Investigational drugs for the treatment of cancer cachexia: a focus on phase I and phase II clinical trials

ABSTRACT

Introduction: Cachexia is frequent in chronic diseases and especially during cancer development. Multiple definitions of cachexia have been proposed; it may be considered a multifactorial complex syndrome that presents with progressive unintentional weight loss and wasting of muscle mass and adipose tissue.

Area covered: This article covers phase-I and phase-II clinical trials of investigational drugs for cancer cachexia. We performed a search on PubMed with keywords as cancer cachexia, phase-I/phase-II trial, drug, identifying articles relevant to this review. Studies were conducted using compounds, including anabolic agents such as ghrelin analogs, selective androgen receptor modulators, as well as anti-inflammatory drugs such as thalidomide, OHR, anti-interleukin antibody, cannabinoids, and omega-3 supplements. We also describe the mechanisms of action of these molecules and their phase-I and phase-II study design. The major outcomes were appetite stimulation, weight gain, improvement of muscle mass and function, modulation of inflammation, and quality of life.

Expert opinion: The molecules discussed act on molecular pathways involved in cancer cachexia; they modulate appetite, anabolic effects, inflammation and direct interaction with muscle. Considering the multifactorial aspects of the cachexia syndrome, the combination of these drugs with metabolic and nutritional interventions may represent the most promising therapeutic approach to cancer cachexia.

KEYWORDS:

• Cachexia
• cachexia treatment
• cancer
• investigational drug
• phase I clinical trial
• phase II clinical trial

Article Highlights

• Cachexia is a multifactorial syndrome and is associated with poor outcome.

• The etiology of cancer cachexia is not yet fully clarified, and central features comprise anorexia, reduced food intake, and increased systemic inflammation.

• Cancer cachexia negatively impacts quality of life.

• Several molecules in phase I and phase II trials have been tested in cancer cachexia targeting appetite and muscle mass and function.

• End points of the described studies vary depending on the target of the drugs. Most frequent weight change is the primary end point when the target is systemic inflammation, and muscle strength or mass when the target is the muscle.

• Lean body mass represents a useful, but not an exclusive tool for assessing the efficacy of pharmacologic interventions for cancer cachexia.

• Due to the complex pathophysiology of cancer cachexia, administering the drugs under study in a multimodal approach with tailored nutritional intervention and exercise training seems promising.

• Effective treatment of cancer cachexia remains an unmet clinical need.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.