Nasopharyngeal Carcinoma (NPC)
Conditions
Keywords
Recurrent Nasopharyngeal Carcinoma, Antibody-Drug Conjugate, Becotatug Vedotin
Brief summary
This is a single-center, single-arm, phase II clinical trial designed to evaluate the efficacy and safety of becotatug vedotin combined with gemcitabine and a PD-1 inhibitor as second-line or later treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) who have experienced treatment failure following prior platinum-based chemotherapy or PD-(L)1 inhibitor therapy. Patients with recurrent or metastatic NPC who are unsuitable for curative local treatment and meet the eligibility criteria will receive becotatug vedotin, gemcitabine, and a PD-1 inhibitor every 3 weeks for 4-6 cycles, followed by PD-1 inhibitor maintenance therapy until disease progression or unacceptable toxicity. Approximately 30 patients will be enrolled. The primary objective is to evaluate the objective response rate (ORR) according to RECIST version 1.1. Secondary objectives include evaluating disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and treatment safety. This study aims to explore a potential treatment option for patients with recurrent or metastatic NPC who have limited therapeutic options after failure of previous systemic therapy.
Detailed description
Study Design This is a prospective, single-center, single-arm, phase II clinical trial conducted at Sun Yat-sen University Cancer Center. The study plans to enroll approximately 30 patients with histologically or cytologically confirmed recurrent or metastatic NPC who have experienced treatment failure following prior platinum-based chemotherapy or PD-(L)1 inhibitor therapy and are unsuitable for curative local treatment. Eligible patients must have at least one measurable lesion according to RECIST version 1.1 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Treatment Plan All eligible patients will receive the following combination treatment in 21-day cycles: * Becotatug vedotin: 2.0 mg/kg intravenously on Day 1. * Gemcitabine: 1,000 mg/m² intravenously on Days 1 and 8. * PD-1 inhibitor (camrelizumab): 200 mg intravenously on Day 1. Combination treatment will be administered for 4-6 cycles, depending on treatment response, tolerability, and investigator assessment. Following combination treatment, patients will receive maintenance therapy with a PD-1 inhibitor (camrelizumab, 200 mg intravenously every 3 weeks) until disease progression or unacceptable toxicity. Dose modifications, treatment delays, and treatment discontinuation will be managed according to the study protocol. Efficacy and Safety Assessments The primary endpoint is objective response rate (ORR), defined as the proportion of patients achieving a complete response (CR) or partial response (PR) according to RECIST version 1.1. Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety outcomes, including treatment-related adverse events, grade 3 or higher treatment-related adverse events, serious adverse events, and adverse events leading to dose modifications or treatment discontinuation. Tumor assessments will be performed at baseline, every 2 treatment cycles during combination therapy, and approximately every 9-12 weeks during maintenance treatment. Safety will be assessed throughout the study using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Exploratory biomarker analyses may be performed using peripheral blood and available tumor tissue samples to investigate potential associations between biological markers, treatment response, and toxicity. Statistical Considerations The sample size is based on a Simon two-stage design, assuming a historical ORR of 35% and an expected ORR of 60%, with a one-sided significance level of 0.05 and a statistical power of 80%. In the first stage, 9 evaluable patients will be enrolled. If 3 or fewer patients achieve an objective response, the study will be terminated early for insufficient efficacy. If at least 4 patients achieve an objective response, an additional 18 evaluable patients will be enrolled in the second stage. A total of 27 evaluable patients are required. If at least 13 patients achieve an objective response, the treatment regimen will be considered worthy of further investigation. Allowing for approximately 10% of patients being unevaluable, the planned enrollment is 30 patients. Safety Monitoring An initial safety run-in will be implemented using staggered enrollment of the first 3 patients. Safety will be reviewed after the first treatment cycle. A subsequent safety review will be conducted after the first 6 patients have completed at least 2 treatment cycles or 42 days of safety observation. Additional periodic safety reviews will be performed during enrollment. Enrollment may be temporarily suspended if serious or unexpected treatment
Interventions
Becotatug vedotin (MRG003), an EGFR-targeting antibody-drug conjugate (ADC), will be administered intravenously at 2.0 mg/kg on Day 1 of each 21-day cycle for 4-6 cycles in combination with gemcitabine and a PD-1 inhibitor. Dose modifications and treatment delays will be permitted according to the study protocol.
Gemcitabine will be administered intravenously at 1,000 mg/m² on Days 1 and 8 of each 21-day cycle for 4-6 cycles, in combination with becotatug vedotin and a PD-1 inhibitor. Dose modifications and treatment delays will be permitted according to the study protocol.
DRUGCamrelizumab
Camrelizumab, a PD-1 inhibitor, will be administered intravenously at a fixed dose of 200 mg on Day 1 of each 21-day cycle for 4-6 cycles in combination with becotatug vedotin and gemcitabine. Following combination treatment, camrelizumab maintenance therapy will continue at 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity.
Sponsors
Sun Yat-sen University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is a single-arm, open-label, phase II study using a Simon two-stage design. All eligible participants will receive becotatug vedotin, gemcitabine, and a PD-1 inhibitor, followed by PD-1 inhibitor maintenance therapy. An initial safety run-in with staggered enrollment and periodic safety reviews will be implemented. The study will enroll approximately 30 participants, aiming to obtain 27 evaluable participants for the primary efficacy analysis.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntary participation in the study and provision of written informed consent. 2. Male or nonpregnant female patients aged 18-70 years. 3. Life expectancy of at least 3 months. 4. Histologically or cytologically confirmed recurrent or metastatic nasopharyngeal carcinoma (NPC) with treatment failure following prior platinum-based chemotherapy or PD-(L)1 inhibitor therapy. The two treatment modalities may have been administered concurrently as part of a first-line regimen or sequentially. Patients must be considered unsuitable for curative local salvage treatment, including surgery, re-irradiation, or other definitive local therapies. 5. At least one measurable lesion according to RECIST version 1.1. Previously irradiated lesions cannot be selected as target lesions unless unequivocal progression has been documented at least 3 months after the last radiotherapy. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Adequate hematologic function, defined as: * Hemoglobin ≥90 g/L; * White blood cell count ≥4.0 × 10⁹/L; * Platelet count ≥100 × 10⁹/L. 8. Adequate hepatic function, defined as: * Total bilirubin \<2.0 × upper limit of normal (ULN); * AST and ALT ≤2.5 × ULN in patients without liver metastases, or ≤3.0 × ULN in patients with liver metastases; * Alkaline phosphatase ≤1.5 × ULN, or ≤2.0 × ULN in patients with liver metastases; * Serum albumin ≥30 g/L. 9. Adequate coagulation function, defined as international normalized ratio (INR) or prothrombin time (PT), and activated partial thromboplastin time (APTT) ≤1.5 × ULN. Patients receiving anticoagulant therapy are eligible if their anticoagulation parameters are within the therapeutic range and are closely monitored by the investigator. 10. Adequate renal function, defined as serum creatinine ≤1.5 × ULN, or creatinine clearance ≥50 mL/min calculated using the adjusted Cockcroft-Gault formula if serum creatinine exceeds 1.5 × ULN. 11. Women of childbearing potential and male patients of reproductive potential must agree to use adequate contraception throughout study treatment and for 180 days after the last dose of study treatment.
Exclusion criteria
1. Histologically confirmed keratinizing squamous cell carcinoma (WHO type I). 2. Grade ≥2 peripheral neuropathy according to CTCAE version 5.0. 3. Anticipated requirement for surgery or any other systemic or local anticancer therapy during the study, including palliative treatment, except for palliative treatment directed at non-target lesions. 4. Receipt of any of the following treatments before the first dose of study treatment: * Systemic chemotherapy within 3 weeks; * Small-molecule targeted therapy within 2 weeks or 5 half-lives, whichever is longer; * Anticancer biological therapy, macromolecular targeted therapy, or immunotherapy within 4 weeks; * Major surgery within 4 weeks, except for minor surgery performed within 2 weeks with complete recovery; * Radiotherapy within 14 days, or radiotherapy to the central nervous system within 28 days. 5. Known active central nervous system (CNS) metastases or carcinomatous meningitis. Patients with previously treated brain metastases may be eligible if clinically stable, without progressive or new neurological deficits, seizures, evidence of increased intracranial pressure, vomiting, or headache, and without evidence of lesion enlargement on MRI during the preceding 4 weeks or a requirement for corticosteroids during the 14 days before the first dose of study treatment. 6. Residual toxicities from previous anticancer treatment, including immunotherapy, targeted therapy, chemotherapy, or radiotherapy, or clinically significant laboratory abnormalities greater than grade 1 according to CTCAE version 5.0, except for alopecia, fatigue, and grade 2 hypothyroidism. 7. Uncontrolled or poorly controlled cardiovascular disease, including any of the following: * Grade ≥2 congestive heart failure within 6 months before enrollment; * Myocardial infarction or unstable angina; * History of ventricular tachycardia or torsades de pointes; * Clinically significant arrhythmias requiring treatment; * QTcF \>450 ms in males or \>470 ms in females; * Complete left bundle branch block or third-degree atrioventricular block. 8. Pulmonary embolism or deep vein thrombosis within 3 months before the first dose of study treatment, except for thrombosis associated with an implanted venous port or peripherally inserted central catheter (PICC). 9. History of another malignancy unless the patient has received potentially curative treatment and remained recurrence-free for at least 5 years. Exceptions include adequately treated basal cell carcinoma of the skin, superficial bladder cancer, cutaneous squamous cell carcinoma, carcinoma in situ, and papillary thyroid carcinoma. 10. Any severe or uncontrolled systemic disease, including poorly controlled hypertension (systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg) or poorly controlled diabetes mellitus (HbA1c \>8%). 11. Active bleeding, history of a bleeding or coagulation disorder, or current treatment with coumarin anticoagulants. 12. Known hypersensitivity to any component or excipient of becotatug vedotin, including citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, sodium chloride, and polysorbate 80; or a history of grade ≥3 hypersensitivity reactions to other anti-EGFR agents or monoclonal antibodies. 13. Active hepatitis B or hepatitis C infection, defined as: * Hepatitis B surface antigen (HBsAg) positivity with HBV DNA ≥500 IU/mL; * Hepatitis C antibody positivity with detectable HCV RNA above the lower limit of detection. Patients with other severe liver diseases, including chronic autoimmune liver disease, primary biliary cirrhosis, sclerosing cholangitis, alcoholic liver disease, or nonalcoholic steatohepatitis (NASH), will also be excluded. 14. Severe uncontrolled infection, known HIV infection, or acquired immunodeficiency syndrome (AIDS); active autoimmune disease, except for type 1 diabetes mellitus, hypothyroidism controlled with replacement therapy, or skin disorders not requiring systemic treatment (such as vitiligo, psoriasis, or alopecia); or a history of allogeneic tissue or organ transplantation, stem cell transplantation, or bone marrow transplantation. 15. Active bacterial, viral, fungal, rickettsial, or parasitic infection requiring systemic antimicrobial treatment, unless adequately treated and resolved before the first dose of study treatment. 16. Receipt of a live-virus vaccine within 30 days before the first dose of study treatment. 17. History of or concurrent interstitial pneumonitis, severe chronic obstructive pulmonary disease with respiratory failure, severe pulmonary dysfunction, or symptomatic bronchospasm. 18. Receipt of immunologically based treatment for any reason, including chronic systemic corticosteroid therapy equivalent to \>10 mg/day of prednisone within 7 days before the first dose of study treatment or during study participation. Inhaled or topical corticosteroids, systemic corticosteroids equivalent to ≤10 mg/day of prednisone, and short-term corticosteroid use at higher doses for specific indications (such as premedication before contrast administration) are permitted. 19. Uncontrolled pleural, abdominal, pelvic, or pericardial effusion requiring drainage at least once per month. 20. Positive pregnancy test, current breastfeeding, or unwillingness to use adequate contraception during study treatment and for 180 days after the last dose of study treatment. 21. Any other disease, clinically significant laboratory abnormality, serious medical or psychiatric condition, or substance abuse (including alcohol abuse) that, in the investigator's judgment, may compromise patient safety, study integrity, study participation, or interpretation of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From the first dose of study treatment until disease progression, initiation of new anticancer therapy, death, or the last tumor assessment, whichever occurs first (assessed up to approximately 24 months). | Objective response rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR), as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, from the first dose of study treatment until disease progression, initiation of new anticancer therapy, death, or the last tumor assessment, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | From the first dose of study treatment until disease progression, initiation of new anticancer therapy, death, or the last tumor assessment, whichever occurs first (assessed up to approximately 24 months). | Disease control rate (DCR) is defined as the proportion of participants whose best overall response is complete response (CR), partial response (PR), or stable disease (SD), as assessed by the investigator according to RECIST version 1.1. |
| Duration of Response (DoR) | From the first documented CR or PR until disease progression or death (assessed up to approximately 24 months). | Duration of response (DoR) is defined as the time from the first documented complete response (CR) or partial response (PR) to the first documented disease progression or death from any cause, whichever occurs first, among participants who achieve an objective response. |
| Progression-Free Survival (PFS) | From the first dose of study treatment until disease progression or death (assessed up to approximately 24 months). | Progression-free survival (PFS) is defined as the time from the first dose of study treatment to the first documented disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first. |
| Overall Survival (OS) | From the first dose of study treatment until death from any cause (assessed up to approximately 24 months). | Overall survival (OS) is defined as the time from the first dose of study treatment to death from any cause. |
| Incidence of Treatment-Related Adverse Events (TRAEs) | During study treatment and protocol-specified safety follow-up (approximately up to 24 months). | The proportion of participants experiencing at least one treatment-related adverse event (TRAE), with severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. |
| Incidence of Serious Adverse Events (SAEs) | During study treatment and protocol-specified safety follow-up (up to approximately 24 months). | The proportion of participants experiencing at least one serious adverse event (SAE), regardless of its relationship to study treatment. |
Countries
China
Contacts
CONTACTZiying Wang
PRINCIPAL_INVESTIGATORYijun Hua, MD
Sun Yat-Sen University Cancer Center
Outcome results
None listed