A phase I and pharmacokinetic study of LAF389 administered to patients with advanced cancer
Abstract
LAF389 is a synthetic analogue of bengamide B, a natural product isolated from Jaspidae sponges. LAF389 has both antiproliferative and antiangiogenetic properties, and preclinical investigations showed a broad antitumour activity. This clinical trial aimed to determine the safety and pharmacokinetic profile of LAF389 administered as a slow intravenous injection for 3 consecutive days every 3 weeks in patients with advanced solid tumours. Eight dose levels were tested: 1, 2.5, 5, 10, 15, 30, 25 and 20 mg/day. A total of 33 patients, median age 52 years (range 33-72), with refractory solid tumours were enroled, 19 men and 14 women with a median World Health Organization performance status of 1 (0-4). Seventy-eight cycles of treatment have been administered (mean 2.5, range 1-10). Four cardiovascular dose-limiting toxicities were reported at 30 mg (2/2 patients) and 25 mg (2/9 patients), eight additional patients at various dose levels had (cardio)vascular toxicity, probably drug related, and one patient died owing to pulmonary embolism at the 5 mg dose. No objective responses were recorded. Pharmacokinetic parameters were variable, although linear and without obvious accumulation from cycle I to cycle II. LAF389 dose escalation was terminated owing to occurrence of unpredictable cardiovascular events. This, associated with the lack of clinical activity, did not warrant further investigation of this agent.
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LAF389 entered phase I trial.
“Squalamine and LAF389 inhibited sodium hydrogen antiporter sodium-proton exchangers thus targeting the phospholipid bilayer, and with LAF389 entered phase I trial [228].”
From Marine Natural Products: A Source of Novel Anticancer Drugs (2019) · cites this paper as [228]
Squalamine and LAF389 inhibit sodium hydrogen antiporter sodium-proton exchangers, targeting the phospholipid bilayer.
“Squalamine and LAF389 inhibited sodium hydrogen antiporter sodium-proton exchangers thus targeting the phospholipid bilayer, and with LAF389 entered phase I trial [228].”
From Marine Natural Products: A Source of Novel Anticancer Drugs (2019) · cites this paper as [228]
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MINING MICROBIAL SYMBIONTS FOR SPONGE-DERIVED NATURAL PRODUCTS: IMPLICATIONS FOR THE WALLACEA
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- Authors
- Dumez, H., Gall, H., Capdeville, R., Dutreix, C., van Oosterom, A. T., & Giaccone, G.
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- Novartis (Switzerland) (CH)
- Corresponding author
- Dumez, Herlinde
- Venue
- Anti-Cancer Drugs
- Published
- 2007-02
- Volume
- 18
- Issue
- 2
- Pages
- 219-225
- ISSN
- 0959-4973 (ISSN-L)
- OpenAlex
- W1985727888
- Cited by
- 52
- References
- 7
- Citations by year
- 2024: 1 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 4 · 2012: 4
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Anti-Cancer Drugs (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Marine Sponges and Natural Products
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- advanced solid tumors, refractory cancer, pharmacokinetics, dose escalation, cardiotoxicity, angiogenesis inhibitors, antiproliferative agents, pulmonary embolism
- MeSH terms
- Adult, Aged, Azepines, Cardiovascular Diseases, Dose-Response Relationship, Drug, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Neoplasms, Area Under Curve, Angiogenesis Inhibitors
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