Liver toxicity in oncology trials and beyond: a simplified concept for management of hepatocellular drug-induced liver injury in patients with abnormal baseline liver tests

ABSTRACT

Background

Management of side effects in clinical trials has to balance generation of meaningful data with risk for patients. A toxicity area requiring detailed management guidelines is drug-induced liver injury (DILI). In oncology trials, patients are often included despite baseline liver test abnormalities, for whom there is no consensus yet on levels of liver test changes that should trigger action, such as drug interruption or discontinuation.

Methods

We provide an innovative approach to manage hepatocellular DILI in oncology trials for patients with abnormal baseline alanine aminotransferase (ALT) levels. The algorithm proposed is based on mathematical derivation of action thresholds from those generally accepted for patients with normal baselines.

Results

The resulting algorithm is grouped by level of baseline abnormality and avoids calculation of baseline multiples. Suggested layered action levels are 4, 6, and 11 × Upper Limit of Normal (ULN) for patients with baseline ALT between 1.5 and 3 × ULN, and 6, 8, and 12 × ULN for patients with baseline ALT between 3 and 5 × ULN, respectively.

Conclusions

Our concept and resulting algorithm are consistent, transparent, and easy to follow, and the method for derivation from consensus-based thresholds may also be applicable to other drug toxicity areas.

KEYWORDS:

• Clinical trial
• drug-induced liver injury
• liver test abnormalities
• toxicity management
• oncology

Declaration of interests

A Fettiplace is an independent consultant and works or worked part-time for AstraZeneca, previously a full-time employee of AstraZeneca (until January 2024). J Marcinak is a full-time employee of AbbVie. HL Tillmann holds stocks in Abbott, AbbVie and Gilead, receives honoraria for consulting from Merck and Bausch Health, paid to the University, and from Novo Nordisk paid to him. GA Kullak-Ublick is a part-time employee of Novartis. M Merz is an independent consultant and works or worked part-time for AstraZeneca and Novartis. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Ethical Approval and Participatory Consent

Our manuscript proposes a theoretical concept to establish toxicity management algorithms for Drug-Induced Liver Injury and as such does not contain results of clinical studies. Thus, no approval of an ethics committee and no participatory consent was needed for the work presented here.

Author contribution statement

All authors listed above have:

1. Made a significant contribution to the work reported, whether that’s in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas,

2. Have drafted or written, or substantially revised or critically reviewed the article,

3. Have agreed on the journal to which the article is submitted,

4. Reviewed and agreed on all versions of the article before submission, during revision, the final version accepted for publication, and any significant changes introduced at the proofing stage,

5. Agree to take responsibility and be accountable for the contents of the article and to share responsibility to resolve any questions raised about the accuracy or integrity of the published work.

Acknowledgments

The authors would like to acknowledge and thank Luciana Kikuchi (Bayer SA, USA) for her contribution to intellectual discussions around the research concept. Principles of our suggested concept were presented on November 10, 2023, in modified form as poster no. 1712-A at The Liver Meeting (TLM) in Boston, organized by the American Association for the Study of Liver Diseases (AASLD).

Notes

1. Of note, in line with recommendations provided recently by [18,25,26] we set the definition of a normal ALT at a ‘near normal’ level, corresponding to < 1.5 × ULN, allowing patients with minor ALT abnormalities to effectively be included in a clinical trial as having a normal baseline.

2. Providing thorough guidance on managing DILI in an oncology trial setting includes other liver test abnormalities for bilirubin or INR, and/or the presence of clinical symptoms. However, for simplification, we here focus on ALT abnormalities only, being aware that our suggested action thresholds for ALT in drug development practice will have to be incorporated into more comprehensive guidance including other key liver safety parameters.

Additional information

Funding

This paper was not funded.