Phase II Study of Ezabenlimab in PD-L1-Expressing Patients with Minimal Residual Disease Following Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma

Trial ID: 2025-523575-36-00
Sponsor: Cliniques Universitaires Saint-Luc

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Diseases & Conditions

Head and neck cancer

Objectives

The primary objective of this study is to evaluate the efficacy of ezabenlimab in patients with HPV-negative locally advanced head and neck squamous cell carcinoma (LA-HNSCC) who exhibit PD-L1 expression ≥20% and are ctDNA positive at baseline, as well as demonstrating minimal residual disease (MRD) 6-8 weeks following curative-intent chemoradiation (CRT). Secondary objectives include:

Assessment of safety and tolerability.
Evaluation of disease-related symptoms and treatment tolerability as reported by participants.
Analysis of the association between MRD status post-CRT and molecular response to clinical activity.
Evaluation of overall survival (OS).
Assessment of event-free survival (EFS).

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of adult patients diagnosed with locally advanced head and neck squamous cell carcinoma. The cohort includes both males and females, specifically focusing on those who are HPV-negative. Eligible individuals must demonstrate a PD-L1 expression score of ≥20 and possess detectable circulating tumor DNA at baseline and 6-8 weeks following chemoradiotherapy. Participants are required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and demonstrate adequate organ function. For the interventional cohort, women of childbearing potential must maintain effective contraception, and those who are breastfeeding must discontinue nursing for a specified period. Additionally, patients must have a left ventricular ejection fraction of at least 50% and no clinically significant abnormalities on an electrocardiogram.

Plans and Procedures

This Phase II clinical trial evaluates the efficacy of ezabenlimab as a treatment intensification strategy for patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The study involves an observational cohort and an interventional cohort. Participants must be PD-L1 positive with a combined positive score (CPS) of $\ge$20 and exhibit minimal residual disease (MRD) via detectable circulating tumor DNA (ctDNA) 6 to 8 weeks following chemoradiation. The interventional cohort receives 240 mg of ezabenlimab via intravenous infusion. The primary endpoint is the event-free survival (EFS) rate at 2 years. Secondary endpoints include overall survival (OS), changes in quality of life, and the correlation of longitudinal ctDNA changes with clinical response. Study procedures include a screening visit to assess eligibility, including electrocardiogram (ECG) and organ function, followed by randomization and subsequent follow-up visits to monitor treatment-emergent adverse events (TEAEs) and molecular response. The end-of-study visit concludes the participant involvement. Participation may be subject to early termination based on disease progression or safety concerns.

Treatment

The experimental treatment consists of ezabenlimab, administered as a solution for infusion. The dosage is 240 mg, delivered via the intravenous route.

Efficacy

The primary efficacy endpoint is the 2-year event-free survival (EFS) rate in patients with minimal residual disease (MRD) positive for head and neck squamous cell carcinoma. EFS is defined as the time from post-chemoradiation MRD assessment to disease progression, recurrence, or death from any cause, whichever occurs first.

Secondary efficacy assessments include:

Overall survival (OS), defined as the time from post-chemoradiation MRD assessment to death from any cause.
Changes in quality of life (QoL) measured using the EORTC QLQ-C30 and QLQ-HN43 instruments.
Patient-reported outcomes regarding the frequency and severity of symptomatic toxicity, assessed via PRO-CTCAE and FACT-GP5, alongside the frequency distribution of PGIS/PGIC over time.
Correlation between circulating tumor DNA (ctDNA) longitudinal changes, such as molecular response, and clinical activity. This includes monitoring changes in ctDNA status approximately every 3 months.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Observational cohort : Patients ≥ 18 years old and must be able to give written informed consent.
Observational cohort : Newly diagnosed locally advanced histologically confirmed HNSCC of the oral cavity, oropharynx, hypopharynx or larynx eligible for curative-intent, platinum-based chemotherapy plus radiotherapy
Observational cohort : Signed and dated written ICF 1 in accordance with International Council for Harmonisation – Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial.
Interventional cohort : Participants must have been treated with platinum-based chemoradiation and meet the following minimum requirements for radiotherapy delivered as part of local SoC: Total Radiation dose of 65 Gy to 70 Gy over 6 – 7 weeks to the high-risk disease site. Note: Patients meeting criteria of progressive disease (PD) according to local standards at screening are not eligible. Patients that need to undergo lymph node dissection according to SOC will not be excluded.
Interventional cohort : Tumor PD-L1 CPS score ≥ 20, performed locally on the diagnostic biopsy using the Agilent 22C3 assay.
Interventional cohort : MRD positive status defined as detectable ctDNA 6-8W after the end of CRT (tested centrally).
Interventional cohort : Has an Eastern Cooperative Oncology Group (ECOG) PS of 0 – 2.
Interventional cohort : Has adequate organ function as defined in the protocol. All screening labs should be performed within 14 days of randomization.
Interventional cohort : 12 lead electrocardiogram (ECG) without clinically relevant abnormalities. Patients with a significant cardiac history, this includes hypertension, even if controlled, should have a LVEF ≥ 50% as assessed either by multi-gated acquisition scan or cardiac ultrasound.
Interventional cohort : Women of child-bearing potential (WOCBP) must have a negative pregnancy test (serum or urine) between registration and cohort allocation).
Interventional cohort : WOCBP and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R3) that result in a low failure rate of less than 1% per year when used consistently and correctly for the course of the study through 180 days after the last dose of study medication.
Interventional cohort : Female subjects who are breast feeding should agree to discontinue nursing prior to the first dose of study treatment and up to 6 months after the last study treatment.
Interventional cohort : Signed and dated written ICF 2 in accordance with ICH-GCP and local legislation prior to admission to the trial.

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Exclusion Criteria

Observational cohort : Has received prior radiation therapy, systemic therapy, targeted therapy, or radical surgery for management of head and neck cancer not considered part of CRT.
Observational cohort : Has cancer outside of the oropharynx, larynx, hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer.
Observational cohort : Has a diagnosed and/ or treated any additional malignancy within the last 2 years prior to registration. Exceptions: localized HNSCC treated by curative surgery alone, curatively treated superficial esophageal cancer (TIS or T1a) fully resected by endoscopy, non-melanoma skin cancer or localized cervical cancer or localized and presumed cured prostatic cancer or basal cell carcinoma of the skin and carcinoma in situ of the cervix or bladder).
Observational cohort : Woman who is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of trial treatment.
Interventional cohort : Meets criteria of PD according to local standards. Patients that need to undergo lymph node dissection according to SOC will not be excluded.
Interventional cohort : Any unresolved toxicity CTCAE >/= Grade 2 from the prior CRT. Participants with irreversible or slowly resolving toxicity Grade 2 that is not reasonably expected to be exacerbated by study drug may be included (e.g., hearing loss, neuropathy), after consultation with the study coordinators.
Interventional cohort : Known diagnosis of immune deficiency or a positive serology of HIV (HIV 1/2 antibodies).
Interventional cohort : Active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected) or pre-existing liver cirrhosis.
Interventional cohort : Known history of active tuberculosis (TB; Bacillus tuberculosis).
Interventional cohort : Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis/interstitial lung disease.
Interventional cohort : Other uncontrolled active illnesses or nonmalignant systemic disease (examples include, but are not limited to, active infections requiring antibiotics, bleeding disorders, uncontrolled diabetes, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome …).
Interventional cohort : Has Grade 3-4 bleeding due to underlying malignancy or has high risk of bleeding (examples include but not limited to tumors encasing or infiltrating a major vessel (i.e., carotid artery, jugular vein) and/or other high-risk features such as an arteriovenous fistula. Patients with disease in such locations or with these features are not eligible for participation.
Interventional cohort : Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
Interventional cohort : Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at doses more than 10 mg prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Note: Corticosteroid use on study for management of AEs and SAEs, as a premedication, for the administration of chemotherapies, and/or a premedication for IV contrast, allergies/reactions or if considered necessary for a participant’s welfare is allowed.
Interventional cohort : If participant have undergone major surgery, they must have adequately recovered from all procedure-related toxicities and/or complications prior to starting therapy. .
Interventional cohort : Has had an allogeneic tissue/solid organ transplant.
Interventional cohort : Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, esophageal/gastric varices, or persistent jaundice. Note: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.
Interventional cohort : Has a history of or evidence of cardiac abnormalities such as serious, uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities within 6 months prior to enrollment, including: • Second degree (Type II) or third-degree atrioventricular block. • Cardiomyopathy, myocarditis, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting. • Symptomatic pericarditis. • Patients with a significant cardiac history, this includes hypertension, even if controlled, should have a LVEF ≥ 50% as assessed either by multi-gated acquisition scan or cardiac ultrasound.
Interventional cohort : Known psychiatric or substance abuse disorder that would impede cooperation with study requirements.
Interventional cohort : Any psychiatric, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Interventional cohort : Concurrent treatment with other investigational drugs or anti-cancer therapy.
Interventional cohort : Previous treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA4, OX-40, CD137).
Interventional cohort : Has received any live vaccine within 30 days of enrollment. Vaccination against COVID-19 using vaccines that are authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application) are not exclusionary. Note: messenger RNA (mRNA) and adenoviral-based COVID-19 vaccines are considered non-live.
Interventional cohort : Concurrent treatment with other investigational drugs or anti-cancer therapy. Or participation in a study of an investigational agent or device within 4 weeks before the first dose of study treatment.
Interventional cohort : History of allergic reactions attributed to compounds of similar chemical or biologic composition to ezabenlimab.