Episcleral Topotecan for Treatment of Group D Retinoblastoma
Episcleral Topotecan for Treatment of Group D Retinoblastoma
This phase I trial will assess primarily the safety and secondarily the efficacy of
 Episcleral Topotecan in patients treated for Group D Retinoblastoma.
Treatment of eyes with advanced intraocular retinoblastoma remains a challenge. The historic
 standard of care for patients with unilateral disease is enucleation and for those with
 bilateral disease, a variety of modalities have been tried. These include radiation therapy,
 systemic chemotherapy, periocular administration of chemotherapy, selective intra-arterial
 chemotherapy, and intravitreal chemotherapy. Unfortunately, all of these modalities are
 associated with significant morbidity and investigators are looking for new ways to treat
 these patients either with novel directed drug delivery methods or with new less toxic
 agents. This study will evaluate the feasibility and toxicity of topotecan delivered directly
 to the eye using a novel episcleral implant (also referred to as an episcleral reservoir).
 Children with newly diagnosed unilateral retinoblastoma classified as Group D according to
 the International Group Classification System will be eligible for the study if: (1) they
 have had no previous treatment, and (2) primary enucleation is a treatment recommendation.
 All enrolled eyes during a day-1 baseline EUA will be fitted with one or two episcleral
 implants (reservoirs) containing sustained release formulations of topotecan HCl as the only
 therapy for a four-week study period. Episcleral Topotecan will be supplied sterile and
 requires no manipulation other than placement on the eye. At a two-week EUA on day-15 of the
 four-week study period, if tumor response criteria are not met or if there is DLT, the
 Episcleral Reservoir will be removed and the patient will be off study and alternate
 interventions begun. In the event of enucleation remaining drug concentrations will be
 determined in the reservoir(s) as well as plasma concentration levels (anticipated to be
 below limits of detection based on preclinical studies). If tumor response criteria are met,
 the eye is eligible for continuing for the final two weeks of the study if there is no local,
 systemic or intraocular dose limiting toxicity (DLT) as defined in this protocol. At the end
 of the 4-week study period on study day-29 the third and final EUA will be conducted and
 tumor response and toxicity assessed. At that time, all reservoirs are removed and the eye is
 off study. Drug concentration/levels are determined in the removed reservoir(s), plasma, and
 tumor in the event of enucleation. The child and the eye shall then be treated at the
 discretion of the managing ophthalmologist and oncologist.
Inclusion Criteria:

 -  Age: Patients must be < 48 months of age and at least 12 months of age at the time the
 consent is signed by the parent(s) or guardian.

 -  Diagnosis: Intraocular retinoblastoma, unilateral (Group D) in which enucleation is a
 recommended therapy.

 -  Must have demonstrated intraocular calcium in the tumor containing eye by ophthalmic
 ultrasound or by neuroimaging.

 -  Demonstration of Light Perception in the tumor-bearing eye either with pupil response
 testing or demonstration of avoidance behavior to light presentation in the affected
 eye

 -  There must be no previous treatment for retinoblastoma or prior therapy with
 Episcleral Topotecan.

 -  Performance Level: Lansky ³ 50.

 -  Organ Function Requirements:

 Organ function criteria:

 1. Adequate Bone Marrow Function Defined as:

 -  Peripheral absolute neutrophil count (ANC) ³ 1000/mm3

 -  Platelet count ³ 100,000/mm3 (transfusion independent, defined as not receiving
 platelet transfusions for at least 7 days prior to enrollment)

 -  Hemoglobin ³ 8.0 g/dL at baseline (may receive RBC transfusions)

 2. Adequate Renal Function Defined as:

 -  Creatinine clearance or radioisotope GFR ³70ml/min/1.73 m2 or

 -  Adequate serum creatinine based on age/gender.

 - Adequate Liver Function Defined as:

 -  Bilirubin (sum of conjugated + unconjugated) £ 1.5 x upper limit of normal (ULN)
 for age

 -  SGPT (ALT) £ 110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.

 -  Serum albumin ³ 2 g/dL.

 Exclusion Criteria:

 -  Reported allergy to camptothecin, topotecan, or derivatives thereof.

 -  Inability to comply with required study follow-up visits and stay within 50 miles of
 the treating institution during the first 15 days of study period (to EUA on Day 15).

 -  Family history of retinoblastoma or retinoma.

 -  Patients with International Stage retinoblastoma more advanced than Stage 0 and
 including:

 -  Extra-ocular extension into orbit or brain, or

 -  Metastatic retinoblastoma with or without CNS involvement, or

 -  MRI showing thickening and enhancement of the optic nerve in either eye.