Intraocular Chemotherapy for Retinoblastoma

Recruiting at 20 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Oncology Group

Disqualifiers: Metastatic spread, Invasive infection, Prior therapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 24 weeks

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of adding melphalan, a chemotherapy injected directly into the eye, to the standard chemotherapy for retinoblastoma, a rare eye cancer. The focus is on cases where the cancer has spread into the eye's fluid, making treatment more challenging. Researchers hope melphalan can kill cancer cells more effectively. Suitable candidates have newly diagnosed retinoblastoma in one or both eyes with specific cancer spread patterns. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group, contributing to advancements in retinoblastoma care.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, it does mention that patients must not have had any prior anti-cancer therapy other than specific eye treatments. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that injecting melphalan directly into the eye is generally well-tolerated for treating retinoblastoma, a type of eye cancer. Studies have found this method to be safe for patients. These studies also report no major differences in eye safety or survival rates with varying doses of melphalan. Thus, melphalan presents a safe option for patients with this eye cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for retinoblastoma?

Unlike the standard treatments for retinoblastoma, which often involve systemic chemotherapy, melphalan is delivered directly into the eye through intraocular chemotherapy. This targeted delivery method allows for higher concentrations of the drug to reach the tumor with potentially fewer systemic side effects. Researchers are excited about melphalan because it offers a promising way to treat eye tumors more effectively and safely, potentially preserving vision and improving quality of life for patients.

What evidence suggests that adding melphalan to standard chemotherapy might be an effective treatment for retinoblastoma?

Research has shown that injecting melphalan directly into the eye can effectively treat retinoblastoma, a type of eye cancer. In this trial, participants will receive melphalan as part of the treatment arm. This method helps control tumors, especially those in the vitreous humor, the jelly-like fluid inside the eye. Delivering melphalan through the main artery of the eye, known as intra-arterial chemotherapy, has resulted in better chances of saving the eye compared to the usual method of administering chemotherapy through a vein. Melphalan damages the DNA of cancer cells, stopping them from growing and dividing. This targeted treatment may lead to better outcomes for retinoblastoma, particularly in challenging cases with cancer cells in the vitreous humor. ^{6 7 8 9 10}

Who Is on the Research Team?

Rachana Shah

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for children under 18 with newly diagnosed retinoblastoma, a cancer of the retina. It's specifically for those with certain types of tumor spread within the eye but no cancer outside it. Kids must have good performance status and adequate organ function, as measured by blood counts and liver/kidney tests.

Inclusion Criteria

I can take care of myself but may not be able to do active work.

Platelet count must be >= 75,000/uL (transfusion independent)

I am under 18 years old.

Exclusion Criteria

Lactating females who plan to breastfeed their infants

I am currently pregnant.

Patients with no reasonable expectation for any useful vision in the Group D eye

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive systemic chemotherapy with carboplatin, vincristine, and etoposide (CVE) for up to 6 cycles, with intravitreal melphalan injections starting from cycle 3 if eligible

24 weeks

Multiple visits for each cycle, including EUA and imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

5 years

Follow-up at 4 weeks, then every 3 months for 1 year, and every 3-6 months for years 2-5

What Are the Treatments Tested in This Trial?

Interventions

• Melphalan

Trial Overview

The study is testing if injecting melphalan into the eye, along with standard chemo drugs like carboplatin, vincristine, and etoposide can better treat retinoblastoma. The focus is on improving treatment for tumors that have spread to the vitreous humor (the jelly-like fluid inside the eye).

How Is the Trial Designed?

Group I: Treatment (CVE, melphalan) Experimental Treatment 8 Interventions

See Detailed Description

Melphalan is already approved in European Union, United States for the following indications:

Approved in European Union as Alkeran for:

• Multiple myeloma
• Malignant lymphoma
• Acute lymphoblastic leukemia
• Acute myeloblastic leukemia
• Childhood neuroblastoma
• Ovarian cancer
• Mammary adenocarcinoma

Approved in United States as Alkeran for:

• Multiple myeloma
• High-dose conditioning before hematopoietic stem cell transplant
• Uveal melanoma with unresectable hepatic metastases

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

Published Research Related to This Trial

A study comparing two formulations of melphalan (Alkeran and Evomela) for treating intraocular retinoblastoma found no significant differences in retinal toxicity or ocular survival, with both formulations showing similar effects on retinal function and survival rates over 24 months.

The results suggest that Evomela, which has increased stability, could be used in treatment centers lacking the infrastructure for Alkeran, while Alkeran remains a cost-effective option for those with the necessary resources.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of efficacy and toxicity of intravitreal melphalan formulations for retinoblastoma. Hsieh, T., Liao, A., Francis, JH., et al.[2020]

In a study of 22 retinoblastoma patients treated with intravitreal carboplatin and melphalan, 77% of primary cases and 89% of refractory cases achieved complete control of vitreous seeds after 6 months, indicating the treatment's efficacy.

The treatment was associated with a low incidence of serious side effects, with no cases of orbital invasion, systemic metastasis, or death, suggesting it is a relatively safe option for managing vitreous seeds in retinoblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of intravitreal carboplatin with melphalan for management of vitreous seeding in retinoblastoma. Riazi-Esfahani, H., Masoomian, B., Khodabandeh, A., et al.[2023]

Intravitreal melphalan (IVM) treatment for vitreous seeding in retinoblastoma patients showed an 83.3% enucleation-free survival rate, indicating its efficacy in managing this condition.

However, the treatment was associated with significant ocular toxicities, including retinal pigment epithelium atrophy and pupillary synechiae, affecting a majority of patients, which highlights the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ocular toxicity of intravitreal melphalan for retinoblastoma in Chinese patients. Xue, K., Ren, H., Meng, F., et al.[2020]

Intravitreal injection of melphalan for retinoblastoma is a safe treatment, with a low risk of serious adverse events; only one case of a postoperative subconjunctival tumor was reported, and no infections or uveitis occurred.

The treatment was effective, achieving complete vitreous seed remission in 68% of eyes, with about half of those maintaining good visual acuity, indicating that melphalan can be a viable option for managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal injection of melphalan for intraocular retinoblastoma. Suzuki, S., Aihara, Y., Fujiwara, M., et al.[2022]

Intravitreal melphalan injections (30 μg weekly) in retinoblastoma patients led to a decrease in retinal function, as indicated by a reduction in electroretinogram (ERG) amplitudes, suggesting retinal toxicity with continued treatment.

Despite the observed retinal toxicity, no significant systemic toxicity was detected in either the human patients or the rabbit model, indicating that while melphalan affects retinal health, it may be safe for systemic use at these doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study. Francis, JH., Schaiquevich, P., Buitrago, E., et al.[2022]

A case study of a 12-month-old girl with retinoblastoma showed that a single low-dose intravitreal melphalan injection led to diffuse chorioretinal atrophy at the injection site, indicating potential retinal toxicity even at standard doses.

Despite the resolution of the main tumor and vitreous seeds after treatment, the patient experienced persistent retinal pigment epithelium alterations and hard exudates for over two years, highlighting the need for careful monitoring of patients receiving intravitreal melphalan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diffuse chorioretinal atrophy after a single standard low- dose intravitreal melphalan injection in a child with retinoblastoma: a case report. Chao, A., Kao, LY., Liu, L., et al.[2022]

A 12-month-old boy with recurrent retinoblastoma successfully retained his functional eye after receiving combined intravitreal and intracameral injections of melphalan, demonstrating the treatment's efficacy.

After 3 years of follow-up, the patient showed no signs of disease recurrence, indicating that this method of administering melphalan can effectively manage retinoblastoma in the anterior chamber.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eye Salvage with Combination of Intravitreal and Intracameral Melphalan Injection for Recurrent Retinoblastoma with Anterior Chamber Involvement: Report of a Case. Cassoux, N., Aerts, I., Lumbroso-Le Rouic, L., et al.[2023]

Evomela, a new formulation of melphalan, shows non-inferior safety and efficacy compared to standard-formulation melphalan (SFM) in treating retinoblastoma, based on a study of 97 operations involving 23 patients.

Both formulations had similar ocular salvage rates and complication rates, with no significant differences found in tumor regression or operation times, indicating that Evomela is a viable alternative to SFM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of a prolonged stability melphalan formulation for intra-arterial treatment of retinoblastoma. Jubran, JH., Luong, H., Naik, A., et al.[2023]

Intravitreal topotecan monotherapy demonstrated no retinal toxicity in rabbit models, while melphalan caused significant retinal damage, indicating that topotecan may be a safer alternative for treating retinoblastoma vitreous seeds.

Both topotecan and melphalan were similarly effective in reducing tumor cells in rabbit models, with topotecan achieving a 96% reduction, suggesting that it can be as effective as melphalan without the associated toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study. Bogan, CM., Kaczmarek, JV., Pierce, JM., et al.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12190955/

Intra-Arterial Melphalan Chemotherapy for Retinoblastoma in ...

Data collection included patients' demographics, tumor staging, eye salvage, complications, and survival, followed by statistical comparisons ...

2.

ophthalmologyretina.org

ophthalmologyretina.org/article/S2468-6530(25)00065-X/fulltext

Intra-arterial Chemotherapy for Retinoblastoma, Outcomes ...

A total of 357 eyes were treated with 1536 IAC infusions, with a median of 4 cycles per eye, and followed for 60.69 months.

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01293539?intr=EVOMELA&aggFilters=studyType:int&viewType=Table&rank=9

Intra-arterial Chemotherapy for the Treatment of Intraocular ...

The purpose of this study is to show that chemotherapy delivered directly through the artery supplying the eye (ophthalmic artery) to patients with ...

4.

jnis.bmj.com

jnis.bmj.com/content/16/6/572.full.pdf

Efficacy of a prolonged stability melphalan formulation for intra

ABSTRACT. Background Melphalan, which is poorly soluble at room temperature, is widely used for the treatment of retinoblastoma by selective ophthalmic ...

5.

sciencedirect.com

sciencedirect.com/science/article/pii/S2162098923001238

Chemotherapy for Retinoblastoma: Impact of Intravitreal ...

Reported outcomes for advanced retinoblastomas (groups D and E eyes) are more favorable after intra-arterial chemotherapy compared to IV chemotherapy. Success ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8311556/

Safety and Efficacy of Intravitreal Chemotherapy (Melphalan ...

Background: Active vitreous seeds in eyes with retinoblastoma (Rb) adversely affects the treatment outcome. This study aimed to investigate ...

7.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S1040842824001665

Safety of intravitreal chemotherapy in the management ...

Intravitreal chemotherapy is used as a salvage therapy for retinoblastoma with persistent or recurrent vitreous seeding after primary treatment.

8.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/35198033/

The Safety and Effectiveness of Melphalan-Based Intra ...

Our meta-analysis showed that melphalan-based IAC treatment was an option for retinoblastoma patients with acceptable efficacy according to retrospective ...

9.

journals.plos.org

journals.plos.org/plosone/article?id=10.1371/journal.pone.0235016

Comparison of efficacy and toxicity of intravitreal melphalan ...

No differences were found in retinal toxicity and ocular survival between 30 μg intravitreal injections of Alkeran or Evomela for intraocular ...

10.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01393769

Study Details | NCT01393769 | Intra-arterial Chemotherapy ...

Retinoblastoma (RTB) is the most frequent tumour of the eye in early childhood and the commonest cancer in the first year of life. Approximately 60% of cases ...