Joseph Chao1, James Lin2, Paul Frankel3, Andrew J Clark4, Devin T Wiley4, Edward Garmey5, Marwan Fakih1, Dean Lim1, Vincent Chung1, Eloise Luevanos1, Scott Eliasof5, Mark E Davis4, Yun Yen6. 1. Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. 2. Division of Gastroenterology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. 3. Department of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. 4. Chemical Engineering, California Institute of Technology, Pasadena, CA, USA. 5. Cerulean Pharma Inc., Waltham, MA, USA. 6. The Graduate Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
Abstract
BACKGROUND: CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. Preclinical evidence indicated preferential uptake in tumors, and tumor xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) using the bimonthly schedule to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in chemotherapy-refractory gastroesophageal cancer. Results from the biopsies were previously reported and herein we present the clinical outcomes. METHODS: Patients initiated CRLX101 dosed at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle. Detection of preferential CRLX101 tumor uptake was the primary endpoint and objective response rate (ORR) was a secondary endpoint. With a sample size of ten patients, the study had 90% power to detect ≥1 responder if the true response rate is ≥21%. RESULTS: Between Dec. 2012 and Dec. 2014, ten patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) gastric adenocarcinoma were enrolled. The median time-to-progression was 1.7 months. Best response was seen in one patient with stable disease (SD) for 8 cycles. Only ≥ grade 3 drug-related toxicity occurred in one patient with grade 3 cardiac chest pain who was able to resume therapy after CRLX101 was reduced to 12 mg/m2. CONCLUSIONS: Bimonthly CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in gastric cancer should focus on combination and more dose-intensive strategies given its favorable toxicity profile and evidence of preferential tumor uptake.
BACKGROUND: CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. Preclinical evidence indicated preferential uptake in tumors, and tumor xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) using the bimonthly schedule to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in chemotherapy-refractory gastroesophageal cancer. Results from the biopsies were previously reported and herein we present the clinical outcomes. METHODS: Patients initiated CRLX101 dosed at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle. Detection of preferential CRLX101 tumor uptake was the primary endpoint and objective response rate (ORR) was a secondary endpoint. With a sample size of ten patients, the study had 90% power to detect ≥1 responder if the true response rate is ≥21%. RESULTS: Between Dec. 2012 and Dec. 2014, ten patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) gastric adenocarcinoma were enrolled. The median time-to-progression was 1.7 months. Best response was seen in one patient with stable disease (SD) for 8 cycles. Only ≥ grade 3 drug-related toxicity occurred in one patient with grade 3 cardiac chest pain who was able to resume therapy after CRLX101 was reduced to 12 mg/m2. CONCLUSIONS: Bimonthly CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in gastric cancer should focus on combination and more dose-intensive strategies given its favorable toxicity profile and evidence of preferential tumor uptake.
Entities:
Keywords:
CRLX101; clinical trial; esophageal cancer; gastric cancer
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