A Phase III Trial to Compare the Efficacy, Safety and Pharmacokinetics of HD201 to Herceptin® in HER2+ Early Breast Cancer Patients

In the TROIKA study, the proposed biosimilar HD201 will be compared to its reference product Herceptin®. The aim of the study is to demonstrate equivalence of HD201 and Herceptin® in terms of efficacy, safety and pharmacokinetics.

This is a randomised, double-blind, parallel group, equivalence, multicentre Phase III study. 500 patients with HER2+ early breast cancer (EBC) will be randomised (1:1) to receive either HD201 in combination with chemotherapy (n=250) or Herceptin® in combination with chemotherapy (n=250).

HD201 or Herceptin® will be administered every 3 weeks for 8 cycles(24 weeks). After administration of the final neoadjuvant study drug dose, surgery will be done within 3-8 weeks followed by an adjuvant treatment period for 10 cycles.

Patients completing the 18 cycles of treatment and those discontinuing the study will attend an End of Treatment (EOT) visit 4 weeks (+/- 2 days), after last administration of study medication, followed by a follow-up period of 2 years.

Patients will attend study visits every 3 weeks. At each visit, patients will undergo a complete physical examination, vital signs, weight, performance status, clinical laboratory tests and adverse events (AEs), concomitant medication will be recorded. After the EOT visit patients will be followed every 6 months for an additional 24 months or until death, whichever occurs first, to collect data on cardiac safety and disease status.

Cardiac safety will be assessed by echocardiography or multigated acquisition (MUGA) scan to evaluate the left ventricular ejection fraction (LVEF) (at screening, before cycle 5, before surgery, before cycles 12 and 16, EOT visit, and at 6 and 12 months after the completion of trastuzumab (more frequent if necessary)) and by means of a 12-lead ECG (at screening, before cycle 5, before surgery, before cycles 12 and 16, EOT visit, and at 6 and 12 months after the completion of trastuzumab).

The primary efficacy endpoint, total pathological complete response (tpCR) will be assessed at the time of surgery after neoadjuvant treatment completion after 24 weeks. tpCR will be assessed both by local and by central reading.

Sampling for pharmacokinetics (PK) analysis (determination of Ctrough values) will be performed in all patients before cycle 5 and cycle 8.

An Independent Data Monitoring Committee will be implemented that reviews accumulating data of the clinical trial with respect to any potential safety issues, study progress and critical efficacy endpoints. The members will be selected on the basis of relevant experience and understanding of clinical research and the issues specific to the therapeutic area, as well as previous data monitoring committee experience.

Eligibility Criteria:
Inclusion Criteria:

1. Able and willing to give written informed consent.
2. Females ≥ 18 years of Age
3. Eastern Cooperative Oncology Group (ECOG) performance Status (PS) \< 2.
4. Known Hormone receptor (oestrogen receptor and progesterone receptor) status.
5. HER2 overexpressed as assessed by

   1. Immunohistochemistry (IHC) or
   2. Fluorescent in situ hybridisation (FISH); FISH positive is defined as FISH amplification Ratio ≥ 2.0 / number of HER2 gene copies per cell \>2
   3. Chromogenetic in stu hybridisation (CISH) positive
   4. Patients with IHC score 3+ or positive FISH/CISH test
   5. Patients with an IHC score 2+ must also have a positive FISH/CISH test
6. LVEF ≥ 50% or within the normal Level of the Institution, as assessed by echocardiography or MUGA scan.
7. Life expectancy \> 12 weeks.
8. Adequate bone marrow function as evidenced by the following:

   1. Absolute neutrophils count ≥ 1,500/μL
   2. Haemoglobin ≥ 9 g/dL
   3. Platelet count ≥ 100,000/μL Up to 5% Deviation is acceptable.
9. Adequate hepatic and renal function as evidenced by the following:

   1. Creatinine clearance ≥ 60mL/min
   2. total Bilirubin ≤ 1.5x upper limit of normal (ULN)
   3. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN Up to 10% deviation is acceptable.
10. Ability to comply with the study protocol.
11. Female patients of childbearing potential must have a negative Serum pregnancy test within 7 days prior to first dose of study treatment and agree to use effective contraception (intrauterine device, diaphragm, diaphragm with spermicide or a reliable barrier method, eg condom with spermicide) throughout the study period and 7 months after discontinuation of study drug.
12. Non-metastatic, unilateral, newly diagnosed, operable early breast cancer (EBC) of clinical stage II and III including inflammatory breast cancer. Histologically confirmed primary invasive carcinoma of the breast.

Exclusion Criteria:

Patients meeting any of the following criteria must not be enrolled in the study:

1. Metastatic (stage IV) with exception of supraclavicular nodes.
2. Bilateral breast cancer
3. Multicentric breast cancer
4. History of any prior invasive breast carcinoma, except for subjects with a past history of ductal carcinoma in situ (DCIS) treated with surgery.
5. History of malignant neoplasms within 5 years prior to randomisation, except for curatively treated carcinoma in situ of uterine cervix, basal cell carcinoma of the skin or squamous cell carcinoma of the skin (malignant neoplasms occurring more than 5 years prior to randomisation are permitted if curatively treated with surgery only).
6. Previous history of radiation therapy, anti-neoplastic immunotherapy, chemotherapy or anti-neoplastic biotherapy (including prior HER2 directed therapy).
7. Major surgery within 2 weeks prior to randomisation
8. Serious cardiac illness that would preclude the use of trastuzumab such as:

   * history of documented congestive heart failure (CHF) (New York Heart Association, NYHA, class III or greater heart disease)
   * LVEF \< 50% by echocardiography or MUGA scan
   * angina pectoris requiring anti-anginal medication
   * evidence of transmural infarction on electrocardiogram (ECG)
   * uncontrolled hypertension (systolic \> 180 mmHg and/or diastolic \> 100 mmHg)
   * clinically significant valvular heart disease
   * high-risk uncontrolled arrhythmias.
9. Serious pulmonary illness enough to cause dyspnoea at rest or requiring supplementary oxygen therapy.
10. Known history of active hepatitis B virus (HBV) and active hepatitis C virus (HCV) infection.
11. Known HIV infection by patient declaration.
12. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
13. Known hypersensitivity to the IMPs, non-IMPs or any of the ingredients or excipients of the IMPs or non-IMPs.
14. Known hypersensitivity to murine proteins.
15. Pre-existing peripheral sensory or motor neuropathy ≥ grade 2 (as defined by NCI-CTCAE v4.03).
16. Lactating or pregnant woman. A pregnancy test is required for all women of childbearing potential including women who had menopause onset within 2 years prior to randomisation. Women of childbearing potential must agree to use contraceptive methods during the study and for 7 months after the last dose of IMP.
17. Participation in any clinical study or having taken any investigational therapy during the 1-month period immediately preceding administration of the first dose.
18. Patients unwilling to follow the study requirements.