PMID- 32694153 OWN - NLM STAT- MEDLINE DCOM- 20211123 LR - 20221207 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 26 IP - 20 DP - 2020 Oct 15 TI - Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer. PG - 5348-5357 LID - 10.1158/1078-0432.CCR-20-0489 [doi] AB - PURPOSE: The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC). PATIENTS AND METHODS: Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had >/=6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy. RESULTS: A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2-4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade >/=3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4-18.4], median overall survival was 9.7 m (95% CI, 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use. CONCLUSIONS: Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC. CI - (c)2020 American Association for Cancer Research. FAU - Dotan, Efrat AU - Dotan E AD - Fox Chase Cancer Center, Philadelphia, Pennsylvania. efrat.dotan@fccc.edu cdweekes@mgh.harvard.edu. FAU - Cardin, Dana B AU - Cardin DB AUID- ORCID: 0000-0002-0269-9615 AD - Vanderbilt University, Medical Center, Nashville, Tennessee. FAU - Lenz, Heinz-Josef AU - Lenz HJ AD - University of Southern California, Los Angeles, California. FAU - Messersmith, Wells AU - Messersmith W AD - University of Colorado, Aurora, Colorado. FAU - O'Neil, Bert AU - O'Neil B AD - Indiana University, Indianapolis, Indiana. FAU - Cohen, Steven J AU - Cohen SJ AD - Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. FAU - Denlinger, Crystal S AU - Denlinger CS AUID- ORCID: 0000-0002-5663-7751 AD - Fox Chase Cancer Center, Philadelphia, Pennsylvania. FAU - Shahda, Safi AU - Shahda S AD - Indiana University, Indianapolis, Indiana. FAU - Astsaturov, Igor AU - Astsaturov I AD - Fox Chase Cancer Center, Philadelphia, Pennsylvania. FAU - Kapoun, Ann M AU - Kapoun AM AD - OncoMed Pharmaceuticals, Redwood City, California. FAU - Brachmann, Rainer K AU - Brachmann RK AD - OncoMed Pharmaceuticals, Redwood City, California. FAU - Uttamsingh, Shailaja AU - Uttamsingh S AD - OncoMed Pharmaceuticals, Redwood City, California. FAU - Stagg, Robert J AU - Stagg RJ AD - OncoMed Pharmaceuticals, Redwood City, California. FAU - Weekes, Colin AU - Weekes C AD - Massachusetts General Hospital, Boston, Massachusetts. efrat.dotan@fccc.edu cdweekes@mgh.harvard.edu. LA - eng GR - P30 CA006927/CA/NCI NIH HHS/United States GR - R01 CA188430/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article DEP - 20200721 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (130-nm albumin-bound paclitaxel) RN - 0 (Albumins) RN - 0 (Immunoglobulin Fc Fragments) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Wnt Proteins) RN - 0W860991D6 (Deoxycytidine) RN - 2N71QUE3NL (OMP-54F28) RN - P88XT4IS4D (Paclitaxel) RN - U3P01618RT (Fluorouracil) RN - 0 (Gemcitabine) SB - IM MH - Adenocarcinoma/*drug therapy/genetics/pathology MH - Adult MH - Aged MH - Albumins/*administration & dosage/adverse effects MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse effects MH - Deoxycytidine/administration & dosage/adverse effects/*analogs & derivatives MH - Fluorouracil/administration & dosage MH - Humans MH - Immunoglobulin Fc Fragments/*administration & dosage/adverse effects MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Staging MH - Paclitaxel/*administration & dosage/adverse effects MH - Pancreatic Neoplasms/*drug therapy/genetics/pathology MH - Receptors, G-Protein-Coupled/*administration & dosage MH - Recombinant Fusion Proteins/*administration & dosage/adverse effects MH - Wnt Proteins/antagonists & inhibitors MH - Gemcitabine PMC - PMC7572624 MID - NIHMS1614595 COIS- Potential Conflict of Interest: [Table: see text] EDAT- 2020/07/23 06:00 MHDA- 2021/11/24 06:00 PMCR- 2021/04/15 CRDT- 2020/07/23 06:00 PHST- 2020/04/01 00:00 [received] PHST- 2020/06/01 00:00 [revised] PHST- 2020/07/17 00:00 [accepted] PHST- 2020/07/23 06:00 [pubmed] PHST- 2021/11/24 06:00 [medline] PHST- 2020/07/23 06:00 [entrez] PHST- 2021/04/15 00:00 [pmc-release] AID - 1078-0432.CCR-20-0489 [pii] AID - 10.1158/1078-0432.CCR-20-0489 [doi] PST - ppublish SO - Clin Cancer Res. 2020 Oct 15;26(20):5348-5357. doi: 10.1158/1078-0432.CCR-20-0489. Epub 2020 Jul 21.