A randomised, double-blind, parallel group, equivalence, multicentre phase III trial to compare the efficacy, safety and pharmakokinetics of HD201 to Herceptin® in patients with HER2+ early breast cancer

• Register: EUCTR
• Last refreshed on: 18 October 2021
• Main ID: EUCTR2016-004019-11-EE
• Date of registration: 15/01/2018
• Prospective Registration: Yes
• Primary sponsor: Prestige BioPharma Pte Ltd
• Public title: A randomised, double-blind, parallel group, equivalence, multicentre phase III trial to compare the efficacy, safety and pharmakokinetics of HD201 to Herceptin® in patients with HER2+ early breast cancer
• Scientific title: A randomised, double-blind, parallel group, equivalence, multicentre phase III trial to compare the efficacy, safety and pharmacokinetics of HD201 to Herceptin® in patients with HER2+ early breast cancer - Troika
• Date of first enrolment: 05/03/2018
• Target sample size: 500
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004019-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: Herceptin; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belarus, Belgium, Bulgaria, Croatia, Czechia, Denmark, Estonia, France, Georgia, Germany, Hungary, Italy, Malaysia, Netherlands, Philippines, Poland, Russian Federation, Spain, Taiwan, Thailand, Ukraine, United Kingdom

Contacts

• Name: Eda Vaker, SrCRA
• Affiliation: CromosPharma

• Name: Eda Vaker, SrCRA
• Affiliation: CromosPharma

Key inclusion & exclusion 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
- Immunhistochemistry (IHC) or
- Fluorescent in site hybridisation (FISH); FISH positive is defined as FISH amplification ratio = 2.0 / number of HER2 gene copies per cell > 2
- Patients with IHC score 3+ or positive FISH test
- Patients with IHC score 2+ must also have a positive FISH 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:
- Absolute neutrophils count = 1,500/µL
- Haemoglobin = 9 g/dL
- Platelet count = 100,000/µL
Up to 5% deviation is acceptable.
9. Adequate hepatic and renal function as evidenced by the following:
- Creatinine clearance = 60 mL/min
- Total bilirubin = 1.5 x upper limit of normal (ULN)
- 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 14 days of first dose of study treatment and agree to use effective contraception (intrauterine device, diaphragm, diaphragm with spermicide or a reliable barrier method, e.g. 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 I-II and IIIa (T3-N0-M0) including inflammatory breast cancer.
- At least one measurable lesion according to RECIST criteria v1.1
- Histologically or cytologically confirmed primary invasive carcinoma of the breast
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 250
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 250

Exclusion criteria:
1. Metastatic (stage IV) or bilateral or multifocal/multicentric breast cancer, with exception of supraclavicular nodes.
2. History of any prior invasive breast carcinoma, except for subjects with a past history of ductal carcinoma in situ (DCIS) and/or lobular carcinoma in situ (LCIS) treated with surgery only.
3. 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).
4. Previous history of radiation therapy, immunotherapy, chemotherapy or biotherapy (including prior HER2 directed therapy).
5. Major surgery within 4 weeks prior to randomisation.
6. 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 II 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.
7. Serious pulmonary illness enough to cause dyspnoea at rest or requiring supplementary oxygen therapy.
8. Known history of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.
9. HIV infection. The HIV test is only to be done when clinically indicated.
10. 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.
11. Known hypersensitivity to the IMPs, non-IMPs or any of the ingredients or excipients of the IMPs or non-IMPs.
12. Known hypersensitivity to murine proteins.
13. Pre-existing peripheral sensory or motor neuropathy = grade 2 (as defined by NCI- CTCAE v4.03).
14. 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.
15. Concurrent hormonal therapy including birth control pills, ovarian hormone replacement for menopause, selective oestrogen receptor modulator (SERM) either for osteoporosis or breast cancer prevention (all those treatments should be stopped before randomization).
16. Participation in any clinical study or having taken any investigational therapy during the 1-month period immediately preceding administration of the first dose.
17. Patients unwilling to follow the study requirements


Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Non-metastatic, unilateral, newly diagnosed, operable early breast cancer (EBC) of clinical stage I-II and IIIa (T3-N0-M0) including inflammatory breast cancer.

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Trastuzumab
Product Code: HD201
Pharmaceutical Form: Lyophilisate for solution for infusion

Primary Outcome(s)

Secondary Objective: • To compare total breast pathological complete response rate (bpCR)
between the two arms at the time of surgery.
• To compare overall response rate (ORR) between the two treatment
arms at the time of surgery.
• To compare event-free survival (EFS) between the two treatment arms one year after end of treatment.
• To compare overall survival (OS) between the two treatment arms one year after end of treatment.
• To compare immunogenicity of HD201 and Herceptin®.
• To compare safety and tolerability between the two treatment arms.
• To compare the PK profile of HD201 and Herceptin®.

Primary end point(s): total pathological complete response rate (tpCR)

Timepoint(s) of evaluation of this end point: at the time of surgery after neoadjuvant treatment completion after 24 weeks

Main Objective: The primary objective of this study is to compare the total pathological complete response rate (tpCR) in patients treated with HD201 plus chemotherapy to that in patients treated with Herceptin® plus chemotherapy. tpCR will be assessed at the time of surgery after neoadjuvant treatment completion after 24 weeks.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: at the time of surgery

Secondary end point(s): Efficacy:
• bpCR defined as ypT0/is at the time of surgery.
• Overall response rate (ORR) defined as proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.1 at the time of surgery.
• Overall survival (OS) defined as the time from randomisation until death from any cause.
• Event-free survival (EFS) defined as the time from randomisation until progression of disease or death from any cause.
Safety and tolerability:
• Safety and tolerability will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events and CTC v4.03.
• Cardiac dysfunction will be monitored by 12-lead ECG and measurement of the LVEF by echocardiography or MUGA scan
• Vital signs
• Clinical laboratory parameters
Immunogenicity:
Incidence of human trastuzumab antibodies at baseline and at Cycles 4, 8 and one year after completion of trastuzumab therapy.
Pharmacokinetics (and Cthrough):
Sparse sampling will be performed in a subset of patients (30 per treatment group) to facilitate a population-based PK approach using nonlinear mixed-effects modelling. At Cycle 4 (Week 9) and Cycle 7 (Week 18) samples will be taken prior to initiation of infusion, immediately prior to the end of the infusion, between 2 to 4 hours postinitiation of infusion and immediately prior to the patient leaving the clinic (but not less than one hour after the 2 to 4 hour sample). At Cycles 5 (Week 12) and Cycle 8 (Week 21), samples will be taken before administration of treatment (Ctrough).

Secondary ID(s)

Troika-1

2016-004019-11-FR

Source(s) of Monetary Support

Prestige BioPharma Pte Ltd

Ethics review

Status: Approved
Approval date: 18/01/2018
Contact: