| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER 2+/HR+ and HR- early breast cancer |
| HER 2+/HR+ and HR- früher Brustkrebs |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006188 |
| E.1.2 | Term | Breast cancer female NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10006192 |
| E.1.2 | Term | Breast cancer NOS |
| 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 |
| Evaluation of the pCR rate with combination therapy consisting of the PD-1 inhibitor pembrolizumab in combination with dual anti-HER2 blockade trastuzumab biosimilar and pertuzumab in patients with HER2-enriched early breast cancer assessed by PAM50 testing. The patient can either be HR-positive (= triple positive) or HR-negative. |
|
| E.2.2 | Secondary objectives of the trial |
| Assess the safety profile of the combination of pembrolizumab, pertuzumab and trastuzumab biosimilar by capturing the occurrence and severity of adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0, compliance and changes in special laboratory results compared between baseline and while on therapy. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Future Biomedical Research / Translational Research: Biomarker assessments for pathway inhibition and efficacy. Assessments in tumor tissue and blood. |
|
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Female participants, who are at least 18 years of age on the day of signing informed consent with newly histologically locally confirmed diagnosis of HER2neu 2+ or 3+ breast cancer.
2. Previously untreated, non-metastatic (M0) HER2-enriched breast cancer defined as the following combined primary tumor (T) and regional lymph node (N) staging per AJCC for breast cancer staging criteria version 7 as assessed by the Investigator based on radiological and/or clinical assessment:
T1c, N0-N2; T2, N0-N2; T3, N0-N2.
3. Patients with HER2-enriched, estrogen and/ or progesterone receptor positive or negative breast cancer defined by ASCO/ CAP guidelines can.
4. Availability of tumor imaging performed within three months prior to start of screening phase: Breast Ultrasound and CT Thorax/Abdomen or Chest X-ray/liver Ultrasound, Bone Scan, Mammography or Breast MRI (according to local standard).
5. Ability to provide archived tumor tissue sample or at least two newly obtained separate tumor cores from the primary tumor or excisional biopsy of a tumor lesion not previously irradiated at screening to the central laboratory. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred over slides. Newly obtained biopsies are preferred over archived tissue.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 7 months after the last dose of study treatment
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.
7. The participant provides written informed consent for the trial. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
8. Confirmed HER2neu [IHC 2+ status and amplification (e.g. FISH)] or [IHC 3+ status] tumor identification by local pathology.
9. Confirmed HER2-enriched status by PAM 50 testing.
10. Confirmed HR + or HR – status.
11. Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or borderline, a serum pregnancy test will be required.
Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.
12. Left ventricular ejection fraction (LVEF) of ≥55% or ≥ institution lower limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening or performed in clinical routine within 6 weeks prior to first treatment allocation.
13. Normal ECG performed at screening or performed in clinical routine within 6 weeks prior to first treatment allocation.
14. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 10 days prior to the date of treatment initiation.
15. Adequate organ function as defined in the following table. Specimens must be collected within 10 days prior to the start of study treatment.
Absolute neutrophil count (ANC) ≥1500/µL, Platelets ≥100 000/µL, Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
Creatinine OR Measured or calculatedb creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT) ≤2.5 × ULN
Albumin ≥3g/dL, Lactate dehydrogenase <2.5 × ULN
International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (eg, CTLA-4, OX 40, CD137) or has participated in MK-3475 clinical trials.
2. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to first dose of study medication.
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
3. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
4. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Participant should be excluded if she received an investigational agent with anti-cancer or anti-proliferative intent within the last 12 months.
5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
6. Prior malignancy with a disease-free survival of ≤ 5 years before signing informed consent. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. ductal carcinoma in situ, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
7. Has a known hypersensitivity to the components of the study therapy, its analogs, murine proteins or any of the excipients.
8. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
9. Has a significant cardiovascular disease.
10. Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study.
11. Inadequate organ function including but not confined to:
• hepatic impairment (Child Pugh Class C),
• pulmonary disease (severe dyspnea at rest due to complications of advanced malignancy or requiring oxygen therapy).
12. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
13. Has an active infection requiring systemic therapy.
14. 14. Patient has a known history of human immunodeficiency virus (HIV), hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (defined as detectable HCV RNA [qualitative]).
15. Has a known history of active TB (Bacillus Tuberculosis).
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
18. Is pregnant or breastfeeding, or expecting to conceive children or planning to breast-feed within the projected duration of the study, starting with the screening visit through 7 months after end of treatment.
19. Male patients with breast cancer.
20. History of breast cancer.
21. Factors indicating risk of poor compliance.
22. Pathological laboratory assessments:
Thrombocytopenia > CTCAE grade 1
Increases in ALT/AST > CTCAE grade 1
Hypokalaemia > CTCAE grade 1
Neutropenia > CTCAE grade 1
Anaemia > CTCAE grade 1
23. Non-operable breast cancer including inflammatory breast cancer.
24. History of an allogeneic stem cell transplant.
25. History of a solid organ transplant of any kind. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| pCR defined as no invasive tumor in breast and lymph nodes (ypT0/is, ypN0) at surgery after study treatment (planned duration of neoadjuvant treatment is 12 weeks) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- at surgery after study treatment (planned duration of neoadjuvant treatment is 12 weeks)
- An interim analysis is planned as soon as 16 patients are evaluable
- The final analysis will be done after the study is closed. |
|
| E.5.2 | Secondary end point(s) |
• System Organ Class (SOC) and Preferred Terms (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA) classification:
o Fatal adverse events
o Serious treatment-emergent adverse events
o Treatment-related adverse events
o Treatment-emergent adverse events of interest
o Adverse events leading to investigational product discontinuation
• Severity of AE
• Causality of AE
• Outcome of AE
• Seriousness of AE
• To examine predictive markers at baseline and on therapy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- An interim analysis is planned as soon as 16 patients are evaluable
- The final analysis will be done after the study is closed. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 |
| Prognosis and predictiion of benefit from therapy. |
|
| 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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
|
| The end of the trial is defined as the date of the last follow-up visit of the last patient in the trial or last scheduled procedure shown in the Trial Flow Chart in 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
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