A phase III single-arm study to evaluate the efficacy and safety of paclitaxel-hyaluronic acid conjugate administered intravesically to patients with BCG-unresponsive carcinoma in situ of the bladder with or without Ta-T1 papillary disease (Orion-BC study).
Authors: Max Kates, Stephen Bardot, Félix Guerrero-Ramos, Laurent Guy, Rodolfo Hurle, Gautier Marcq, Marco Moschini, Geraldine Pignot, Angelo Porreca, Francesco Soria, Alberto Macchi, Gregoire Robert, Stephen Savage, Rafal Walczak
Journal: Journal of Clinical Oncology (2025)

TPS885 Background: Non-muscle invasive bladder cancer (NMIBC) is the most common bladder cancer, with Carcinoma in situ (CIS) being a precursor to muscle-invasive disease. Intravesical BCG is the first-line treatment for high-risk NMIBC, including CIS; however over 50% of patients experience recurrence. Radical cystectomy (RC) is recommended for patients with BCG-unresponsive CIS, but it is associated with high morbidity and mortality. Consequently, some patients are ineligible or decline this option, posing a challenge in the management of the disease. Currently, there is a lack of alternative treatments for patients with BCG-unresponsive CIS in Europe, highlighting an unmet clinical need, while FDA-approved treatments are associated with significant adverse events (AEs). A new conjugate of hyaluronic acid (HA) and paclitaxel (Oncofid-P-B) enhances intracellular drug concentration up to 800-fold by targeting CD44, overexpressed on bladder cancer cells. In a phase I clinical trial, the conjugate showed promising complete response rates (CRR) of 75% at the end of the induction, and of 40% at the end of one-year maintenance phase in patients with BCG-unresponsive CIS, with no significant Grade 3-5 AEs (Hurle 2021). Methods: This is a phase III, single-arm, multicenter study (Clinical trial ID: NCT05024773) assessing the efficacy and safety of intravesical instillations of Oncofid-P-B in BCG-unresponsive patients with CIS +/- Ta-T1 unfit or refusing RC. The study is ongoing at 34 centers in Europe and the US (8 in Italy, 11 in Spain, 7 in France, 3 in Poland, 5 in US). Patients receive 12 weekly intravesical instillations of the drug (600 mg) (induction phase), followed by 12 monthly instillations in those achieving a CR (maintenance phase). Eligibility criteria include an ECOG performance status of 0-2 and persistent or recurrent CIS +/- Ta-T1 within 12 months post-BCG. Tumor response is evaluated by cystoscopy and cytology at the end of the induction, every 3 months for up to 24 months during the maintenance/follow-up, and every 6 months for additional two years. Biopsies are performed at the end of the induction and in case of positive cystoscopy/cytology during treatment and follow-up. Random biopsies are conducted at 9, 15, and 21 months in responding patients. Primary efficacy objective is to evaluate the antitumor activity with centrally assessed CRR following induction. Secondary efficacy objectives include measures of CR rates, duration of response, progression rates, time to progression, and cystectomy rates. Safety evaluation over the study represents the safety objective. The study is currently enrolling in Europe and US. So far, 63 patients were screened and 49 were enrolled (Ta/T1 subgroup: 10 subjects). Clinical trial information: NCT05024773 .