A Comparative Study of Pharmacokinetics, Safety, and Immunogenicity of RPH-030 and Vectibix® in Patients With Metastatic Colorectal Cancer With Wild-type RAS as First-line Therapy in Combination With FOLFIRI

Multicenter, Double-blind, Randomized, Comparative Study of the Pharmacokinetics, Safety, and Immunogenicity of RPH-030 and Vectibix® in Patients With With Metastatic Colorectal Cancer (mCRC) With Wild-type RAS as First-line Therapy in Combination With FOLFIRI

The primary objective of this study is to demonstrate equivalence of pharmacokinetic properties, and comparability of safety and immunogenicity parameters of RPH-030 and Vectibix® following a single (first) intravenous administration to patients with mCRC with wild-type RAS genes as 1-line therapy in combination with FOLFIRI. The additional objective is to perform a pilot evaluation of the efficacy of RPH-030 and Vectibix® following a single (first) intravenous administration to patients with mCRC with wild-type RAS genes as 1-line therapy in combination with FOLFIRI.

This study is a multicenter, double-blind, randomized, comparative, phase I study

Treatment with panitumumab in combination with FOLFIRI (de Gramont) within of this study will continue for up to 2 years or disease progression/unacceptable toxicity/patient refusal to continue therapy (in whichever comes first)

The study will include the following periods:

1. Screening period: days -27 to 0 (up to 1 administration of the study therapy)

   If a tumor biopsy is required for histological diagnosis verification and testing of KRAS/NRAS, BRAF mutation status, Her2/neu status, and MSI status, the screening period may be extended up to 42 days

2. Main period: days 1 to 182

   Eligible patients will be randomized at the ratio of 1:1 to one of the two study arms: RPH-030 and Vectibix®. During the Main Period of the study, patients will receive panitumumab (RPH-030 or Vectibix®) at a dose of 6 mg/kg intravenously (IV) once every 2 weeks (2 weeks = 1 cycle) in combination with FOLFIRI (after 8 cycles, patients will be switched to the de Gramont regimen)

   Therapy during the Main Study Period will continue until the earliest of the following:

   • Completion of 6 months (up to 13 cycles inclusive)
   • Disease progression (according to RECIST 1.1 criteria or clinical progression)
   • Development of unacceptable toxicity
   • Patient's withdrawal of consent to continue treatment

   Tumor response assessment during the Main Study Period will be performed approximately every 6 weeks

   Patients will be hospitalized at least twice: at Visit 1 (Day 1) and Visit 3 (Day 29) either before drug administration or on the eve of it; the duration of hospitalization will be at least 24 hours from the start of panitumumab infusion

3. Period of continued therapy: days 183 to 365

   During the period of continued therapy, all patients will receive RPH-030 therapy, including those patients who received Vectibix® therapy during the Main Period

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

   • Up to 1 year of therapy
   • Disease progression (according to RECIST 1.1 criteria or clinical progression)
   • Development of unacceptable toxicity
   • Patient's withdrawal of consent to continue treatment

   Assessment of the tumor response to therapy during the period of continued therapy will be performed approximately once every 8 weeks

4. Treatment Extension Period: days 366 to 729

   Participants in the Treatment Extension Period will be patients who demonstrate stable disease (SD) or tumor response after 1 year of therapy. The decision to enter this period will be made by the investigator

   Therapy during the Treatment Extension Period will continue until the earliest of the following:

   • For a total duration of up to 2 years
   • Disease progression (according to RECIST 1.1 criteria or clinical progression)
   • Development of unacceptable toxicity
   • Patient's withdrawal of consent to continue treatment

5. Follow-up period (follow-up/FU)

For patients who complete the Treatment Extension Period (either as scheduled or prematurely), a Follow-up visit will be scheduled 28 ± 3 days after the last dose of panitumumab. Following this visit, the patient's participation in the study will be considered complete

Follow-up (FU) visits will be conducted every 8 weeks (±7 days) until Day 365, death, or withdrawal of consent (whichever occurs first):

• For patients who discontinue study therapy due to disease progression or start a new line of treatment (including surgery), FU will be conducted via telephone contact with the patient or relatives to collect overall survival data
• For patients who discontinue study therapy for reasons other than progression and have not started new treatment, FU will include CT/MRI assessments until disease progression, initiation of new therapy, or Day 365. Once progression occurs or new therapy starts, these patients will switch to telephone survival follow-up

Inclusion Criteria:

1. A voluntarily signed and dated Informed Consent form (ICF) of the patient
2. Histologically verified (documented results of respective examinations available) metastatic colorectal adenocarcinoma (in case the results of previous examinations are not available, the diagnosis will be verified in the central laboratory during screening upon receipt and evaluation of the results before randomization)
3. Patient consent to undergo a screening biopsy if archival tissue samples are unavailable for histological diagnosis verification
4. Patients with metastatic colorectal cancer (mCRC), either de novo metastatic or recurrent with distant metastases, who are candidates for first-line therapy
5. RAS wild-type (WT) status
6. ECOG status 0-1
7. Presence of at least one measurable lesion according to RECIST 1.1 criteria (patients with a single measurable bone lesion are not eligible)
8. Absence or resolution of toxic effects from prior therapy (neoadjuvant/adjuvant) or surgical complications to ≤ Grade 1 according to CTCAE v5.0, except for chronic/irreversible adverse events that do not impact the safety profile of the study treatment (e.g., alopecia)
9. Serum magnesium ≥ 0.66 mmol/L, total calcium ≥ 2.15 mmol/L, and potassium ≥ 3.5 mmol/L at the time of randomization
10. Life expectancy of ≥ 13 weeks from the time of randomization (as per the investigator's assessment)
11. Agreement of patients of childbearing potential to remain abstinent from heterosexual intercourse or use highly effective methods of contraception starting from the date of signing the ICF, throughout the treatment period, and for 6 months after the last dose of FOLFIRI and 2 months after the last infusion of panitumumab. Female participants are considered not of childbearing potential if they have experienced permanent cessation of menstruation (self-reported) established retrospectively after 12 months of natural amenorrhea with appropriate clinical status, such as age (range 45-55 years)
12. Ability to comply with protocol procedures in the opinion of the investigator
13. For patients participating in the pharmacokinetic study, body weight must be within 50-100 kg at the time of informed consent signing

Exclusion Criteria:

1. Prior systemic antitumor therapy (except for neoadjuvant or adjuvant fluoropyrimidine-based chemotherapy)

2. Prior therapy with anti-EGFR monoclonal antibodies (e.g., cetuximab, panitumumab) or small molecule EGFR tyrosine kinase inhibitors (e.g., gefitinib, erlotinib, afatinib)

3. Concomitant systemic immunotherapy or hormonal cancer therapy, or concurrent use of other cancer treatments not specified in the Protocol

4. Major surgery within 28 days, or radiotherapy (except for palliative radiotherapy) with residual signs of radiation toxicity within 14 days prior to the planned date of randomization

5. Presence of BRAF gene mutation (if BRAF testing results are unavailable, testing will be performed at a central laboratory; results must be obtained and evaluated prior to randomization)

6. Severe comorbidities or life-threatening acute complications of the underlying disease (including massive pleural, pericardial, or peritoneal effusion requiring intervention)

7. Paralytic ileus, gastrointestinal obstruction, or uncontrolled diarrhea (disabling symptoms despite adequate treatment)

8. Central nervous system (CNS) metastases that are progressive, symptomatic (e.g., cerebral edema, spinal cord compression), or requiring glucocorticosteroids at doses >10 mg/day (prednisolone equivalent), >1.5 mg/day (dexamethasone equivalent), or anticonvulsants, whereas patients with treated and stable brain metastases (for ≥4 weeks), asymptomatic non-progressive lesions not requiring steroids/anticonvulsants for ≥4 weeks, or newly diagnosed asymptomatic lesions requiring no therapy may be included

9. Ongoing comorbidities at the time of screening that increase the risk of adverse events during study therapy, including:

   • Stable angina pectoris (Canadian Cardiovascular Society Grade III-IV), unstable angina, or a history of myocardial infarction within 1 month prior to the planned date of randomization
   • Clinically significant cardiac arrhythmias (patients with controlled heart rate/rhythm are eligible)
   • Chronic heart failure (New York Heart Association [NYHA] Class III-IV)
   • Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg despite antihypertensive therapy)
   • Severe respiratory failure
   • Current severe uncontrolled systemic disease
   • Any other medical condition or comorbidity that, in the investigator's opinion, significantly increases the risk of adverse events during the study

10. Gilbert's syndrome at randomization or in medical history

11. Hematologic abnormalities:

    • Absolute neutrophil count (ANC) <1.5 × 10^9/L
    • Platelet count <100 × 10^9/L
    • Hemoglobin <90 g/L

12. Renal impairment:

    - Serum creatinine >1.5 × ULN or Glomerular Filtration Rate (GFR) <45 mL/min (calculated via CKD-EPI formula)

13. Hepatic impairment:

    • Total bilirubin ≥ 1.5 × ULN
    • AST or ALT ≥ 3.0 ULN (≥ 5 × ULN for patients with liver metastases)
    • Alkaline phosphatase (ALP) ≥ 5 × ULN

14. Feasibility of radical resection of all metastatic lesions

15. History of other malignancies that are progressive or required treatment within 5 years prior to signing the ICF, excluding radically treated cervical carcinoma in situ, breast cancer in situ, or basal/squamous cell skin carcinoma

16. Conditions limiting the patient's ability to comply with protocol requirements (e.g., dementia, neurological or psychiatric disorders, drug addiction (excluding the use of narcotic analgesics for pain management), alcohol dependence, etc.). Religious or personal beliefs that may potentially limit standard therapies within the study (e.g., refusal of blood transfusions) are considered conditions limiting protocol compliance

17. Concurrent participation in other interventional clinical trials, participation in other clinical trials within 30 days prior to signing the ICF (provided the patient received at least one dose of investigational therapy), or prior participation in this clinical trial (provided the patient received at least one dose of panitumumab)

18. Acute infectious diseases or exacerbation of chronic infections within 28 days prior to the planned date of randomization

19. Major surgery within 28 days prior to the planned date of randomization. Major surgery is defined as procedures involving entry into a major body cavity (abdomen, chest, or skull) performed under general anesthesia. Placement of a venous port system for antitumor therapy or an intestinal stoma is not considered major surgery

20. Positive test result for any of the following: hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV), antibodies to human immunodeficiency virus types 1 and 2 (anti-HIV-1 and anti-HIV-2), or a blood test for syphilis at screening or within 3 months prior to the planned date of randomization

21. Inability to receive intravenous (IV) administration of the investigational product

22. Contraindication to any type of intravenous contrast enhancement (non-contrast chest CT is permitted if medically indicated)

23. Current continuous daily treatment with corticosteroids at doses >10 mg/day (prednisolone equivalent) or >1.5 mg/day (dexamethasone equivalent), excluding topical steroids

24. Hypersensitivity to any components of the study drugs specified in the protocol or intolerance to any premedication drugs

25. History of hypersensitivity to monoclonal antibody (mAb) therapies

26. Pregnancy or breastfeeding

27. Consumption of more than 10 units of alcohol per week or a history of alcoholism or drug addiction. One unit of alcohol is defined as 250 mL of beer, 125 mL of wine, or 30 mL of spirits

28. Presence of any other significant comorbidities or conditions that, in the reasonable opinion of the Investigator, may adversely affect the patient's participation and well-being in the study and/or confound the evaluation of study results

29. Inability to perform venous blood sampling or to insert a venous catheter required for biosample collection (applicable to patients enrolled in the pharmacokinetic study)