A phase 1 study of CRLX301, a novel nanoparticle-drug conjugate (NDC) containing docetaxel (DOC), in patients with refractory solid tumors.

Abstract

2526 Background: CRLX301 is an investigational NDC with DOC covalently conjugated to a cyclodextrin-polyethylene glycol co-polymer designed to enhance delivery to tumor tissue. Preclinical studies of CRLX301 showed enhanced drug accumulation in tumor and greater tumor growth suppression in murine models compared to DOC. Methods: Patients (pt) with advanced solid tumors were treated with escalating doses of CRLX301 IV once every 21 days (Q3W). The first two cohorts were single pt cohorts and then adjusted to 3+3 design. Primary objective: MTD and/or RP2D. Secondary objectives: safety, anti-tumor activity and PK. Results: 20 pts were enrolled. All were evaluable for DLT. Prior lines of chemotherapy: median 3 (range 0 to 6); 8 pts had prior taxane therapy. Tumor types: cholangiocarcinoma (5), head and neck (3), lung (2) and others (10). All drug-related AEs were toxicities typically associated with DOC. The most common drug-related AEs (all grades) were fatigue (70%), infusion reaction (40%), nausea (35%), diarrhea (30%), neutropenia (30%), and peripheral neuropathy (20%). Most AEs were ≤ grade 2. Two DLTs, reversible grade 3 transaminases with grade 2 bilirubin ( < 3 d) and grade 4 febrile neutropenia ( < 3 d), were observed at 90 mg/m2. One gr3 and one gr4 infusion reactions were observed at 90 mg/m2; both resolved within 24 hours. Certain common AEs related to DOC, such as fluid retention, were not observed. MTD with Q3W dosing is 75 mg/m2. A pt with B-RAF mutant unknown primary and resistant to a prior B-Raf inhibitor had tumor shrinkage per CT and partial metabolic response per FDG-PET. Stable disease lasting ≥ 3 cycles was observed in 5 pts (max 15 cycles). Plasma PK compared to commercial DOC at equivalent dose of 75 mg/m2: increased Cmax (5 – 8 fold) and increased AUC (60 fold) of total DOC and 25 fold less peak concentrations but more prolonged exposures of released DOC. Conclusions: The data suggest CRLX301 has a predictable and acceptable safety profile with preliminary signs of anti-tumor activity and distinct PK compared to DOC. MTD/RP2D were established as 75 mg/m2 for Q3W dosing. Weekly dosing and expansion cohorts in selected tumor types are planned. Clinical trial information: NCT02380677.