Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (CTX-SPL9111) in men with metastatic castration-resistant prostate cancer (mCRPC) in a phase I/II trial

Dendrimers enable sustained delivery of cytotoxic drugs and achieve selective tumour targeting via an enhanced permeability and retention effect. DEP cabazitaxel is a lysine-based dendrimer modified with polyethylene glycol and with cabazitaxel attached to lysine branches via a hydrolysable linker. Unlike standard cabazitaxel, DEP cabazitaxel is highly water soluble, does not contain toxic excipients associated with anaphylaxis and avoids the need for steroid pre-medication. Safety and preliminary efficacy of DEP cabazitaxel was assessed in a phase 1/2 trial of with patients (pts) with advanced solid tumours, including mCRPC. 3-weekly intravenous dosing of pts was escalated to study the safety profile and identify a recommended phase 2 dose (RP2D) for an expansion cohort. Eligible prostate pts had one or more of rising PSA, measurable disease progression, or bone progression per Prostate Cancer Working Group 3 (PCWG3) guidelines. Anti-tumour activity was assessed using these 3 PCWG3 criteria. A RP2D of 20 mg/m2 cabazitaxel was confirmed; 2 Dose Limiting Toxicities of Grade 3 febrile neutropenia and grade 4 neutropenia > 7 days were observed. Most common toxicities were Grade 1/2 and those typically observed with standard cabazitaxel. There was no neutropenic sepsis or anaphylaxis. 25 mCRPC pts were enrolled at the RP2D; median age of 73 yrs and with an average 4 prior anticancer treatments, including taxanes. Responses were seen in one or more of the efficacy outcomes for all (100%) evaluable mCRPC pts. Of those evaluable for all PCWG3 criteria 56% responded in all three. In pts with soft tissue lesions, 64% had prolonged disease control, including 2 partial responses sustained for up ≥24 weeks. Of pts with assessable PSA, 90% had a reduction, with a response of >50% in 52%. Of pts with bone metastases, 83% had no progression or an improvement. DEP cabazitaxel is well tolerated with rates of severe myelosuppression, including neutropenia, lower than published data for standard cabazitaxel. No steroid pre-medication was required. We report encouraging anti-tumour activity in heavily pre-treated mCRPC pts.