| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with HER2+ AR+ Metastatic or Locally Advanced Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Female subjects with metastatic or locally advanced breast cancer |
|
| 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 | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10072740 |
| E.1.2 | Term | Locally advanced breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate the efficacy of enzalutamide with trastuzumab in evaluable subjects with human epidermal growth factor receptor 2 positive (HER2+), and androgen receptor positive (AR+), metastatic or locally advanced breast cancer, as measured by Clinical Benefit Rate (CBR) (defined as the proportion of evaluable subjects with best objective response of confirmed CR or PR per RECIST 1.1, or prolonged SD (≥ 24 weeks). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the following efficacy measures:
o Best Overall Response Rate (BORR)
o Overall Response Rate (ORR) at 24 weeks
o Progression Free Survival (PFS)
o Time to Progression (TTP)
o Duration of Response (DOR)
o Time to Response (TTR)
o To evaluate safety and tolerability. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject has consented and signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] for U.S. sites) prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. The subject is a female ≥ 18 years of age.
3. The subject has histologically or cytologically proven adenocarcinoma of the breast that is HER2+ defined as a score of 3+ for staining by immunohistochemistry (IHC), or IHC 2+ with HER2 gene amplification as
determined by a locally approved in situ hybridization (ISH) assay, or (for patients without IHC data) HER2 gene amplification.
4. The subject has AR+ breast cancer, which is defined as any tumor cells with nuclear AR staining by immunohistochemistry (IHC). Enrollment may be based on the local pathologist's findings; however,
tissue will be sent to a central pathology laboratory for assessment.
NOTE: If a subject is enrolled in the study based on local pathologist results, but subsequent central assessment cannot confirm AR+ disease, the subject may remain in the study.
5. The subject has metastatic disease or has locally advanced disease that is not amendable to curative treatment.
6. The subject has measurable disease or nonmeasurable, evaluable disease per RECIST 1.1 (NOTE: pleural effusions, ascites or other third fluid space are not evaluable diseases per RECIST 1.1).
7. The subject has received at least 1 line of therapy in the metastatic or locally advanced disease setting:
-A line of therapy is defined as a course of treatment at the end of which there was disease progression, toxicity, or in the investigator's opinion, maximum benefit has been achieved. If the subject discontinued therapy due to any other reason but progressed without receiving other treatment, this would be considered a line of therapy.
-The subject has been documented to have progressed by determination of the investigator on a regimen containing an anti-HER2 agent (includes trastuzumab emtansine in countries where it is not approved) as the most recent regimen or the most recent anti-HER2 regimen was discontinued for any toxicity, with the exception of a cardiotoxicity.
- Subjects who received <28 days of therapy in the most recent regimen may be eligible upon approval from the medical monitor.
- The subject progressed on a trastuzumab containing regimen. If progression occurred within 12 months after completing trastuzumabcontaining adjuvant treatment, this counts as having received trastuzumab but not as a line of therapy.
8. The subject has adequately recovered from toxicities due to prior therapy.
9. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status < 1 at Screening and Day 1.
10. The subject has available at the site a representative, formalin-fixed, paraffin-embedded, tumor specimen that enabled the definitive diagnosis of breast cancer with adequate viable tumor cells in a tissue block
(preferred) or ≥ 10 (20 preferred) freshly cut, unstained, serial slides and the associated pathology report:
- Archival tissue from the most recent biopsy available is preferred.
- For subjects who are known AR+ per local pathology report, a fresh biopsy can be done per investigator discretion, to obtain tissue for central AR confirmation if the archival specimen is insufficient or unavailable.
- Cytological or fine-needle aspiration samples are not acceptable.
11. The subject has an estimated life expectancy of at least 6 months at Day 1, in the opinion of the Investigator.
Waivers to the inclusion criteria will NOT be allowed.
For other inclusion criteria see protocol. |
|
| E.4 | Principal exclusion criteria |
1. The subject has a severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment.
2. The subject has current or previously treated brain metastasis or active leptomeningeal disease. Brain imaging is required during screening in all subjects to exclude the presence of unequivocal central nervous system disease.
3. The subject has a history of a non-breast cancer malignancy with the following exceptions:
● The subject with a previous history of a non-invasive carcinoma is eligible if in the opinion of the Investigator he/she has had successful curative treatment any time prior to Screening.
● For all other malignancies, the subject is eligible if they have undergone potentially curative therapy and they have been considered disease free for at least 5 years prior to Screening.
4. The subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit defined as:
● Absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3)
● Platelet count < 75 x109/L (< 75,000 cells/mm3)
● Hemoglobin < 5.6 mmol/L (< 9 g/dL)
● Total bilirubin > 1.5 x Upper Limit of Normal (ULN) unless there is an alternate nonmalignant etiology (e.g., Gilbert's syndrome).
● Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN (or >5 xULN if hepatic metastasis is present).
● Creatinine > 1.5 x ULN or Glomerular Filtration Rate (eGFR)/Creatinine Clearance (CrCL) < 30 mL/min, whichever is more restrictive.
● NOTE: May not have received any growth factors or blood transfusions within 7 days before the hematology values obtained at screening.
5. The subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma).
6. The subject has a history of loss of consciousness, cerebrovascular accident or transient ischemic attack within 12 months before the Day 1 visit.
7. The subject has had a hypoglycemic episode requiring medical intervention while on insulin (or other anti-diabetic) treatment within 12 months before Day 1.
8. The subject has clinically significant cardiovascular disease including:
● Myocardial infarction within 6 months before the Day 1 visit.
● Uncontrolled angina within 6 months before the Day 1 visit.
● Congestive heart failure New York Heart Association (NYHA) Class III or IV or history of congestive heart failure NYHA Class III or IV in the past, unless a screening echocardiogram, myocardial perfusion scintigraphy (MPS), or multi-gated acquisition scan performed within 3 months before the Day 1 visit reveals a left ventricular ejection fraction that is ≥ 50%.
● History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsade de Pointes).
● History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
● Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive measurements at the Screening visit.
● Bradycardia (in the presence of known cardiovascular disease) as indicated by a heart rate of < 50 beats per minute on the Screening electrocardiogram (ECG) recording.
● Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the Screening visit.
9. The subject has significant respiratory disease, including severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
10. The subject has an active gastrointestinal disorder affecting absorption (e.g., gastrectomy,active peptic ulcer disease) within the 3 months prior to the Day 1 visit.
11. The subject had a major surgical procedure, substantial open biopsy, or significant traumatic experience within 28 days before the Day 1 visit, or anticipation of need for major surgical procedure during the course of the study.
12. The subject has had palliative radiation therapy to bone metastases within 14 days prior to the Day 1 visit (side effects from radiation must be resolved).
13. The subject has received chemotherapy, immunotherapy, or any other systemic anti-cancer therapy, with the exception of anti-HER2 therapy (e.g., trastuzumab and trastuzumab emtansine), within 14 days prior to the Day 1 visit.
14. The subject has been treated with any investigational drugs within 14 days prior to the Day 1 visit.
For other exclusion criteria see protocol.
Waivers to the exclusion criteria will NOT be allowed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| CBR defined as the proportion of evaluable subjects with best objective response of confirmed CR or PR per RECIST 1.1 criteria, or prolonged SD ( ≥ 24 weeks). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Overall response rate (CR+PR) at 24 weeks according to RECIST 1.1 criteria
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Belgium |
| Canada |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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