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

Summary

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.

Eligibility

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)

Conditions2

Interventions5

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