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

An Open-label, Randomized, Multicenter Comparative Study of the Pharmacokinetics, Safety, and Efficacy of RPH-002 and Erbitux® in Patients With Unresectable Metastatic or Recurrent Head and Neck Squamous Cell Carcinoma

The primary objective of this clinical study is to compare the pharmacokinetic parameters of drugs RPH-002 and Erbitux® after a single intravenous administration, as well as to evaluate the safety of drug RPH-002 in comparison with drug Erbitux® when used in combination with Docetaxel and Cisplatin as first-line therapy in patients with Recurrent Head and Neck Squamous Cell Carcinoma. In addition, this study will include a comparative assessment of immunogenicity and a pilot evaluation of efficacy

This study is a multicenter, open-label, randomized Phase I study

This clinical study includes the following stages:

• Stage 1: Evaluation of the pharmacokinetics of drugs RPH-002 and Erbitux® after the first administration, and evaluation of the safety and immunogenicity of drugs RPH-002 and Erbitux® after four administrations of the study therapy
• Stage 2: Evaluation of pharmacokinetics, safety, immunogenicity, and pilot efficacy of drugs RPH-002 and Erbitux® during up to 18 weeks of therapy
• Stage 3: Evaluation of safety, immunogenicity, and pilot efficacy of RPH-002 and Erbitux® after 6 months of therapy, as well as evaluation of safety, immunogenicity, and pilot efficacy of drug RPH-002 after 1 year of therapy

Therapy with cetuximab within this clinical study will continue until disease progression or the development of unacceptable toxicity

Disease progression is defined as the presence of one or more of the following criteria:

• Clinical progression as assessed by the investigator
• Radiologically confirmed progression according to RECIST 1.1 criteria: 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

The maximum duration of therapy with cetuximab within the study will be 54 weeks

The study will include the following periods:

1. Screening Period 1 (up to 15 days)

   Includes Days -14 to 0 (prior to the first administration of the investigational product/comparator)

2. Main Period (Period 1)

   The main study period includes Days 1-126

   Patients will be randomized in a 1:1 ratio into one of two study groups: RPH-002 and Erbitux®. Patients will receive combination therapy with RPH-002 or Erbitux®, docetaxel, and cisplatin for 18 weeks, or until the development of unacceptable toxicity or disease progression

   The Main Period includes collection of data on complaints and symptoms, physical examination, assessment of vital signs (body temperature, blood pressure, pulse), monitoring of laboratory parameters (hematology, serum biochemistry, coagulation tests, blood analysis, and urinalysis), blood sampling for determination of serum cetuximab concentration and immunogenicity assessment, ECG, and evaluation of Karnofsky performance status. Tumor response assessment will be performed every 6 weeks during Period 1

3. Screening Period 2 (up to 8 days)

   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 will be evaluated to determine eligibility for continuation of therapy in the Maintenance Therapy Period

4. Maintenance Therapy Period (Period 2)

   Days 127-386

   Patients eligible for the Maintenance Therapy Period will be those who have achieved stable disease or an objective tumor response according to RECIST 1.1 at Week 18 of the Main Period

   During the Maintenance Therapy Period, patients will receive monotherapy with RPH-002 or Erbitux® at the same dose regimen (250 mg/m²) once weekly. The maximum number of administrations of cetuximab during this period will be 36

   Treatment during this period will continue until the earliest of the following:

   • 54 weeks from the start of study therapy;
   • Disease progression (according to RECIST 1.1 or clinical progression);
   • Development of unacceptable toxicity

   The Period includes collection of data on complaints and symptoms, physical examination, assessment of vital signs (body temperature, blood pressure, pulse), monitoring of laboratory parameters (hematology, serum biochemistry, coagulation tests, and urinalysis), collection of biological samples for immunogenicity analysis, ECG, and evaluation of Karnofsky performance status. Tumor response assessment will be performed every 6 weeks during Period 2

5. Follow-up Period

This study period includes safety evaluation of the investigational therapy in all patients who completed Period 1 and did not enter Period 2, as well as all patients who completed therapy during Period 2. The follow-up visit will be conducted 28 ± 3 days after the last administration of the study treatment

Inclusion Criteria:

Main Period (Period 1)

1. A voluntarily signed and dated Informed Consent form (ICF) of the patient

2. Histologically confirmed squamous cell carcinoma of the head and neck

3. Body mass index (BMI) between 18 and 30 kg/m^2, inclusive

4. 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

5. At least one measurable lesion per RECIST 1.1

6. Karnofsky performance status ≥70%

7. 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

8. 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

9. Ability and willingness to comply with study protocol and procedures for the planned duration of participation

10. Ability to undergo required pharmacokinetic sample collection, as judged by the investigator

Maintenance Therapy Period (Period 2)

1. Documented tumor response or disease stabilization per RECIST 1.1 by computed tomography (CT) or magnetic resonance imaging (MRI) at Week 18 of the Main Period

2. Ability and willingness to provide written informed consent for participation in Period 2

3. Karnofsky performance status ≥ 70%

4. 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

5. 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)

1. Prior therapy with cetuximab or other monoclonal antibody-based biologics
2. Chemotherapy, radiotherapy, or surgery for head and neck cancer within 3 months before screening
3. Any other surgery (except biopsy, implantable venous port placement, or urgent non-cancer surgery) within 3 months before screening
4. Nasopharyngeal carcinoma
5. 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)
6. Expected survival < 3 months
7. Women who are pregnant or breastfeeding, or unwilling to use effective contraception during the study and for at least 6 months after
8. 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
9. Active infection requiring systemic antibiotic therapy
10. Ongoing systemic immunotherapy, hormone therapy, or other cancer treatments not specified in the protocol within 6 months prior to screening or during the study
11. Known or suspected brain metastases, including parenchymal, leptomeningeal, or dural involvement associated with symptoms
12. Positive screening for HBsAg, anti-HCV, anti-HIV1/2 antibodies, or syphilis within 3 months prior to screening
13. Conditions preventing compliance with the study protocol per investigator
14. Participation in another investigational drug study within 6 months prior to screening
15. Unstable medical conditions, including uncontrolled diabetes, psychiatric disorders, or uncontrolled seizures, that could interfere with protocol adherence
16. Known hypersensitivity to any component of study therapy or combination chemotherapy drugs
17. 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)

1. No documented tumor response or disease stabilization per RECIST 1.1 by CT or MRI at Week 18 of the Main Period
2. Women who are pregnant or breastfeeding, or unwilling to use effective contraception during the study and for at least 6 months after
3. 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
4. Active infection requiring systemic antibiotics
5. Ongoing systemic immunotherapy, hormone therapy, or other cancer treatments not specified in the protocol for Period 2
6. Known or suspected brain metastases, including parenchymal, leptomeningeal, or dural involvement associated with symptoms
7. Conditions preventing compliance with study procedures per investigator
8. Participation in another investigational drug study
9. Unstable medical conditions, including uncontrolled diabetes, psychiatric disorders, or uncontrolled seizures, that could interfere with protocol adherence
10. 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