Dendrimer-nanoparticle (DEP) delivery of cabazitaxel (DEP-cabazitaxel): A first-in-human phase 1/2 trial in patients...

This phase 1/2 trial evaluated safety, tolerability, pharmacokinetics, and antitumour activity of DEP-cabazitaxel (CTX-SPL9111), a dendrimer-cabazitaxel nanoparticle, in solid tumours.

Adult patients received DEP-cabazitaxel once every 3 weeks. The primary phase 1 objective was to establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives were to assess safety and tolerability, define the recommended phase 2 dose (RP2D), and evaluate pharmacokinetics and preliminary efficacy.

Eighty-nine patients enrolled; most phase 2 patients had metastatic castrate-resistant prostate cancer (mCRPC; n = 25), platinum-resistant ovarian cancer (PROC; n = 22), or esophago-gastric cancer (EGC; n = 15). No DLTs were observed at the MTD and RP2D of 20 mg/m² cabazitaxel. Most common treatment-emergent adverse events attributed to DEP-cabazitaxel were fatigue, peripheral neuropathy, nausea, anaemia, neutropenia, diarrhoea, and vomiting. In 75 phase 2 patients, Grade 3/4 neutropenia occurred in 22.7% and febrile neutropenia in 1.3%. In RECIST-evaluable phase 2 patients, the objective response rate (ORR) was 20% (9/45 measurable) and disease control rate (DCR) was 70.6% (36/51). By tumor type, ORRs were 16.7%, 17.6%, 30.0%, and 100% for mCRPC, PROC, EGC, and a thymic cancer patient, respectively. In evaluable phase 2 patients, 90.5% with mCRPC had PSA reductions (52.4% by >50%) and 86.7% had stable or improved bone metastases, and 75% with PROC had reduced CA‑125 or CEA. Median progression-free and overall survival were 3.8 and 9.0 months, respectively.

DEP-cabazitaxel was well tolerated and showed durable antitumour activity across advanced solid tumours, with reduced bone marrow toxicity compared to that reported for conventional cabazitaxel.