Finding better ways to detect resistance to antibody‑drug conjugates in solid tumors and identify useful biomarkers

International Multicenter Multicohort Open-label Phase II Trial Aiming to Define Optimal Methods for Predicting Response/Resistance to Antibody-drug Conjugates in Patients With Solid Tumors Treated According to Current Standard Indications.

This trial tests whether tissue and blood biomarkers collected before and after treatment can reveal why antibody‑drug conjugates stop working in adults with advanced breast, gastric, urothelial, or non‑small cell lung cancer.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 400 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Unicancer (Academic / other)
• Drugs / interventions: chemotherapy, radiation
• Locations: 1 site (Villejuif)
• Trial ID: NCT07259226 on ClinicalTrials.gov

What this trial studies

This phase 2 interventional effort will enroll patients with advanced breast, gastric, urothelial, or non‑small cell lung cancer who are receiving an approved or early‑access ADC. Participants will provide pretreatment and post‑treatment tumor biopsies, serial blood samples, and patient‑reported outcome questionnaires. Samples will undergo genomic profiling, immunohistochemistry, and other molecular assays to measure prespecified and exploratory biomarkers linked to known ADC resistance mechanisms. Biomarker results will be correlated with imaging and clinical response using RECIST v1.1 to identify signals that predict or explain resistance.

Who should consider this trial

Good fit: Adults (≥18) with unresectable locally advanced or metastatic breast, gastric, urothelial, or non‑small cell lung cancer who are planned to receive an approved or early‑access ADC and can undergo pre‑ and post‑treatment biopsies are the intended participants.

Not a fit: Patients who cannot safely undergo tumor biopsies, have only bone or brain metastases available for sampling, or who are not receiving an ADC are unlikely to gain direct benefit from this protocol.

Why it matters

Potential benefit: If successful, this work could help doctors pick the most effective ADC and avoid ineffective options by identifying biomarkers that predict or explain resistance.

How similar studies have performed: Preclinical studies and small clinical reports have described potential ADC resistance mechanisms, but validated, clinically useful biomarkers are still largely lacking, so this is a timely translational effort building on preliminary findings.

Eligibility criteria

Inclusion Criteria:

1. Patients must have signed a written informed consent form prior to any trial specific procedures;
2. Patients must be ≥18 years old;
3. Histologically confirmed or radiologically documented unresectable locally advanced or metastatic cancer (Breast, Urothelial, Non small Cell Lung or Gastric) with an indication to receive an Antibody-Drug Conjugate (ADC) approved or accessible through an early access program;
4. Patients must have at least 2 tumor lesions (primary tumor can be included): at least one measurable tumor lesion for tumor evaluation according to response evaluation criteria in solid tumors (RECIST) V1.1 and at least one tumor lesion other than bone and brain for biopsy;
5. Patients must have a metastatic or locally advanced tumor site easily accessible to biopsy (with exception of bone and brain metastasis) and must have agreed to perform pretreatment and post-treatment biopsies; an archival pre-treatment biopsy may be used if it was collected within one month of enrolment, if no anticancer therapy was administered after the biopsy and if sufficient material is available for research;
6. Life expectancy must be ≥12 weeks according to the discretion of the investigator;
7. ECOG performance status ≤ 2;
8. Patients must have adequate hematologic and organ function, compatible with ADC administration, as per drug-specific recommendations;
9. Women of childbearing potential and male patient must agree to use adequate contraception for the duration of trial participation and up to 7 months after completing treatment for women and up to 4 months for men;
10. Patients must be affiliated to a social security system (or equivalent);
11. Patients must be willing and able to comply with the protocol for the duration of the trial;
12. Patients must consent to the use of their collected tumor specimen, as well as, blood samples as detailed in the protocol for future scientific research, which includes but is not limited to DNA, RNA, and protein-based biomarker analysis.

Exclusion Criteria:

1. Patients treated with an antibody drug conjugate in a curative setting;
2. Patients who did not consent to sample use;
3. Presence of another progressive pathology with short-term life-threatening prognosis;
4. Patients undergoing concurrent treatment for a malignancy or hematologic disorder distinct from the indication for which the ADC is being administered.
5. Patients with inadequate washout period prior to Cycle 1 Day 1, defined as:

   * Whole brain radiation therapy \<14 days or stereotactic brain radiation therapy \<7 days.
   * Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) (including another ADC) from a previous cancer treatment regimen or clinical study (other than epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI)), \<14 days or 5 half-lives, whichever is longer.
   * Immune checkpoint inhibitor therapy \<21 days.
   * Hormonal therapy \<21 days.
   * Major surgery (excluding placement of vascular access) \<28 days.
   * Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation \<28 days or palliative radiation therapy \<14 days.
6. Female participant who is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 90 days after the final administration of study treatment;
7. Person deprived of their liberty or under protective custody or guardianship.

Where this trial is running

Villejuif

• Gustave Roussy Cancer Center — Villejuif, France (Recruiting)

Study contacts

• Principal investigator: Barbara Pistilli, MD, PhD — Gustave Roussy Cancer Center
• Study coordinator: Marjorie Mauduit

Conditions Advanced Breast Cancer; Advanced Gastric Cancer; Advanced Urothelial Cancer; Advanced Non Small Cell Lung Cancer; ADC; resistance