Cerulean's nanoparticle-drug conjugates (NDCs) are designed to enhance delivery of drugs to tumors while sparing healthy tissues and to gradually release drug payloads once inside tumors with the goal of improving antitumor activity and reducing systemic toxicity. CRLX301 is a novel investigational NDC containing the payload docetaxel covalently conjugated to a cyclodextrin-polyethylene glycol copolymer currently being investigated in a phase 1/2a study of patients with advanced solid tumors. The first portion of the study determined the maximum tolerated dose (MTD) for intravenous (IV) CRLX301 every 3 weeks (Q3W) to be 75 mg/m2 and showed that CRLX301 was generally well tolerated with hints of antitumor activity and a differentiated pharmacokinetic (PK) compared to docetaxel (Wang H, ASCO 2016, Abs. 2526). This portion aims to determine the MTD for weekly administration (QW) of CRLX301.
We will enroll adults with advanced solid tumors, adequate organ function and ECOG Performance Status 0–1. Simulation modeling with the Q3W PK data suggest that total and released docetaxel will not accumulate in plasma after 9 weeks of QW CRLX301 at 20, 25, 30 or 40 mg/m2. Also, at these doses the estimated total and released docetaxel area under the plasma drug concentration-time curves (AUCs) after the 1st, 4th and 7th doses would not exceed those observed with CRLX301 at 75 mg/m2 Q3W. These results support a weekly starting dose between 20 and 40 mg/m2, so 25 mg/m2 QW (1/3 of the Q3W MTD) was selected. Escalating doses will be tested in a 3 + 3 design. The primary objective is to determine the CRLX301 QW MTD. Secondary objectives include assessments of safety, PK and antitumor activity. Serial plasma samples for PK evaluation will be collected during weeks 1, 4 and 7. Tumors will be evaluated every 8 to 9 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A recommended phase 2 dose will be determined for use in the phase 2a expansion in patients with specific tumor types, including taxane-naïve bladder cancer. Data from QW and Q3W studies will be evaluated to select the optimal dosing schedule for future clinical trials of CRLX301.
Clinical trial identification
Legal entity responsible for the study
Cerulean Pharma, Inc.
Cerulean Pharma, Inc.
H. Wang, C. Murphy, A. Senderowicz: Employee of Cerulean Pharma Inc. B. Markman, P. de Souza: Grants from Cerulean Pharma Inc. E.C. Dees: Non-financial support and other from Cerulean, during the conduct of the study; other from Pfizer, personal fees and other from Novartis, other from Bayer, Merck, Lilly, Roche, outside the submitted work. T.C. Gangadhar: Grants from Merck, outside the submitted work W.C. Zamboni: Personal fees from Cerulean Pharma during the conduct of the study; personal fees from Cerulean Pharma, outside the submitted work. All other authors have declared no conflicts of interest.