Phase II study of ezabenlimab in patients with PD-L1-positive head and neck cancer with residual disease detected by ctDNA after chemoradiotherapy

Prior treatment

• 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.
• 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 : 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.
• 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).
• 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.

Other illness

• 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 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 : Known psychiatric or substance abuse disorder that would impede cooperation with study requirements.
• 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.
• Interventional cohort : Any psychiatric, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Interventional cohort : History of allergic reactions attributed to compounds of similar chemical or biologic composition to ezabenlimab.
• 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).

Lab values

• 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.

Other

• 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.

• Observational cohort : Patients ≥ 18 years old and must be able to give written informed consent.
• 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.
• 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 ≥ 10, 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.