A Comparative Study of Efficacy and Safety of RPH-002 and Erbitux® in Unresectable Metastatic or Recurrent Head and Neck Squamous Cell Carcinoma

This study is a international, multicenter, open-label, randomized, parallel-group Phase III study

The study will include the following periods:

• Screening Period 1

Includes Days -14 to -1 (prior to the first administration of the investigational product/comparator)

• Main Period (Period 1)

The main study period includes Days 1-126

The Main Period begins with administration of cetuximab (RPH-002 or Erbitux®) and chemotherapy on Day 1 of Cycle 1. Chemotherapy continues for up to 6 cycles, each lasting 3 weeks (21 days). Chemotherapy agents are administered no earlier than 1 hour after completion of cetuximab infusion. Cetuximab is administered weekly for up to 18 doses

In Period 1, tumor response is assessed every 6 weeks

• Screening Period 2

Includes Days -7 to 0 (prior to Visit 1 of the Maintenance Therapy Period)

During Screening Period 2, the patient's general condition and laboratory and instrumental test results are evaluated to determine eligibility for continuation of therapy in the Maintenance Therapy Period

• Maintenance Therapy Period (Period 2)

Includes Days 127-386

In the Maintenance Therapy Period, patients with a tumor response or stable disease at Week 18 of Period 1 are included in the study. Tumor response is assessed according to RECIST 1.1 criteria:

• Complete Response (CR) - disappearance of all target lesions, confirmed by CT scans for at least 4 weeks; the short axis of any lymph node previously considered pathological (target or non-target) must be <10 mm
• Partial Response (PR) - at least a 30% decrease in the sum of diameters of target lesions, maintained for at least 4 weeks compared with baseline (screening) measurements
• Progressive Disease (PD) - at least a 20% increase in the sum of diameters of target lesions compared with the smallest sum recorded during the study (with an absolute increase of at least 5 mm), or the appearance of one or more new lesions
• Stable Disease (SD) - neither sufficient shrinkage in the sum of diameters to qualify as partial response nor sufficient increase to qualify as progressive disease compared with the smallest sum recorded during the study

During the Maintenance Therapy Period, patients receive monotherapy with cetuximab at 250 mg/m² once weekly. The maximum number of administrations of cetuximab during this period is 36

Therapy continues until the earliest of the following:

• up to 54 weeks from the start of study treatment
• disease progression (per RECIST 1.1 or clinical progression)
• unacceptable toxicity

Radiologically confirmed progression according to RECIST 1.1 criteria is defined as an increase of at least 20% in the sum of diameters of target lesions compared with the smallest sum recorded during the study (with an absolute increase of at least 5 mm), or the appearance of one or more new lesions

In Period 2, tumor response is assessed every 6 weeks

• Follow-up Period

The Follow-Up Period assesses the safety of study therapy in all patients who complete Period 1 and do not enter Period 2, as well as in patients who complete therapy in Period 2. The period lasts 28 ± 3 days after the last study drug administration (if therapy completes as planned at 54 weeks) or until death, loss to follow-up, or Day 365, whichever occurs first. A single follow-up visit is conducted 28 ± 3 days after the last study drug administration

Inclusion criteria

Main Period (Period 1)

• A voluntarily signed and dated Informed Consent form (ICF) of the patient
• Histologically confirmed squamous cell carcinoma of the head and neck
• Documented unresectable locoregional recurrence or distant metastases, or progression after prior chemoradiotherapy or combination therapy completed >3 months before screening, not amenable to local treatment (except cases with high risk of tumor lysis or bleeding), or newly diagnosed metastatic disease not previously treated with systemic therapy. Study treatment is first-line therapy
• At least one measurable lesion per RECIST 1.1
• Karnofsky performance status ≥70%
• Screening laboratory values within the following limits (per local lab normal ranges):

• Hemoglobin ≥90 g/L
• Leukocytes ≥3.0 × 10^9/L
• Neutrophils ≥1.5 × 10^9/L
• Platelets ≥100 × 10^9/L
• Total bilirubin ≤2 × Upper Limit of Normal (ULN)
• Aspartate aminotransferase (AST) ≤3 × ULN
• Alanine aminotransferase (ALT) ≤3 × ULN
• Estimated glomerular filtration rate (eGFR) ≥60 mL/min
• Men and women of childbearing potential, and women within 2 years of menopause, must agree to use reliable contraception from informed consent through at least 6 months after study treatment; women of childbearing potential must have a negative urine pregnancy test. Women with no reproductive potential (≥2 years post-menopause or surgically sterile) are exempt
• Ability and willingness to comply with study protocol and procedures for the planned duration of participation

Maintenance Therapy Period (Period 2)

• Registered objective response (stable disease or partial/complete response according to RECIST 1.1 criteria) to the therapy administered during the main study period
• Ability and willingness to provide written informed consent for participation in Period 2
• Karnofsky performance status ≥ 70%
• Laboratory values within the following limits (per local lab normal ranges):

• Hemoglobin ≥ 90 g/L
• Leukocytes ≥ 3.0 × 10^9/L
• Neutrophils ≥ 1.5 × 10^9/L
• Platelets ≥ 100 × 10^9/L
• Total bilirubin ≤ 2 × ULN (upper limit of normal)
• AST ≤ 3 × ULN
• ALT ≤ 3 × ULN
• eGFR ≥ 60 mL/min
• Men and women of childbearing potential, and women within 2 years of menopause, must agree to use reliable contraception from informed consent through at least 6 months after study treatment; women of childbearing potential must have a negative urine pregnancy test. Women with no reproductive potential (≥2 years post-menopause or surgically sterile) are exempt

Exclusion criteria

Main Period (Period 1)

• Prior therapy with cetuximab or other monoclonal antibody-based biologics
• Chemotherapy, radiotherapy, or surgery for head and neck cancer within 3 months before screening
• Any other surgery (except biopsy, implantable venous port placement, or urgent non-cancer surgery) within 3 months before screening
• Nasopharyngeal carcinoma
• Other malignancy within the past 5 years or prior/concurrent squamous cell carcinoma (except cured in situ ductal carcinoma, cervical carcinoma in situ, basal cell or squamous cell skin cancer)
• Expected survival < 3 months
• Women who are pregnant or breastfeeding, or unwilling to use effective contraception during the study and for at least 6 months after
• Significant cardiovascular disease per investigator, including uncontrolled hypertension (systolic ≥180 mmHg or diastolic ≥130 mmHg), coronary artery disease, myocardial infarction within 12 months, high-risk uncontrolled arrhythmias, or uncontrolled heart failure
• Active infection requiring systemic antibiotic therapy
• Ongoing systemic immunotherapy, hormone therapy, or other cancer treatments not specified in the protocol within 6 months prior to screening or during the study
• Known or suspected brain metastases, including parenchymal, leptomeningeal, or dural involvement associated with symptoms
• Positive screening for HBsAg, anti-HCV, anti-HIV1/2 antibodies, or syphilis within 3 months prior to screening
• Conditions preventing compliance with the study protocol per investigator
• Participation in another investigational drug study within 6 months prior to screening
• Unstable medical conditions, including uncontrolled diabetes, psychiatric disorders, or uncontrolled seizures, that could interfere with protocol adherence
• Known hypersensitivity to any component of study therapy or combination chemotherapy drugs
• Excessive alcohol use (>10 standard drinks/week) or history of alcoholism or substance abuse associated with symptoms. One standard drink = 250 mL beer, 125 mL wine, or 30 mL spirits

Maintenance Therapy Period (Period 2)

• Absence of a confirmed objective response to the administered therapy during the main study period, defined as failure to achieve disease stabilization or a partial/complete response according to RECIST v1.1
• Women who are pregnant or breastfeeding, or unwilling to use effective contraception during the study and for at least 6 months after
• Significant cardiovascular disease per investigator, including uncontrolled hypertension (systolic ≥180 mmHg or diastolic ≥130 mmHg), coronary artery disease, myocardial infarction within 12 months, high-risk uncontrolled arrhythmias, or uncontrolled heart failure
• Active infection requiring systemic antibiotics
• Ongoing systemic immunotherapy, hormone therapy, or other cancer treatments not specified in the protocol for Period 2
• Known or suspected brain metastases, including parenchymal, leptomeningeal, or dural involvement associated with symptoms
• Conditions preventing compliance with study procedures per investigator
• Participation in another investigational drug study
• Unstable medical conditions, including uncontrolled diabetes, psychiatric disorders, or uncontrolled seizures, that could interfere with protocol adherence
• Excessive alcohol use (>10 standard drinks/week) or history of alcoholism or substance abuse associated with symptoms. One standard drink = 250 mL beer, 125 mL wine, or 30 mL spirits