Retinoblastoma Phase II Expanded Access Clinical Trial

Abstract

Retinoblastoma (RB) is a micro-orphan disease intraocular cancer in infants and children (typically diagnosed

between birth and 5 years of age). Approximately 250 new cases are diagnosed annually in the United States.

Standard of care for retinoblastoma includes removing the affected eye (safest) or attempted salvage of the eye

starting with systemic or intra-arterial chemotherapy. Since external beam radiotherapy incurs life-long high risk of

second cancers in RB H1 patients carrying the RB1 cancer predisposition gene, it is reserved for last effort to save

a last eye. There is no FDA approved intervention for retinoblastoma. Topotecan Chemoplaque (IND #112785) as

a single (one) treatment achieves sustained local six-week delivery of Topotecan directly to the interior of the eye

while sequestering Topotecan from washout to peripheral circulation. The RP2D was determined to be 2 doses: 0.9

mg (single Chemoplaque) or 1.2 mg (two 0.6 mg Chemoplaques), depending on patient age and tumor features.

Sustained CR (absence of Standard of Care therapies after the Chemoplaque) was achieved in 10/12, 0.9 mg,

83% and 8/9, 1.2 mg, 89% evaluable for efficacy.

In the 1.2 mg dose that we plan to progress in the proposed trial, the sustained CR rate is 89%. All the CRs are

out > 2 years. All the CRs were in refractory settings, including refractory solid tumor, refractory vitreous seeds,

and refractory subretinal seeds. At the RP2D based on swimmer plot analysis, for patients that were refractory to

IAC, treatments before and after Chemoplaque are as follows:

As such, the Chemoplaque significantly reduces subsequent treatment burden in patients refractory to IAC.

Toxicity analysis includes 22 participants treated at the RPD2 (12, 0.9 mg /10, 1.2 mg).

No systemic toxicity was observed. At all time points, plasma Topotecan levels were below limits of detection

except one trace ( 2 years). All eyes have a full thickness chorio-retinal scar directly opposite the

Chemoplaque. All participants reported signs of inflammation and reduced well-being, similar to babies teething

that resolves in all cases following Chemoplaque removal and (if applied) is responsive to local steroids. The

Phase I Trial RP2D analysis suggests that Topotecan Chemoplaque has good, sustained effectiveness in refractory

settings including refractory solid tumor, refractory vitreous and subretinal seeds—given as a single application

(one treatment) without need for repeat treatment or multiple cycles. To our knowledge, there are no

retinoblastoma interventions that are effective (result in CRs) after a single application, and further, there are none

that are effective across all lesion types let alone as a single application. The chemoplaque has demonstrated

robust activity across all lesions as a one-time treatment with no systemic toxicity.

This FDA Orphan Drug Grant application requests support for Expansion Phase II clinical trial of Topotecan

Chemoplaque at the 1.2 mg RP2D dose. EUAs will follow standard of care at 0, 4, 8 and 12 weeks. In the

proposed study, we will enhance study of impact beyond Progression-free Survival by quantitating invasiveness of

subsequent therapies, extending the Swimmer RB analysis. The Topotecan Chemoplaque has potential to be the

first FDA-approved therapy for this micro-orphan childhood disease and offer simple treatment—important in low

resource settings where the majority of RB children live.

The efficacy and safety of the RP2D (1.2 mg) Chemoplaque in refractory disease addresses a critical need

(provides an alternative to radiation and life-long increased risk of secondary cancers) providing an important

addition to the armamentarium of RB interventions.