CRLX101, a novel investigational nanoparticle-drug conjugate containing camptothecin, is a dual inhibitor of topoisomerase I and hypoxia-inducible factors 1α and 2α. The maximum tolerated dose (MTD) from the first-in- human study is 15 mg/m2 biweekly (QOW; Weiss, 2013. Invest New Drugs. 31:986), used clinically in combination with bev in several tumor types. This study is exploring the tolerability of weekly (QW) dosing of CRLX101.
CRLX101 QW (12 mg/m2 or 15 mg/m2) alone (arm 1) or in combination with bev QOW (10 mg/kg, arm 2) was evaluated. Primary objective: MTD of each arm. Secondary objectives: safety and antitumor activity.
As of Apr 7, 2016, the most commonly reported AEs (all grades [gr]) for arm 1 (n = 15) and arm 2 (n = 15) were fatigue (46%, 46%), nausea (40%, 46%), vomiting (33%, 33%), constipation (40%, 0%) and cystitis (27%, 33%), respectively. Arm 1 reported 1 dose-limiting toxicity (DLT): gr 3 febrile neutropenia after 4 QW doses at 12 mg /m2. MTD for arm 1: CRLX101 at 15 mg/m2 QW. In arm 2, 3 DLTs were observed in 3 pts: gr 3 cystitis at 12 mg/m2; gr 3 febrile neutropenia after 4 QW doses and prolonged gr 3/4 neutropenia after 2 doses at 15 mg/m2. Urine alkalization with oral or intravenous sodium bicarbonate was implemented to mitigate cystitis. MTD for arm 2: CRLX101 at 15 mg/m2 QW for 3 of 4 weeks in combination with bev QOW. 20 pts were evaluable for antitumor activity with 3 partial responses (PRs): 1 small cell lung cancer pt refractory to cisplatin in arm 1 at 15 mg/m2, 1 rectal cancer pt refractory to irinotecan and 1 renal cell carcinoma (RCC) pt in arm 2 at 12 mg/m2 (61%, 40% and 30% lesion shrinkage, respectively). 10 pts had stable disease with 2 near PRs (>20% but
MTD for CRLX101 QW monotherapy is 15 mg/m2, representing a 100% increase in dose intensity over the QOW MTD. In arm 2, either 12 mg/m2 QW or 15 mg/m2 for 3 of 4 weeks in combination with bev QOW could be the MTD. No new safety concerns were observed except an increase in cystitis in arm 2 for which urine alkalization was implemented to mitigate the risk. PRs were observed in 3 pts. This more dose-intensive CRLX101 schedule will be tested in future combination studies.
Clinical trial identification
Legal entity responsible for the study
Cerulean Pharma, Inc.
Cerulean Pharma Inc.
N. Lakhani: Non-financial support from Cerulean, during the conduct of the study; non-financial support from Cerulean, Merck,Pfizer, Abbvie,ArQule Pharma, Regeneron Pharma,Novartis, BMS, Foundation Medicine, LAM Therapeutics, Pronai outside the submitted work.A. Senderowicz, K. Caliri, T. Crowell, H. Wang: Employee at Cerulean Pharma Inc.A. Tolcher: Received fees: Bind Therapeutics, Blend Therapeutics, Celator, Decerna, Janssen, Merus, Nanobiotix, Pharmacyclics, Pierre Fabre Medicament, Symphogen, Valent Tech, Heron, J&J, Asana Biosciences, Akebia, Genmab, Mersana, Endocyte, Proximagan, Upsher-Smith.All other authors have declared no conflicts of interest.