| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast Cancer that has spread within the body |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the objective response rate (ORR) in patients with metastatic HER2-positive breast cancer who receive trastuzumab-Pfizer to those who receive trastuzumab-EU in combination with paclitaxel. |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the safety of PF-05280014 plus paclitaxel versus trastuzumab-EU plus paclitaxel;
•To evaluate secondary measures of tumor control;
•To evaluate the population pharmacokinetics (PK) of PF-05280014 and trastuzumab-EU;
•To evaluate the immunogenicity of PF-05280014 and trastuzumab-EU.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female patients aged 18 years or older. (Where required by regulations, consent from a legally acceptable representative is required for all patients who are younger than 20 years of age.)
2. Histologically confirmed diagnosis of breast cancer.
3. Presence of metastatic disease.
4. Documentation of HER2 gene amplification or overexpression by one of the following:
a. Gene amplification by fluorescent in-situ hybridization (FISH) or chromogenic in-situ hybridization (CISH) or dual inisitu hybridization (DISH) (as defined by the manufacturer’s kit instruction); OR
b. Overexpression by immunohistochemistry (IHC) categorized as IHC3+; OR
c. Overexpression by immunohistochemistry categorized as IHC2+ with FISH, CISH or DISH confirmation.
Determination of HER2 positive status using one of the Sponsor accepted analytical test methods listed in Appendix 1 of the protocol must be documented in the patient’s source documentation.
If HER2 status is unavailable or was determined using a test other than a Sponsor-approved assay, eligibility must be documented prior to randomization either by:
a. The Sponsor-provided central laboratory OR
b. HER2 local testing using boht an IHC and an in-situ hybridization analytical test neither of which are considered Sponsor approved. The results from both assays must be unequivocal (ie. IHC result must be categorized as IHC3+)
5. Available tumor tissue (ie, formalin fixed-paraffin embedded blocks or unstained slides) for central review of HER2 status. Tumor tissue should be from metastatic disease or, if not obtainable, may be from the primary tumor at the time of initial or current diagnosis.
6. Documentation of ER status (positive or negative) based on local laboratory or Sponsor-identified central laboratory.
7. At least 1 measurable lesion as defined by RECIST 1.1, in the assessment of the investigator; measurable lesions must be outside prior radiation fields. The following kinds of lesions are not measurable according to RECIST 1.1: ascites, pleural or pericardial effusion, osteoblastic or osteolytic bone metastases, and carcinomatous lymphangitis of the lung. The site must forward the radiographs to the independent central review laboratory to obtain confirmation of the presence of measurable disease prior to patient randomization.
8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 (as per Appendix 2 of the protocol).
9. Left ventricular ejection fraction (LVEF) within institutional range of normal, measured by either two dimensional echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
10. Screening laboratory values within the following limits:
a. Absolute neutrophil count (ANC) ≥1.5 x 109 cells/L (1500/mm3);
b. Platelet count ≥100 x 109cells/L (100,000/mm3);
c. Hemoglobin ≥9.0 g/dL (90 g/L);
d. Serum creatinine ≤1.5 x upper limit of normal (ULN);
e. Total bilirubin ≤1.5 x ULN (<3 ULN if Gilbert’s disease);
f. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 x ULN (≤5 x ULN if liver metastases are present).
11. Recovery (to grade 1 or baseline) from all clinically significant adverse effects of prior therapies (excluding alopecia).
12. Patients of childbearing potential must agree to use 2 highly effective methods of contraception (as described in section 4.4 of the protocol) throughout the study and for 12 months after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the investigator, she is biologically capable of having children and is sexually active.
13. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
14. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.
2. Relapse within 1 year of last dose of previous adjuvant (including neoadjuvant) treatment (except endocrine therapy) and within 1 year before randomization.
3. Prior systemic therapy for metastatic disease (except endocrine therapy).
4. Prior cumulative dose of doxorubicin of >400 mg/m2, epirubicin dose >800 mg/m2, or the equivalent dose for other anthracyclines or derivatives (e.g., 72 mg/m2 of mitoxantrone). If the patient has received more than one anthracycline, then the cumulative dose must not exceed the equivalent of 400 mg/m2 of doxorubicin.
5. Inflammatory breast cancer.
6. Superficial disease site that cannot be assessed by radiographic method as the only site of measurable disease. Patients with superficial lesions that can be measured by computed tomography (CT) scan or magnetic resonance imaging (MRI) are eligible.
7. Major surgery, radiotherapy, or any investigational agents, within 4 weeks before the administration of the first dose of study treatment.
8. Concurrent administration of other anticancer therapies. Bisphosphonate or Receptor Activator for Nuclear Factor KB (RANK) Ligand inhibitor therapy for pre-existing bone metastases or osteoporosis is allowed; prophylactic use to prevent bone metastasis is exclusionary.
9. Active uncontrolled or symptomatic central nervous system (CNS) metastases, as evidenced by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have completed definitive treated and have not received anticonvulsants or steroids for at least 4 weeks before first dose of study treatment. Patients with newly detected asymptomatic CNS metastases must complete definitive treatment (e.g., radiotherapy, stereotactic surgery) before being considered for study entry. Patients with a history of carcinomatous meningitis (leptomeningeal disease) are not eligible.
10. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (CHF) New York Heart Association (NYHA) functional classification of ≥3, unstable angina, or myocardial infarction within 12 months before first dose of study treatment.
11. Preexisting grade 2 or greater motor or sensory neuropathy.
12. History of severe hypersensitivity reaction to taxanes, trastuzumab, murine proteins, or excipients in their formulations.
13. Clinical contraindication to treatment with steroids preventing use as part of paclitaxel premedication.
14. Pregnant females; breastfeeding females; females of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in this protocol for the duration of the study and for 12 months after last dose of investigational product.
15. Known or demonstrated viral infection as listed below. Testing to demonstrate eligibility is required only in countries where regulations mandate testing. In all other countries, testing should be considered if a patient is at risk for having undiagnosed infection (for example due to history of injection drug use or due to geographic location).
a. Seropositivity for human immunodeficiency virus (HIV);
b. Hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to hepatitis C virus [anti HCV] with confirmatory testing).
16. History of another cancer diagnosis (including contralateral breast cancer) within 5 years prior to screening for this study, with the exception of adequately treated ductal carcinoma in situ, cervical carcinoma in situ, or basal or squamous cell skin cancer.
17. Unwilling or unable to comply with the lifestyle guidelines described in this protocol.
18. Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks before randomization and/or during study participation. Patients participating in observational studies not involving an investigational drug(s) and/or long-term follow up of studies involving and investigational drug(s) in which treatment was completed >=4 weeks before randomization are not excluded.
19. Other severe acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate (ORR), evaluating responses achieved by Week 25 and subsequently confirmed, based on the assessments of the central radiology review in accordance with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Safety characterized by type, incidence, severity, timing, seriousness, and relationship to study therapy of adverse events and laboratory abnormalities;
• Duration of Response (DOR), One-year progression-free survival (PFS) rate and 1-year survival rate;
• Peak and trough PF-05280014 and trastuzumab-EU concentrations at selected cycles;
• Incidence of anti-drug (trastuzumab) antibodies (ADA), including neutralizing antibodies (Nab).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Variable. See Study Flow Charts 1-4, pages 7-14 of the protocol. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| biosimilar, immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Trastuzumab Plus Paclitaxel |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Chile |
| Colombia |
| Czech Republic |
| Hungary |
| India |
| Japan |
| Korea, Republic of |
| Latvia |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Thailand |
| Turkey |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of trial in a Member State of the European Union is defined as the
time at which it is deemed that sufficient patients have been recruited
and completed the study as stated in the regulatory application (ie
CTA) and ethics application in the Member State. Poor recruitment
(recruiting less than the anticipated number in the CTA) by a Member
State is not a reason for premature termination but is considered a
normal conclusion to the study in that Member State.
Please see protocol s 13. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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