Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer
Open Access
- 21 July 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (20), 5348-5357
- https://doi.org/10.1158/1078-0432.ccr-20-0489
Abstract
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). 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. 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. Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.Keywords
Funding Information
- HHS | NIH | National Cancer Institute (3P30 CA0062927)
This publication has 32 references indexed in Scilit:
- Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumorsProceedings of the National Academy of Sciences of the United States of America, 2012
- Three decades of Wnts: a personal perspective on how a scientific field developedThe EMBO Journal, 2012
- FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic CancerThe New England Journal of Medicine, 2011
- KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinomaNature Reviews Cancer, 2010
- Targeting Wnt Signaling: Can We Safely Eradicate Cancer Stem Cells?Clinical Cancer Research, 2010
- Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancerNature Chemical Biology, 2009
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutationsOncogene, 2005
- Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray ExperimentsStatistical Applications in Genetics and Molecular Biology, 2004
- Bootstrap confidence intervalsStatistical Science, 1996