study is to assess the safety, efficacy, pharmacokinetics, and immunogenicity of MRG003 in patients with recurrent metastatic nasopharyngeal carcinoma.

The study consists of two stages.

Part A of this study is an open-label, single arm, multicenter Phase IIa clinical study in patients with inoperable, radiotherapy ineligible RM-NPC who have failed (or are intolerable) at least 1 prior line platinum-based systemic chemotherapy and PD-1 (L1) inhibitors.

Part B is an open-label, randomized, multicenter Phase IIb study to compare the efficacy and safety of MRG003 versus capecitabine/docetaxel in patients with RM-NPC who have failed at least 2 prior lines of systemic chemotherapy and PD-1 (L1) inhibitors.

Eligibility Criteria:
Inclusion Criteria:

* Willing to sign the ICF and follow the requirements specified in the protocol.
* Age: ≥18 years, ≤75 years
* Expected survival time\>3 months.
* Patients with histologically confirmed unresectable, radiation-ineligible recurrent metastatic nasopharyngeal carcinoma.
* Part A: Metastatic nasopharyngeal carcinoma that has failed or recurred or was intolerant to at least 1 prior line platinum-based systemic chemotherapy and PD-1/PD-L1 inhibitors
* Part B: have documented failure of at least 2 prior lines of PD-1 (L1) and therapysystemic chemotherapy, which include at least platinum-based regimen, gemcitabine, taxanes/capecitabine.
* Patients must have measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
* ECOG performance score 0 or 1.
* Organ functions and coagulation function must meet the basic requirements.
* No severe cardiac dysfunction with left ventricular ejection fraction (LVEF) ≥ 50%.
* Serum or urine pregnancy test negative within 72 hours before the first dose of investigational drug.
* Patients with childbearing potential must use effective contraception during the treatment and for 6 months after the last dose of treatment.

Exclusion Criteria:

* Grade ≥2 peripheral neuropathy per CTCAE v5.0.
* Is expected to require surgery or any other form of systemic or local anti-tumor therapy during the study.
* Received systemic chemotherapy, targeted therapy, biologics or immunotherapy, or major surgery (except for minor surgery within 2 weeks and fully recovered) within 3 weeks prior to the first dose of study treatment; received thoracic radiotherapy \>30 Gy within 6 months prior to the first dose of study treatment; received prior radiotherapy (except radiotherapy for CNS, wash-out period ≥ 28 days is required) within 14 days before the first dose of study treatment, received traditional Chinese medicine with anti-tumor indications within the 2 weeks before the first dose of study treatment.
* Known active central nervous system (CNS) metastases and/or meningeal metastases. Patients with brain metastases may participate provided they are treated and stable
* Residual toxicities due to prior anti-tumor therapy (including biologics, targeted therapy, immunotherapy, chemotherapy or radiotherapy) or ≥ Grade 1 (CTCAE v5.0) clinically significant laboratory abnormality.
* History of severe cardiac dysfunction, stroke, or transient ischemic attack (TIA) within 6 months prior to enrollment. History of ventricular tachycardia or torsades de pointes. Any clinically important abnormality in the rhythm, conduction, or morphology of the resting ECG. Note: Patients with arrhythmia are eligible if they are receiving antiarrhythmic medication and the screening electrocardiogram (ECG) shows controllable rhythm and heart rate.
* Pulmonary embolism or deep venous thrombosis within 3 months prior to the first dose of study drug.
* Known history of malignancy (except for patients with cutaneous basal cell carcinoma, superficial bladder carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in situ, or papillary thyroid carcinoma who have undergone successful curative treatment) unless the patient has received potentially curative therapy and has not had disease recurrence within 5 years starting from the treatment.
* Note: The 5-year recurrence-free time requirement does not apply to NPC for which the patient is enrolled.
* Uncontrolled or poorly controlled hypertension (e.g., systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg) or diabetes mellitus (glycosylated hemoglobin (HbA1c) \> 8%).
* Patients with active bleeding, history of coagulopathy, or receiving coumarin anticoagulant therapy.
* History of ≥ Grade 3 immune-related AEs (irAEs), including skin toxicity, diarrhea, enteritis, fatigue, immune-related nephritis, immune-related hepatitis, and infusion reactions.
* Known allergic reactions to any component or excipients of MRG003 (citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, sodium chloride, and polysorbate 80) or capecitabine/docetaxel, or known allergic reactions to other anti-EGFR agents (including investigational drug) or to other monoclonal antibodies ≥ Grade 3.
* Known active hepatitis B or C. Presence of other serious liver diseases, including chronic autoimmune hepatic disorders, primary biliary cirrhosis or sclerosing cholangitis, alcoholic liver disease, or nonalcoholic steatohepatitis (NASH).
* Concurrent, serious, uncontrolled infection or known infection with human immunodeficiency virus (HIV) (HIV antibody positive), or diagnosis of acquired immunodeficiency syndrome (AIDS); or uncontrolled autoimmune disease; or previous allogeneic tissue/organ transplantation, stem cell or bone marrow transplantation, or previous solid organ transplantation.
* Active bacterial, viral, fungal, rickettsial, or parasitic infection requiring systemic anti-infection therapy (unless treated and resolved prior to study treatment).
* Received live-virus vaccines within 30 days prior to the first dose of study treatment. Seasonal influenza vaccines or approved COVID-19 vaccines that do not contain live virus are permitted.
* History of moderate to severe dyspnea at rest or severe primary lung disease (current need for continuous oxygen therapy and oxygen saturation \< 93% without oxygen therapy) due to advanced cancer or its complications, or history of any interstitial lung disease (ILD) (including ILD that requires oral or intravenous corticosteroids) or noninfectious pneumonitis
* Patients who are receiving an immunologically based treatment for any reason, including chronic use of systemic steroids equivalent to \> 10 mg/day of prednisone within 7 days prior to the first dose of study treatment or at any time during the study. Note: Use of inhaled or topical steroids or systemic corticosteroids equivalent to ≤ 10 mg/day prednisone is permitted, as is short-term use of corticosteroids at doses equivalent to \> 10 mg/day prednisone (e.g., pre-medication prior to contrast).
* Chronic autoimmune or inflammatory disease requiring or receiving systemic therapy within the last 2 years, including but not limited to inflammatory bowel disease, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, Wegener's granulomatosis, Sjogren's syndrome, Guillain - Barre's syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (exceptions: vitiligo, hypothyroidism on stable hormone replacement therapy, controlled asthma, type I diabetes mellitus, Graves' disease, Hashimoto's disease, or with medical monitor's approval).
* Uncontrolled pleural, abdominal, pelvic effusion or pericardial effusion that requires ≥ 1 drainage per month.
* Patients who are using strong CYP3A4 inhibitors or inducers and for who stop the use is not recommended.
* Any patient with a positive pregnancy or is breast-feeding. Female and male patients who are not expected to use adequate contraception during treatment and for 180 days after the last dose of treatment.
* Any other disease or clinically significant abnormality in laboratory parameters, or serious medical or psychiatric illnesses/conditions, substance abuse disorder including alcoholism, which in the judgment of the Investigator might compromise the safety of the patient, integrity of the study, interfere with the patient participation in the study, or confound or compromise the study objectives and their interpretability.