Impact of Genetic Variants on the Toxicity of Antibody-Drug Conjugates in Locally Advanced or Metastatic Breast Cancer: The Role of the UGT1A1 Gene as a Predictive Biomarker of Therapeutic Response

Sponsor
Fundación Pública Andaluza para la Investigación Biomédica Andalucía Oriental
Study ID
NCT07582887
Status
Recruiting
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Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Sacituzumab Govitecan — DRUG
    Administered according to standard clinical practice and product label.
  • Trastuzumab deruxtecan — DRUG
    Administered according to standard clinical practice and product label.
  • Datopotamab Deruxtecan — DRUG
    Administered according to standard clinical practice and product label.

Study Details

The metabolism of anticancer drugs is influenced by genetic variants that affect their bioavailability and toxicity. In the case of antibody-drug conjugates (ADCs), such as sacituzumab-govitecan (SG), trastuzumab-deruxtecan (T-DXd), and datopotamab-deruxtecan (Dato-DXd), the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a central role in the glucuronidation and elimination of their cytotoxic components. In particular, the metabolism of SN-38, the active metabolite of irinotecan and SG, is highly influenced by variants in UGT1A1, leading to drug accumulation and the development of severe toxicities. Patients with variants such as UGT1A1\*28 (rs3064744) and UGT1A1\*6 (rs4148323) exhibit reduced enzyme activity, increasing the risk of neutropenia and severe diarrhea. The relevance of UGT1A1 is not limited to sacituzumab-govitecan; its role in the elimination of camptothecin derivatives suggests it could also impact the toxicity of trastuzumab-deruxtecan and datopotamab-deruxtecan, which contain deruxtecan, a cytotoxic agent 10 times more potent than irinotecan. Despite strong evidence linking the UGT1A1 genotype to irinotecan toxicity, there are currently no established pharmacogenetic recommendations for antidiuretic peptides (ADCs) in metastatic breast cancer.

Key Dates

Start date
Jul 15, 2025
Status verified
May 2026
Primary completion
Dec 31, 2026
Completion
Mar 31, 2027

Study Design

Enrollment
70 participants (estimated)

Arms

  • Arm: Patients undergoing treatment with sacituzumab govitecan
    Standard clinical dose of sacituzumab govitecan administered as per routine clinical practice.
  • Arm: Patients undergoing treatment with trastuzumab-deruxtecan
    Standard clinical dose of trastuzumab-deruxtecan administered as per routine clinical practice.
  • Arm: Patients undergoing treatment with datopotamab deruxtecan
    Standard clinical dose of datopotamab deruxtecan administered as per routine clinical practice.

Primary Outcome Measure

Incidence of Severe Drug-Related Toxicities (Grade ≥ 3) [ Time Frame: From the start of treatment until the end of the follow-up period (up to 2 years). ]

Central Contacts

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