A Study of Becotatug Vedotin (MRG003) Combined With Epirubicin as Neoadjuvant Therapy for EGFR-Positive, Unresectable Recurrent Sinonasal Adenoid Cystic Carcinoma

This is a prospective, multicenter, single-arm, open-label phase II clinical study. Patients with histologically confirmed recurrent sinonasal adenoid cystic carcinoma (SNACC) that is deemed unresectable by a multidisciplinary team (MDT) and positive for EGFR expression (IHC) are eligible.

Intervention:

* MRG003 (Becotatug vedotin): 2.0 mg/kg IV on day 1 of each 21-day cycle.
* Epirubicin: 75 mg/m² IV on day 1 of each 21-day cycle.
* Total of 3 neoadjuvant cycles.

Primary Outcome Measure: Objective response rate (ORR) according to RECIST v1.1, assessed 21 days (±7 days) after the third cycle.

Secondary Outcome Measures:

* Safety and tolerability (CTCAE v5.0)
* Surgical conversion rate (proportion of patients achieving R0/R1 resection after neoadjuvant therapy)
* R0 resection rate and pathological response rate (major pathological response ≤10% viable tumor cells; pathological complete response 0%)
* Disease control rate (DCR), progression-free survival (PFS), and overall survival (OS)

Sample Size: 40 evaluable patients. Assuming a historical ORR of 10% with single-agent epirubicin, the study is designed to detect an improvement to 35% with the combination (one-sided exact binomial test, α=0.05, power 80%). The sample size also ensures sufficient power for key secondary endpoints and supports the translational sub-study (≥28 successful organoid models).

Translational Research Component: Pre-treatment tumor biopsies will be used to establish patient-derived organoids (PDOs). Organoids will be characterized (H\&E, immunofluorescence, STR genotyping) and tested ex vivo for sensitivity to MRG003, epirubicin, and their combination. Associations between organoid drug sensitivity and clinical response (ORR, tumor shrinkage, PFS) will be explored.

Statistical Analysis: Primary analysis will be performed on the full analysis set (all treated patients). ORR and other binary endpoints will be reported with exact 95% confidence intervals (Clopper-Pearson method). PFS and OS will be estimated using Kaplan-Meier method. Translational data will be analyzed using Spearman rank correlation, Chi-square or Fisher's exact tests, and exploratory Cox regression.

Study Duration: Approximately 48 months, including 24 months enrollment, 3-6 months treatment/short-term follow-up per patient, and 24 months long-term survival follow-up after last patient enrollment.

Data Monitoring: An independent Data Safety Monitoring Board (DSMB) will conduct interim safety review after 20 patients are enrolled.

• Becotatug Vedotin (Drug): Becotatug vedotin (also known as MRG003) is an antibody-drug conjugate (ADC) targeting epidermal growth factor receptor (EGFR). It consists of a recombinant anti-EGFR humanized monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a valine-citrulline linker. It is administered intravenously at 2.0 mg/kg on day 1 of each 21-day cycle for 3 cycles. Epirubicin is an anthracycline chemotherapeutic agent that inhibits topoisomerase II, thereby interfering with DNA replication and transcription. It is administered intravenously at 75 mg/m² on day 1 of each 21-day cycle for 3 cycles.

Primary outcomes

• Objective Response Rate (ORR) [21 days (±7 days) after completion of the third cycle of neoadjuvant therapy (each cycle is 21 days).]: Proportion of participants achieving complete response (CR) or partial response (PR) as assessed by the investigator according to RECIST v1.1 criteria.

Secondary outcomes

• Safety and tolerability [From first dose of study treatment up to 30 days after last dose (approximately 4 months per participant).]: Incidence, severity, and relationship of adverse events (AEs) and serious adverse events (SAEs) graded according to CTCAE v5.0.
• Surgical conversion rate [Within 4 weeks after completion of neoadjuvant therapy (i.e., approximately 3.5 months from treatment start).]: Proportion of participants who undergo radical surgery (R0 or R1 resection) after neoadjuvant therapy, as assessed by multidisciplinary team (MDT).
• Disease control rate (DCR) [21 days (±7 days) after completion of the third cycle of neoadjuvant therapy.]: Proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1.
• R0 resection rate [At time of surgery (within 4 weeks after neoadjuvant therapy completion).]: Among participants who undergo surgery, proportion with negative microscopic margins (R0) on final histopathology.
• Pathologic response rate [At time of surgery (within 4 weeks after neoadjuvant therapy completion).]: Among participants who undergo surgery, proportion achieving major pathologic response (≤10% viable tumor cells) or pathologic complete response (0% viable tumor cells).
• Progression-free survival (PFS) [Assessed every 3 months for the first 2 years, then every 6 months up to 5 years, or until death or study completion (up to 48 months from first participant enrolled).]: Time from enrollment to first documented disease progression (by RECIST v1.1) or death from any cause, whichever occurs first.
• Overall survival (OS) [Assessed every 3 months for the first 2 years, then every 6 months up to 5 years, or until death or study completion (up to 48 months from first participant enrolled).]: Time from enrollment to death from any cause.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

Age ≥ 18 years, male or female. Histopathologically confirmed sinonasal adenoid cystic carcinoma (SNACC) with measurable recurrent disease located in the sinonasal/skull base region, irrespective of the presence of regional lymph node or distant metastases.

EGFR expression positive by immunohistochemistry (IHC) performed at a central laboratory.

Multidisciplinary team (MDT) assessment at baseline confirms that the tumor is not amenable to radical (R0) surgical resection.

At least one measurable lesion in the skull base/sinonasal region according to RECIST v1.1 (longest diameter ≥ 10 mm).

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate bone marrow, hepatic, renal, and cardiac function as defined by protocol-specified laboratory parameters.

Willing to provide written informed consent (including consent for clinical treatment and biospecimen research) and able to comply with study procedures.

Exclusion Criteria:

Prior treatment with any antibody-drug conjugate (ADC) that contains monomethyl auristatin E (MMAE) as the payload.

Prior systemic chemotherapy containing epirubicin or any other anthracycline within 6 months before study enrollment.

Active uncontrolled infection, or active autoimmune disease requiring systemic therapy.

Symptomatic or urgent (e.g., requiring radiotherapy or surgery) central nervous system (CNS) metastases.

Known severe hypersensitivity to any component of the study drugs. Pregnant or breastfeeding women, or men/women planning to become pregnant within 6 months after the last dose of study treatment.

Any medical or psychosocial condition that, in the investigator's judgment, may interfere with study participation, increase patient risk, or confound data interpretation.

• Results publication: Agulnik M, Cohen EW, Cohen RB, Chen EX, Vokes EE, Hotte SJ, Winquist E, Laurie S, Hayes DN, Dancey JE, Brown S, Pond GR, Lorimer I, Daneshmand M, Ho J, Tsao MS, Siu LL. Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erbB2 expressing adenoid cystic carcinoma and non adenoid cystic carcinoma malignant tumors of the salivary glands. J Clin Oncol. 2007 Sep 1;25(25):3978-84. doi: 10.1200/JCO.2007.11.8612. PMID 17761983
• Results publication: Vered M, Braunstein E, Buchner A. Immunohistochemical study of epidermal growth factor receptor in adenoid cystic carcinoma of salivary gland origin. Head Neck. 2002 Jul;24(7):632-6. doi: 10.1002/hed.10104. PMID 12112535
• Results publication: Zhou J, Zhao G, Wang S, Li N. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review of the last decade. Br J Cancer. 2024 Oct;131(6):1021-1031. doi: 10.1038/s41416-024-02795-4. Epub 2024 Aug 3. PMID 39097677
• Results publication: Lupinetti AD, Roberts DB, Williams MD, Kupferman ME, Rosenthal DI, Demonte F, El-Naggar A, Weber RS, Hanna EY. Sinonasal adenoid cystic carcinoma: the M. D. Anderson Cancer Center experience. Cancer. 2007 Dec 15;110(12):2726-31. doi: 10.1002/cncr.23096. PMID 17960615
• Results publication: Mavrikios A, Goudjil F, Beddok A, Zefkili S, Bolle S, Feuvret L, Le Tourneau C, Choussy O, Sauvaget E, Herman P, Dendale R, Calugaru V. Proton therapy and/or helical tomotherapy for locally advanced sinonasal skull base adenoid cystic carcinoma: Focus on experience of the Institut Curie and review of literature. Head Neck. 2023 Jul;45(7):1619-1631. doi: 10.1002/hed.27371. Epub 2023 Apr 25. PMID 37097003