Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer.
Adenocarcinoma
/ drug therapy
Adult
Aged
Albumins
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Deoxycytidine
/ administration & dosage
Fluorouracil
/ administration & dosage
Humans
Immunoglobulin Fc Fragments
/ administration & dosage
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Staging
Paclitaxel
/ administration & dosage
Pancreatic Neoplasms
/ drug therapy
Receptors, G-Protein-Coupled
/ administration & dosage
Recombinant Fusion Proteins
/ administration & dosage
Wnt Proteins
/ antagonists & inhibitors
Gemcitabine
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 10 2020
15 10 2020
Historique:
received:
01
04
2020
revised:
01
06
2020
accepted:
17
07
2020
pubmed:
23
7
2020
medline:
24
11
2021
entrez:
23
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32694153
pii: 1078-0432.CCR-20-0489
doi: 10.1158/1078-0432.CCR-20-0489
pmc: PMC7572624
mid: NIHMS1614595
doi:
Substances chimiques
130-nm albumin-bound paclitaxel
0
Albumins
0
Immunoglobulin Fc Fragments
0
Receptors, G-Protein-Coupled
0
Recombinant Fusion Proteins
0
Wnt Proteins
0
Deoxycytidine
0W860991D6
OMP-54F28
2N71QUE3NL
Paclitaxel
P88XT4IS4D
Fluorouracil
U3P01618RT
Gemcitabine
0
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5348-5357Subventions
Organisme : NCI NIH HHS
ID : P30 CA006927
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188430
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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