| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Women with a diagnosis of invasive unilateral non metastatic
HER2-positive and ER-positive breast cancer suitable for
neoadjuvant therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
Women with a diagnosis of invasive unilateral non metastatic
HER2-positive and ER-positive breast cancer suitable for
neoadjuvant therapy |
|
| 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 | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006283 |
| E.1.2 | Term | Breast neoplasm malignant female |
| 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 |
. Characterize changes of Ki67 from baseline before therapy and
at 2 weeks and at surgery (approximately 22 weeks after start
of neoadjuvant therapy with HPPF).
. Characterize changes in apoptosis from baseline before
therapy and at surgery (approximately 22 weeks after start of
neoadjuvant therapy with HPPF).
. Study the tolerability profile of the combination |
|
| E.2.2 | Secondary objectives of the trial |
. Assess the rate of pathological complete response (pCR)
defined as ypT0-ypTis ypN0 at surgery
. Define the clinical objective response rate at the end of the
combination
. Conduct molecular and clinical analyses to assess the
presence of informative markers of benefit in addition to Ki67
and apoptosis |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female patients aged 18 years or older with tumors
suitable for neoadjuvant treatment
2. Early (> 1.5 cm) or locally advanced untreated breast
cancer
3. Histologically confirmed invasive unilateral breast cancer
4. HER2-positive disease centrally confirmed
5. Positive estrogen receptor (ER) > 10% and known
progesterone receptor (PgR)
6. Available paraffin-embedded tumor block taken at
diagnostic biopsy for central retrospective confirmation of
HER2 and ER eligibility and for assessment of Ki67 value
and apoptosis is mandatory
7. All patients must agree to provide tumor tissues for
centralized assessment of KI67 values and apoptosis at the
required timelines (2 weeks from starting protocol therapy
and at surgery)
8. ECOG performance status 0 or 1
9. Written informed consent to participate in the trial
(approved by the Institutional Review Board [IRB]/
Independent Ethics Committee [IEC]) obtained prior to any
study specific screening procedures
10. Willing and able to comply with the protocol |
|
| E.4 | Principal exclusion criteria |
1. Evidence of bilateral invasive breast cancer or metastatic disease (M1)
2. Pregnant or lactating women. Documentation of a negative serum pregnancy test must be available for premenopausal women with intact reproductive organs and for women less than one year after the last menstrual cycle
3. Women with childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception, for example abstinence, an intra-uterine device, or double barrier method of contraception up to 7 months from the last dose of either anticancer study drug
4. Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy
5. Previous extensive radiotherapy
6. Previous investigational treatment for any condition within 4 weeks of registration date
7. Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol
8. Previous or concomitant malignancy of any other type that could affect compliance with the protocol or interpretation of results. Patients with curatively treated basal cell carcinoma of the skin, stage 1 uterine cancer or in situ cervix cancer are generally eligible.
9. Other serious illness or medical condition including: history of documented congestive cardiac failure; angina pectoris requiring anti-anginal medication; evidence of transmural infarction on ECG; poorly controlled hypertension (e.g. systolic >180 mm Hg or diastolic >100 mm Hg; however, patients with hypertension which is well controlled on medication are eligible); clinically significant valvular heart disease; high-risk uncontrolled arrhythmias
10. Baseline left ventricular ejection fraction (LVEF) < 55% by echocardiography or multi-gated scintigraphic scan (MUGA)
11. QTc >480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP)
12. Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or adversely affecting compliance with study drugs
13. Serious uncontrolled infections (bacterial or viral) or poorly controlled diabetes mellitus
14. Current use or anticipated need for food or drugs that are known strong CYP3A4 inhibitors or inducers
15. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia)
16. Any of the following abnormal baseline hematological values:
a. Absolute Neutrophil Count (ANC) < 1.5 109/L
b. Platelet count < 100 109/L
c. Hemoglobin (Hb) < 10 g/dL
17. Any of the following abnormal baseline laboratory tests
a. Serum total bilirubin > 1.5 ULN (upper limit of normal) (except for patients with clearly documented Gilbert’s syndrome)
b. Alanine transaminase (ALT) or aspartate transaminase (AST) > 1.25 ULN
c. Alkaline phosphatase > 2.5 ULN
d. Serum creatinine > 1.5 ULN
e. INR > 2
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Changes from baseline in KI67 score
• Changes from baseline in apoptosis score
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary end point will be evaluated, for each patient, 6 months after the registration date.
Considering an enrollment period of 12 months, the primary end point will be evaluated 20 months after the first patient enrolled. |
|
| E.5.2 | Secondary end point(s) |
• Assess the rate of pathological complete response (pCR) defined as ypT0-ypTis ypN0 at surgery
• Define the clinical objective response rate at the end of the combination
• Conduct molecular and clinical analyses to assess the presence of informative markers of benefit in addition to Ki67 and apoptosis
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Considering an enrollment period of 12 months, the secondary end point will be evaluated 20 months after the first patient enrolled. |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | No |
| 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 |
| Characterize changes of Ki67 and changes in apoptosis. |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
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