Gemcitabine/Nab-Paclitaxel and Pamrevlumab in Locally Advanced Pancreatic Cancer (LAPC): A Phase 1/2 Trial

Abstract

Background: Pancreatic ductal adenocarcinomas (PDAC) exhibit a high degree of desmoplasia with extensive connective tissue growth factor (CTGF) expression and extracellular matrix production. Tumor response and potential for resection in locally advanced unresectable pancreatic cancer (LAPC) may be affected by pamrevlumab via improved antitumor effect and/or by affecting tumor margins through inhibition of CTGF overexpression. Methods: This is Phase I/II safety/efficacy study in locally advanced pancreatic patients. 37 patients were randomized 2:1 to gemcitabine/nab-paclitaxel plus pamrevlumab (Arm A, n=24) or gemcitabine/nab-paclitaxel alone (Arm B, n=13). Those who completed 6 cycles of treatment were assessed for surgical eligibility, and if eligible, underwent surgical exploration for resection. Patients who did not finish initial chemotherapy received second-line treatment as per standard of care. The study is registered at ClinicalTrials.gov, with a registry number of NCT02210559. Findings: 75% of patients in Arm A and 54% in Arm B completed 6 cycles of therapy. In Arms A and B, CA 19-9 response, as defined by ≥50% decline from baseline occurred in 65% and 42%, respectively; median decline was 93% versus 78%, respectively. Best objective RECIST response was ~30% in each treatment arm. Sixteen percent of patients were radiographically down-staged by NCCN criteria (5 in Arm A and 1 in Arm B). PET SUVmax declined by ≥30% at end of treatment in 60% of patients overall. PET normalized in 38% vs 23% of patients in Arm A vs Arm B, respectively. PET SUVmax normalization at EOT strongly correlated with eligibility for surgical exploration and resection in Arm A and B. Eligibility for surgical exploration was 71% vs 15%, (p=.0019) and resection was achieved in 33% vs 8% of patients in Arm A vs Arm B (p=0.1193), respectively. Interpretation: Pamrevlumab may be a valuable addition to gemcitabine/nab-paclitaxel neoadjuvant therapy in LAPC without added toxicity. This combination merits evaluation in a larger patient population. Trial Registration Number: The study is registered at ClinicalTrials.gov, with a registry number of NCT02210559. Funding: The study was funded by FibroGen, Inc. Declaration of Interest: VP reports other from Ipsen, other from Novocure, other from OncoMed, other from Tyme, other from Celgene, other from Lilly, other from Aduro, FR I/We declare no competing interests, JW I/We declare no competing interests, MP reports other from Genentech, other from Pfizer, other from Merck, other from Astra Zeneca, other from Medimmune, other from Celldex, personal fees and other from ARMO, personal fees and other from Celgene, other from Boston Biomedical, other from Tesaro, other from Bavarian Nordic, other from Novartis, other from BMS, other from Abbvie, other from Halozyme, other from Karyopharm, other from Bayer, other from Regeneron, personal fees from Sirtex, personal fees from Caris, personal fees from Rafael, personal fees from Eisai, personal fees from Ignyta, personal fees from Ipsen, personal fees from Merrimack, outside the submitted work, KM reports other from Agios, other from Senwah Biosciences, other from Taiho, other from Arqule, other from Astra Zeneca, other from Genentech, other from Incyte, other from Tracon Pharmaceuticals, other from Medimmune, other from Puma Biotechnology, personal fees from Astra Zeneca, personal fees from Bayer, personal fees from Celgene, personal fees from Eisai, personal fees from Exelixis, personal fees from Merrimack, personal fees from Vicus, personal feels from Ipsen, outside the submitted work, JG reports other from Genentech, other from Generon, other from GlaxoSmithKline, other from Hana Biosciences, other from Kyowa, other from Novartis, other from Odonate, other from Pfizer, other from Polynoma, other from Terapure, TL I/We declare no competing interests, MM I/We declare no competing interests, MC is employed by FibroGen, MZ is employed by FibroGen, SP is employed by FibroGen, EK is employed by FibroGen, TN is employed by FibroGen, EC is employed by Fibrogen Ethical Approval: The study was approved by individual institutional review boards at 9 US institutions and conducted according to the Declaration of Helsinki.