A Study of the Efficacy, Safety and Pharmacokinetics of RPH-051 and Perjeta® in Combination With Trastuzumab and Docetaxel as the 1st Line Therapy in Patients With HER2-positive Breast Cancer

Criteria the registry did not label

• The patients must meet all the following inclusion criteria:
• Voluntarily signed and dated Informed Consent Form (ICF) of the patient agreed to take part in this Study
• Histologically verified (documented results of respective examinations available) metastatic or locally recurrent unresectable breast 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)
• Patients with metastatic or locally recurrent unresectable breast cancer (BC) who have indications for the 1st line therapy
• HER2-positive tumor status, defined as 3+ points according to the results of immunohistochemical examination (IHC) and/or detected amplification of HER2 according to the results of fluorescence in situ hybridization (as defined by a ratio ≥ 2,0), evaluated using a validated test. The HER2 status analysis is carried out in the invasive component of a biopsy sample of tumor tissue during screening in the central laboratory. The results must be obtained before making a decision on randomization of the patient. For analysis, it is required to provide the blocks no more than 1 year old, obtained from the treatment-naive lesions, or a biopsy is performed as a part of screening
• ECOG status 0-1.
• Left ventricular ejection fraction (LVEF) ≥ 55 % during the screening.
• Presence of at least one measurable lesion in accordance with the RECIST 1.1 criteria (if the patient's only measurable lesion is a bone one, she cannot be enrolled in the study).
• Absence or resolution of the previous therapy toxic effects or negative consequences of surgeries of up to ≤ 1 gr. according to CTCAE 5.0, with the exception of chronic/irreversible adverse events that do not affect the safety parameters of the study therapy (for example, alopecia)
• Life expectancy of at least 18 weeks from the date of randomization (in the opinion of the Investigator)
• Consent of a patient with preserved childbearing potential to abstain from heterosexual contact or use reliable methods of contraception, starting from the time the Informed Consent Form is signed, throughout the entire period of treatment within the study and 7 months after receiving the last infusion of pertuzumab and trastuzumab. Female patients are considered to be incapable of childbearing if the final cessation of menstruation is confirmed retrospectively after 12 months of natural amenorrhea, i.e. amenorrhea with an appropriate clinical status, for example, a suitable age
  • Additional criteria for inclusion in PK subgroups
• Availability of the signed Informed Consent Form to participate in the pharmacokinetic study
• Body weight in the range of 40-100 kg at the time the ICF is signed
• Patient's capability, in the justified opinion of the Investigator, to participate in the pharmacokinetic study and possibility to take the required number of blood samples
  • The patients cannot be included in the study if any of the following exclusion criteria is met:
• Previous antitumor therapy for metastatic or locally recurrent unresectable BC (neoadjuvant/adjuvant therapy with trastuzumab and one hormone therapy regimen for the metastatic process are allowed)
• Previous pertuzumab therapy
• The period without the signs of disease from the completion of the systemic neoadjuvant or adjuvant BC therapy (except hormonal therapy) to the established diagnosis of the metastatic process or recurrence in \< 12 months
• The period from completion of the systemic neoadjuvant or adjuvant BC therapy with trastuzumab and docetaxel to the start of the systemic therapy for metastatic or locally recurrent unresectable process with a combination of pertuzumab + trastuzumab + docetaxel is \< 12 months
• Sustained hematological toxicity (hemoglobin, leukocytes, neutrophils, platelets) ≥ grade 2, resulting from the previous adjuvant therapy
• Peripheral neuropathy ≥ grade 3 at the time the ICF is signed
• Other oncological pathology that is progressing or requires antitumor therapy (including hormonal therapy) within 5 years before signing the ICF, except radically removed cervical carcinoma in situ or radically removed basal cell/squamous cell skin carcinoma
• Central nervous system metastases that are progressive or accompanied by clinical symptoms (for example, cerebral edema, compression of the spinal cord), or require the application of glucocorticosteroids (GCS) at a dose equivalent to daily intake of prednisolone \> 10 mg (or dexamethasone \> 1.5 mg), and/or anticonvulsants. Patients with brain metastases can be included in the study if they receive adequate therapy (surgery or radiotherapy) and are stabilized according to the imaging studies data for at least 4 weeks before the expected date of randomization into the study. Patients with CNS metastases detected for the first time as a part of screening, which are not accompanied by neurological symptoms and do not require any therapy, can be included in the study
• History of treatment with cumulative doses of anthracyclines
• Patients with severe concomitant diseases, with life-threatening acute complications of the underlying disease
• Concomitant diseases that are ongoing at the time of the screening examination and that increase the patient's risk of developing adverse events during the application of study therapy:
  • stable effort angina, Functional Class III-IV, unstable angina
  • history of myocardial infarction or stroke occurred less than 6 months before signing of the IC form
  • clinically significant rhythm disturbances (patients with asymptomatic atrial fibrillation can be included in the study provided the ventricular rhythm is controlled)
  • chronic cardiac failure, Class III-IV according to New York Heart Association (NYHA) classification
  • uncontrolled arterial hypertension (systolic blood pressure over 150 mmHg or diastolic blood pressure over 90 mmHg during antihypertensive therapy)
  • decrease in LVEF to \< 50 % in the medical history during or after the previous neoadjuvant or adjuvant trastuzumab therapy
  • severe respiratory failure, as well as dyspnea at rest due to complications of advanced cancer or other diseases requiring continuous oxygen therapy
  • current severe uncontrolled systemic disease
  • any other concomitant disease or condition that significantly increases the risk of developing an AE during the study, in the opinion of the Investigator
• Major surgery or significant injury less than 28 days before, radiation therapy (other than palliative) less than 14 days before the IC form is signed, or a planned major surgery during treatment within this study
• Non-healing wounds, ulcers at the time the ICF is signed
• Hematological disorders (in case any of the following):
  • neutrophils \< 1.5 x 109/L
  • platelets \<100 x 109/L
  • hemoglobin \< 90 g/L
• Renal dysfunction:
  • creatinine \> 1.5 × ULN or glomerular filtration rate \< 45 mL/min (calculated using CKD-EPI formula)
• Liver dysfunction (in case any of the following):
  • bilirubin ≥ 1.5 × ULN (except for patients with Gilbert's syndrome, whose total bilirubin values should not exceed 50 µmol/L)
  • AST or ALT ≥ 3 × ULN (5 × ULN for patients with liver metastases)
• Administration of injectable anticoagulants during the screening period and 3 months before is prohibited. The maximum permissible daily dose of tableted anticoagulants: rivaroxaban - no more than 20 mg, apixaban - no more than 10 mg per day for patients with non-valvular atrial fibrillation and no more than 5 mg for the prevention of recurrence of deep vein thrombosis and/or PATE
• Conditions that limit the patient's ability to comply with the requirements of the protocol (dementia, neurological or psychiatric disorders, drug addiction, alcohol addiction, religious or personal beliefs of the patient, which may potentially limit standard therapy methods within the study, etc.)
• Concurrent participation in other interventional and non-interventional clinical studies less than 28 days before the IC form is signed (provided the patient has received at least one dose of experimental therapy), and previous participation in this clinical study (provided the patient has received at least one administration of RPH-051)
• Current continuous daily treatment with corticosteroids (at a dose equivalent to \> 10 mg/day of methylprednisolone) (excluding inhaled steroids)
• Acute infectious diseases or activation of chronic infectious diseases, including those requiring intravenous injection of antibacterial drugs, less than 28 days before signing of the IC form
• Active hepatitis B or C, HIV infection, syphilis
• Inability to administer the study drug intravenously
• Inability to perform intravenous contrast
• Hypersensitivity to any of the components of the study drugs specified in the protocol, or intolerance to any of the drug products for premedication
• Pregnancy or breastfeeding
• Any other significant concomitant diseases or conditions that could, in the reasonable opinion of the Investigator, adversely affect the patient's participation and well-being in the study and/or distort the evaluation of the study results