Carboplatin + Topotecan for Retinoblastoma

Overseen By Carlos Rodriguez-Galindo, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must be taking: Chemotherapy

Disqualifiers: Metastatic disease, Invasive infection, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 months

174 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination of carboplatin and topotecan for retinoblastoma?

Research shows that a combination of topotecan and carboplatin, along with other therapies, is effective in treating advanced retinoblastoma, helping to save the eye and preserve vision in many patients. In a study, 69.2% of patients avoided more invasive treatments like radiation or eye removal, and most patients maintained good vision in at least one eye. ^{1 2 3 4 5}

Is the combination of Carboplatin and Topotecan safe for treating retinoblastoma?

The combination of Carboplatin and Topotecan has been used in treating retinoblastoma, with some patients experiencing side effects like low blood cell counts (myelosuppression), fever with low white blood cells (febrile neutropenia), and diarrhea. However, these side effects were anticipated and managed with supportive care, and no severe toxicity was reported in studies involving intravitreal (eye) injections of Topotecan. ^{1 2 3 4 6}

What makes the Carboplatin and Topotecan drug combination unique for treating retinoblastoma?

The combination of Carboplatin and Topotecan is unique for treating retinoblastoma because it has shown effectiveness in preserving the eye and vision in advanced cases, with a focus on avoiding more invasive treatments like external-beam radiotherapy. This regimen, when combined with focal therapies, offers a promising approach to manage the condition while minimizing severe side effects. ^{1 2 4 7 8}

What is the purpose of this trial?

The primary objective of this protocol is to evaluate the response rate of bilateral disease participants who have at least one eye with advanced intra-ocular retinoblastoma (stratum B) using upfront therapy with chemotherapy delivered directly to the eye. The main biology objective is to improve our understanding of the biology and tumorigenesis (how tumor develops) of retinoblastoma when biology specimens are available. As clinicians, the primary goal of the investigators for children with retinoblastoma is to provide optimal therapy using multiple treatment approaches \[chemotherapy (into the vein and directly into membrane of eyeball), cryotherapy (freeze and destroy tumor), thermotherapy (laser or heat to destroy tumor), radiation therapy, and surgical removal of eye if needed) in an attempt to preserve the eye and vision whenever possible, while still curing the disease. Therefore, all children with non-metastatic retinoblastoma at St. Jude will be offered enrollment on this study. PRIMARY OBJECTIVE: * To evaluate the response (complete + partial response) rate of bilateral disease participants who have at least one eye with advanced intraocular retinoblastoma (Stratum B) to two upfront courses of therapy consisting of subconjunctival carboplatin and systemic topotecan. SECONDARY OBJECTIVES: * To evaluate the ocular survival of eyes and event-free survival of participants by strata. * To prospectively analyze intraocular disease tissue for participants with at least one eye undergoing enucleation in order to identify the mechanism of RB1 bi-allelic inactivation. Participants may undergo upfront enucleation (due to advanced disease at diagnosis) or may receive enucleation due to progressive disease during protocol therapy.

Research Team

Carlos Rodriguez-Galindo, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children with newly diagnosed, untreated intraocular retinoblastoma. It includes those who had unilateral retinoblastoma and now have it in the other eye. They must be able to perform daily activities (ECOG ≤ 2) and have normal kidney and liver function. Those with previous treatments, metastatic disease, active infections or unable to consent are excluded.

Inclusion Criteria

I have been mostly active and able to care for myself in the last two weeks.

I have a new, untreated eye cancer or my other eye has now been affected.

Legal guardians must sign an informed consent indicating that they are aware of this study, the possible benefits, and toxic side effects. Legal guardians will be given a signed copy of the consent form.

Exclusion Criteria

Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

My cancer has spread to other parts of my body or affects my eye socket.

I do not have a serious infection right now.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive chemotherapy and focal therapies based on stratification. Treatment includes vincristine, carboplatin, topotecan, etoposide, and focal therapies such as cryotherapy, laser photocoagulation, thermo-therapy, and plaque radiotherapy.

6-8 months

Follow-up

Participants are monitored for ocular survival and event-free survival, with assessments for enucleation and external beam radiation if necessary.

3 years

Exploratory Research

Participants may engage in exploratory research objectives, including cognitive and functional development assessments, pharmacokinetics of topotecan, and evaluation of ototoxicity.

Treatment Details

Interventions

• Carboplatin
• Enucleation
• External Beam Radiation
• Focal Therapy
• Proton Beam Radiation
• Topotecan

Trial Overview The study tests how well advanced intraocular retinoblastoma responds to direct-eye chemotherapy (carboplatin) plus systemic topotecan. It also uses various therapies like cryotherapy, thermotherapy, radiation therapy, surgery or enucleation if necessary while trying to preserve vision.

Participant Groups

Group I: Stratum D Experimental Treatment 9 Interventions

Participants with bilateral retinoblastoma who may require upfront enucleation for one eye due to advanced disease (R-E IV-V and IC E). Interventions (see Detailed Description): vincristine, carboplatin, topotecan, etoposide, enucleation, filgrastim or PEG-filgrastim, focal therapy, including cryotherapy, laser photocoagulation, thermotherapy (and thermo-chemotherapy) and episcleral plaque brachytherapy, and external beam radiation or proton beam radiation in select cases.

Group II: Stratum C Experimental Treatment 9 Interventions

Participants with advanced (R-E IV-V and IC D-E) unilateral retinoblastoma who require upfront enucleation. Participants will be assessed and treated by low, intermediate or high risk. Interventions (see Detailed Description): vincristine, cyclophosphamide, MESNA, doxorubicin, etoposide, carboplatin, filgrastim or PEG-filgrastim, enucleation

Group III: Stratum B Experimental Treatment 7 Interventions

Participants considered candidates for conservative management including those: 1. Participants with bilateral retinoblastoma who have R-E IV-V and IC D in one eye 2. Participants with advanced unilateral (unifocal or multifocal) retinoblastoma (R-E IV-V and IC D-E) who demonstrate foveal sparing by the tumor during EUA. Due to foveal sparing, these patients have potential for vision preservation. Interventions (see Detailed Description): vincristine, topotecan, carboplatin, etoposide, filgrastim or PEG-filgrastim and focal therapy, including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.

Group IV: Stratum A Experimental Treatment 6 Interventions

Participants with early bilateral or unilateral (unifocal or multifocal) retinoblastoma (R-E I-III, IC A-B; R-E IV with IC A or B; or IC C with limited sub-retinal seeding), and participants with bilateral disease in whom the advanced eye has been enucleated upfront (without any high risk histopathology) and the remaining eye has early stage disease (as defined above). Interventions (see detailed description): vincristine, carboplatin, topotecan, filgrastim or PEG-filgrastim, and focal therapy, including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

Intravitreal injection of 90 µg of topotecan resulted in complete regression of recurrent retinal tumors in three children with retinoblastoma, demonstrating its efficacy after prior treatments failed.

The treatment was well-tolerated, with no observed toxicity, marking the first human report of this approach for retinal tumors in retinoblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal Topotecan 90 µg for Recurrent Solid Retinoblastoma Tumors Is Effective and Not Toxic. Abramson, DH., Francis, JH.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ocular Salvage and Vision Preservation Using a Topotecan-Based Regimen for Advanced Intraocular Retinoblastoma. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Subconjunctival carboplatin and systemic topotecan treatment in preclinical models of retinoblastoma. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Activity of topotecan in retinoblastoma. [2022]

4. Australia pubmed.ncbi.nlm.nih.gov

Low retinal toxicity of intravitreal carboplatin associated with good retinal tumour control in transgenic murine retinoblastoma. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Carboplatin +/- topotecan ophthalmic artery chemosurgery for intraocular retinoblastoma. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Intravitreal Topotecan 90 µg for Recurrent Solid Retinoblastoma Tumors Is Effective and Not Toxic. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Role of chemotherapy alone or in combination with hyperthermia in the primary treatment of intraocular retinoblastoma: preliminary results. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Comparison of two methods for carboplatin dosing in children with retinoblastoma. [2021]