Targeting NUDT21 siRNA Drugs for Patients With Refractory Retinoblastoma

Early Phase 1

Recruiting

• Conditions: Retinoblastoma; Refractory
• Interventions: Drug: Targeting NUDT21 siRNA drugs

• Registration Number: NCT06424301
• Lead Sponsor: Eye & ENT Hospital of Fudan University

Brief Summary

Retinoblastoma (RB) is the most common intraocular malignancy in children, accounting for approximately 11% of all cancers diagnosed in children under the age of one. Although its incidence is relatively low-about 1 in 15,000 to 20,000 live births-RB has a high risk of intracranial metastasis via the optic nerve, often leading to poor prognosis in advanced cases.

Recent advances in administration routes, such as intravitreal and intra-arterial chemotherapy, have significantly improved eye preservation rates. However, these strategies are limited by cumulative retinal toxicity and drug resistance. In refractory cases, enucleation remains the only definitive treatment to prevent extraocular spread and death.

In light of these challenges, current research efforts are focused on developing novel targeted therapies that enhance anti-tumor efficacy while minimizing local toxicity. In this context, we introduce a first-in-class siRNA-based drug targeting NUDT21, which promotes tumor regression by modulating the 3'UTR tail of SMC1A, thereby suppressing tumor cell proliferation. Importantly, the siRNA drug selectively targets tumor cells, offering a favorable safety profile compared to conventional chemotherapeutic regimens.

Given that both the target (NUDT21) and the mode of administration (intraocular siRNA injection) are novel in retinoblastoma treatment, there is an urgent need for early-phase investigator-initiated clinical research. This study is therefore designed to assess the short-term safety and preliminary efficacy of NUDT21 siRNA in patients with refractory retinoblastoma, and to provide an evidence base for future large-scale clinical trials.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-05-16
• Study First Submitted QC: 2024-05-16
• Study First Posted: 2024-05-22
• Study Start: 2024-12-20
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-20
• Last Update Posted: 2025-06-26
• Primary Completion: 2025-09-30
• Study Completion: 2025-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 2

Inclusion Criteria

1. Patients with retinoblastoma with a somatic mutation of the gene RB1 and active tumor in a single eye, or germinal mutation of RB1 with active tumor/s in an eye and the contralateral eye unaffected, enucleated or without tumor activity. In both cases, relapsed or refractory with the use of systemic, intraarterial or intravitreal chemotherapy or radiotherapy, in accordance with the availability at his/her referral site, in whom enucleation is the only recommended treatment under opinion of the medical team treating the case at the originating referral site. But the patient has a strong desire to preserve the eye.
2. Normal renal function: serum creatinine: < 45 μmol/L (0-2 years); < 57 μmol/L (3-6 years); < 60 μmol/L (7-10 years); < 80 μmol/L (11-13 years).
3. Normal Hepatic function: serum ALT: < 0,52 μkat/L (de 9 months -12 years); serum AST: 61-80 g/L (8 months - 5 years); 63-83 g/L (5-9 years); 63-82 g/L (9-12 years).
4. Age greater than 6 months at the time of inclusion in the study.
5. Sign the informed consent form and be willing to follow up at the specified time.

Exclusion Criteria

1. Presence of factors that require immediate enucleation of the affected eye such as glaucoma, rubeosis iridis, anterior chamber involvement.
2. Comorbidities: Uncontrolled epilepsy with anticonvulsant treatment, cardiac disease not compensated by treatment.
3. Active Infections.
4. Other chronic or active acute diseases that under the criterion of the researcher were an exclusion criterion.
5. History of having received attenuated or live vaccines in the 30 days prior to inclusion in the study.
6. Any cause of Immunosuppression.
7. Trilateral Retinoblastoma.
8. Extraocular spread.
9. History of having received treatment for retinoblastoma with chemotherapy or radiation therapy by any means within 30 days prior to inclusion in the study.
10. Patients who can not complete the study procedures.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Intravitreal chemotherapy in patients with refractory retinoblastoma	Targeting NUDT21 siRNA drugs	Prior to the first administration of the targeted drug, enrolled patients underwent peripheral blood sampling and comprehensive clinical evaluation. Intravitreal injections of the targeted drug were administered at a dosage of 100-200 μg (100 μg for patients under 2 years of age; 200 μg for patients aged 2 years and above) on Day 1 of Weeks 1, 3, and 7. Aqueous humor samples were collected at the time of injection during Weeks 1, 3, and 7. Clinical assessments were conducted monthly, with continuous follow-up extending through Week 24.

Primary Outcome Measures

Name	Time	Method
Incidence of Treatment-Emergent Adverse Events	6 months	Treatment-emergent adverse events (TEAEs) are defined as any unfavorable or unintended sign, symptom, or disease temporally associated with the administration of intravitreal siRNA therapy, whether or not considered related to the drug. Use CTCAE v5.0 (Common Terminology Criteria for Adverse Events) for grading severity.

Secondary Outcome Measures

Name	Time	Method
Tumor size	6 months	Tumor size will be assessed by measuring tumor thickness (height) from the retinal surface to the apex of the lesion on optical coherence tomography (OCT) scan. Serial OCT scans will be used to track tumor regression or progression over time. This outcome aims to assess anatomical response to treatment and provide imaging-based evidence of therapeutic efficacy.
Retinal function	6 months	Photopic flicker electroretinography (ERG) will be conducted in accordance with ISCEV standards, typically using a 30 Hz stimulus. The amplitude will be measured and compared pre- and post-treatment. This outcome will assess the potential impact of the investigational therapy on cone system integrity and retinal functional preservation.
Target engagement	6 months	We will measure the concentrations of NUDT21 and SMC1A proteins in aqueous humor samples using enzyme-linked immunosorbent assay (ELISA) before and after treatment. This assessment will confirm pharmacodynamic target engagement of the NUDT21 siRNA therapy by evaluating changes in NUDT21 and downstream effector SMC1A expression levels.

Trial Locations

Locations (1)

Fudan Eye & ENT Hospital; 🇨🇳 Shanghai, China