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

International, Multicenter, Double-blind, Randomized, Comparative Study of Efficacy, Safety and Pharmacokinetics of RPH-051 and Perjeta® Drug Products Combined With Trastuzumab and Docetaxel as the 1st Line Therapy in Patients With HER2-positive Metastatic or Locally Recurrent Unresectable Breast Cancer

The main purpose of this study is to prove non-inferiority, as well as to demonstrate the comparability of safety and immunogenicity of RPH-051 and Perjeta® in combination with trastuzumab and docetaxel as the 1st line therapy for patients with HER2-positive breast cancer (BC). Secondary Purposes are to evaluate the pharmacokinetics of RPH-051 in comparison with Perjeta® after a single-dose and repeated intravenous administration

This study is an international, multicenter, double-blind, randomized, comparative, phase III study

Pertuzumab therapy combined with trastuzumab and docetaxel (6 cycles) within this study will last up to 2 years or until the disease progression/development of unacceptable toxicity (whichever comes first)

A subgroup of participants (at least 60 participants, approximately 30 participants in each treatment group) is planned to be included for pharmacokinetic evaluation

The study will include the following periods:

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

   If a biopsy of the tumor material to study the HER2 status is required, the screening period can be extended to 42 days

2. Main period: days 1 to 126

   Eligible patients will be randomized at the ratio of 1:1 to one of the two study arms: RPH-051 + trastuzumab + docetaxel or Perjeta® + trastuzumab + docetaxel. On Day 1 (and Day 43 in the PK-subgroup) or the day before, the patients may be hospitalized and will remain in the clinic for up to 24 hours after administration of the first dose of the study drug

   Within the Main period of the Study, the patients will receive pertuzumab (RPH-051 or Perjeta® drug products) combined with trastuzumab and docetaxel according to the following scheme: pertuzumab 420 mg (loading dose 840 mg in the 1st cycle) IV on Day 1 once every 3 weeks + trastuzumab 6 mg/kg (loading dose 8 mg/kg in the 1st cycle) IV on Day 1 once every 3 weeks + docetaxel 75 mg/m2 IV on Day 1 once every 3 weeks, 6 cycles

   In case of significant adverse events (AEs), treatment could be delayed for at least 3 weeks

   The therapy within the Main period will continue until (whichever comes first):

   • 18 weeks (6 cycles)
   • disease progression (according to RECIST 1.1 / clinical progression criteria)
   • development of unacceptable toxicity.

3. Period of extended therapy: days 127 to 365

   During the period of extended therapy, all patients will receive RPH-051 therapy in combination with trastuzumab, including those who received Perjeta® during the Main period. Therapy will be carried out according to the scheme: pertuzumab 420 mg IV once every 3 weeks + trastuzumab 6 mg/kg IV once every 3 weeks

   In case of significant adverse events (AEs), treatment could be delayed for at least 3 weeks

   The therapy during the Period of extended therapy will continue until (whichever comes first):

   • up to 1 year
   • until disease progression (according to RECIST 1.1/clinical progression criteria)
   • development of unacceptable toxicity

   If, after a year of therapy, the patient who achieved control of the disease, she goes into the follow-up care period

4. Follow-up care period: days 366 to 730

   During the follow-up care period, all patients will continue RPH-051 therapy in combination with trastuzumab, including those who received Perjeta® during the Main study period. The therapy will be carried out according to the previous scheme: pertuzumab 420 mg IV once every 3 weeks + trastuzumab 6 mg/kg IV once every 3 weeks

   In case of significant adverse events (AEs), treatment could be delayed for at least 3 weeks

   The therapy during the follow-up care period will continue until (whichever comes first):

   • up to 2 years
   • until disease progression (according to RECIST 1.1/clinical progression criteria)
   • development of unacceptable toxicity
   • the patient's refusal to continue therapy

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

One follow-up visit (FU-visit) will be scheduled 28 ± 3 days after the last administration

For the patients who early withdraw due to progression of the disease, FU visits will take place once every 6 weeks (counting from the date of the early termination visit) until Day 365 of the study or until lethal outcome

If a patient discontinues the therapy within the main period and the extended therapy period for a reason other than progression of the disease, and other treatment regimen is not prescribed to her, further FU visits will be held in the form of evaluation of the tumor response by CT/MRI once every 6 weeks until Day 126 and then once every 12 weeks until Day 365 of the study or until the disease progression/prescription of other therapy, whichever comes first. Upon the disease progression/prescription of another therapy, the patient follow-up will continue in the form of telephone contacts once every 6 weeks until Study Day 365 or until lethal outcome

If a patient discontinues the therapy with the study drug within the follow-up care period for any reason, FU visits will take place once every 6 weeks (counting from the date of the early termination visit) in the form of telephone contacts until Day 730 of the study or until lethal outcome

The patients must meet all the following inclusion criteria:

1. Voluntarily signed and dated Informed Consent Form (ICF) of the patient agreed to take part in this Study
2. 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)
3. Patients with metastatic or locally recurrent unresectable breast cancer (BC) who have indications for the 1st line therapy
4. 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
5. ECOG status 0-1.
6. Left ventricular ejection fraction (LVEF) ≥ 55 % during the screening.
7. 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).
8. 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)
9. Life expectancy of at least 18 weeks from the date of randomization (in the opinion of the Investigator)
10. 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

1. Availability of the signed Informed Consent Form to participate in the pharmacokinetic study
2. Body weight in the range of 40-100 kg at the time the ICF is signed
3. 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:

1. 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)

2. Previous pertuzumab therapy

3. 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

4. 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

5. Sustained hematological toxicity (hemoglobin, leukocytes, neutrophils, platelets) ≥ grade 2, resulting from the previous adjuvant therapy

6. Peripheral neuropathy ≥ grade 3 at the time the ICF is signed

7. 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

8. 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

9. History of treatment with cumulative doses of anthracyclines

10. Patients with severe concomitant diseases, with life-threatening acute complications of the underlying disease

11. 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

12. 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

13. Non-healing wounds, ulcers at the time the ICF is signed

14. Hematological disorders (in case any of the following):

    • neutrophils < 1.5 x 109/L
    • platelets <100 x 109/L
    • hemoglobin < 90 g/L

15. Renal dysfunction:

    • creatinine > 1.5 × ULN or glomerular filtration rate < 45 mL/min (calculated using CKD-EPI formula)

16. 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)

17. 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

18. 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.)

19. 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)

20. Current continuous daily treatment with corticosteroids (at a dose equivalent to > 10 mg/day of methylprednisolone) (excluding inhaled steroids)

21. 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

22. Active hepatitis B or C, HIV infection, syphilis

23. Inability to administer the study drug intravenously

24. Inability to perform intravenous contrast

25. Hypersensitivity to any of the components of the study drugs specified in the protocol, or intolerance to any of the drug products for premedication

26. Pregnancy or breastfeeding

27. 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