Monday, May 5, 2025
5/5/2025
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 (<1 ng/ml detection only on day 1 in the smallest child). Vitritis/scleritis developed in 2 participants after 4 weeks (1/12 at 0.9 dose, and 1/10 at 1.2 dose), which responded to local steroids with resulting sustained CRs (now out > 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).